21	26492180	either progression from one histotype to another histotype, divergence from a common progenitor into different histotypes, or a single tumor histotype that focally displays a variant morphology that mimics a different histotype.	('variant', 'Var', (175, 182))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
41	26492180	We performed sequencing analysis to detect mutations in 26 genes that have been previously found to be recurrently mutated in endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (126, 148))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (126, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('endometrial carcinomas', 'Disease', (126, 148))	('mutations', 'Var', (43, 52))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (126, 148))
71	26492180	The mutations were either identical or partially shared between the SC and EC components in 7 of 9 cases, Of the 7 cases with identical or partially shared mutations, 3 MMR-intact tumors (case 2, 3 and 7) harbored prototypical serous-type mutations with concurrent somatic TP53 and PPP2R1A (hotspot) mutations with notable absence of PTEN, ARID1A, CTNNB1 or KRAS mutations in both the histologically apparent EC and SC components, while one MMR-intact tumor (case 1) showed the same missense somatic TP53 mutations in both components.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('ARID1A', 'Gene', '8289', (340, 346))	('PPP2R1A', 'Gene', (282, 289))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutations', 'Var', (239, 248))	('tumor', 'Phenotype', 'HP:0002664', (452, 457))	('TP53', 'Gene', '7157', (500, 504))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('KRAS', 'Gene', '3845', (358, 362))	('tumors', 'Disease', (180, 186))	('absence', 'NegReg', (323, 330))	('TP53', 'Gene', (273, 277))	('PTEN', 'Gene', (334, 338))	('serous', 'Chemical', '-', (227, 233))	('KRAS', 'Gene', (358, 362))	('CTNNB1', 'Gene', '1499', (348, 354))	('mutations', 'Var', (300, 309))	('MMR', 'biological_process', 'GO:0006298', ('169', '172'))	('EC', 'Chemical', '-', (75, 77))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', (452, 457))	('TP53', 'Gene', (500, 504))	('SC', 'Chemical', 'MESH:D012538', (68, 70))	('SC', 'Chemical', 'MESH:D012538', (416, 418))	('PTEN', 'Gene', '5728', (334, 338))	('EC', 'Chemical', '-', (409, 411))	('tumor', 'Disease', 'MESH:D009369', (452, 457))	('ARID1A', 'Gene', (340, 346))	('tumor', 'Disease', (180, 185))	('PPP2R1A', 'Gene', '5518', (282, 289))	('TP53', 'Gene', '7157', (273, 277))	('CTNNB1', 'Gene', (348, 354))	('MMR', 'biological_process', 'GO:0006298', ('441', '444'))
72	26492180	This was further confirmed by p53 immunohistochemistry that demonstrated aberrant p53 staining in the corresponding EC and SC components in these cases (Figure 3A-D).	('aberrant', 'Var', (73, 81))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('EC', 'Chemical', '-', (116, 118))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('SC', 'Chemical', 'MESH:D012538', (123, 125))	('staining', 'MPA', (86, 94))
73	26492180	Two other tumors (case 4 and 8) showed the same somatic mutations in ARID1A, PTEN and RPL22 between the corresponding EC and SC components.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('RPL22', 'Gene', '6146', (86, 91))	('mutations', 'Var', (56, 65))	('SC', 'Chemical', 'MESH:D012538', (125, 127))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('EC', 'Chemical', '-', (118, 120))	('ARID1A', 'Gene', '8289', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('ARID1A', 'Gene', (69, 75))	('RPL22', 'Gene', (86, 91))
75	26492180	The remaining case (case 9) with partially shared mutations between the EC and SC components harbored POLE exonuclease domain mutation (L424V) and showed isolated MSH6 loss in both components (Figure 1E-F and 3E-F).	('loss', 'NegReg', (168, 172))	('EC', 'Chemical', '-', (72, 74))	('mutations', 'Var', (50, 59))	('SC', 'Chemical', 'MESH:D012538', (79, 81))	('L424V', 'Mutation', 'rs768299607', (136, 141))	('MSH6', 'Gene', (163, 167))	('L424V', 'Var', (136, 141))	('MSH6', 'Gene', '2956', (163, 167))
76	26492180	This tumor possessed a large number of point mutations, with some mutations being shared by both EC and SC components and other mutations that were unique to either the EC or SC component only (Table 2).	('mutations', 'Var', (66, 75))	('point mutations', 'Var', (39, 54))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('SC', 'Chemical', 'MESH:D012538', (104, 106))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('EC', 'Chemical', '-', (169, 171))	('EC', 'Chemical', '-', (97, 99))	('tumor', 'Disease', (5, 10))	('SC', 'Chemical', 'MESH:D012538', (175, 177))
79	26492180	The EC component in both cases harbored prototypical endometrioid-type mutations (PTEN and ARID1A mutations) while the SC component harbored prototypical serous-type mutations (TP53, PPP2R1A and/or FBXW7).	('ARID1A', 'Gene', '8289', (91, 97))	('FBXW7', 'Gene', (198, 203))	('ARID1A', 'Gene', (91, 97))	('EC', 'Chemical', '-', (4, 6))	('PPP2R1A', 'Gene', (183, 190))	('mutations', 'Var', (98, 107))	('PPP2R1A', 'Gene', '5518', (183, 190))	('TP53', 'Gene', '7157', (177, 181))	('serous', 'Chemical', '-', (154, 160))	('FBXW7', 'Gene', '55294', (198, 203))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))	('TP53', 'Gene', (177, 181))	('SC', 'Chemical', 'MESH:D012538', (119, 121))
88	26492180	Genetically, the EC and CCC components in 3 of the 4 MMR-deficient tumors showed shared somatic mutations involving genes such as PTEN, ARID1A and RPL22, indicating a common genetic origin (Table 3).	('ARID1A', 'Gene', '8289', (136, 142))	('RPL22', 'Gene', '6146', (147, 152))	('ARID1A', 'Gene', (136, 142))	('CCC', 'cellular_component', 'GO:0030896', ('24', '27'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MMR', 'biological_process', 'GO:0006298', ('53', '56'))	('RPL22', 'Gene', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('EC', 'Chemical', '-', (17, 19))	('PTEN', 'Gene', (130, 134))	('PTEN', 'Gene', '5728', (130, 134))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (53, 73))	('mutations', 'Var', (96, 105))	('MMR-deficient tumors', 'Disease', (53, 73))
90	26492180	While there were several mutations identified in both components, there were no mutations that were in common between the apparent EC and CCC components.	('mutations', 'Var', (25, 34))	('CCC', 'Disease', (138, 141))	('CCC', 'cellular_component', 'GO:0030896', ('138', '141'))	('EC', 'Chemical', '-', (131, 133))
91	26492180	The remaining mixed EC and CCC tumor (case 16) showed identical TP53 frameshift mutation and a loss of tumoral p53 expression in both the endometrioid component (napsin A/HNF-1beta-negative) and the clear cell component (napsin A/HNF-1beta-positive).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('TP53', 'Gene', '7157', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('napsin A', 'Gene', (162, 170))	('p53', 'Gene', '7157', (111, 114))	('HNF-1beta', 'Gene', '6928', (230, 239))	('napsin A', 'Gene', '9476', (221, 229))	('CCC tumor', 'Disease', (27, 36))	('HNF-1beta', 'Gene', (171, 180))	('EC', 'Chemical', '-', (20, 22))	('loss of tumoral', 'Disease', 'MESH:D009369', (95, 110))	('p53', 'Gene', (111, 114))	('TP53', 'Gene', (64, 68))	('loss of tumoral', 'Disease', (95, 110))	('CCC', 'cellular_component', 'GO:0030896', ('27', '30'))	('frameshift mutation', 'Var', (69, 88))	('napsin A', 'Gene', (221, 229))	('napsin A', 'Gene', '9476', (162, 170))	('expression', 'MPA', (115, 125))	('HNF-1beta', 'Gene', '6928', (171, 180))	('HNF-1beta', 'Gene', (230, 239))	('CCC tumor', 'Disease', 'MESH:C535313', (27, 36))
95	26492180	Our mutation screen showed two somatic point mutations in PIK3CA, with N345I (C2 domain of PIK3CA) present in both the SC and CCC components and M1004I (exon 20 PIK3CA mutation) found only in the SC component.	('PIK3CA', 'Gene', (91, 97))	('SC', 'Chemical', 'MESH:D012538', (196, 198))	('M1004I', 'Var', (145, 151))	('PIK3CA', 'Gene', '5290', (91, 97))	('N345I', 'Mutation', 'rs1057519938', (71, 76))	('PIK3CA', 'Gene', (161, 167))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('PIK3CA', 'Gene', '5290', (161, 167))	('N345I', 'Var', (71, 76))	('M1004I', 'Mutation', 'p.M1004I', (145, 151))	('CCC', 'cellular_component', 'GO:0030896', ('126', '129'))	('SC', 'Chemical', 'MESH:D012538', (119, 121))
100	26492180	The SC and CCC components harbored identical somatic TP53, PPP2R1A and PIK3CA mutations, and both showed aberrant (strong nuclear) p53 staining (Figure 5G-H).	('SC', 'Chemical', 'MESH:D012538', (4, 6))	('PPP2R1A', 'Gene', (59, 66))	('PIK3CA', 'Gene', '5290', (71, 77))	('PPP2R1A', 'Gene', '5518', (59, 66))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('mutations', 'Var', (78, 87))	('TP53', 'Gene', '7157', (53, 57))	('CCC', 'cellular_component', 'GO:0030896', ('11', '14'))	('TP53', 'Gene', (53, 57))	('PIK3CA', 'Gene', (71, 77))
109	26492180	Based on TCGA finding, the serous/serous-like molecular type of endometrial carcinoma harbored frequent TP53 mutations with PPP2R1A and/or FBXW7 mutations occurring in a smaller subset, and lacked evidence of a high degree of microsatellite instability (MSI-H) and POLE exonuclease domain mutations.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (64, 85))	('FBXW7', 'Gene', (139, 144))	('serous', 'Chemical', '-', (27, 33))	('TP53', 'Gene', '7157', (104, 108))	('PPP2R1A', 'Gene', (124, 131))	('TP53', 'Gene', (104, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('PPP2R1A', 'Gene', '5518', (124, 131))	('MSI-H', 'Disease', (254, 259))	('FBXW7', 'Gene', '55294', (139, 144))	('mutations', 'Var', (109, 118))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (64, 85))	('serous', 'Chemical', '-', (34, 40))	('MSI-H', 'Disease', 'MESH:D000848', (254, 259))	('endometrial carcinoma', 'Disease', (64, 85))
110	26492180	There were 8 cases (case 1, 2, 3, 5, 6, 7, 16 and 18) that showed identical serous-type molecular abnormalities between the corresponding histologic components (concurrent TP53 and PPP2R1A mutations, or TP53 abnormality only without other demonstrable molecular abnormalities).	('TP53', 'Gene', '7157', (203, 207))	('PPP2R1A', 'Gene', (181, 188))	('PPP2R1A', 'Gene', '5518', (181, 188))	('TP53', 'Gene', '7157', (172, 176))	('serous', 'Chemical', '-', (76, 82))	('TP53', 'Gene', (172, 176))	('TP53', 'Gene', (203, 207))	('mutations', 'Var', (189, 198))
113	26492180	Similar to tubo-ovarian high-grade serous carcinoma, endometrial serous carcinomas also harbor TP53 mutations and show a high degree of somatic copy number alterations, which reflect chromosomal instability.	('mutations', 'Var', (100, 109))	('serous carcinoma', 'Disease', 'MESH:D018284', (65, 81))	('serous carcinoma', 'Disease', 'MESH:D018284', (35, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('harbor', 'Reg', (88, 94))	('endometrial serous carcinomas', 'Disease', 'MESH:D016889', (53, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('-ovarian high', 'Phenotype', 'HP:0008209', (15, 28))	('chromosomal instability', 'Phenotype', 'HP:0040012', (183, 206))	('tubo-ovarian', 'Disease', (11, 23))	('endometrial serous carcinomas', 'Disease', (53, 82))	('tubo-ovarian', 'Disease', 'MESH:D010051', (11, 23))	('serous carcinoma', 'Disease', (35, 51))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
116	26492180	We have previously observed that a subset of TP53-mutated pure endometrial clear cell carcinomas harbor prototypical serous-type mutation profiles (with concurrent TP53 and PPP2R1A mutations, in the absence of ARID1A or PTEN mutations).	('TP53', 'Gene', '7157', (164, 168))	('pure', 'molecular_function', 'GO:0034023', ('58', '62'))	('TP53', 'Gene', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('TP53', 'Gene', (45, 49))	('serous', 'Chemical', '-', (117, 123))	('endometrial clear cell carcinomas', 'Phenotype', 'HP:0031522', (63, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('ARID1A', 'Gene', '8289', (210, 216))	('PPP2R1A', 'Gene', '5518', (173, 180))	('ARID1A', 'Gene', (210, 216))	('PPP2R1A', 'Gene', (173, 180))	('endometrial clear cell carcinomas', 'Disease', 'MESH:C538614', (63, 96))	('mutations', 'Var', (181, 190))	('endometrial clear cell carcinomas', 'Disease', (63, 96))	('PTEN', 'Gene', (220, 224))	('TP53', 'Gene', '7157', (45, 49))	('PTEN', 'Gene', '5728', (220, 224))
120	26492180	If p53 immunostaining results suggest TP53 mutation (diffuse strong tumor nuclear staining or a complete absence of tumor nuclear staining in the presence of appropriate internal stromal positive control) in both apparent histologic components, the most likely diagnosis is serous carcinoma (with endometrioid-like area and/or clear cell-like area), as these tumors show serous-like molecular profiles.	('TP53', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (359, 365))	('serous carcinoma', 'Disease', 'MESH:D018284', (274, 290))	('tumor', 'Disease', (68, 73))	('mutation', 'Var', (43, 51))	('tumor', 'Disease', (359, 364))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TP53', 'Gene', '7157', (38, 42))	('serous', 'Chemical', '-', (371, 377))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('tumors', 'Phenotype', 'HP:0002664', (359, 365))	('serous', 'Chemical', '-', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p53', 'Gene', '7157', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('serous carcinoma', 'Disease', (274, 290))	('tumors', 'Disease', (359, 365))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('p53', 'Gene', (3, 6))	('tumor', 'Disease', (116, 121))
121	26492180	However, we do acknowledge that accurate classification of tumors with pure clear cell morphology, abnormal TP53 and expression of napsin A/ HNF-1beta requires further study and ideally a greater insight into the defining molecular features of endometrial clear cell carcinoma.	('abnormal', 'Var', (99, 107))	('HNF-1beta', 'Gene', '6928', (141, 150))	('HNF-1beta', 'Gene', (141, 150))	('pure', 'molecular_function', 'GO:0034023', ('71', '75'))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('napsin A', 'Gene', (131, 139))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('endometrial clear cell carcinoma', 'Disease', 'MESH:C538614', (244, 276))	('napsin A', 'Gene', '9476', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('endometrial clear cell carcinoma', 'Disease', (244, 276))
123	26492180	Case 9 was a POLE ultramutated endometrial carcinoma (case 9) with a POLE exonuclease domain mutation (L424V) and a loss of MSH6 expression that was present in both the endometrioid and the serous components.	('expression', 'MPA', (129, 139))	('MSH6', 'Gene', (124, 128))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (31, 52))	('serous', 'Chemical', '-', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('MSH6', 'Gene', '2956', (124, 128))	('L424V', 'Mutation', 'rs768299607', (103, 108))	('endometrial carcinoma', 'Disease', (31, 52))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (31, 52))	('loss', 'NegReg', (116, 120))	('L424V', 'Var', (103, 108))
124	26492180	This POLE exonuclease domain mutation was previously documented to be present in endometrial carcinoma with an ultramutated genomic landscape and a subset of POLE-mutated tumors can also be MSI-H. A large number of somatic mutations (point mutations and small insertions/ deletions) were identified in this case, some of which were common but some were different between the corresponding endometrioid and serous component.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('endometrial carcinoma', 'Disease', (81, 102))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('MSI-H', 'Disease', 'MESH:D000848', (190, 195))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (81, 102))	('point mutations', 'Var', (234, 249))	('serous', 'Chemical', '-', (406, 412))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('MSI-H', 'Disease', (190, 195))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
126	26492180	In these 3 mixed EC/SC cases with DNA nucleotide repair deficiency (MMR-deficiency and/or POLE exonuclease domain mutation), the serous-like component exhibited prototypical histologic features of serous carcinoma, with at least focally high-grade nuclear features, significant mitotic activity (> 10 MF/10 HPF), prominent nuclear stratification/tumor budding and papillary architectural features.	('MMR-deficiency', 'Disease', 'MESH:C536143', (68, 82))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('mitotic activity', 'CPA', (278, 294))	('MMR', 'biological_process', 'GO:0006298', ('68', '71'))	('papillary architectural features', 'Phenotype', 'HP:0007482', (364, 396))	('serous', 'Chemical', '-', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('SC', 'Chemical', 'MESH:D012538', (20, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('serous carcinoma', 'Disease', (197, 213))	('MMR-deficiency', 'Disease', (68, 82))	('tumor', 'Disease', (346, 351))	('papillary architectural features', 'CPA', (364, 396))	('serous carcinoma', 'Disease', 'MESH:D018284', (197, 213))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('budding', 'biological_process', 'GO:0007114', ('352', '359'))	('deficiency', 'Var', (56, 66))	('serous', 'Chemical', '-', (129, 135))	('EC', 'Chemical', '-', (17, 19))
137	26492180	The serous component also harbored an exon 20 PIK3CA mutation (M1004I) that was not identified in the clear cell component.	('M1004I', 'Var', (63, 69))	('serous', 'Chemical', '-', (4, 10))	('PIK3CA', 'Gene', '5290', (46, 52))	('M1004I', 'Mutation', 'p.M1004I', (63, 69))	('PIK3CA', 'Gene', (46, 52))
138	26492180	While these findings would suggest that these are two unrelated and distinct tumors - synchronous serous carcinoma and clear cell carcinoma, they do share in common a somatic activating mutation involving the C2 domain of PIK3CA.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('PIK3CA', 'Gene', (222, 228))	('activating', 'PosReg', (175, 185))	('clear cell carcinoma', 'Disease', (119, 139))	('C2 domain', 'Var', (209, 218))	('PIK3CA', 'Gene', '5290', (222, 228))	('tumors - synchronous serous carcinoma', 'Disease', 'MESH:D009378', (77, 114))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (119, 139))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors - synchronous serous carcinoma', 'Disease', (77, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
140	26492180	It is plausible that the serous and the clear cell components share the same precursor progenitor cells in the endometrial polyp that harbored this PIK3CA (N345I) mutation, with the serous component going on to acquire a further mutation in exon 20 of PIK3CA and alterations involving TP53, and with the clear cell component presumably going on to acquire other molecular abnormalities.	('PIK3CA', 'Gene', '5290', (148, 154))	('endometrial polyp', 'Disease', (111, 128))	('PIK3CA', 'Gene', '5290', (252, 258))	('TP53', 'Gene', '7157', (285, 289))	('endometrial polyp', 'Disease', 'MESH:D011127', (111, 128))	('mutation in', 'Var', (229, 240))	('N345I', 'Mutation', 'rs1057519938', (156, 161))	('TP53', 'Gene', (285, 289))	('alterations', 'Var', (263, 274))	('PIK3CA', 'Gene', (148, 154))	('serous', 'Chemical', '-', (182, 188))	('mutation', 'Var', (163, 171))	('serous', 'Chemical', '-', (25, 31))	('PIK3CA', 'Gene', (252, 258))
143	26492180	Based on these findings, the most probable explanation is that there is likely a germline MSH6 mutation (Lynch syndrome) that led to the development of two synchronous MSH6-deficient endometrioid carcinomas (one showing endometrioid morphology and one showing clear cell morphology).	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('MSH6', 'Gene', (168, 172))	('MSH6', 'Gene', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('MSH6', 'Gene', '2956', (168, 172))	('Lynch syndrome', 'Disease', (105, 119))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (183, 206))	('MSH6', 'Gene', '2956', (90, 94))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (183, 205))	('synchronous MSH6-deficient endometrioid carcinomas', 'Disease', (156, 206))	('led to', 'Reg', (126, 132))	('Lynch syndrome', 'Disease', 'MESH:D003123', (105, 119))	('synchronous MSH6-deficient endometrioid carcinomas', 'Disease', 'MESH:D016889', (156, 206))	('mutation', 'Var', (95, 103))
160	26492180	For instance, case 11 showed MMR-deficiency and wild-type p53 immunostaining in the histologically endometrioid component and intact MMR proteins but mutated p53 immunostaining in the histologically serous component.	('p53', 'Gene', '7157', (158, 161))	('MMR-deficiency', 'Disease', (29, 43))	('MMR', 'biological_process', 'GO:0006298', ('133', '136'))	('p53', 'Gene', (158, 161))	('mutated', 'Var', (150, 157))	('MMR-deficiency', 'Disease', 'MESH:C536143', (29, 43))	('p53', 'Gene', (58, 61))	('serous', 'Chemical', '-', (199, 205))	('MMR', 'biological_process', 'GO:0006298', ('29', '32'))	('p53', 'Gene', '7157', (58, 61))
167	26492180	Tumors with DNA repair defects, with resulting intratumoral heterogeneity, are the second largest group.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('defects', 'Var', (23, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('DNA repair', 'biological_process', 'GO:0006281', ('12', '22'))
169	26492180	These results suggest that the integration of selected ancillary studies such as p53 and MMR protein immunohistochemistry, and mutation analysis of POLE exonuclease domain should be considered when dealing with a mixed endometrial carcinoma, as these results may provide useful diagnostic insights.	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('endometrial carcinoma', 'Disease', (219, 240))	('mutation', 'Var', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (219, 240))	('MMR', 'biological_process', 'GO:0006298', ('89', '92'))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('mixed', 'Disease', (213, 218))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (219, 240))
