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 we