171	20368795	The molecular changes in type I endometrial carcinomas include mutations in PTEN, PIK3CA, KRAS, and beta-catenin, along with microsatellite instability, whereas type II endometrial carcinomas are characterized by genetic alterations in p53, HER2/neu, p16, and E-cadherin.	('E-cadherin', 'Gene', (260, 270))	('type II endometrial carcinomas', 'Disease', 'MESH:D016889', (161, 191))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (169, 191))	('PIK3CA', 'Gene', '5290', (82, 88))	('E-cadherin', 'Gene', '999', (260, 270))	('HER2/neu', 'Gene', '2064', (241, 249))	('type I endometrial carcinomas', 'Disease', 'MESH:D016889', (25, 54))	('mutations', 'Var', (63, 72))	('type II endometrial carcinomas', 'Disease', (161, 191))	('PTEN', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (90, 94))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (32, 54))	('p53', 'Gene', '7157', (236, 239))	('cadherin', 'molecular_function', 'GO:0008014', ('262', '270'))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('type I endometrial carcinomas', 'Disease', (25, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('beta-catenin', 'Gene', (100, 112))	('PIK3CA', 'Gene', (82, 88))	('beta-catenin', 'Gene', '1499', (100, 112))	('KRAS', 'Gene', (90, 94))	('p53', 'Gene', (236, 239))	('PTEN', 'Gene', '5728', (76, 80))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (32, 53))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (169, 190))	('HER2/neu', 'Gene', (241, 249))	('p16', 'Gene', (251, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('p16', 'Gene', '1029', (251, 254))
172	20368795	For endometrial neoplasms with a malignant mesenchymal component, C-MYC mutations and loss of heterozygosity are frequently seen in carcinosarcomas, and a fusion gene, JAZF1/JJAZ1, is distinctive for endometrial stromal sarcoma.	('seen', 'Reg', (124, 128))	('endometrial stromal sarcoma', 'Disease', (200, 227))	('C-MYC', 'Gene', '4609', (66, 71))	('mutations', 'Var', (72, 81))	('C-MYC', 'Gene', (66, 71))	('JJAZ1', 'Gene', '23512', (174, 179))	('JAZF1', 'Gene', '221895', (168, 173))	('JJAZ1', 'Gene', (174, 179))	('carcinosarcomas', 'Disease', 'MESH:D002296', (132, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('JAZF1', 'Gene', (168, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('endometrial neoplasms', 'Disease', 'MESH:D016889', (4, 25))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (200, 227))	('carcinosarcomas', 'Disease', (132, 147))	('endometrial neoplasms', 'Disease', (4, 25))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (16, 24))
173	20368795	In addition, p53 mutations may play an important role in tumorigenesis of undifferentiated endometrial sarcoma.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (91, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('endometrial sarcoma', 'Disease', (91, 110))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p53', 'Gene', (13, 16))	('tumor', 'Disease', (57, 62))	('play', 'Reg', (31, 35))	('mutations', 'Var', (17, 26))	('p53', 'Gene', '7157', (13, 16))
203	20368795	The two distinct histological types of carcinomas are associated with genetic alterations of independent sets of genes.	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('carcinomas', 'Disease', (39, 49))	('carcinomas', 'Disease', 'MESH:D002277', (39, 49))	('genetic alterations', 'Var', (70, 89))
206	20368795	According to this model, normal endometrial cells would transform into endometrioid endometrial carcinoma through 5 different molecular changes, including, mutations of PTEN, PIK3CA, KRAS, and CTNNB1 (beta-catenin) genes and microsatellite instability (MSI) while non-endometrioid endometrial carcinoma is frequently related to alterations of p53 and chromosomal instability.	('MSI', 'Disease', (253, 256))	('CTNNB1', 'Gene', '1499', (193, 199))	('PIK3CA', 'Gene', '5290', (175, 181))	('p53', 'Gene', (343, 346))	('transform', 'Reg', (56, 65))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (84, 105))	('microsatellite', 'MPA', (225, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('KRAS', 'Gene', '3845', (183, 187))	('CTNNB1', 'Gene', (193, 199))	('PIK3CA', 'Gene', (175, 181))	('endometrioid endometrial carcinoma', 'Disease', (71, 105))	('KRAS', 'Gene', (183, 187))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (281, 302))	('mutations', 'Var', (156, 165))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (71, 105))	('PTEN', 'Gene', (169, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('endometrioid endometrial carcinoma', 'Disease', (268, 302))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (268, 302))	('beta-catenin', 'Gene', (201, 213))	('PTEN', 'Gene', '5728', (169, 173))	('chromosomal instability', 'Phenotype', 'HP:0040012', (351, 374))	('p53', 'Gene', '7157', (343, 346))	('beta-catenin', 'Gene', '1499', (201, 213))	('MSI', 'Disease', 'None', (253, 256))
208	20368795	Furthermore, none of the five main alterations of endometrioid endometrial carcinoma (mutations of PTEN, PIK3CA, KRAS, and CTNNB1 genes and MSI) plays a major role in non-endometrioid endometrial carcinoma.	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (50, 84))	('endometrioid endometrial carcinoma', 'Disease', (50, 84))	('PIK3CA', 'Gene', '5290', (105, 111))	('KRAS', 'Gene', '3845', (113, 117))	('MSI', 'Disease', 'None', (140, 143))	('CTNNB1', 'Gene', (123, 129))	('MSI', 'Disease', (140, 143))	('KRAS', 'Gene', (113, 117))	('PTEN', 'Gene', (99, 103))	('PIK3CA', 'Gene', (105, 111))	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (184, 205))	('PTEN', 'Gene', '5728', (99, 103))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (171, 205))	('endometrioid endometrial carcinoma', 'Disease', (171, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (63, 84))	('CTNNB1', 'Gene', '1499', (123, 129))
210	20368795	described the development of non-endometrioid endometrial carcinoma through these possible pathways: (i) de novo, through p53 mutations, loss of heterozygosity (LOH) at several loci, and some other still unknown gene alterations; or (ii) through dedifferentiation of a pre-existing endometrioid carcinoma.	('endometrioid endometrial carcinoma', 'Disease', (33, 67))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (33, 67))	('loss of heterozygosity', 'Var', (137, 159))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (282, 304))	('p53', 'Gene', '7157', (122, 125))	('pre', 'molecular_function', 'GO:0003904', ('269', '272'))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (282, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('endometrioid carcinoma', 'Disease', (282, 304))	('mutations', 'Var', (126, 135))	('dedifferentiation', 'biological_process', 'GO:0043696', ('246', '263'))	('alterations', 'Var', (217, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (46, 67))	('p53', 'Gene', (122, 125))
219	20368795	PTEN may be inactivated by several mechanisms such as mutation, LOH, and promoter hypermethylation.	('promoter hypermethylation', 'Var', (73, 98))	('LOH', 'Var', (64, 67))	('mutation', 'Var', (54, 62))	('inactivated', 'NegReg', (12, 23))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
220	20368795	Somatic PTEN mutations are common in endometrial carcinoma, and they are almost exclusively restricted to endometrioid endometrial carcinomas, occurring up to 83% of them.	('endometrial carcinoma', 'Disease', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (119, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('PTEN', 'Gene', (8, 12))	('endometrioid endometrial carcinomas', 'Disease', (106, 141))	('PTEN', 'Gene', '5728', (8, 12))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (119, 140))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (119, 141))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (37, 58))	('mutations', 'Var', (13, 22))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (106, 141))	('common', 'Reg', (27, 33))
221	20368795	Germline mutations of PTEN are responsible for Cowden syndrome.	('Germline mutations', 'Var', (0, 18))	('Cowden syndrome', 'Disease', 'MESH:D006223', (47, 62))	('Cowden syndrome', 'Disease', (47, 62))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('responsible', 'Reg', (31, 42))
222	20368795	PTEN may be also inactivated by deletion, as shown by LOH in 40% of endometrial carcinomas.	('deletion', 'Var', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (68, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('endometrial carcinomas', 'Disease', (68, 90))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (68, 90))
223	20368795	Promoter hypermethylation leading to PTEN inactivation, is found in about 20% of tumors, most of which are high-stage.	('inactivation', 'NegReg', (42, 54))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('Promoter hypermethylation', 'Var', (0, 25))
224	20368795	PTEN mutations have been detected in 15-55% of endometrial hyperplasias with and without atypia.	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (47, 70))	('mutations', 'Var', (5, 14))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (47, 71))	('endometrial hyperplasias', 'Disease', (47, 71))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (47, 71))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('detected', 'Reg', (25, 33))
226	20368795	This suggests that PTEN could be a target for mutations in the context of DNA repair deficiency.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('mutations', 'Var', (46, 55))	('PTEN', 'Gene', (19, 23))	('DNA repair', 'biological_process', 'GO:0006281', ('74', '84'))	('PTEN', 'Gene', '5728', (19, 23))
227	20368795	In addition, identical PTEN mutations have been also identified in hyperplasias coexisting with MSI-positive endometrioid endometrial carcinoma, which suggests that PTEN mutations are early events in their development.	('MSI-positive endometrioid endometrial carcinoma', 'Disease', (96, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (122, 143))	('PTEN', 'Gene', (165, 169))	('PTEN', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('hyperplasias', 'Disease', (67, 79))	('identified', 'Reg', (53, 63))	('PTEN', 'Gene', '5728', (23, 27))	('MSI-positive endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 143))	('mutations', 'Var', (28, 37))	('hyperplasias', 'Disease', 'MESH:D006965', (67, 79))	('PTEN', 'Gene', '5728', (165, 169))
228	20368795	On the other hand, identical PTEN mutations have been detected in MSI-negative endometrial hyperplasia with coexisting MSI-positive endometrioid endometrial carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('MSI', 'Disease', 'None', (66, 69))	('MSI-positive endometrioid endometrial carcinomas', 'Disease', (119, 167))	('MSI', 'Disease', (119, 122))	('PTEN', 'Gene', (29, 33))	('endometrial hyperplasia', 'Disease', (79, 102))	('MSI-positive endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (119, 167))	('PTEN', 'Gene', '5728', (29, 33))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (79, 102))	('MSI', 'Disease', (66, 69))	('detected', 'Reg', (54, 62))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (145, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (79, 102))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (145, 166))	('mutations', 'Var', (34, 43))	('MSI', 'Disease', 'None', (119, 122))
229	20368795	Thus, some PTEN mutations may precede MSI, and coexistence of both alterations does not necessarily mean a cause-effect relationship.	('PTEN', 'Gene', (11, 15))	('PTEN', 'Gene', '5728', (11, 15))	('MSI', 'Disease', 'None', (38, 41))	('mutations', 'Var', (16, 25))	('MSI', 'Disease', (38, 41))
233	20368795	In addition, recent data suggest that only PTEN mutations outside exons 5-7 may predict favorable survival, independent of the clinical and pathological features of the tumors.	('favorable survival', 'CPA', (88, 106))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('predict', 'Reg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('mutations', 'Var', (48, 57))
237	20368795	Activation of PI3K produces the second messenger PIP3 which subsequently activates various down-stream pathways such as AKT.	('AKT', 'Gene', (120, 123))	('PI3K', 'Var', (14, 18))	('down-stream pathways', 'Pathway', (91, 111))	('AKT', 'Gene', '207', (120, 123))	('activates', 'PosReg', (73, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))
239	20368795	Mutations in AKT family members and their correlation with other gene alterations are found in endometrial carcinoma, including AKT2 (D399N), AKT2 (D32H) and AKT3 (E438D) mutations.	('AKT3', 'Gene', '10000', (158, 162))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (95, 116))	('D399N', 'Mutation', 'rs1319165364', (134, 139))	('AKT', 'Gene', (142, 145))	('AKT', 'Gene', '207', (128, 131))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (95, 116))	('AKT3', 'Gene', (158, 162))	('AKT', 'Gene', (13, 16))	('AKT2', 'Gene', '208', (128, 132))	('D32H', 'Mutation', 'p.D32H', (148, 152))	('AKT', 'Gene', '207', (158, 161))	('AKT', 'Gene', '207', (142, 145))	('E438D', 'Mutation', 'p.E438D', (164, 169))	('AKT2', 'Gene', (128, 132))	('D32H', 'Var', (148, 152))	('AKT2', 'Gene', '208', (142, 146))	('AKT', 'Gene', '207', (13, 16))	('E438D) mutations', 'Var', (164, 180))	('AKT2', 'Gene', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('endometrial carcinoma', 'Disease', (95, 116))	('AKT', 'Gene', (128, 131))	('AKT', 'Gene', (158, 161))
240	20368795	Mutations of AKT3 (E438D) also have amplification of and a mutation in PIK3CA .	('amplification', 'MPA', (36, 49))	('E438D', 'Var', (19, 24))	('PIK3CA', 'Gene', '5290', (71, 77))	('E438D', 'Mutation', 'p.E438D', (19, 24))	('AKT3', 'Gene', (13, 17))	('AKT3', 'Gene', '10000', (13, 17))	('PIK3CA', 'Gene', (71, 77))
241	20368795	AKT1 E17K mutation is not associated with either PTEN or PIK3CA genomic alteration.	('PTEN', 'Gene', '5728', (49, 53))	('AKT1', 'Gene', '207', (0, 4))	('PIK3CA', 'Gene', '5290', (57, 63))	('AKT1', 'Gene', (0, 4))	('E17K', 'Mutation', 'rs121434592', (5, 9))	('E17K', 'Var', (5, 9))	('PTEN', 'Gene', (49, 53))	('PIK3CA', 'Gene', (57, 63))
242	20368795	In vitro studies showed that activating mutations of PIK3CA in combination with PTEN mutations led to an additional increase in phosphorylated AKT when compared with cells with only inactivated PTEN.	('PTEN', 'Gene', (80, 84))	('PIK3CA', 'Gene', '5290', (53, 59))	('PTEN', 'Gene', '5728', (80, 84))	('PTEN', 'Gene', (194, 198))	('PIK3CA', 'Gene', (53, 59))	('phosphorylated', 'MPA', (128, 142))	('PTEN', 'Gene', '5728', (194, 198))	('AKT', 'Gene', '207', (143, 146))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (85, 94))	('increase', 'PosReg', (116, 124))	('activating', 'PosReg', (29, 39))	('AKT', 'Gene', (143, 146))
243	20368795	Some investigators have claimed that PIK3CA mutations are mutually exclusive of PTEN mutations, suggesting that tumorigenic signaling through this pathway can occur either through activation of PIK3CA or inactivation of PTEN.	('activation', 'PosReg', (180, 190))	('PIK3CA', 'Gene', (37, 43))	('PIK3CA', 'Gene', '5290', (37, 43))	('PIK3CA', 'Gene', '5290', (194, 200))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('inactivation', 'Var', (204, 216))	('tumor', 'Disease', (112, 117))	('PIK3CA', 'Gene', (194, 200))	('PTEN', 'Gene', '5728', (220, 224))	('PTEN', 'Gene', (220, 224))
244	20368795	Recently, interactions between the PI3K/AKT and p53 signaling pathways have been described in which activation of the PI3K/AKT pathway through PTEN or PIK3CA mutations, together with p53 inactivation, results in malignant transformation.	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('p53', 'Gene', '7157', (183, 186))	('results in', 'Reg', (201, 211))	('p53', 'Gene', '7157', (48, 51))	('interactions', 'Interaction', (10, 22))	('AKT', 'Gene', '207', (40, 43))	('p53', 'Gene', (183, 186))	('PIK3CA', 'Gene', '5290', (151, 157))	('mutations', 'Var', (158, 167))	('AKT', 'Gene', (123, 126))	('PI3K', 'molecular_function', 'GO:0016303', ('118', '122'))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))	('p53', 'Gene', (48, 51))	('activation', 'PosReg', (100, 110))	('PTEN', 'Gene', (143, 147))	('PIK3CA', 'Gene', (151, 157))	('AKT', 'Gene', '207', (123, 126))	('AKT', 'Gene', (40, 43))	('PTEN', 'Gene', '5728', (143, 147))	('malignant transformation', 'CPA', (212, 236))
245	20368795	Moreover, patients with dysregulation of PI3K/AKT signaling pathway and p53 alterations had shorter survival than patients with only p53 alterations.	('survival', 'MPA', (100, 108))	('signaling pathway', 'biological_process', 'GO:0007165', ('50', '67'))	('alterations', 'Var', (76, 87))	('AKT', 'Gene', '207', (46, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('p53', 'Gene', '7157', (133, 136))	('dysregulation', 'Var', (24, 37))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('AKT', 'Gene', (46, 49))	('patients', 'Species', '9606', (10, 18))	('p53', 'Gene', (133, 136))	('patients', 'Species', '9606', (114, 122))	('AKT signaling', 'biological_process', 'GO:0043491', ('46', '59'))	('shorter', 'NegReg', (92, 99))
246	20368795	Mutations were more common in mixed endometrioid-nonendometrioid adenocarcinomas (44%) than in pure endometrioid adenocarcinomas (28%) or pure nonendometrioid adenocarcinomas (21%).	('endometrioid adenocarcinomas', 'Disease', (146, 174))	('endometrioid adenocarcinomas', 'Disease', (52, 80))	('pure', 'molecular_function', 'GO:0034023', ('138', '142'))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('Mutations', 'Var', (0, 9))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (100, 128))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (52, 80))	('pure', 'molecular_function', 'GO:0034023', ('95', '99'))	('common', 'Reg', (20, 26))	('endometrioid adenocarcinomas', 'Disease', (100, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
247	20368795	In fact, PIK3CA mutations are usually missense and cluster in exons 9 (helical domain) and 20 (kinase domain).	('PIK3CA', 'Gene', '5290', (9, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))
248	20368795	The tumors carrying exon 9 PIK3CA mutations are more likely to be low-grade carcinomas; in contrast, carcinomas with exon 20 mutations or PIK3CA mRNA overexpression are often high-grade carcinomas associated with myometrial invasion and tended to have lymphovascular invasion.	('myometrial invasion', 'Disease', (213, 232))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('carcinomas', 'Disease', (76, 86))	('PIK3CA', 'Gene', (27, 33))	('PIK3CA', 'Gene', (138, 144))	('carcinomas', 'Disease', (186, 196))	('carcinomas', 'Disease', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('associated', 'Reg', (197, 207))	('mutations', 'Var', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('exon 9', 'Var', (20, 26))	('lymphovascular invasion', 'CPA', (252, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('tumors', 'Disease', (4, 10))	('carcinomas', 'Disease', 'MESH:D002277', (76, 86))	('overexpression', 'PosReg', (150, 164))	('carcinomas', 'Disease', 'MESH:D002277', (186, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('carcinomas', 'Disease', 'MESH:D002277', (101, 111))	('PIK3CA', 'Gene', '5290', (27, 33))	('PIK3CA', 'Gene', '5290', (138, 144))
249	20368795	Furthermore, in high-grade endometrioid adenocarcinomas and mixed carcinomas, PIK3CA mutations in exon 20 coexist with p53 alterations more frequently than in nonendometrioid adenocarcinomas.	('PIK3CA', 'Gene', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (66, 76))	('carcinomas', 'Disease', (180, 190))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (27, 55))	('p53', 'Gene', '7157', (119, 122))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (162, 190))	('alterations', 'Var', (123, 134))	('carcinomas', 'Disease', (45, 55))	('mixed', 'Disease', (60, 65))	('mutations in', 'Var', (85, 97))	('p53', 'Gene', (119, 122))	('carcinomas', 'Disease', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('PIK3CA', 'Gene', '5290', (78, 84))	('endometrioid adenocarcinomas', 'Disease', (27, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrioid adenocarcinomas', 'Disease', (162, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('carcinomas', 'Disease', 'MESH:D002277', (45, 55))
251	20368795	PIK3CA mutations did not correlate with MSI or beta-catenin/CTNNB1 mutations.	('beta-catenin', 'Gene', '1499', (47, 59))	('CTNNB1', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('beta-catenin', 'Gene', (47, 59))	('MSI', 'Disease', 'None', (40, 43))	('CTNNB1', 'Gene', '1499', (60, 66))	('MSI', 'Disease', (40, 43))	('mutations', 'Var', (7, 16))
252	20368795	PIK3CA mutations, particularly exon 20 mutations or PIK3CA mRNA overexpression, are frequent in endometrioid endometrial carcinoma in association with invasion and adverse prognostic factors such as blood vessel invasion.	('blood vessel invasion', 'CPA', (199, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('exon 20 mutations', 'Var', (31, 48))	('frequent', 'Reg', (84, 92))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (109, 130))	('PIK3CA', 'Gene', (52, 58))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 130))	('endometrioid endometrial carcinoma', 'Disease', (96, 130))	('PIK3CA', 'Gene', '5290', (52, 58))	('mRNA', 'MPA', (59, 63))	('mutations', 'Var', (7, 16))
254	20368795	KRAS mutations have been identified in 10-30% of endometrioid endometrial carcinomas while some investigators have reported an almost complete absence of KRAS mutations in serous and clear cell carcinomas of endometrium.	('KRAS', 'Gene', '3845', (154, 158))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (62, 84))	('clear cell carcinomas', 'Disease', (183, 204))	('identified', 'Reg', (25, 35))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (49, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (62, 83))	('endometrioid endometrial carcinomas', 'Disease', (49, 84))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (183, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', (154, 158))	('KRAS', 'Gene', '3845', (0, 4))
255	20368795	Some studies found a higher frequency of KRAS mutations in MSI-positive carcinomas than in MSI-negative tumors suggesting that both events may occur simultaneously before clonal expansion.	('MSI', 'Disease', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('KRAS', 'Gene', '3845', (41, 45))	('mutations', 'Var', (46, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MSI', 'Disease', 'None', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MSI-positive carcinomas', 'Disease', 'MESH:D002277', (59, 82))	('MSI-positive carcinomas', 'Disease', (59, 82))	('tumors', 'Disease', (104, 110))	('MSI', 'Disease', (59, 62))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('MSI', 'Disease', 'None', (91, 94))	('KRAS', 'Gene', (41, 45))
256	20368795	KRAS mutations were detected in endometrial hyperplasias at a similar rate to that observed in endometrioid endometrial carcinomas, suggesting that KRAS mutations are early events in endometrial carcinogensis.	('KRAS', 'Gene', (148, 152))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (32, 55))	('endometrial hyperplasias', 'Disease', (32, 56))	('endometrioid endometrial carcinomas', 'Disease', (95, 130))	('mutations', 'Var', (153, 162))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (32, 56))	('KRAS', 'Gene', (0, 4))	('endometrial carcinogensis', 'Disease', 'MESH:D014591', (183, 208))	('endometrial carcinogensis', 'Phenotype', 'HP:0012114', (183, 208))	('KRAS', 'Gene', '3845', (148, 152))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (108, 130))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (32, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (95, 130))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (108, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('endometrial carcinogensis', 'Disease', (183, 208))	('KRAS', 'Gene', '3845', (0, 4))
257	20368795	No relationship has been found between KRAS mutations and tumor stage, histologic grade, depth of myometrial invasion, age, or clinical outcome in endometrioid endometrial carcinomas.	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (147, 182))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('endometrioid endometrial carcinomas', 'Disease', (147, 182))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (160, 182))	('KRAS', 'Gene', '3845', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (160, 181))
261	20368795	Mutations in exon 3 of CTNNB1 result in stabilization of a protein that resists degradation, leading to nuclear accumulation of beta-catenin, have been described in endometrioid endometrial carcinoma.	('CTNNB1', 'Gene', (23, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('described', 'Reg', (152, 161))	('beta-catenin', 'Gene', (128, 140))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (178, 199))	('stabilization', 'MPA', (40, 53))	('beta-catenin', 'Gene', '1499', (128, 140))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (165, 199))	('endometrioid endometrial carcinoma', 'Disease', (165, 199))	('Mutations in', 'Var', (0, 12))	('CTNNB1', 'Gene', '1499', (23, 29))	('degradation', 'biological_process', 'GO:0009056', ('80', '91'))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
264	20368795	By comparison in colonic adenocarcinomas, elevated beta-catenin levels caused by mutations in CTNNB1 or APC result in activation of the Wnt/beta-catenin/LEF1 pathway through a LEF1 binding site in the cyclin D1 promotor, triggering cyclin D1 gene expression, and subsequently, uncontrolled progression of tumor cells into the cell cycle.	('cyclin D1', 'Gene', '595', (201, 210))	('colonic adenocarcinomas', 'Disease', (17, 40))	('binding', 'Interaction', (181, 188))	('cyclin D1', 'Gene', (232, 241))	('mutations', 'Var', (81, 90))	('tumor', 'Disease', (305, 310))	('triggering', 'Reg', (221, 231))	('binding', 'molecular_function', 'GO:0005488', ('181', '188'))	('gene expression', 'biological_process', 'GO:0010467', ('242', '257'))	('expression', 'MPA', (247, 257))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('cyclin D1', 'Gene', '595', (232, 241))	('APC', 'cellular_component', 'GO:0005680', ('104', '107'))	('cyclin', 'molecular_function', 'GO:0016538', ('232', '238'))	('elevated', 'PosReg', (42, 50))	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (17, 40))	('LEF1', 'Gene', (176, 180))	('LEF1', 'Gene', (153, 157))	('CTNNB1', 'Gene', '1499', (94, 100))	('cyclin', 'molecular_function', 'GO:0016538', ('201', '207'))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('beta-catenin', 'Gene', (51, 63))	('beta-catenin', 'Gene', (140, 152))	('activation', 'PosReg', (118, 128))	('beta-catenin', 'Gene', '1499', (140, 152))	('cell cycle', 'biological_process', 'GO:0007049', ('326', '336'))	('cyclin D1', 'Gene', (201, 210))	('beta-catenin', 'Gene', '1499', (51, 63))	('APC', 'Disease', 'MESH:D011125', (104, 107))	('APC', 'Disease', (104, 107))	('LEF1', 'Gene', '51176', (153, 157))	('CTNNB1', 'Gene', (94, 100))	('LEF1', 'Gene', '51176', (176, 180))
266	20368795	The reported frequency of CTNNB1 mutations in endometrioid endometrial carcinoma ranges from 14-44%.	('CTNNB1', 'Gene', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutations', 'Var', (33, 42))	('CTNNB1', 'Gene', '1499', (26, 32))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (59, 80))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (46, 80))	('endometrioid endometrial carcinoma', 'Disease', (46, 80))
268	20368795	In all cases, the mutations were homogeneously distributed in different areas of the tumors suggesting that they play a role in early steps of endometrial tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('play', 'Reg', (113, 117))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('role', 'Reg', (120, 124))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (18, 27))
269	20368795	Alterations in beta-catenin have been reported in endometrial hyperplasias with squamous metaplasia.	('squamous metaplasia', 'Phenotype', 'HP:0002860', (80, 99))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (50, 73))	('reported', 'Reg', (38, 46))	('endometrial hyperplasias', 'Disease', (50, 74))	('Alterations', 'Var', (0, 11))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (50, 74))	('metaplasia', 'biological_process', 'GO:0036074', ('89', '99'))	('beta-catenin', 'Gene', (15, 27))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (50, 74))	('beta-catenin', 'Gene', '1499', (15, 27))	('squamous metaplasia', 'Disease', (80, 99))	('squamous metaplasia', 'Disease', 'MESH:D008679', (80, 99))
270	20368795	Although there was a good correlation between CTNNB1 mutations and beta-catenin nuclear immunostaining, the presence of cytoplasmic and nuclear beta-catenin immunoreactivity in some endometrial carcinomas without CTNNB mutation suggests that the changes of other genes in the Wnt/beta-catenin/LEF-1 pathway may be responsible for the stabilization and putative transcription activator role of beta-catenin.	('CTNNB', 'Gene', '1499', (213, 218))	('endometrial carcinomas', 'Disease', (182, 204))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (182, 203))	('CTNNB', 'Gene', (213, 218))	('beta-catenin', 'Gene', (144, 156))	('LEF-1', 'Gene', '51176', (293, 298))	('beta-catenin', 'Gene', '1499', (144, 156))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (182, 204))	('LEF-1', 'Gene', (293, 298))	('CTNNB1', 'Gene', (46, 52))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (182, 204))	('transcription', 'biological_process', 'GO:0006351', ('361', '374'))	('beta-catenin', 'Gene', (393, 405))	('mutations', 'Var', (53, 62))	('CTNNB1', 'Gene', '1499', (46, 52))	('beta-catenin', 'Gene', '1499', (393, 405))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('beta-catenin', 'Gene', (280, 292))	('CTNNB', 'Gene', '1499', (46, 51))	('beta-catenin', 'Gene', (67, 79))	('beta-catenin', 'Gene', '1499', (280, 292))	('beta-catenin', 'Gene', '1499', (67, 79))	('CTNNB', 'Gene', (46, 51))
271	20368795	Endometrioid endometrial carcinomas with CTNNB1 mutations are characteristically early stage tumors associated with favorable prognosis.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (13, 34))	('stage tumors', 'Disease', 'MESH:D062706', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (13, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('CTNNB1', 'Gene', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('endometrial carcinomas', 'Disease', (13, 35))	('stage tumors', 'Disease', (87, 99))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (13, 35))	('mutations', 'Var', (48, 57))	('CTNNB1', 'Gene', '1499', (41, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))
280	20368795	In sporadic endometrial carcinoma, epigenetic cause of MSI is more common involving MLH1 promotor hypermethylation which is the main cause of MMR deficiency.	('MMR deficiency', 'Disease', (142, 156))	('epigenetic', 'Var', (35, 45))	('MMR deficiency', 'Disease', 'MESH:C536143', (142, 156))	('MLH1', 'Gene', (84, 88))	('MLH1', 'Gene', '4292', (84, 88))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (12, 33))	('MSI', 'Disease', 'None', (55, 58))	('common', 'Reg', (67, 73))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (12, 33))	('MMR', 'biological_process', 'GO:0006298', ('142', '145'))	('MSI', 'Disease', (55, 58))	('cause', 'Reg', (46, 51))	('endometrial carcinoma', 'Disease', (12, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('hypermethylation', 'Var', (98, 114))
281	20368795	This epigenetic inactivation usually occurs in atypical hyperplasia, most of which coexists with carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (47, 67))	('atypical hyperplasia', 'Disease', (47, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('carcinomas', 'Disease', (97, 107))	('carcinomas', 'Disease', 'MESH:D002277', (97, 107))	('occurs', 'Reg', (37, 43))	('epigenetic inactivation', 'Var', (5, 28))
282	20368795	Thus, MLH1 hypermethylation is an early event in the pathogenesis of endometrioid endometrial carcinoma, which precedes the development of MSI.	('pathogenesis', 'biological_process', 'GO:0009405', ('53', '65'))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('MSI', 'Disease', (139, 142))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (82, 103))	('hypermethylation', 'Var', (11, 27))	('MLH1', 'Gene', '4292', (6, 10))	('MLH1', 'Gene', (6, 10))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (69, 103))	('endometrioid endometrial carcinoma', 'Disease', (69, 103))	('MSI', 'Disease', 'None', (139, 142))
283	20368795	The remaining unmethylated MLH1 cases reveal MSH2 mutations (15%) and MSH6 mutations (60%), of which almost half are germline mutations.	('mutations', 'Var', (50, 59))	('MSH2', 'Gene', (45, 49))	('MSH6', 'Gene', (70, 74))	('MLH1', 'Gene', '4292', (27, 31))	('MSH2', 'Gene', '4436', (45, 49))	('MLH1', 'Gene', (27, 31))	('MSH6', 'Gene', '2956', (70, 74))	('mutations', 'Var', (75, 84))
284	20368795	Thus, MSH6 mutations seem to be a frequent cause of MSI.	('mutations', 'Var', (11, 20))	('cause', 'Reg', (43, 48))	('MSI', 'Disease', 'None', (52, 55))	('MSH6', 'Gene', '2956', (6, 10))	('MSI', 'Disease', (52, 55))	('MSH6', 'Gene', (6, 10))
285	20368795	Tumors with MSI of CpG island methylation in the promoter region have been identified in some other genes, for example, p16, PTEN, and E-cadherin (CDH1), suggesting altered methylation may be a coexisting independent early change.	('methylation', 'Var', (30, 41))	('PTEN', 'Gene', (125, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('137', '145'))	('CDH1', 'Gene', '999', (147, 151))	('PTEN', 'Gene', '5728', (125, 129))	('p16', 'Gene', (120, 123))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('methylation', 'biological_process', 'GO:0032259', ('173', '184'))	('E-cadherin', 'Gene', '999', (135, 145))	('MSI', 'Disease', 'None', (12, 15))	('methylation', 'MPA', (173, 184))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p16', 'Gene', '1029', (120, 123))	('CDH1', 'Gene', (147, 151))	('E-cadherin', 'Gene', (135, 145))	('MSI', 'Disease', (12, 15))
286	20368795	The presentation of some small short-tandem repeats such as mononucleotide repeats located within the coding sequence of important genes for example, transforming growth factor beta receptor type II (TGF-betaRII), BAX, insulin-like growth factor II receptor (IGFIIR), MSH3, MSH6, caspase-5, and PTEN may promote MSI-positive endometrial carcinoma.	('mononucleotide', 'Chemical', '-', (60, 74))	('promote', 'PosReg', (304, 311))	('caspase-5', 'Gene', '838', (280, 289))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (325, 346))	('short-tandem repeats', 'Var', (31, 51))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (325, 346))	('MSH3', 'Gene', (268, 272))	('insulin-like growth factor II receptor', 'Gene', '3482', (219, 257))	('MSH3', 'Gene', '4437', (268, 272))	('MSH6', 'Gene', (274, 278))	('TGF-betaRII', 'Gene', '7048', (200, 211))	('MSI', 'Disease', 'None', (312, 315))	('BAX', 'Gene', (214, 217))	('MSH6', 'Gene', '2956', (274, 278))	('insulin-like growth factor II receptor', 'Gene', (219, 257))	('BAX', 'Gene', '581', (214, 217))	('MSI', 'Disease', (312, 315))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('150', '181'))	('caspase-5', 'Gene', (280, 289))	('PTEN', 'Gene', (295, 299))	('transforming growth factor beta receptor type II', 'Gene', '7048', (150, 198))	('TGF-betaRII', 'Gene', (200, 211))	('endometrial carcinoma', 'Disease', (325, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (337, 346))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('219', '245'))	('mononucleotide repeats', 'Var', (60, 82))	('transforming growth factor beta receptor type II', 'Gene', (150, 198))	('IGFIIR', 'Gene', '3482', (259, 265))	('PTEN', 'Gene', '5728', (295, 299))	('IGFIIR', 'Gene', (259, 265))
291	20368795	While p53 mutations occur in 90% of non-endometrioid endometrial carcinoma, they are only present in 10-20% of endometrioid endometrial carcinoma, which are mostly high-grade.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (53, 74))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (40, 74))	('endometrioid endometrial carcinoma', 'Disease', (40, 74))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (124, 145))	('mutations', 'Var', (10, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (111, 145))	('endometrioid endometrial carcinoma', 'Disease', (111, 145))
292	20368795	The abnormal p53 expression has been found in 11% of grade 1 endometrioid endometrial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (74, 95))	('abnormal', 'Var', (4, 12))	('endometrioid endometrial carcinoma', 'Disease', (61, 95))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 95))	('found', 'Reg', (37, 42))	('expression', 'MPA', (17, 27))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))
293	20368795	This finding supports that p53 mutations may influence progression of endometrioid endometrial carcinomas to non-endometrioid endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('mutations', 'Var', (31, 40))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (70, 105))	('p53', 'Gene', '7157', (27, 30))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (83, 105))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (126, 147))	('endometrioid endometrial carcinomas', 'Disease', (113, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (83, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('influence', 'Reg', (45, 54))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (113, 148))	('endometrioid endometrial carcinomas', 'Disease', (70, 105))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (126, 148))	('p53', 'Gene', (27, 30))
294	20368795	In fact, p53 mutation is the most characteristic genetic alteration of non-endometrioid endometrial carcinomas and may be useful in their distinction from endometrioid endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (88, 109))	('endometrioid endometrial carcinomas', 'Disease', (75, 110))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (155, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('mutation', 'Var', (13, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (168, 189))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (88, 110))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (75, 110))	('endometrioid endometrial carcinomas', 'Disease', (155, 190))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (168, 190))
299	20368795	p53 mutations produce a non-functional protein that resists degradation and can be visualized by immunostaining.	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('non-functional protein', 'MPA', (24, 46))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('mutations', 'Var', (4, 13))
300	20368795	However, loss of function of p53 resulting from LOH may not correlate with protein overexpression.	('LOH', 'Var', (48, 51))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '7157', (29, 32))	('loss of function', 'NegReg', (9, 25))
301	20368795	In addition, frameshift mutations and stop codons lead to a truncated protein, which is not detected by antibodies and leads to negative immunohistochemistry After DNA damage, nuclear p53 accumulates and causes cell cycle arrest by inhibiting cyclin D1 phosphorylation of the Rb gene and thereby promoting apoptosis.	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('p53', 'Gene', '7157', (184, 187))	('apoptosis', 'biological_process', 'GO:0097194', ('306', '315'))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('frameshift mutations', 'Var', (13, 33))	('apoptosis', 'biological_process', 'GO:0006915', ('306', '315'))	('p53', 'Gene', (184, 187))	('cell cycle arrest', 'CPA', (211, 228))	('phosphorylation', 'biological_process', 'GO:0016310', ('253', '268'))	('causes', 'Reg', (204, 210))	('apoptosis', 'CPA', (306, 315))	('inhibiting', 'NegReg', (232, 242))	('phosphorylation', 'MPA', (253, 268))	('lead to', 'Reg', (50, 57))	('promoting', 'PosReg', (296, 305))	('accumulates', 'PosReg', (188, 199))	('cyclin D1', 'Gene', (243, 252))	('cyclin', 'molecular_function', 'GO:0016538', ('243', '249'))	('truncated', 'MPA', (60, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (211, 228))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('211', '228'))	('cyclin D1', 'Gene', '595', (243, 252))
302	20368795	Overexpression of p53 is associated with high histological grade and advanced stage as well as unfavorable prognosis.	('p53', 'Gene', '7157', (18, 21))	('advanced stage', 'CPA', (69, 83))	('p53', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))
305	20368795	Mutations of p53 are also found in 75-80% of EIC.	('p53', 'Gene', (13, 16))	('found', 'Reg', (26, 31))	('Mutations', 'Var', (0, 9))	('EIC', 'Disease', (45, 48))	('p53', 'Gene', '7157', (13, 16))
306	20368795	It is postulated that mutation in one allele occurs early during the development of serous carcinoma, and loss of the second normal allele occurs late in the progression to carcinoma.	('mutation', 'Var', (22, 30))	('serous carcinoma', 'Disease', (84, 100))	('carcinoma', 'Disease', 'MESH:D002277', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('serous carcinoma', 'Disease', 'MESH:D018284', (84, 100))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Disease', (173, 182))	('carcinoma', 'Disease', (91, 100))
307	20368795	p53 mutations are almost always associated with aneuploidy and do not seem to occur with PTEN mutations in the same tumor.	('p53', 'Gene', (0, 3))	('aneuploidy', 'Disease', (48, 58))	('p53', 'Gene', '7157', (0, 3))	('aneuploidy', 'Disease', 'MESH:D000782', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('associated', 'Reg', (32, 42))	('mutations', 'Var', (4, 13))	('PTEN', 'Gene', (89, 93))	('tumor', 'Disease', (116, 121))	('PTEN', 'Gene', '5728', (89, 93))
309	20368795	HER2/neu overexpression or amplification is more frequently found in non-endometrioid endometrial carcinoma (18-80%) than in grade 2 and 3 endometrioid carcinoma (10-30%) and has been associated with adverse prognostic parameters including advanced stage, high histologic grade, and low overall survival.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('overexpression', 'PosReg', (9, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('HER2/neu', 'Gene', (0, 8))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (139, 161))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (73, 107))	('endometrioid endometrial carcinoma', 'Disease', (73, 107))	('HER2/neu', 'Gene', '2064', (0, 8))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (139, 161))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (86, 107))	('amplification', 'Var', (27, 40))	('endometrioid carcinoma', 'Disease', (139, 161))
312	20368795	p16 inactivation can lead to uncontrolled cell growth.	('uncontrolled cell growth', 'CPA', (29, 53))	('inactivation', 'Var', (4, 16))	('p16', 'Gene', (0, 3))	('cell growth', 'biological_process', 'GO:0016049', ('42', '53'))	('lead to', 'Reg', (21, 28))	('p16', 'Gene', '1029', (0, 3))
313	20368795	Inactivation of p16 is more frequent in non-endometrioid endometrial carcinoma (40-45%) than in endometrioid endometrial carcinoma (10%).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (109, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (57, 78))	('p16', 'Gene', '1029', (16, 19))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (44, 78))	('endometrioid endometrial carcinoma', 'Disease', (44, 78))	('frequent', 'Reg', (28, 36))	('endometrioid endometrial carcinoma', 'Disease', (96, 130))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 130))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))
314	20368795	Loss of p16 expression is correlated with KRAS and p53 mutations and is associated with high stage, high grade, and poor survival.	('high stage', 'CPA', (88, 98))	('KRAS', 'Gene', (42, 46))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('p16', 'Gene', '1029', (8, 11))	('KRAS', 'Gene', '3845', (42, 46))	('mutations', 'Var', (55, 64))	('associated', 'Reg', (72, 82))	('Loss', 'NegReg', (0, 4))	('p16', 'Gene', (8, 11))	('expression', 'MPA', (12, 22))	('high grade', 'CPA', (100, 110))
316	20368795	It is thought to be a tumor suppressor gene, the loss of which has been demonstrated to promote tumor invasion and metastasis.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss', 'Var', (49, 53))	('metastasis', 'CPA', (115, 125))	('promote', 'PosReg', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))
321	20368795	p53 mutations are only present in about 30-40% of clear cell carcinomas compared to 90% of serous carcinomas.	('serous carcinomas', 'Disease', (91, 108))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('clear cell carcinomas', 'Disease', (50, 71))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (50, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('mutations', 'Var', (4, 13))	('serous carcinomas', 'Disease', 'MESH:D018284', (91, 108))
322	20368795	However, the frequency of MSI and PTEN alterations in clear cell carcinoma is higher than in serous carcinoma (15% versus <5 for MSI and 30% versus 10% for PTEN) but lower compared with endometrioid carcinoma (20-40% and 35-50%, resp.).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('PTEN', 'Gene', (156, 160))	('serous carcinoma', 'Disease', 'MESH:D018284', (93, 109))	('endometrioid carcinoma', 'Disease', (186, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('PTEN', 'Gene', '5728', (156, 160))	('MSI', 'Disease', 'None', (26, 29))	('PTEN', 'Gene', (34, 38))	('MSI', 'Disease', 'None', (129, 132))	('MSI', 'Disease', (129, 132))	('MSI', 'Disease', (26, 29))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (186, 208))	('lower', 'NegReg', (166, 171))	('PTEN', 'Gene', '5728', (34, 38))	('clear cell carcinoma', 'Disease', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('serous carcinoma', 'Disease', (93, 109))	('alterations', 'Var', (39, 50))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (186, 208))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (54, 74))
323	20368795	A recent molecular study demonstrated that the majority of pure clear cell carcinomas do not show mutations in either PTEN or p53, the most commonly altered genes in type I and type II tumors, respectively.	('pure', 'molecular_function', 'GO:0034023', ('59', '63'))	('type II tumors', 'Disease', (177, 191))	('p53', 'Gene', '7157', (126, 129))	('type II tumors', 'Disease', 'MESH:D009369', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('PTEN', 'Gene', '5728', (118, 122))	('clear cell carcinomas', 'Disease', (64, 85))	('mutations', 'Var', (98, 107))	('PTEN', 'Gene', (118, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('p53', 'Gene', (126, 129))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (64, 85))
339	20368795	One study found STK15 amplification in 9 of 15 (60%) non-endometrioid endometrial carcinomas but in none of endometrioid endometrial carcinomas.	('STK15', 'Gene', (16, 21))	('STK15', 'Gene', '6790', (16, 21))	('endometrioid endometrial carcinomas', 'Disease', (57, 92))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (121, 143))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (108, 143))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (70, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('amplification', 'Var', (22, 35))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (57, 92))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (121, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('STK15', 'molecular_function', 'GO:0047696', ('16', '21'))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (70, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('endometrioid endometrial carcinomas', 'Disease', (108, 143))
350	20368795	In addition, the number of chromosomal aberrations in complex hyperplasia is significantly higher than simple hyperplasia and close to the number found in atypical hyperplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (164, 175))	('hyperplasia', 'Disease', (110, 121))	('chromosomal aberrations', 'Var', (27, 50))	('higher', 'PosReg', (91, 97))	('hyperplasia', 'Disease', 'MESH:D006965', (62, 73))	('hyperplasia', 'Disease', 'MESH:D006965', (110, 121))	('atypical hyperplasia', 'Disease', (155, 175))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 50))	('hyperplasia', 'Disease', (164, 175))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (155, 175))	('hyperplasia', 'Disease', (62, 73))
353	20368795	However, PTEN and KRAS mutations seem to occur earlier, since they were found in simple hyperplasia, partially associated with monoclonality.	('hyperplasia', 'Disease', 'MESH:D006965', (88, 99))	('found', 'Reg', (72, 77))	('KRAS', 'Gene', (18, 22))	('PTEN', 'Gene', (9, 13))	('KRAS', 'Gene', '3845', (18, 22))	('PTEN', 'Gene', '5728', (9, 13))	('hyperplasia', 'Disease', (88, 99))	('mutations', 'Var', (23, 32))
355	20368795	The inactivation of E-cadherin gene by methylation seems to play a role during progression of endometrioid carcinoma, since it is most frequently found in grade 3 and least frequently in grade 1 tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('methylation', 'Var', (39, 50))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (94, 116))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('E-cadherin', 'Gene', (20, 30))	('E-cadherin', 'Gene', '999', (20, 30))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (94, 116))	('endometrioid carcinoma', 'Disease', (94, 116))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cadherin', 'molecular_function', 'GO:0008014', ('22', '30'))	('inactivation', 'NegReg', (4, 16))
356	20368795	Furthermore, p53 mutations, HER2/neu overexpression or amplification, and p16 inactivation are considered in late events during carcinogenesis of endometrioid carcinoma, since they are predominantly identified in grade 3 tumors, but rarely in grade 1 tumors, and are absent in atypical hyperplastic lesions.	('overexpression', 'PosReg', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('mutations', 'Var', (17, 26))	('p16', 'Gene', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinogenesis of endometrioid carcinoma', 'Disease', (128, 168))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('p16', 'Gene', '1029', (74, 77))	('tumors', 'Disease', (221, 227))	('p53', 'Gene', '7157', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('HER2/neu', 'Gene', (28, 36))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('p53', 'Gene', (13, 16))	('inactivation', 'NegReg', (78, 90))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (146, 168))	('carcinogenesis of endometrioid carcinoma', 'Disease', 'MESH:D016889', (128, 168))	('HER2/neu', 'Gene', '2064', (28, 36))
357	20368795	Hypothetically, p53 mutations and HER2/neu amplification might also be early events in de novo poorly differentiated endometrioid carcinomas (Figure 2).	('HER2/neu', 'Gene', (34, 42))	('endometrioid carcinomas', 'Disease', (117, 140))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (117, 139))	('p53', 'Gene', (16, 19))	('amplification', 'Var', (43, 56))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (117, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('p53', 'Gene', '7157', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (117, 140))	('HER2/neu', 'Gene', '2064', (34, 42))	('mutations', 'Var', (20, 29))
358	20368795	Endometrial pre-cancers (e.g., EIC) have been postulated to share common genetic alterations with endometrioid endometrial carcinoma, including PTEN mutations and MSI.	('cancers', 'Disease', (16, 23))	('mutations', 'Var', (149, 158))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (98, 132))	('endometrioid endometrial carcinoma', 'Disease', (98, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('pre', 'molecular_function', 'GO:0003904', ('12', '15'))	('MSI', 'Disease', 'None', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('PTEN', 'Gene', (144, 148))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (111, 132))	('MSI', 'Disease', (163, 166))	('PTEN', 'Gene', '5728', (144, 148))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
359	20368795	Mutations of p53 were found in approximately 80% of EIC, but in contrast to most serous carcinomas, there is no LOH at the locus TP53.	('EIC', 'Disease', (52, 55))	('serous carcinomas', 'Disease', (81, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('TP53', 'Gene', '7157', (129, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('TP53', 'Gene', (129, 133))	('p53', 'Gene', '7157', (13, 16))	('serous carcinomas', 'Disease', 'MESH:D018284', (81, 98))
360	20368795	Thus, it is hypothesized that p53 mutation of one allele occurs early, whereas loss of the normal second allele accompanies progression into serous carcinoma.	('serous carcinoma', 'Disease', (141, 157))	('serous carcinoma', 'Disease', 'MESH:D018284', (141, 157))	('mutation', 'Var', (34, 42))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
361	20368795	The alterations of E-cadherin, p16, and HER2/neu seem to affect the progression from EIC to serous carcinoma.	('p16', 'Gene', '1029', (31, 34))	('alterations', 'Var', (4, 15))	('HER2/neu', 'Gene', '2064', (40, 48))	('E-cadherin', 'Gene', (19, 29))	('HER2/neu', 'Gene', (40, 48))	('affect', 'Reg', (57, 63))	('serous carcinoma', 'Disease', (92, 108))	('EIC', 'Disease', (85, 88))	('p16', 'Gene', (31, 34))	('serous carcinoma', 'Disease', 'MESH:D018284', (92, 108))	('E-cadherin', 'Gene', '999', (19, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))
362	20368795	Another group hypothesized that serous carcinoma may develop from endometrioid carcinoma through p53 mutation based on findings in mixed endometrioid and serous carcinomas.	('serous carcinomas', 'Disease', 'MESH:D018284', (154, 171))	('serous carcinoma', 'Disease', 'MESH:D018284', (154, 170))	('serous carcinomas', 'Disease', (154, 171))	('serous carcinoma', 'Disease', (32, 48))	('p53', 'Gene', (97, 100))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (66, 88))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (66, 88))	('p53', 'Gene', '7157', (97, 100))	('serous carcinoma', 'Disease', 'MESH:D018284', (32, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('develop', 'Reg', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('endometrioid carcinoma', 'Disease', (66, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('mutation', 'Var', (101, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))
366	20368795	It is an autosomal dominant syndrome that predisposes its carriers to multiple malignancies particularly colorectal, and endometrial carcinomas, caused by a germline mutation in one of the DNA MMR genes occurring in 30-60% of cases.	('DNA MMR', 'Gene', (189, 196))	('caused by', 'Reg', (145, 154))	('malignancies particularly colorectal', 'Disease', 'MESH:D009369', (79, 115))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (121, 143))	('autosomal dominant syndrome', 'Disease', (9, 36))	('germline mutation', 'Var', (157, 174))	('malignancies particularly colorectal', 'Disease', (79, 115))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (121, 143))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (9, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (121, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('endometrial carcinomas', 'Disease', (121, 143))	('MMR', 'biological_process', 'GO:0006298', ('193', '196'))
369	20368795	The frequency of germline DNA MMR gene mutations among unselected patients with endometrial carcinoma has been found to be 1.8-2.1%, which is similar to the frequency of HNPCC in colorectal carcinoma.	('HNPCC in colorectal carcinoma', 'Disease', 'MESH:D015179', (170, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('HNPCC', 'Phenotype', 'HP:0006716', (170, 175))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('HNPCC in colorectal carcinoma', 'Disease', (170, 199))	('DNA MMR', 'Gene', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('MMR', 'biological_process', 'GO:0006298', ('30', '33'))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (80, 101))	('mutations', 'Var', (39, 48))	('endometrial carcinoma', 'Disease', (80, 101))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('patients', 'Species', '9606', (66, 74))
370	20368795	Patients with endometrial carcinoma in the HNPCC population have an inherited germline mutation in MLH1, MSH2, MSH6, or PMS2 (first hit) but endometrial carcinoma develops only after the initiation of a deletion or mutation in the contralateral MLH1, MSH2, MSH6, or PMS2 allele (second hit) in endometrial cells.	('MLH1', 'Gene', (245, 249))	('MSH2', 'Gene', '4436', (105, 109))	('MSH6', 'Gene', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (14, 35))	('PMS2', 'Gene', (266, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (141, 162))	('HNPCC', 'Disease', 'None', (43, 48))	('MSH6', 'Gene', '2956', (111, 115))	('HNPCC', 'Disease', (43, 48))	('MLH1', 'Gene', '4292', (245, 249))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (14, 35))	('MSH2', 'Gene', (251, 255))	('PMS2', 'Gene', '5395', (120, 124))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (141, 162))	('Patients', 'Species', '9606', (0, 8))	('MSH6', 'Gene', (257, 261))	('mutation', 'Var', (215, 223))	('MSH6', 'Gene', '2956', (257, 261))	('MSH2', 'Gene', '4436', (251, 255))	('MLH1', 'Gene', (99, 103))	('HNPCC', 'Phenotype', 'HP:0006716', (43, 48))	('deletion', 'Var', (203, 211))	('PMS2', 'Gene', '5395', (266, 270))	('mutation', 'Var', (87, 95))	('PMS2', 'Gene', (120, 124))	('MSH2', 'Gene', (105, 109))	('MLH1', 'Gene', '4292', (99, 103))	('endometrial carcinoma', 'Disease', (14, 35))	('endometrial carcinoma', 'Disease', (141, 162))
372	20368795	Unlike HNPCC associated colorectal carcinoma, which appears to frequently have MLH1 and MSH2 mutations, endometrial carcinomas have a higher probability of MSH2 and MSH6 mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (24, 44))	('MLH1', 'Gene', '4292', (79, 83))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (104, 126))	('HNPCC', 'Phenotype', 'HP:0006716', (7, 12))	('MSH6', 'Gene', (165, 169))	('MSH2', 'Gene', '4436', (88, 92))	('MSH6', 'Gene', '2956', (165, 169))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (104, 126))	('MSH2', 'Gene', (156, 160))	('mutations', 'Var', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('endometrial carcinomas', 'Disease', (104, 126))	('MSH2', 'Gene', '4436', (156, 160))	('HNPCC', 'Disease', (7, 12))	('HNPCC', 'Disease', 'None', (7, 12))	('mutations', 'Var', (170, 179))	('MLH1', 'Gene', (79, 83))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (104, 125))	('colorectal carcinoma', 'Disease', (24, 44))	('MSH2', 'Gene', (88, 92))
373	20368795	Women with HNPCC who carry MSH2 and MSH6 mutations have a higher chance to present initially with endometrial rather than colorectal cancer.	('mutations', 'Var', (41, 50))	('HNPCC', 'Disease', 'None', (11, 16))	('HNPCC', 'Phenotype', 'HP:0006716', (11, 16))	('HNPCC', 'Disease', (11, 16))	('Women', 'Species', '9606', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('colorectal cancer', 'Disease', (122, 139))	('MSH2', 'Gene', (27, 31))	('MSH6', 'Gene', (36, 40))	('MSH2', 'Gene', '4436', (27, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('MSH6', 'Gene', '2956', (36, 40))	('endometrial', 'Disease', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
382	20368795	PTEN inactivation by mutation seems to also be involved in tumorigenesis, since it occurs in about 90% of type I carcinomas.	('type I carcinomas', 'Disease', 'MESH:D017827', (106, 123))	('tumor', 'Disease', (59, 64))	('involved', 'Reg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutation', 'Var', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('inactivation', 'NegReg', (5, 17))	('type I carcinomas', 'Disease', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
385	20368795	studied serial endometrial biopsy samples taken during a 10-year followup of HPNCC mutation carriers and found abnormal MMR protein expression, MSI, or tumor suppressor promotor hypermethylation in various endometrial histologies, including normal and hyperplastic endometria.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('MSI', 'Disease', 'None', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('hyperplastic endometria', 'Phenotype', 'HP:0040298', (252, 275))	('MMR', 'biological_process', 'GO:0006298', ('120', '123'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('HPNCC', 'Gene', (77, 82))	('MSI', 'Disease', (144, 147))	('tumor', 'Disease', (152, 157))	('mutation', 'Var', (83, 91))	('MMR protein', 'Protein', (120, 131))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('abnormal', 'Reg', (111, 119))	('hypermethylation', 'Var', (178, 194))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
386	20368795	The most frequently methylated genes were CDH13, RASSF1A, and GSTP1.	('methylated', 'Var', (20, 30))	('CDH13', 'Gene', '1012', (42, 47))	('RASSF1A', 'Gene', (49, 56))	('GSTP1', 'Gene', (62, 67))	('RASSF1A', 'Gene', '11186', (49, 56))	('CDH13', 'Gene', (42, 47))	('GSTP1', 'Gene', '2950', (62, 67))
388	20368795	PTEN hamartoma tumor syndrome, caused by a germline mutation in PTEN gene on chromosome 10q, comprises a group of disorders including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, Proteus-like syndrome, and autism spectrum disorder with macrocephaly.	('Cowden syndrome', 'Disease', (134, 149))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('autism', 'Phenotype', 'HP:0000717', (231, 237))	('hamartoma', 'Phenotype', 'HP:0010566', (5, 14))	('macrocephaly', 'Disease', (261, 273))	('Proteus-like syndrome', 'Disease', 'MESH:D016715', (204, 225))	('autism spectrum disorder', 'Disease', 'MESH:D000067877', (231, 255))	('macrocephaly', 'Disease', 'MESH:D058627', (261, 273))	('Proteus syndrome', 'Disease', (186, 202))	('hamartoma tumor syndrome', 'Disease', (5, 29))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', 'MESH:D006223', (151, 184))	('autism spectrum disorder', 'Disease', (231, 255))	('Proteus-like syndrome', 'Disease', (204, 225))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (231, 255))	('PTEN', 'Gene', (64, 68))	('Proteus syndrome', 'Disease', 'MESH:D016715', (186, 202))	('PTEN', 'Gene', (0, 4))	('caused by', 'Reg', (31, 40))	('macrocephaly', 'Phenotype', 'HP:0000256', (261, 273))	('Cowden syndrome', 'Disease', 'MESH:D006223', (134, 149))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('hamartoma tumor syndrome', 'Disease', 'MESH:D006222', (5, 29))	('germline mutation', 'Var', (43, 60))	('PTEN', 'Gene', '5728', (64, 68))	('PTEN', 'Gene', '5728', (0, 4))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', (151, 184))
392	20368795	PTEN mutations in exon 5, coding for the active site and flanking amino acids, is a common site for mutations in patients with Cowden syndrome, and missense mutations are only found in this active area.	('mutations', 'Var', (100, 109))	('Cowden syndrome', 'Disease', 'MESH:D006223', (127, 142))	('patients', 'Species', '9606', (113, 121))	('Cowden syndrome', 'Disease', (127, 142))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
393	20368795	However, germline PTEN mutation has been detected in approximately 80% of Cowden syndrome patients.	('Cowden syndrome', 'Disease', 'MESH:D006223', (74, 89))	('PTEN', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))	('PTEN', 'Gene', '5728', (18, 22))	('Cowden syndrome', 'Disease', (74, 89))	('patients', 'Species', '9606', (90, 98))	('detected', 'Reg', (41, 49))
407	20368795	Many carcinosarcomas contained aberrations on chromosome 8 and 20 detected by FISH.	('aberrations', 'Var', (31, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('carcinosarcomas', 'Disease', 'MESH:D002296', (5, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('carcinosarcomas', 'Disease', (5, 20))
409	20368795	Gains or amplifications of 8q are the most common genetic aberration in carcinosarcomas.	('Gains', 'Var', (0, 5))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('carcinosarcomas', 'Disease', 'MESH:D002296', (72, 87))	('carcinosarcomas', 'Disease', (72, 87))
413	20368795	p53 mutations and LOH for TP53 occur frequently in both carcinosarcoma components which are associated with frequent protein overexpression.	('TP53', 'Gene', (26, 30))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('carcinosarcoma', 'Disease', 'MESH:D002296', (56, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('carcinosarcoma', 'Disease', (56, 70))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (4, 13))
446	20368795	In contrast to epithelial endometrial carcinoma, endometrial stromal tumors are characterized by distinct cytogenetic abnormalities, particularly translocations leading to gene fusion.	('epithelial endometrial carcinoma', 'Disease', 'MESH:D016889', (15, 47))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (49, 75))	('translocations', 'Var', (146, 160))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (26, 47))	('epithelial endometrial carcinoma', 'Disease', (15, 47))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('gene', 'MPA', (172, 176))	('endometrial stromal tumors', 'Disease', (49, 75))	('genetic abnormalities', 'Disease', 'MESH:D030342', (110, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('genetic abnormalities', 'Disease', (110, 131))
447	20368795	Cytogenetic studies reported to-date are primarily for low grade endometrial stromal sarcomas, mostly showing rearrangement of chromosomes 6, 7, and 17.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (65, 93))	('rearrangement', 'Var', (110, 123))	('endometrial stromal sarcomas', 'Disease', (65, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
448	20368795	Loss of chromosome arm 7p (55.6% of the cases) is the most frequent aberration and may play a role in tumor development and progression.	('tumor', 'Disease', (102, 107))	('role', 'Reg', (94, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Loss', 'Var', (0, 4))	('play', 'Reg', (87, 91))
460	20368795	A major subgroup of endometrial stromal sarcomas has been found to have translocations involving short arm of chromosome 6, particularly band 6p21.	('p21', 'Gene', (143, 146))	('p21', 'Gene', '644914', (143, 146))	('translocations', 'Var', (72, 86))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (20, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('endometrial stromal sarcomas', 'Disease', (20, 48))	('short arm', 'Phenotype', 'HP:0009824', (97, 106))
462	20368795	introduced that a low-grade endometrial stromal sarcoma cell line carrying a der(7)t(6;7)(p21;p22) also harbors a JAZF1/PHF1 fusion.	('PHF1', 'Gene', (120, 124))	('der(7)t(6;7)(p21;p22', 'Var', (77, 97))	('JAZF1', 'Gene', '221895', (114, 119))	('PHF1', 'Gene', '5252', (120, 124))	('endometrial stromal sarcoma', 'Disease', (28, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('der(7)t(6;7)(p21;p22)', 'STRUCTURAL_ABNORMALITY', 'None', (77, 98))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (28, 55))	('JAZF1', 'Gene', (114, 119))
464	20368795	Additionally, few endometrial stromal sarcoma cases were reported with a t(X;17)(p11.2;q23) and a t(10;17)(q22;p13).	('t(10;17)(q22;p13', 'Var', (98, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('endometrial stromal sarcoma', 'Disease', (18, 45))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (98, 115))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (18, 45))	('t(X;17)(p11.2;q23', 'Var', (73, 90))	('t(X;17)(p11.2;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (73, 91))
480	20368795	The importance of p53 mutations for the development of undifferentiated endometrial sarcomas is not evident, but p53 overexpression was detected in three of four high-grade stromal sarcomas.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('undifferentiated endometrial sarcomas', 'Disease', (55, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('p53', 'Gene', '7157', (113, 116))	('overexpression', 'PosReg', (117, 131))	('mutations', 'Var', (22, 31))	('stromal sarcomas', 'Disease', (173, 189))	('p53', 'Gene', (113, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('stromal sarcomas', 'Disease', 'MESH:D046152', (173, 189))	('undifferentiated endometrial sarcomas', 'Disease', 'MESH:D018203', (55, 92))
481	20368795	have recently found frequent nuclear accumulation of p53 and TP53 gene missense mutations in undifferentiated endometrial sarcoma with nuclear pleomorphism, 3 (50%) of 6 cases.	('missense mutations', 'Var', (71, 89))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (110, 129))	('endometrial sarcoma', 'Disease', (110, 129))	('nuclear accumulation', 'MPA', (29, 49))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
483	20368795	p53 alteration may be one different pathway that contributes the tumorigenesis of undifferentiated endometrial sarcoma.	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('alteration', 'Var', (4, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (99, 118))	('endometrial sarcoma', 'Disease', (99, 118))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
490	20368795	Dysregulation of these pathways allows beta-catenin to accumulate and translocate to the nucleus, where it forms complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) leading to uncontrolled cell growth and carcinogenesis.	('TCF/LEF', 'Gene', '3172', (169, 176))	('complexes', 'Interaction', (113, 122))	('Dysregulation', 'Var', (0, 13))	('carcinogenesis', 'Disease', (218, 232))	('accumulate', 'PosReg', (55, 65))	('nucleus', 'cellular_component', 'GO:0005634', ('89', '96'))	('uncontrolled cell growth', 'CPA', (189, 213))	('carcinogenesis', 'Disease', 'MESH:D063646', (218, 232))	('beta-catenin', 'Gene', (39, 51))	('cell growth', 'biological_process', 'GO:0016049', ('202', '213'))	('beta-catenin', 'Gene', '1499', (39, 51))	('TCF/LEF', 'Gene', (169, 176))
494	20368795	Therefore, we can exploit our knowledge of the dualistic model and their typical gene mutations and use the immunoprofile as a diagnostic tool, in concert with the histomorphologic features to specify the tumor type, particularly in difficult cases such as in the differentiation between high-grade endometrioid carcinoma and serous carcinoma (Table 3).	('mutations', 'Var', (86, 95))	('endometrioid carcinoma and serous carcinoma', 'Disease', 'MESH:D016889', (299, 342))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (299, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))
495	20368795	The distinct molecular alteration described in the majority of endometrial stromal sarcomas is the t(7;17)(p15;q21) leading to the formation of fusion gene JAZF1/JJAZ1, which can be detected by RT-PCR or FISH assays.	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('JAZF1', 'Gene', (156, 161))	('JJAZ1', 'Gene', '23512', (162, 167))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (63, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('t(7;17)(p15;q21', 'Var', (99, 114))	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('JJAZ1', 'Gene', (162, 167))	('JAZF1', 'Gene', '221895', (156, 161))	('formation', 'biological_process', 'GO:0009058', ('131', '140'))	('endometrial stromal sarcomas', 'Disease', (63, 91))
504	20368795	By CGH, leiomyosarcomas have the most frequent losses including 10q, 11q, 13q, and 2p while the most common gains are Xp, 1q, 5p, 8q, 12q, 17p and 19p.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (8, 22))	('leiomyosarcomas', 'Disease', (8, 23))	('10q', 'Var', (64, 67))	('losses', 'NegReg', (47, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (8, 23))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (8, 23))
505	20368795	There are a variety of genetic changes and mutations inclusive of TP53 and MDM2 expression associated with progression of leiomyosarcomas.	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (122, 137))	('MDM2', 'Gene', '4193', (75, 79))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (122, 137))	('MDM2', 'Gene', (75, 79))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (122, 136))	('mutations', 'Var', (43, 52))	('leiomyosarcomas', 'Disease', (122, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('associated', 'Reg', (91, 101))
506	20368795	LOH of 10q is found in more than half of leiomyosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (41, 56))	('LOH of 10q', 'Var', (0, 10))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (41, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('leiomyosarcomas', 'Disease', (41, 56))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (41, 55))
509	20368795	Drug targets may focus on genes that affect apoptosis, signal transduction, epigenetic modification, drug resistance, protein folding and degradation, cell cycle progression, hormone receptor activity, and angiogenesis.	('drug resistance', 'MPA', (101, 116))	('affect', 'Reg', (37, 43))	('degradation', 'biological_process', 'GO:0009056', ('138', '149'))	('drug resistance', 'Phenotype', 'HP:0020174', (101, 116))	('drug resistance', 'biological_process', 'GO:0009315', ('101', '116'))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('drug resistance', 'biological_process', 'GO:0042493', ('101', '116'))	('cell cycle', 'biological_process', 'GO:0007049', ('151', '161'))	('hormone receptor', 'Gene', (175, 191))	('angiogenesis', 'biological_process', 'GO:0001525', ('206', '218'))	('protein folding', 'biological_process', 'GO:0006457', ('118', '133'))	('angiogenesis', 'CPA', (206, 218))	('receptor activity', 'molecular_function', 'GO:0038024', ('183', '200'))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('degradation', 'MPA', (138, 149))	('cell cycle', 'CPA', (151, 161))	('genes', 'Var', (26, 31))	('apoptosis', 'CPA', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('protein folding', 'MPA', (118, 133))	('hormone receptor', 'Gene', '3164', (175, 191))	('receptor activity', 'molecular_function', 'GO:0038023', ('183', '200'))	('epigenetic modification', 'Var', (76, 99))	('signal transduction', 'biological_process', 'GO:0007165', ('55', '74'))
513	20368795	In in vitro studies, cells with PTEN inactivation in endometrioid carcinoma are sensitive to mTOR inhibitors, since the loss of PTEN leads to constitutive activation of downstream components, which in turn up-regulates mTOR activity.	('mTOR', 'Gene', (219, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('up-regulates', 'PosReg', (206, 218))	('PTEN', 'Gene', (128, 132))	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (93, 97))	('PTEN', 'Gene', (32, 36))	('constitutive', 'MPA', (142, 154))	('PTEN', 'Gene', '5728', (128, 132))	('PTEN', 'Gene', '5728', (32, 36))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (53, 75))	('mTOR', 'Gene', '2475', (219, 223))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (53, 75))	('loss', 'Var', (120, 124))	('activation', 'PosReg', (155, 165))	('endometrioid carcinoma', 'Disease', (53, 75))
540	20368795	They are associated with a number of well-described genetic alterations including mutations of PTEN, KRAS, beta-catenin, PIK3CA, and inactivation of DNA mismatch repair.	('beta-catenin', 'Gene', (107, 119))	('mismatch repair', 'biological_process', 'GO:0006298', ('153', '168'))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('associated', 'Reg', (9, 19))	('beta-catenin', 'Gene', '1499', (107, 119))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', (121, 127))	('PTEN', 'Gene', (95, 99))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))	('PIK3CA', 'Gene', '5290', (121, 127))	('PTEN', 'Gene', '5728', (95, 99))	('DNA mismatch repair', 'Protein', (149, 168))	('inactivation', 'Var', (133, 145))
543	20368795	Mutations of p53 are present in approximately 90% of this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('p53', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('p53', 'Gene', '7157', (13, 16))
544	20368795	Carcinosarcoma is considered to be a high-grade carcinoma with sarcomatous differentiation and a high frequency of C-MYC mutations and LOH of p53.	('Carcinosarcoma', 'Disease', 'MESH:D002296', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('C-MYC', 'Gene', '4609', (115, 120))	('sarcomatous', 'Disease', (63, 74))	('p53', 'Gene', (142, 145))	('carcinoma', 'Disease', (48, 57))	('p53', 'Gene', '7157', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Carcinosarcoma', 'Disease', (0, 14))	('LOH', 'Var', (135, 138))	('sarcomatous', 'Disease', 'MESH:D018316', (63, 74))	('C-MYC', 'Gene', (115, 120))	('carcinoma', 'Disease', 'MESH:D002277', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
548	27101785	Inactivation of SMARCA4 (BRG1) and SMARCB1 (INI1) were recently described as potential mechanisms underlying the histologic dedifferentiation.	('dedifferentiation', 'biological_process', 'GO:0043696', ('124', '141'))	('BRG1', 'Gene', '6597', (25, 29))	('INI1', 'Gene', '6598', (44, 48))	('INI1', 'Gene', (44, 48))	('SMARCA4', 'Gene', (16, 23))	('SMARCA4', 'Gene', '6597', (16, 23))	('BRG1', 'Gene', (25, 29))	('SMARCB1', 'Gene', '6598', (35, 42))	('Inactivation', 'Var', (0, 12))	('SMARCB1', 'Gene', (35, 42))
553	27101785	PAX8 and ER expression in the undifferentiated component was absent in 67% and 80% of BRG1/INI1-intact DDECs respectively, while 47% of the BRG1/INI1-intact DDECs showed mutated p53 staining pattern.	('PAX8', 'Gene', '7849', (0, 4))	('BRG1', 'Gene', '6597', (140, 144))	('p53', 'Gene', (178, 181))	('INI1', 'Gene', '6598', (91, 95))	('PAX8', 'Gene', (0, 4))	('BRG1', 'Gene', (86, 90))	('INI1', 'Gene', (91, 95))	('BRG1', 'Gene', '6597', (86, 90))	('mutated', 'Var', (170, 177))	('BRG1', 'Gene', (140, 144))	('ER', 'Gene', '2099', (9, 11))	('absent', 'NegReg', (61, 67))	('p53', 'Gene', '7157', (178, 181))	('INI1', 'Gene', (145, 149))	('INI1', 'Gene', '6598', (145, 149))
556	27101785	The frequent findings of mutated p53 staining pattern in BRG1/INI1-intact DDECs indicate that BRG1/INI1-intact DDECs may be biologically different from BRG1/INI1-deficient tumors.	('BRG1', 'Gene', (94, 98))	('INI1-deficient tumors', 'Disease', 'MESH:D009369', (157, 178))	('p53', 'Gene', '7157', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('BRG1', 'Gene', '6597', (152, 156))	('INI1', 'Gene', (99, 103))	('INI1', 'Gene', '6598', (99, 103))	('p53', 'Gene', (33, 36))	('BRG1', 'Gene', '6597', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('BRG1', 'Gene', (152, 156))	('BRG1', 'Gene', (57, 61))	('INI1-deficient tumors', 'Disease', (157, 178))	('mutated', 'Var', (25, 32))	('INI1', 'Gene', (157, 161))	('BRG1', 'Gene', '6597', (94, 98))	('INI1', 'Gene', '6598', (157, 161))	('INI1', 'Gene', (62, 66))	('INI1', 'Gene', '6598', (62, 66))
566	27101785	BRG1 (encoded by SMARCA4) and INI1 (encoded by SMARCB1) are both core component proteins of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, and inactivating mutations involving these proteins have been documented in several other types of human malignancy.	('BRG1', 'Gene', '6597', (0, 4))	('SMARCA4', 'Gene', (17, 24))	('SMARCA4', 'Gene', '6597', (17, 24))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('136', '156'))	('malignancy', 'Disease', (271, 281))	('SMARCB1', 'Gene', '6598', (47, 54))	('INI1', 'Gene', (30, 34))	('sucrose', 'Chemical', 'MESH:D013395', (103, 110))	('inactivating mutations', 'Var', (170, 192))	('human', 'Species', '9606', (265, 270))	('INI1', 'Gene', '6598', (30, 34))	('SMARCB1', 'Gene', (47, 54))	('BRG1', 'Gene', (0, 4))	('core', 'cellular_component', 'GO:0019013', ('65', '69'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('136', '164'))	('malignancy', 'Disease', 'MESH:D009369', (271, 281))
567	27101785	We and others recently identified inactivating mutations involving SMARCA4 or SMARCB1 that result in the loss of BRG1 or INI1 expression in a significant subset of DDECs.	('expression', 'MPA', (126, 136))	('BRG1', 'Gene', (113, 117))	('SMARCB1', 'Gene', '6598', (78, 85))	('loss', 'NegReg', (105, 109))	('BRG1', 'Gene', '6597', (113, 117))	('SMARCB1', 'Gene', (78, 85))	('SMARCA4', 'Gene', (67, 74))	('DDECs', 'Disease', (164, 169))	('SMARCA4', 'Gene', '6597', (67, 74))	('INI1', 'Gene', (121, 125))	('INI1', 'Gene', '6598', (121, 125))	('inactivating mutations', 'Var', (34, 56))
568	27101785	These SWI/SNF core protein mutations and consequent loss of expression were only found in the undifferentiated component of these tumors, whereas the differentiated component lacked these mutations and showed intact protein expression.	('tumors', 'Disease', (130, 136))	('expression', 'MPA', (60, 70))	('mutations', 'Var', (27, 36))	('loss', 'NegReg', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('core', 'cellular_component', 'GO:0019013', ('14', '18'))	('SWI/SNF core protein', 'Gene', (6, 26))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
571	27101785	As most of the immunophenotypic surveys published to date predate the recent recognition of BRG1/INI1 inactivation as frequent molecular events in DDECs, currently little is known about the immunophenotypic features of BRG1/INI1-deficient tumors.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('inactivation', 'Var', (102, 114))	('BRG1', 'Gene', '6597', (219, 223))	('INI1-deficient tumors', 'Disease', (224, 245))	('BRG1', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('INI1-deficient tumors', 'Disease', 'MESH:D009369', (224, 245))	('INI1', 'Gene', (224, 228))	('BRG1', 'Gene', '6597', (92, 96))	('BRG1', 'Gene', (219, 223))	('INI1', 'Gene', '6598', (224, 228))	('INI1', 'Gene', (97, 101))	('DDECs', 'Disease', (147, 152))	('INI1', 'Gene', '6598', (97, 101))
603	27101785	One tumor, the only case that contained a grade 3 endometrioid carcinoma in the differentiated component, showed a complete absence of nuclear p53 staining in both the grade 3 endometrioid and the undifferentiated carcinomas, suggesting the presence of inactivating TP53 mutations in both histologic components.	('tumor', 'Disease', (4, 9))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (50, 72))	('endometrioid carcinoma', 'Disease', (50, 72))	('p53', 'Gene', '7157', (143, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('TP53', 'Gene', '7157', (266, 270))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (197, 224))	('inactivating', 'Reg', (253, 265))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (214, 224))	('absence', 'NegReg', (124, 131))	('undifferentiated carcinomas', 'Disease', (197, 224))	('TP53', 'Gene', (266, 270))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (50, 72))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('p53', 'Gene', (143, 146))	('mutations', 'Var', (271, 280))
608	27101785	Seven of 15 BRG1/INI1-intact DDECs showed a mutated p53 staining pattern in the undifferentiated component (Figure 2) (p = 0.0053 compared to BRG1/INI1-deficient DDECs).	('BRG1', 'Gene', (12, 16))	('BRG1', 'Gene', '6597', (142, 146))	('INI1-deficient', 'Disease', 'MESH:D007153', (147, 161))	('INI1', 'Gene', (17, 21))	('p53', 'Gene', (52, 55))	('INI1', 'Gene', '6598', (17, 21))	('p53', 'Gene', '7157', (52, 55))	('mutated', 'Var', (44, 51))	('INI1', 'Gene', (147, 151))	('BRG1', 'Gene', '6597', (12, 16))	('INI1', 'Gene', '6598', (147, 151))	('INI1-deficient', 'Disease', (147, 161))	('BRG1', 'Gene', (142, 146))
620	27101785	Given that BRG1 and INI1 are both core members of the SWI/SNF chromatin remodeling complex, the inactivation of BRG1/INI1 is expected to cause significant disruption in the transcriptional regulation mediated by this complex.	('disruption', 'Reg', (155, 165))	('transcriptional regulation', 'MPA', (173, 199))	('core', 'cellular_component', 'GO:0019013', ('34', '38'))	('BRG1', 'Gene', '6597', (11, 15))	('inactivation', 'Var', (96, 108))	('BRG1', 'Gene', (112, 116))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('62', '90'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('62', '82'))	('INI1', 'Gene', (20, 24))	('INI1', 'Gene', '6598', (20, 24))	('BRG1', 'Gene', '6597', (112, 116))	('INI1', 'Gene', '6598', (117, 121))	('regulation', 'biological_process', 'GO:0065007', ('189', '199'))	('INI1', 'Gene', (117, 121))	('BRG1', 'Gene', (11, 15))
630	27101785	In comparison, our series incorporated an additional defining molecular feature, namely BRG1/INI1 inactivation (loss of protein expression).	('inactivation', 'Var', (98, 110))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('BRG1', 'Gene', (88, 92))	('BRG1', 'Gene', '6597', (88, 92))	('loss', 'NegReg', (112, 116))	('INI1', 'Gene', (93, 97))	('INI1', 'Gene', '6598', (93, 97))
633	27101785	As such, our findings in the undifferentiated component of histologically typical and molecularly defined DDECs suggest that the loss of PAX8 and ER expression is a fundamental phenomenon associated with dedifferentiation.	('PAX8', 'Gene', (137, 141))	('loss', 'Var', (129, 133))	('DDECs', 'Disease', (106, 111))	('ER', 'Gene', '2099', (146, 148))	('dedifferentiation', 'biological_process', 'GO:0043696', ('204', '221'))	('PAX8', 'Gene', '7849', (137, 141))
638	27101785	All except one of the BRG1/INI1-deficient DDECs showed wild-type p53 staining pattern in both tumor components, indicating TP53 mutation is probably not involved in the development or progression (dedifferentiation) of these tumors.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('p53', 'Gene', '7157', (65, 68))	('tumors', 'Disease', (225, 231))	('tumor', 'Disease', (225, 230))	('INI1-deficient', 'Disease', 'MESH:D007153', (27, 41))	('BRG1', 'Gene', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('TP53', 'Gene', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('p53', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutation', 'Var', (128, 136))	('INI1-deficient', 'Disease', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('dedifferentiation', 'biological_process', 'GO:0043696', ('197', '214'))	('TP53', 'Gene', '7157', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Disease', (94, 99))	('BRG1', 'Gene', '6597', (22, 26))
639	27101785	The case with aberrant p53 staining was the only tumor that had a grade 3 endometrioid carcinoma as the differentiated component, where both the differentiated and undifferentiated component showed complete loss of p53 staining.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('loss', 'NegReg', (207, 211))	('p53', 'Gene', (215, 218))	('tumor', 'Disease', (49, 54))	('aberrant', 'Var', (14, 22))	('p53', 'Gene', '7157', (215, 218))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (74, 96))	('endometrioid carcinoma', 'Disease', (74, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
640	27101785	In this particular case, the high-grade endometrioid component appeared to have already acquired a TP53 mutation before a further mutation involving SMARCA4 resulted in tumor dedifferentiation.	('TP53', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('mutation', 'Var', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('resulted in', 'Reg', (157, 168))	('SMARCA4', 'Gene', (149, 156))	('mutation', 'Var', (104, 112))	('tumor', 'Disease', (169, 174))	('SMARCA4', 'Gene', '6597', (149, 156))	('dedifferentiation', 'biological_process', 'GO:0043696', ('175', '192'))	('TP53', 'Gene', '7157', (99, 103))
642	27101785	identified TP53 mutations by Sanger sequencing in 33% of DDECs.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('DDECs', 'Disease', (57, 62))
643	27101785	observed aberrant p53 expression (diffuse) in 26% of DDECs and 38% of undifferentiated endometrial carcinomas.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (87, 109))	('DDECs', 'Disease', (53, 58))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (87, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (87, 108))	('aberrant', 'Var', (9, 17))	('endometrial carcinomas', 'Disease', (87, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('expression', 'MPA', (22, 32))
645	27101785	This observation suggests that there may be significant biologic differences between BRG1/INI1-deficient tumors (5% with mutation pattern p53 staining) and BRG1/INI1-intact tumors (47% with mutation pattern p53 staining).	('p53', 'Gene', (138, 141))	('BRG1', 'Gene', (156, 160))	('p53', 'Gene', '7157', (138, 141))	('INI1-intact tumors', 'Disease', 'MESH:C562832', (161, 179))	('INI1-deficient tumors', 'Disease', (90, 111))	('BRG1', 'Gene', (85, 89))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('mutation pattern', 'Var', (121, 137))	('BRG1', 'Gene', '6597', (156, 160))	('INI1-intact tumors', 'Disease', (161, 179))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('INI1-deficient tumors', 'Disease', 'MESH:D009369', (90, 111))	('BRG1', 'Gene', '6597', (85, 89))
646	27101785	Moreover, about half of the BRG1/INI1-intact DDECs with mutated p53 staining in the undifferentiated component showed wild-type p53 staining pattern in the differentiated endometrioid component.	('INI1', 'Gene', (33, 37))	('INI1', 'Gene', '6598', (33, 37))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('BRG1', 'Gene', '6597', (28, 32))	('mutated', 'Var', (56, 63))	('BRG1', 'Gene', (28, 32))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
647	27101785	Therefore, it is possible that TP53 mutation may either contribute in part to dedifferentiation or facilitate the growth of the undifferentiated component in these cases.	('dedifferentiation', 'biological_process', 'GO:0043696', ('78', '95'))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('dedifferentiation', 'CPA', (78, 95))	('growth', 'CPA', (114, 120))	('facilitate', 'PosReg', (99, 109))	('contribute', 'Reg', (56, 66))	('mutation', 'Var', (36, 44))
657	24851142	Families that fulfilled the criteria for hereditary cancer syndromes were tested for mutations in the causative genes.	('mutations', 'Var', (85, 94))	('hereditary cancer syndromes', 'Disease', (41, 68))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (41, 68))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))
680	24851142	Cowden syndrome is caused by a germline mutation in the PTEN gene and women with this mutation have a 5-10% lifetime risk of developing endometrial carcinoma.	('endometrial carcinoma', 'Disease', (136, 157))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (136, 157))	('PTEN', 'Gene', (56, 60))	('caused by', 'Reg', (19, 28))	('Cowden syndrome', 'Disease', 'MESH:D006223', (0, 15))	('PTEN', 'Gene', '5728', (56, 60))	('Cowden syndrome', 'Disease', (0, 15))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (136, 157))	('women', 'Species', '9606', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('germline mutation', 'Var', (31, 48))
681	24851142	A recent study concluded that 5% of serous uterine cancer was caused by mutations in BRCA1, TP53 or CHEK2 , suggesting that some rare types of uterine cancer may have a family history consistent with hereditary breast and ovarian cancer syndrome (HBOC).	('BRCA1', 'Gene', (85, 90))	('CHEK2', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('TP53', 'Gene', (92, 96))	('mutations', 'Var', (72, 81))	('CHEK2', 'Gene', '11200', (100, 105))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (230, 236))	('uterine cancer', 'Phenotype', 'HP:0010784', (143, 157))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ovarian cancer', 'Phenotype', 'HP:0100615', (222, 236))	('TP53', 'Gene', '7157', (92, 96))	('caused by', 'Reg', (62, 71))	('uterine cancer', 'Phenotype', 'HP:0010784', (43, 57))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (200, 245))	('cancer', 'Disease', (51, 57))	('BRCA1', 'Gene', '672', (85, 90))
703	24851142	Screening for mutations in MLH1, MSH2, and MSH6 for LS and BRCA1 and BRCA2 for HBOC was performed according to standard procedures.	('BRCA1', 'Gene', '672', (59, 64))	('MSH6', 'Gene', '2956', (43, 47))	('BRCA2', 'Gene', '675', (69, 74))	('MSH2', 'Gene', (33, 37))	('BRCA1', 'Gene', (59, 64))	('MLH1', 'Gene', '4292', (27, 31))	('MLH1', 'Gene', (27, 31))	('MSH6', 'Gene', (43, 47))	('BRCA2', 'Gene', (69, 74))	('mutations', 'Var', (14, 23))	('MSH2', 'Gene', '4436', (33, 37))
736	24851142	Seven of the nine had deleterious mutations in mismatch repair genes: three in MLH1 (c.546-2A > G; c.790 + 1G > C and deletion of exon 1-3) and four in MSH2 (c.1147C > T; c.1786_1788del; deletion of exon 7-10 and deletion from exon 3 of the EPCAM gene to exon 6 of MSH2).	('c.790', 'Var', (99, 104))	('MLH1', 'Gene', '4292', (79, 83))	('MSH2', 'Gene', '4436', (265, 269))	('MSH2', 'Gene', '4436', (152, 156))	('EPCAM', 'Gene', '4072', (241, 246))	('mismatch repair genes', 'Gene', (47, 68))	('1G > C', 'SUBSTITUTION', 'None', (107, 113))	('deletion', 'Var', (213, 221))	('c.1147C > T; c.1786_1788del', 'Var', (158, 185))	('c.546-2A > G', 'Mutation', 'rs267607759', (85, 97))	('deletion', 'Var', (187, 195))	('1G > C', 'Var', (107, 113))	('EPCAM', 'Gene', (241, 246))	('c.1147C > T', 'Mutation', 'rs63749849', (158, 169))	('c.546-2A > G; c.790', 'Var', (85, 104))	('mismatch repair', 'biological_process', 'GO:0006298', ('47', '62'))	('MLH1', 'Gene', (79, 83))	('MSH2', 'Gene', (265, 269))	('MSH2', 'Gene', (152, 156))	('c.1786_1788del', 'Mutation', 'c.1786_1788del', (171, 185))	('mutations', 'Var', (34, 43))
740	24851142	Six families were screened for mutations in BRCA1 and BRCA2, but no mutations were found.	('BRCA1', 'Gene', (44, 49))	('mutations', 'Var', (31, 40))	('BRCA2', 'Gene', (54, 59))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA2', 'Gene', '675', (54, 59))
790	24851142	recently reported on a study population in which seven (5%) of women with serous carcinoma had mutations in breast cancer genes, but only two of the seven had breast cancer in their family history.	('serous carcinoma', 'Disease', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('women', 'Species', '9606', (63, 68))	('mutations', 'Var', (95, 104))	('serous carcinoma', 'Disease', 'MESH:D018284', (74, 90))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
801	24851142	In the present study, nine families (1.9%) fulfilled the Amsterdam II criteria and of these seven (1.5%) had mutation-verified LS: three with mutations in MLH1 and four in MSH2.	('mutations', 'Var', (142, 151))	('MSH2', 'Gene', (172, 176))	('MSH2', 'Gene', '4436', (172, 176))	('MLH1', 'Gene', '4292', (155, 159))	('MLH1', 'Gene', (155, 159))
803	24851142	Thirty-six percent had mutations in MSH6 and 39% in MSH2.	('MSH6', 'Gene', (36, 40))	('mutations', 'Var', (23, 32))	('MSH2', 'Gene', (52, 56))	('MSH2', 'Gene', '4436', (52, 56))	('MSH6', 'Gene', '2956', (36, 40))
804	24851142	MSH6 mutation carriers are less likely to meet Amsterdam II criteria and have a lower risk of colorectal cancer (10-22% cumulative risk by 70 years of age) and of other LS-related cancers.	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('MSH6', 'Gene', '2956', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('lower', 'NegReg', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('MSH6', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
805	24851142	As the Amsterdam II criteria have a reported sensitivity of 60-80% for colorectal cancer, but of only 20-30% in consecutive endometrial cancers, it is likely that our selection criteria have missed a number of LS families, especially those caused by MSH6 mutations.	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MSH6', 'Gene', '2956', (250, 254))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('endometrial cancer', 'Phenotype', 'HP:0012114', (124, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('MSH6', 'Gene', (250, 254))	('endometrial cancers', 'Disease', (124, 143))	('endometrial cancers', 'Disease', 'MESH:D016889', (124, 143))	('caused by', 'Reg', (240, 249))	('missed', 'NegReg', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (255, 264))
817	24400102	Alterations in DNA methylation (DNAm) levels are among the earliest changes in human carcinogenesis, and hence offer novel strategies to identify individuals who might be at risk of developing such illnesses or individuals with early stage cancers.	('human', 'Species', '9606', (79, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('carcinogenesis', 'Disease', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('DNA methylation', 'MPA', (15, 30))
822	24400102	We show that this measure associates significantly with overall survival outcome independent of known prognostic markers in several data sets and cancer types, and that groups of these significant gene-gene network interactions identify subnetwork modules, with a well-controlled false discovery rate.	('cancer', 'Disease', (146, 152))	('interactions', 'Var', (215, 227))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('false', 'biological_process', 'GO:0071877', ('280', '285'))	('overall', 'MPA', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('false', 'biological_process', 'GO:0071878', ('280', '285'))
854	24400102	F5 is factor five, a protein of the coagulation system; its deficiency leads to predisposition for haemorrhage.	('haemorrhage', 'Disease', (99, 110))	('deficiency', 'Var', (60, 70))	('haemorrhage', 'Disease', 'MESH:D006470', (99, 110))	('coagulation', 'biological_process', 'GO:0050817', ('36', '47'))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
882	24400102	The key point in this metazoan model is that, whereas the conventional model of tumourigenesis holds that proliferative characteristics acquired by cancers occur as a result of random genetic and epigenetic mutation, these archaic metazoan characteristics are present in humans all along, but lie dormant until they are released in cancer.	('cancer', 'Disease', (148, 154))	('tumour', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('epigenetic mutation', 'Var', (196, 215))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (332, 338))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('humans', 'Species', '9606', (271, 277))
905	21412130	Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas.	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (210, 241))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('tumor suppressor', 'biological_process', 'GO:0051726', ('118', '134'))	('ARID1A', 'Gene', (35, 41))	('mutated', 'Var', (148, 155))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (63, 85))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('ARID1A', 'Gene', '8289', (35, 41))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (218, 241))	('ovarian clear cell', 'Disease', (180, 198))	('ARID1A', 'Gene', (86, 92))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (63, 85))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (218, 240))	('ovarian endometrioid carcinomas', 'Disease', (210, 241))	('loss of expression', 'NegReg', (13, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ARID1A', 'Gene', '8289', (86, 92))	('tumor', 'Disease', (118, 123))	('endometrioid carcinoma', 'Disease', (63, 85))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('118', '134'))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (218, 240))
907	21412130	Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutation', 'Var', (68, 76))	('inactivation', 'Var', (52, 64))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ARID1A', 'Gene', (80, 86))
911	21412130	All mutations in endometrioid carcinomas were nonsense or insertion/deletion mutations and tumors with ARID1A mutations demonstrated complete loss or clonal loss of ARID1A expression.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (17, 39))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (17, 40))	('ARID1A', 'Gene', (103, 109))	('insertion/deletion', 'Var', (58, 76))	('endometrioid carcinomas', 'Disease', (17, 40))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('mutations', 'Var', (4, 13))	('tumors', 'Disease', (91, 97))	('nonsense', 'Var', (46, 54))	('loss', 'NegReg', (142, 146))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (17, 40))	('ARID1A', 'Gene', (165, 171))	('expression', 'MPA', (172, 182))	('loss', 'NegReg', (157, 161))
912	21412130	In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression.	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (123, 145))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (123, 145))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('endometrioid carcinoma', 'Disease', (123, 145))	('ARID1A', 'Gene', (224, 230))	('mutations', 'Var', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('loss', 'NegReg', (216, 220))	('carcinomas', 'Disease', 'MESH:D002277', (81, 91))	('ARID1A', 'Gene', (186, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Disease', (81, 91))	('expression', 'MPA', (231, 241))	('tumor', 'Disease', (165, 170))
913	21412130	These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high frequency of loss of expression and mutation of ARID1A.	('expression', 'MPA', (253, 263))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (76, 98))	('pathogenesis', 'biological_process', 'GO:0009405', ('42', '54'))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (76, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('mutation', 'Var', (268, 276))	('endometrioid carcinoma', 'Disease', (76, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('loss of', 'NegReg', (245, 252))	('clear cell carcinoma', 'Disease', (156, 176))	('ARID1A', 'Gene', (280, 286))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (156, 176))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
915	21412130	Sequence mutations that are acquired during tumor evolution can lead to activation of oncogenes and inactivation of tumor suppressors and DNA repair genes, thereby propelling tumor development and progression.	('activation', 'PosReg', (72, 82))	('inactivation', 'NegReg', (100, 112))	('tumor', 'Disease', (175, 180))	('oncogenes', 'Protein', (86, 95))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('DNA repair genes', 'Gene', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('propelling', 'PosReg', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('DNA repair', 'biological_process', 'GO:0006281', ('138', '148'))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (44, 49))	('progression', 'CPA', (197, 208))
917	21412130	With the use of whole exome sequencing and transcriptome sequencing, two independent studies recently reported ARID1A (also known as BAF250A) mutations in 43-56% of ovarian clear cell carcinomas and 30% of ovarian low-grade endometrioid carcinomas but not in matched controls, confirming the somatic nature of the mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('mutations', 'Var', (142, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('endometrioid carcinomas', 'Disease', (224, 247))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (165, 194))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (224, 246))	('BAF250A', 'Gene', (133, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('ovarian clear cell carcinomas', 'Disease', (165, 194))	('ARID1A', 'Gene', (111, 117))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (224, 247))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (224, 247))	('BAF250A', 'Gene', '8289', (133, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
918	21412130	Since both of these tumor types are believed to be derived from endometriosis and because one of these studies also found ARID1A mutations in adjacent atypical endometriosis it is conceivable that ARID1A loss is a relatively specific molecular event in the genesis of these tumors.	('endometriosis', 'Disease', (64, 77))	('endometriosis', 'Phenotype', 'HP:0030127', (64, 77))	('ARID1A', 'Gene', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('endometriosis', 'Phenotype', 'HP:0030127', (160, 173))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('found', 'Reg', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('endometriosis', 'Disease', 'MESH:D004715', (160, 173))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (20, 25))	('endometriosis', 'Disease', 'MESH:D004715', (64, 77))	('endometriosis', 'Disease', (160, 173))	('tumors', 'Disease', (274, 280))
923	21412130	Inactivation of ARID1A is thought to enhance cell cycle progression by potentially involving c-myc, thereby contributing to uncontrolled cellular proliferation in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cell cycle progression', 'CPA', (45, 67))	('c-myc', 'Gene', '4609', (93, 98))	('contributing', 'Reg', (108, 120))	('c-myc', 'Gene', (93, 98))	('enhance', 'PosReg', (37, 44))	('involving', 'Reg', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cell cycle', 'biological_process', 'GO:0007049', ('45', '55'))	('Inactivation', 'Var', (0, 12))	('cancer', 'Disease', (163, 169))	('ARID1A', 'Gene', (16, 22))
924	21412130	Although ARID1A has emerged as a new cancer-associated gene which is frequently mutated in endometriosis-related ovarian neoplasms, it is not known whether its mutation, like FOXL2 and APC, is detected only in specific types of cancer or, like in TP53 and KRAS, occurs in a variety of neoplastic diseases.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('ovarian neoplasms', 'Phenotype', 'HP:0100615', (113, 130))	('neoplastic diseases', 'Disease', 'MESH:D009386', (285, 304))	('mutated', 'Var', (80, 87))	('ARID1A', 'Gene', (9, 15))	('KRAS', 'Gene', '3845', (256, 260))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('endometriosis', 'Disease', 'MESH:D004715', (91, 104))	('TP53', 'Gene', (247, 251))	('endometriosis', 'Disease', (91, 104))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', (37, 43))	('FOXL2', 'Gene', '668', (175, 180))	('ovarian neoplasms', 'Disease', 'MESH:D010051', (113, 130))	('neoplastic diseases', 'Disease', (285, 304))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('KRAS', 'Gene', (256, 260))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('FOXL2', 'Gene', (175, 180))	('APC', 'cellular_component', 'GO:0005680', ('185', '188'))	('ovarian neoplasms', 'Disease', (113, 130))	('endometriosis', 'Phenotype', 'HP:0030127', (91, 104))	('APC', 'Disease', 'MESH:D011125', (185, 188))	('APC', 'Disease', (185, 188))	('TP53', 'Gene', '7157', (247, 251))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
925	21412130	Because ARID1A mutations are randomly distributed in 20 exons and are insertion/deletion type of mutations that lead to truncated proteins, we used loss of ARID1A immunoreactivity as a surrogate marker for a mutation to screen a variety of carcinomas.	('truncated', 'MPA', (120, 129))	('loss', 'NegReg', (148, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (240, 250))	('carcinomas', 'Disease', (240, 250))	('lead', 'Reg', (112, 116))	('mutations', 'Var', (15, 24))	('carcinomas', 'Disease', 'MESH:D002277', (240, 250))	('ARID1A', 'Gene', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('proteins', 'Protein', (130, 138))	('ARID1A', 'Gene', (156, 162))
930	21412130	Since the ARID1A mutation status has been previously reported in ovarian clear cell and ovarian low-grade endometrioid carcinomas, these carcinomas were not included in the current study.	('carcinomas', 'Disease', (119, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('carcinomas', 'Disease', (137, 147))	('carcinomas', 'Disease', 'MESH:D002277', (137, 147))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (106, 129))	('mutation', 'Var', (17, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('ARID1A', 'Gene', (10, 16))	('ovarian clear cell and ovarian low-grade endometrioid carcinomas', 'Disease', 'MESH:D010051', (65, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('reported', 'Reg', (53, 61))	('carcinomas', 'Disease', 'MESH:D002277', (119, 129))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (106, 128))
936	21412130	A total of 93 tumor samples were analyzed for somatic ARID1A mutations.	('ARID1A', 'Gene', (54, 60))	('tumor', 'Disease', (14, 19))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
945	21412130	Western blot analysis demonstrated a significant decrease of ARID1A protein in HeLa cells after transfection with ARID1A specific shRNAs, especially the shRNA-2 and shRNA-3, as compared to control shRNA, indicating the specificity of the ARID1A antibody (Fig.	('antibody', 'cellular_component', 'GO:0042571', ('245', '253'))	('ARID1A', 'Gene', (61, 67))	('antibody', 'cellular_component', 'GO:0019815', ('245', '253'))	('specific', 'Var', (121, 129))	('antibody', 'cellular_component', 'GO:0019814', ('245', '253'))	('decrease', 'NegReg', (49, 57))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('antibody', 'molecular_function', 'GO:0003823', ('245', '253'))	('ARID1A', 'Gene', (114, 120))	('HeLa', 'CellLine', 'CVCL:0030', (79, 83))	('protein', 'Protein', (68, 75))
947	21412130	Since the ARID1A mutation status has been previously reported in ovarian clear cell and ovarian endometrioid carcinomas, these carcinomas were not included in the current study.	('carcinomas', 'Disease', 'MESH:D002277', (127, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('carcinomas', 'Disease', (127, 137))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (96, 119))	('mutation', 'Var', (17, 25))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (96, 118))	('ARID1A', 'Gene', (10, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ovarian clear cell and ovarian endometrioid carcinomas', 'Disease', 'MESH:D010051', (65, 119))	('reported', 'Reg', (53, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Disease', (109, 119))	('carcinomas', 'Disease', 'MESH:D002277', (109, 119))
958	21412130	As shown in Table 2, somatic ARID1A mutation was detected in 10 (40%) of 25 uterine low-grade endometrioid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('detected', 'Reg', (49, 57))	('endometrioid carcinomas', 'Disease', (94, 117))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (94, 116))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (94, 117))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (94, 117))	('ARID1A', 'Gene', (29, 35))	('mutation', 'Var', (36, 44))
959	21412130	As in ovarian clear cell and ovarian endometrioid carcinomas, the mutations were either insertion/deletion mutations or nonsense mutations which were widely distributed in the ARID1A gene (Table 3).	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('ovarian clear cell and ovarian endometrioid carcinomas', 'Disease', 'MESH:D010051', (6, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (37, 59))	('insertion/deletion mutations', 'Var', (88, 116))	('nonsense mutations', 'Var', (120, 138))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (37, 60))
961	21412130	We found that 5 (50%) of 10 tumors with ARID1A mutations did not demonstrate any detectable level of ARID1A immunoreactivity.	('ARID1A', 'Gene', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
962	21412130	Interestingly, four ARID1A positive cases with ARID1A mutations exhibited a pattern of immunoreactivity in which areas of negative cells were present adjacent to positive areas suggesting that mutations arose in clones within the tumor (Fig.	('tumor', 'Disease', (230, 235))	('ARID1A', 'Gene', (47, 53))	('ARID1A', 'Gene', (20, 26))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
966	21412130	One of the main findings has been the identification of somatic mutations of several chromatin remodeling genes in certain types of human cancer.	('cancer', 'Disease', (138, 144))	('chromatin remodeling genes', 'Gene', (85, 111))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (64, 73))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('85', '105'))	('human', 'Species', '9606', (132, 137))	('chromatin', 'cellular_component', 'GO:0000785', ('85', '94'))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
968	21412130	The findings in the present study extend previous observations and provide cogent evidence that epigenetic changes, like genetic alteration, is a "driver" rather than a "passenger" that is directly involved in tumor development of uterine low-grade endometrioid carcinoma.	('endometrioid carcinoma', 'Disease', (249, 271))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (249, 271))	('epigenetic changes', 'Var', (96, 114))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (249, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
970	21412130	The main findings were the loss of ARID1A immunoreactivity and mutation of ARDIA in low-grade uterine endometrioid carcinoma as compared to other types of carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('immunoreactivity', 'MPA', (42, 58))	('endometrioid carcinoma', 'Disease', (102, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('ARDIA', 'Gene', (75, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('carcinomas', 'Disease', (155, 165))	('carcinomas', 'Disease', 'MESH:D002277', (155, 165))	('mutation', 'Var', (63, 71))	('ARID1A', 'Gene', (35, 41))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (102, 124))	('loss', 'NegReg', (27, 31))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (102, 124))
971	21412130	Although loss of ARID1A expression also occurs in other tumor types, the frequency of loss of expression is low, indicating that ARID1A mutations are associated with specific types of carcinoma.	('associated', 'Reg', (150, 160))	('carcinoma', 'Disease', 'MESH:D002277', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ARID1A', 'Gene', (129, 135))	('tumor', 'Disease', (56, 61))	('ARID1A', 'Gene', (17, 23))	('carcinoma', 'Disease', (184, 193))	('mutations', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
972	21412130	Mutational analysis demonstrated somatic ARID1A mutations in 40% of uterine endometrioid carcinoma, a finding that has not been previously reported.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (76, 98))	('ARID1A', 'Gene', (41, 47))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (76, 98))	('endometrioid carcinoma', 'Disease', (76, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('mutations', 'Var', (48, 57))
974	21412130	Type I tumors are composed of endometrioid carcinomas which frequently harbor sequence mutations in CCNB1, PTEN and PIK3CA while type II tumors are largely serous carcinomas that contain TP53 mutations in the majority of cases.	('PIK3CA', 'Gene', (116, 122))	('harbor', 'Reg', (71, 77))	('type II tumors', 'Disease', 'MESH:D009369', (129, 143))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('TP53', 'Gene', (187, 191))	('mutations', 'Var', (87, 96))	('CCNB1', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (30, 53))	('PTEN', 'Gene', (107, 111))	('serous carcinomas', 'Disease', (156, 173))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (30, 52))	('type II tumors', 'Disease', (129, 143))	('PTEN', 'Gene', '5728', (107, 111))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (30, 53))	('TP53', 'Gene', '7157', (187, 191))	('PIK3CA', 'Gene', '5290', (116, 122))	('Type I tumors', 'Disease', (0, 13))	('CCNB1', 'Gene', '891', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('serous carcinomas', 'Disease', 'MESH:D018284', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('endometrioid carcinomas', 'Disease', (30, 53))
977	21412130	Thus the relatively frequent loss of ARID1A expression and ARID1A mutations in uterine endometrioid carcinoma but not in uterine serous carcinoma further supports their distinct pathogenesis.	('mutations', 'Var', (66, 75))	('expression', 'MPA', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (87, 109))	('serous carcinoma', 'Disease', (129, 145))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (87, 109))	('pathogenesis', 'biological_process', 'GO:0009405', ('178', '190'))	('loss', 'NegReg', (29, 33))	('ARID1A', 'Gene', (59, 65))	('endometrioid carcinoma', 'Disease', (87, 109))	('serous carcinoma', 'Disease', 'MESH:D018284', (129, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('ARID1A', 'Gene', (37, 43))
978	21412130	Given the well established roles of Pten-AKT pathway and Wnt pathway in the development of low-grade uterine endometrioid carcinoma (type I tumor), it will be important to determine if the ARID1A pathway cross-talks with those signaling pathways and to assess how inactivation of ARID1A contributes to tumor initiation and progression in this type of carcinoma.	('Pten', 'Gene', '5728', (36, 40))	('Pten', 'Gene', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('endometrioid carcinoma', 'Disease', (109, 131))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('carcinoma', 'Disease', (351, 360))	('AKT', 'Gene', '207', (41, 44))	('contributes', 'Reg', (287, 298))	('ARID1A', 'Gene', (280, 286))	('type I tumor', 'Disease', (133, 145))	('carcinoma', 'Disease', 'MESH:D002277', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinoma', 'Disease', 'MESH:D002277', (351, 360))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (109, 131))	('inactivation', 'Var', (264, 276))	('cross-talks', 'Reg', (204, 215))	('AKT', 'Gene', (41, 44))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (109, 131))	('type I tumor', 'Disease', 'MESH:D005776', (133, 145))	('tumor initiation', 'Disease', 'MESH:D009369', (302, 318))	('tumor initiation', 'Disease', (302, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Disease', (122, 131))
979	21412130	Although ARID1A mutations were most often associated with complete loss of its protein expression in low-grade uterine endometrioid carcinoma, we observed several uterine endometrioid carcinomas with ARID1A mutations that showed a heterogeneous staining pattern.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (119, 141))	('endometrioid carcinomas', 'Disease', (171, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (119, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('protein expression', 'MPA', (79, 97))	('endometrioid carcinoma', 'Disease', (119, 141))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (171, 194))	('mutations', 'Var', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('mutations', 'Var', (207, 216))	('loss', 'NegReg', (67, 71))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (171, 194))	('ARID1A', 'Gene', (200, 206))	('ARID1A', 'Gene', (9, 15))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (171, 193))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (171, 193))
981	21412130	This type of clonal loss of ARID1A immunoreactivity was only detected in uterine endometrioid carcinomas with ARID1A mutations but not in those without mutations or in ovarian clear cell carcinomas.	('mutations', 'Var', (117, 126))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (81, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (81, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('ARID1A', 'Gene', (28, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('ovarian clear cell carcinomas', 'Disease', (168, 197))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (168, 197))	('ARID1A', 'Gene', (110, 116))	('endometrioid carcinomas', 'Disease', (81, 104))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (81, 103))
982	21412130	It is likely that ARID1A mutations occur after tumor initiation in endometrioid carcinoma, creating tumor subclones during evolution of the carcinoma.	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('carcinoma', 'Disease', 'MESH:D002277', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('endometrioid carcinoma', 'Disease', (67, 89))	('mutations', 'Var', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Disease', (80, 89))	('ARID1A', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (67, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('creating', 'Reg', (91, 99))	('tumor', 'Disease', (47, 52))	('carcinoma', 'Disease', (140, 149))	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor initiation', 'Disease', 'MESH:D009369', (47, 63))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (67, 89))	('tumor initiation', 'Disease', (47, 63))
986	21412130	The results from this study along with our previous reports strongly suggest that loss of ARID1A expression and/or its mutations are confined to ovarian clear cell and ovarian endometrioid carcinomas, because the high-grade and low-grade serous carcinomas as well as mucinous carcinomas did not show ARID1A mutations or loss of expression.	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (267, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('ovarian clear cell and ovarian endometrioid carcinomas', 'Disease', 'MESH:D010051', (145, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (176, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (176, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (276, 286))	('ARID1A', 'Gene', (90, 96))	('loss', 'NegReg', (82, 86))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (267, 286))	('mutations', 'Var', (119, 128))	('serous carcinomas', 'Disease', 'MESH:D018284', (238, 255))	('expression', 'MPA', (97, 107))	('mucinous carcinomas', 'Disease', (267, 286))	('serous carcinomas', 'Disease', (238, 255))
987	21412130	It is, therefore, conceivable that ARID1A mutation plays an important role in the development of ovarian tumors derived from endometriosis.	('endometriosis', 'Phenotype', 'HP:0030127', (125, 138))	('ovarian tumors', 'Disease', (97, 111))	('ovarian tumors', 'Phenotype', 'HP:0100615', (97, 111))	('mutation', 'Var', (42, 50))	('ovarian tumors', 'Disease', 'MESH:D010051', (97, 111))	('endometriosis', 'Disease', 'MESH:D004715', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('ARID1A', 'Gene', (35, 41))	('endometriosis', 'Disease', (125, 138))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
988	21412130	Since it is generally thought that endometriosis develops from retrograde menstruation, the underlying critical molecular event for the development of uterine low-grade endometrioid, ovarian endometrioid, and clear cell carcinomas in some cases is mutation of ARIDIA in endometrial tissue.	('clear cell carcinomas', 'Disease', 'MESH:C538614', (209, 230))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('ovarian endometrioid', 'Disease', 'MESH:D016889', (183, 203))	('endometriosis', 'Phenotype', 'HP:0030127', (35, 48))	('mutation', 'Var', (248, 256))	('endometriosis', 'Disease', 'MESH:D004715', (35, 48))	('clear cell carcinomas', 'Disease', (209, 230))	('ovarian endometrioid', 'Disease', (183, 203))	('endometriosis', 'Disease', (35, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('menstruation', 'biological_process', 'GO:0042703', ('74', '86'))
990	21412130	In conclusion, based on ARID1A immunohistochemistry and mutational analysis, we found that ARID1A inactivation, either by somatic mutations or by loss of expression, frequently occurs in uterine low-grade endometrioid carcinomas in addition to ovarian low-grade endometrioid and ovarian clear cell carcinomas.	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (205, 228))	('ARID1A', 'Gene', (91, 97))	('ovarian low-grade endometrioid', 'Disease', (244, 274))	('carcinomas', 'Phenotype', 'HP:0030731', (298, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('ovarian clear cell carcinomas', 'Disease', (279, 308))	('loss of expression', 'NegReg', (146, 164))	('endometrioid carcinomas', 'Disease', (205, 228))	('mutations', 'Var', (130, 139))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (279, 308))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (205, 228))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (205, 227))	('inactivation', 'NegReg', (98, 110))
1100	24681739	Additionally, loss of heterozygosity (LOH) and PTEN mutational analysis have also been reported as useful investigative tools in differentiating primary versus metastatic endometrioid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('mutational', 'Var', (52, 62))	('endometrioid carcinoma', 'Disease', (171, 193))	('loss of heterozygosity', 'Var', (14, 36))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('primary', 'Disease', (145, 152))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (171, 193))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (171, 193))
1131	24681739	One of the ancillary techniques to differentiate double primary from metastatic carcinoma is using molecular methods as microsatellite instability (MSI), mutations in PTEN and the beta-catenin genes (CTNNB1).	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('CTNNB1', 'Gene', '1499', (200, 206))	('beta-catenin', 'Gene', (180, 192))	('MSI', 'Disease', 'None', (148, 151))	('carcinoma', 'Disease', (80, 89))	('beta-catenin', 'Gene', '1499', (180, 192))	('PTEN', 'Gene', (167, 171))	('CTNNB1', 'Gene', (200, 206))	('PTEN', 'Gene', '5728', (167, 171))	('mutations', 'Var', (154, 163))	('microsatellite instability', 'MPA', (120, 146))	('MSI', 'Disease', (148, 151))
1132	24681739	Endometrioid carcinomas of primary ovarian origin have been reported to exhibit similar frequency of beta - catenin abnormalities and lower incidence of MSI and PTEN mutations compared to uterine corpus counterparts.	('MSI', 'Disease', (153, 156))	('lower', 'NegReg', (134, 139))	('mutations', 'Var', (166, 175))	('Endometrioid carcinomas of primary ovarian', 'Disease', 'MESH:D016889', (0, 42))	('beta - catenin', 'Gene', (101, 115))	('Endometrioid carcinomas of primary ovarian', 'Disease', (0, 42))	('beta - catenin', 'Gene', '1499', (101, 115))	('Endometrioid carcinomas', 'Phenotype', 'HP:0012114', (0, 23))	('PTEN', 'Gene', (161, 165))	('MSI', 'Disease', 'None', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('PTEN', 'Gene', '5728', (161, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (13, 23))
1150	24681739	In conclusion, ovary and uterine corpus endometrioid adenocarcinomas have different patterns of vimentin expression, with vimentin negativity having a high sensitivity and specificity for primary ovarian tumors and vimentin positivity having the same for primary endometrial tumors.	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('vimentin', 'Gene', '7431', (122, 130))	('negativity', 'Var', (131, 141))	('vimentin', 'Gene', '7431', (96, 104))	('vimentin', 'cellular_component', 'GO:0045099', ('96', '104'))	('vimentin', 'Gene', (122, 130))	('corpus endometrioid adenocarcinomas', 'Disease', (33, 68))	('vimentin', 'Gene', (96, 104))	('vimentin', 'Gene', '7431', (215, 223))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('vimentin', 'Gene', (215, 223))	('vimentin', 'cellular_component', 'GO:0045098', ('215', '223'))	('endometrial tumors', 'Disease', 'MESH:D016889', (263, 281))	('ovarian tumor', 'Phenotype', 'HP:0100615', (196, 209))	('ovarian tumors', 'Phenotype', 'HP:0100615', (196, 210))	('vimentin', 'cellular_component', 'GO:0045099', ('122', '130'))	('vimentin', 'cellular_component', 'GO:0045098', ('122', '130'))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('endometrial tumors', 'Disease', (263, 281))	('corpus endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (33, 68))	('primary ovarian tumors', 'Disease', (188, 210))	('vimentin', 'cellular_component', 'GO:0045098', ('96', '104'))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (40, 67))	('primary ovarian tumors', 'Disease', 'MESH:D010051', (188, 210))	('vimentin', 'cellular_component', 'GO:0045099', ('215', '223'))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
1159	21683865	They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors.	('TP53', 'Gene', (82, 86))	('type I tumors', 'Disease', 'MESH:D005776', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('type I tumors', 'Disease', (141, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('TP53', 'Gene', '7157', (82, 86))	('mutations', 'Var', (87, 96))
1160	21683865	In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promotor methylation.	('perturb', 'Reg', (60, 67))	('methylation', 'biological_process', 'GO:0032259', ('133', '144'))	('BRCA', 'Gene', (82, 86))	('expression', 'MPA', (68, 78))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('type II tumors', 'Disease', (13, 27))	('type II tumors', 'Disease', 'MESH:D009369', (13, 27))	('mutation', 'Var', (97, 105))	('BRCA', 'Gene', '672', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
1179	21683865	The type I tumors are relatively genetically stable and typically display a variety of somatic sequence mutations that include KRAS, BRAF, PTEN, PIK3CA CTNNB1 (the gene encoding beta catenin), ARID1A and PPP2R1A but very rarely TP53 .	('beta catenin', 'Gene', (178, 190))	('beta catenin', 'Gene', '1499', (178, 190))	('TP53', 'Gene', (228, 232))	('ARID1A', 'Gene', (193, 199))	('mutations', 'Var', (104, 113))	('BRAF', 'Gene', '673', (133, 137))	('CTNNB1', 'Gene', '1499', (152, 158))	('PTEN', 'Gene', (139, 143))	('BRAF', 'Gene', (133, 137))	('PIK3CA', 'Gene', (145, 151))	('ARID1A', 'Gene', '8289', (193, 199))	('type I tumors', 'Disease', 'MESH:D005776', (4, 17))	('KRAS', 'Gene', '3845', (127, 131))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('PTEN', 'Gene', '5728', (139, 143))	('KRAS', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (228, 232))	('PPP2R1A', 'Gene', '5518', (204, 211))	('CTNNB1', 'Gene', (152, 158))	('type I tumors', 'Disease', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('PPP2R1A', 'Gene', (204, 211))	('PIK3CA', 'Gene', '5290', (145, 151))
1181	21683865	Type II tumors, of which HGSC is the prototypic type, are chromosomally highly unstable and harbor TP53 mutations in >95% of cases ; they rarely display the mutations found in the type I tumors.	('TP53', 'Gene', (99, 103))	('type I tumors', 'Disease', 'MESH:D005776', (180, 193))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('type I tumors', 'Disease', (180, 193))	('TP53', 'Gene', '7157', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('Type II tumors', 'Disease', (0, 14))	('Type II tumors', 'Disease', 'MESH:D009369', (0, 14))
1182	21683865	BRCA inactivation, either by mutation or inactivation of expression of BRCA and its downstream genes via promoter methylation occurs in up to 40-50% of HGSC .	('mutation', 'Var', (29, 37))	('inactivation', 'NegReg', (41, 53))	('expression', 'MPA', (57, 67))	('BRCA', 'Gene', (0, 4))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))	('inactivation', 'NegReg', (5, 17))	('BRCA', 'Gene', '672', (71, 75))	('BRCA', 'Gene', (71, 75))	('BRCA', 'Gene', '672', (0, 4))
1185	21683865	For example, the MAPK signaling pathway is important for the cellular response to a variety of growth and differentiation factors and activating mutations in KRAS or one of its downstream effectors, BRAF, (mutations of KRAS and BRAF are mutually exclusive) results in constitutive activation of MAPK-mediated signaling in more than half of APSTs, MPSCs and LGSCs .	('MPSCs', 'Disease', (347, 352))	('MAPK', 'molecular_function', 'GO:0004707', ('295', '299'))	('KRAS', 'Gene', '3845', (219, 223))	('KRAS', 'Gene', '3845', (158, 162))	('BRAF', 'Gene', '673', (228, 232))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('mutations', 'Var', (145, 154))	('BRAF', 'Gene', (228, 232))	('MAPK-mediated signaling', 'MPA', (295, 318))	('APSTs', 'Disease', (340, 345))	('activation', 'PosReg', (281, 291))	('signaling pathway', 'biological_process', 'GO:0007165', ('22', '39'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('17', '31'))	('BRAF', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (199, 203))	('KRAS', 'Gene', (158, 162))	('signaling', 'biological_process', 'GO:0023052', ('309', '318'))	('KRAS', 'Gene', (219, 223))
1187	21683865	Interestingly, tumors with ERBB2 mutations lack KRAS and BRAF mutations .	('KRAS', 'Gene', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('KRAS', 'Gene', '3845', (48, 52))	('BRAF', 'Gene', '673', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mutations', 'Var', (33, 42))	('BRAF', 'Gene', (57, 61))	('ERBB2', 'Gene', '2064', (27, 32))	('ERBB2', 'Gene', (27, 32))	('lack', 'NegReg', (43, 47))	('tumors', 'Disease', (15, 21))
1189	21683865	First, KRAS and BRAF mutations have not been detected in serous cystadenomas, the putative precursor of SBTs, but laser capture microdissection studies have detected these mutations in the adenoma epithelium and APST epithelium in serous cystadenomas containing small APSTs suggesting that these mutations occur early in the development of APST .	('serous cystadenomas', 'Phenotype', 'HP:0012887', (231, 250))	('serous cystadenomas', 'Disease', (57, 76))	('serous cystadenomas', 'Disease', 'MESH:D018293', (57, 76))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('serous cystadenoma', 'Phenotype', 'HP:0012887', (57, 75))	('serous cystadenomas', 'Disease', (231, 250))	('serous cystadenomas', 'Disease', 'MESH:D018293', (231, 250))	('serous cystadenoma', 'Phenotype', 'HP:0012887', (231, 249))	('adenoma', 'Disease', (189, 196))	('adenoma', 'Disease', (242, 249))	('mutations', 'Var', (172, 181))	('KRAS', 'Gene', '3845', (7, 11))	('adenoma', 'Disease', (68, 75))	('serous cystadenomas', 'Phenotype', 'HP:0012887', (57, 76))	('adenoma', 'Disease', 'MESH:D000236', (189, 196))	('adenoma', 'Disease', 'MESH:D000236', (242, 249))	('detected', 'Reg', (157, 165))	('adenoma', 'Disease', 'MESH:D000236', (68, 75))	('KRAS', 'Gene', (7, 11))
1193	21683865	In contrast to LGSC, HGSC harbors TP53 mutations in >95% of cases , but rarely contains KRAS or BRAF mutations.	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('KRAS', 'Gene', (88, 92))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('KRAS', 'Gene', '3845', (88, 92))	('TP53', 'Gene', '7157', (34, 38))
1194	21683865	Aside from TP53 mutations no other mutations are consistently found in sporadic (nonfamilial) HGSCs including mutations of BRCA1 and BRCA2, which characterize familial HGSC (The Cancer Genome Atlas, unpublished).	('BRCA1', 'Gene', '672', (123, 128))	('mutations', 'Var', (110, 119))	('TP53', 'Gene', '7157', (11, 15))	('familial HGSC', 'Disease', (159, 172))	('TP53', 'Gene', (11, 15))	('BRCA1', 'Gene', (123, 128))	('Cancer', 'Disease', (178, 184))	('BRCA2', 'Gene', (133, 138))	('Cancer', 'Disease', 'MESH:D009369', (178, 184))	('Cancer', 'Phenotype', 'HP:0002664', (178, 184))	('BRCA2', 'Gene', '675', (133, 138))
1195	21683865	On the other hand, inactivation of the BRCA1/2 genes by other mechanisms, such as hypermethylation of the BRCA1 promoter, occurs relatively frequently and as a result inactivation of BRCA1/2 by mutation or other mechanisms occurs in 40-50% of sporadic HGSCs .	('mutation', 'Var', (194, 202))	('BRCA1', 'Gene', (106, 111))	('BRCA1/2', 'Gene', (183, 190))	('BRCA1/2', 'Gene', (39, 46))	('sporadic HGSCs', 'Disease', (243, 257))	('inactivation', 'MPA', (19, 31))	('BRCA1/2', 'Gene', '672;675', (183, 190))	('BRCA1', 'Gene', '672', (183, 188))	('BRCA1', 'Gene', '672', (39, 44))	('BRCA1', 'Gene', '672', (106, 111))	('BRCA1', 'Gene', (183, 188))	('inactivation', 'NegReg', (167, 179))	('BRCA1', 'Gene', (39, 44))	('BRCA1/2', 'Gene', '672;675', (39, 46))
1199	21683865	Based on genome-wide mutational analysis, the most common molecular genetic changes in clear cell carcinoma are a somatic inactivating mutation of ARID1A , a tumor suppressor gene detected in about 50% of cases, an activating mutation of PIK3CA in about 50% of tumors  and deletion of PTEN, a tumor suppressor gene involved in the PI3K/PTEN signaling pathway, in about 20%, supporting the role of an aberrant PI3K/PTEN pathway in the development of clear cell carcinoma.	('clear cell carcinoma', 'Disease', (449, 469))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('PTEN', 'Gene', '5728', (285, 289))	('ARID1A', 'Gene', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('signaling pathway', 'biological_process', 'GO:0007165', ('341', '358'))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('PI3K', 'molecular_function', 'GO:0016303', ('331', '335'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('activating', 'PosReg', (215, 225))	('PIK3CA', 'Gene', '5290', (238, 244))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (449, 469))	('ARID1A', 'Gene', '8289', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumors', 'Disease', (261, 267))	('PI3K', 'molecular_function', 'GO:0016303', ('409', '413'))	('PTEN', 'Gene', (336, 340))	('PTEN', 'Gene', (414, 418))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('293', '309'))	('clear cell carcinoma', 'Disease', (87, 107))	('PIK3CA', 'Gene', (238, 244))	('mutation', 'Var', (135, 143))	('PTEN', 'Gene', '5728', (336, 340))	('tumor', 'Disease', (158, 163))	('PTEN', 'Gene', (285, 289))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('tumor', 'Disease', (261, 266))	('tumor suppressor', 'biological_process', 'GO:0051726', ('293', '309'))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('deletion', 'Var', (273, 281))	('PTEN', 'Gene', '5728', (414, 418))	('tumor', 'Disease', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (87, 107))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
1200	21683865	In addition, SNP array analysis has identified frequent amplification of the ZNF217 (zinc finger protein 217) locus and deletion of the CDKN2A/2B locus in clear cell carcinomas, suggesting that the pathways involving these two genes are also important in their development.	('CDKN2A/2B', 'Gene', '1029', (136, 145))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('zinc finger protein 217', 'Gene', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('CDKN2A/2B', 'Gene', (136, 145))	('zinc finger protein 217', 'Gene', '7764', (85, 108))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (155, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('deletion', 'Var', (120, 128))	('ZNF217', 'Gene', (77, 83))	('ZNF217', 'Gene', '7764', (77, 83))	('clear cell carcinomas', 'Disease', (155, 176))
1201	21683865	Like clear cell carcinoma, mutations that deregulate PI3K/PTEN signaling are common in low-grade endometrioid carcinoma and, in fact, mutation of the tumor suppressor gene PTEN, which occurs rarely in other types of EOC, has been reported in approximately 20% of ovarian low-grade endometrioid carcinomas .	('mutations', 'Var', (27, 36))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (281, 303))	('EOC', 'Phenotype', 'HP:0025318', (216, 219))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (97, 119))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (281, 304))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PTEN', 'Gene', (172, 176))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (5, 25))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('endometrioid carcinoma', 'Disease', (97, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (294, 304))	('PTEN', 'Gene', (58, 62))	('reported', 'Reg', (230, 238))	('PTEN', 'Gene', '5728', (172, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('150', '166'))	('endometrioid carcinomas', 'Disease', (281, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumor suppressor', 'biological_process', 'GO:0051726', ('150', '166'))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (281, 303))	('tumor', 'Disease', (150, 155))	('PTEN', 'Gene', '5728', (58, 62))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (97, 119))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (281, 304))	('mutation', 'Var', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('PI3K', 'molecular_function', 'GO:0016303', ('53', '57'))	('clear cell carcinoma', 'Disease', (5, 25))
1203	21683865	The Wnt/b-catenin signaling pathway, which is involved in the regulation of several important cellular processes including proliferation, motility and survival, is deregulated in up to 40% of ovarian endometrioid carcinomas, usually on the basis of activating mutations of CTNNB1, the gene that encodes beta-catenin .	('activating', 'PosReg', (249, 259))	('CTNNB1', 'Gene', (273, 279))	('beta-catenin', 'Gene', (303, 315))	('beta-catenin', 'Gene', '1499', (303, 315))	('ovarian endometrioid carcinomas', 'Disease', (192, 223))	('CTNNB1', 'Gene', '1499', (273, 279))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (200, 222))	('signaling pathway', 'biological_process', 'GO:0007165', ('18', '35'))	('deregulated', 'Reg', (164, 175))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (200, 223))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (192, 223))	('Wnt/b-catenin signaling pathway', 'Pathway', (4, 35))	('mutations', 'Var', (260, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('carcinomas', 'Phenotype', 'HP:0030731', (213, 223))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))
1204	21683865	Notably, mutation of CTNNB1 has been associated with squamous differentiation, low tumor grade and a favorable outcome, features that characterize low-grade endometrioid carcinoma .	('mutation', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('low tumor', 'Disease', (79, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('endometrioid carcinoma', 'Disease', (157, 179))	('low tumor', 'Disease', 'MESH:D009800', (79, 88))	('CTNNB1', 'Gene', '1499', (21, 27))	('CTNNB1', 'Gene', (21, 27))	('associated', 'Reg', (37, 47))	('squamous', 'Disease', (53, 61))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (157, 179))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (157, 179))
1207	21683865	It is therefore of interest that in a study of ovarian endometrioid carcinomas of all grades, low-grade endometrioid carcinomas were characterized by mutations that deregulate the canonical Wnt/beta-catenin and PI3K/PTEN signaling pathways and lacked TP53 mutations whereas high-grade endometrioid carcinomas lacked Wnt/beta catenin or PI3K/PTEN signaling pathway defects and frequently harbored TP53 mutations .	('signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('TP53', 'Gene', (251, 255))	('PTEN', 'Gene', '5728', (341, 345))	('ovarian endometrioid carcinomas', 'Disease', (47, 78))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (285, 308))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (104, 126))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (55, 78))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (104, 127))	('PI3K', 'molecular_function', 'GO:0016303', ('211', '215'))	('TP53', 'Gene', '7157', (396, 400))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (47, 78))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (285, 307))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (55, 77))	('mutations', 'Var', (150, 159))	('PTEN', 'Gene', (216, 220))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (285, 308))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (55, 78))	('beta catenin', 'Gene', '1499', (320, 332))	('TP53', 'Gene', '7157', (251, 255))	('beta catenin', 'Gene', (320, 332))	('harbored', 'Reg', (387, 395))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('signaling pathway', 'biological_process', 'GO:0007165', ('346', '363'))	('endometrioid carcinomas', 'Disease', (104, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (298, 308))	('PI3K', 'molecular_function', 'GO:0016303', ('336', '340'))	('mutations', 'Var', (401, 410))	('lacked', 'NegReg', (309, 315))	('deregulate', 'PosReg', (165, 175))	('PTEN', 'Gene', '5728', (216, 220))	('PTEN', 'Gene', (341, 345))	('beta-catenin', 'Gene', (194, 206))	('endometrioid carcinomas', 'Disease', (285, 308))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (104, 127))	('TP53', 'Gene', (396, 400))	('lacked', 'NegReg', (244, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('beta-catenin', 'Gene', '1499', (194, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
1210	21683865	The similar high frequency of TP53 mutations in the high-grade endometrioid carcinoma as in HGSC suggests that both develop in a similar fashion, via TP53 mutation, and that most high-grade endometrioid carcinoma is closely related or is a variant of HGSC.	('TP53', 'Gene', (150, 154))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (63, 85))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (190, 212))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (63, 85))	('endometrioid carcinoma', 'Disease', (63, 85))	('mutation', 'Var', (155, 163))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (190, 212))	('endometrioid carcinoma', 'Disease', (190, 212))	('TP53', 'Gene', '7157', (150, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('mutations', 'Var', (35, 44))
1211	21683865	Morphologic studies over the past two to three decades have repeatedly shown an association of endometrioid and clear cell carcinoma with endometriosis and early molecular genetic studies demonstrated LOH in the same chromosomal regions in endometrioid carcinoma and adjacent endometriosis  confirming a clonal relationship between endometriosis and endometrioid carcinoma.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (350, 372))	('endometriosis', 'Disease', 'MESH:D004715', (332, 345))	('endometriosis', 'Disease', (332, 345))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (240, 262))	('endometriosis', 'Phenotype', 'HP:0030127', (276, 289))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (350, 372))	('endometriosis', 'Phenotype', 'HP:0030127', (332, 345))	('endometrioid carcinoma', 'Disease', (240, 262))	('endometriosis', 'Disease', (138, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('endometriosis', 'Disease', 'MESH:D004715', (138, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (363, 372))	('clear cell carcinoma', 'Disease', (112, 132))	('endometrioid carcinoma', 'Disease', (350, 372))	('endometrioid', 'Disease', (95, 107))	('endometriosis', 'Phenotype', 'HP:0030127', (138, 151))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (240, 262))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (112, 132))	('association', 'Interaction', (80, 91))	('LOH', 'Var', (201, 204))	('endometriosis', 'Disease', 'MESH:D004715', (276, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('endometriosis', 'Disease', (276, 289))
1212	21683865	In addition, a recent study reported mutation of ARID1A in atypical endometriosis adjacent to clear cell carcinoma but not in distant sites of endometriosis further linking endometriosis to clear cell carcinoma and thereby providing further evidence that endometriosis is the likely precursor of endometrioid and clear cell carcinoma .	('mutation', 'Var', (37, 45))	('endometriosis', 'Phenotype', 'HP:0030127', (143, 156))	('clear cell carcinoma', 'Disease', (313, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('endometriosis', 'Phenotype', 'HP:0030127', (255, 268))	('endometriosis', 'Disease', 'MESH:D004715', (173, 186))	('endometriosis', 'Disease', (173, 186))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (313, 333))	('ARID1A', 'Gene', (49, 55))	('endometriosis', 'Phenotype', 'HP:0030127', (173, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometriosis', 'Disease', 'MESH:D004715', (68, 81))	('clear cell carcinoma', 'Disease', (94, 114))	('endometriosis', 'Disease', (68, 81))	('ARID1A', 'Gene', '8289', (49, 55))	('clear cell carcinoma', 'Disease', (190, 210))	('endometriosis', 'Disease', 'MESH:D004715', (143, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('endometriosis', 'Disease', (143, 156))	('endometriosis', 'Disease', 'MESH:D004715', (255, 268))	('endometriosis', 'Disease', (255, 268))	('endometriosis further linking endometriosis to clear cell carcinoma', 'Disease', 'MESH:D004715', (143, 210))	('endometriosis', 'Phenotype', 'HP:0030127', (68, 81))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (94, 114))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (190, 210))
1213	21683865	Although both clear cell and endometrioid carcinomas are derived from endometriosis and share some molecular genetic features, such as mutation of ARID1A and deletion of PTEN, they clearly adopt different molecular programs for their development, as is evident by their distinctly different morphologic phenotype and clinical behavior.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('endometriosis', 'Phenotype', 'HP:0030127', (70, 83))	('PTEN', 'Gene', (170, 174))	('ARID1A', 'Gene', '8289', (147, 153))	('ARID1A', 'Gene', (147, 153))	('PTEN', 'Gene', '5728', (170, 174))	('endometrioid carcinomas', 'Disease', (29, 52))	('endometriosis', 'Disease', 'MESH:D004715', (70, 83))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (29, 51))	('endometriosis', 'Disease', (70, 83))	('deletion', 'Var', (158, 166))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (29, 52))	('mutation', 'Var', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (29, 52))
1214	21683865	For example, canonical Wnt signaling pathway defects and microsatellite instability, which occur frequently in low-grade endometrioid carcinoma have only rarely been detected in clear cell carcinoma .	('canonical Wnt signaling pathway', 'biological_process', 'GO:0060070', ('13', '44'))	('clear cell carcinoma', 'Disease', (178, 198))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (178, 198))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (121, 143))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (121, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('microsatellite instability', 'Var', (57, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrioid carcinoma', 'Disease', (121, 143))	('defects', 'Var', (45, 52))	('canonical Wnt signaling pathway', 'Pathway', (13, 44))
1217	21683865	We are unaware of any molecular genetic studies of these neoplasms, however, we have recently detected ARID1A mutations in two of these neoplasms suggesting that they are more closely related to endometrioid than to serous or mucinous tumors (unpublished data) further confirming the role of endometriosis as a precursor for a variety of "endometrioid-related" ovarian neoplasms.	('endometriosis', 'Disease', 'MESH:D004715', (292, 305))	('endometriosis', 'Disease', (292, 305))	('neoplasms', 'Disease', (57, 66))	('endometrioid', 'Disease', (195, 207))	('neoplasms', 'Disease', (136, 145))	('neoplasms', 'Phenotype', 'HP:0002664', (369, 378))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('ARID1A', 'Gene', (103, 109))	('endometriosis', 'Phenotype', 'HP:0030127', (292, 305))	('mucinous tumors', 'Disease', (226, 241))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('ovarian neoplasms', 'Disease', 'MESH:D010051', (361, 378))	('mutations', 'Var', (110, 119))	('neoplasms', 'Phenotype', 'HP:0002664', (57, 66))	('mucinous tumors', 'Disease', 'MESH:D002288', (226, 241))	('ARID1A', 'Gene', '8289', (103, 109))	('neoplasms', 'Disease', 'MESH:D009369', (369, 378))	('neoplasms', 'Phenotype', 'HP:0002664', (136, 145))	('ovarian neoplasms', 'Disease', (361, 378))	('related', 'Reg', (184, 191))	('neoplasms', 'Disease', (369, 378))	('neoplasms', 'Disease', 'MESH:D009369', (57, 66))	('ovarian neoplasms', 'Phenotype', 'HP:0100615', (361, 378))	('neoplasms', 'Disease', 'MESH:D009369', (136, 145))
1219	21683865	KRAS mutations occur in up to 75% of primary mucinous carcinomas and using KRAS as a molecular marker, laser capture microdissection studies have shown the identical KRAS mutation in mucinous carcinomas and adjacent mucinous cystadenomas and borderline tumors  supporting the morphological continuum and tumor progression in ovarian mucinous neoplasms.	('mucinous carcinomas', 'Disease', (45, 64))	('mutation', 'Var', (171, 179))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (183, 202))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (304, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('KRAS', 'Gene', '3845', (75, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('mucinous cystadenomas', 'Disease', (216, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('ovarian mucinous neoplasms', 'Disease', 'MESH:D010051', (325, 351))	('KRAS', 'Gene', (75, 79))	('mucinous cystadenomas', 'Disease', 'MESH:D018291', (216, 237))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (333, 351))	('KRAS', 'Gene', '3845', (0, 4))	('borderline tumors', 'Disease', (242, 259))	('ovarian mucinous neoplasms', 'Phenotype', 'HP:0031494', (325, 351))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (45, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (342, 351))	('mutations', 'Var', (5, 14))	('borderline tumors', 'Disease', 'MESH:D012569', (242, 259))	('mucinous carcinomas', 'Disease', (183, 202))	('KRAS', 'Gene', '3845', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('tumor', 'Disease', (253, 258))	('KRAS', 'Gene', (0, 4))	('ovarian mucinous neoplasms', 'Disease', (325, 351))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('KRAS', 'Gene', (166, 170))
1221	21683865	In contrast, the type II tumors, aside from a very high frequency of TP53 mutations and molecular alterations of BRCA1/2, are characterized by marked genetic instability and lack other mutations.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TP53', 'Gene', '7157', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('TP53', 'Gene', (69, 73))	('type II tumors', 'Disease', (17, 31))	('mutations', 'Var', (74, 83))	('type II tumors', 'Disease', 'MESH:D009369', (17, 31))	('BRCA1/2', 'Gene', (113, 120))	('genetic instability', 'Disease', 'MESH:D030342', (150, 169))	('BRCA1/2', 'Gene', '672;675', (113, 120))	('genetic instability', 'Disease', (150, 169))
1227	21683865	Additional studies in which fallopian tubes were carefully examined confirmed that STICs and small, early invasive tubal carcinomas occurred not only in women with a genetic predisposition for the development of ovarian cancer but also in 50-60% of women without known BRCA mutations (sporadic ovarian cancer) (Fig 4) .	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('women', 'Species', '9606', (153, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (294, 308))	('BRCA', 'Gene', '672', (269, 273))	('fallopian tubes', 'Disease', (28, 43))	('STICs', 'Disease', (83, 88))	('ovarian cancer', 'Disease', (212, 226))	('TICs', 'Phenotype', 'HP:0100033', (84, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('invasive tubal carcinomas', 'Disease', 'MESH:D011274', (106, 131))	('sporadic ovarian cancer', 'Disease', 'MESH:D010051', (285, 308))	('BRCA', 'Gene', (269, 273))	('invasive tubal carcinomas', 'Disease', (106, 131))	('fallopian tubes', 'Disease', 'MESH:D005184', (28, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (294, 308))	('fall', 'Phenotype', 'HP:0002527', (28, 32))	('sporadic ovarian cancer', 'Disease', (285, 308))	('women', 'Species', '9606', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancer', 'Disease', 'MESH:D010051', (212, 226))	('mutations', 'Var', (274, 283))
1229	21683865	Further evidence supporting the proposal that STICs are precursors was the identification of STICs in women without ovarian cancer as well as the presence of identical TP53 mutations in STICs and concomitant ovarian HGSCs, indicating a clonal relationship between them .	('TP53', 'Gene', '7157', (168, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('TP53', 'Gene', (168, 172))	('presence', 'Var', (146, 154))	('ovarian HGSCs', 'Disease', 'MESH:D010051', (208, 221))	('TICs', 'Phenotype', 'HP:0100033', (47, 51))	('ovarian cancer', 'Disease', (116, 130))	('ovarian HGSCs', 'Disease', (208, 221))	('women', 'Species', '9606', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (173, 182))	('TICs', 'Phenotype', 'HP:0100033', (187, 191))	('TICs', 'Phenotype', 'HP:0100033', (94, 98))	('STICs', 'Disease', (93, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))
1272	21683865	Type I tumors (low-grade serous, low-grade endometrioid, clear cell, and mucinous) are slow growing and attain a large size while still confined to the ovary.	('clear cell', 'Disease', (57, 67))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('Type I tumors', 'Disease', (0, 13))	('low-grade', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
1286	21683865	For example, in many type I carcinomas, there is constitutive activation of the MAPK signaling pathway because of mutations in ERBB2, KRAS or BRAF, the upstream regulators of MAPK.	('KRAS', 'Gene', '3845', (134, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('signaling pathway', 'biological_process', 'GO:0007165', ('85', '102'))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('MAPK signaling', 'biological_process', 'GO:0000165', ('80', '94'))	('mutations', 'Var', (114, 123))	('type I carcinomas', 'Disease', 'MESH:D017827', (21, 38))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('MAPK signaling pathway', 'Pathway', (80, 102))	('ERBB2', 'Gene', (127, 132))	('ERBB2', 'Gene', '2064', (127, 132))	('KRAS', 'Gene', (134, 138))	('MAPK', 'molecular_function', 'GO:0004707', ('175', '179'))	('BRAF', 'Gene', '673', (142, 146))	('activation', 'PosReg', (62, 72))	('BRAF', 'Gene', (142, 146))	('type I carcinomas', 'Disease', (21, 38))
1297	21683865	Thus, the risk of EOC is reduced by as much as 50% for women using oral contraceptives for 5 or more years  and parity compared with nulliparity confers approximately a 50% decrease in risk .	('EOC', 'Phenotype', 'HP:0025318', (18, 21))	('women', 'Species', '9606', (55, 60))	('EOC', 'Disease', (18, 21))	('parity', 'Var', (112, 118))
1300	21683865	The traditional approach for reducing risk for women with a family history of ovarian traditional approach for reducing risk for women with a family history of ovarian carcinoma or who are found to have BRCA1/2 mutations has been hysterectomy and bilateral salpingo-oophorectomy.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('BRCA1/2', 'Gene', (203, 210))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (160, 177))	('BRCA1/2', 'Gene', '672;675', (203, 210))	('women', 'Species', '9606', (129, 134))	('ovarian carcinoma', 'Disease', (160, 177))	('mutations', 'Var', (211, 220))	('women', 'Species', '9606', (47, 52))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (160, 177))
1304	21683865	However, in a recent prospective study of nearly 30,000 women in the Nurses' Health Study, it was shown that compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy was associated with an increased risk of death from all causes as well as being associated with at increased risk of nonfatal coronary heart disease .	('coronary heart disease', 'Disease', (322, 344))	('coronary heart disease', 'Phenotype', 'HP:0001677', (322, 344))	('coronary heart disease', 'Disease', 'MESH:D003324', (322, 344))	('death', 'Disease', 'MESH:D003643', (237, 242))	('death', 'Disease', (237, 242))	('bilateral oophorectomy', 'Var', (145, 167))	('associated', 'Reg', (276, 286))	('women', 'Species', '9606', (56, 61))
1312	21683865	They have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors.	('type I tumors', 'Disease', 'MESH:D005776', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('type I tumors', 'Disease', (94, 107))	('mutations', 'Var', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))
1335	31739799	Although UTROSCT demonstrates FOXL2 protein positivity, FOXL2 and DICER1 mutations are not identified in this tumor.	('FOXL2', 'Gene', '668', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('DICER1', 'Gene', (66, 72))	('DICER1', 'Gene', '23405', (66, 72))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('FOXL2', 'Gene', (30, 35))	('FOXL2', 'Gene', '668', (56, 61))	('protein', 'Protein', (36, 43))	('positivity', 'Var', (44, 54))	('FOXL2', 'Gene', (56, 61))
1337	31739799	Meanwhile, UTROSCT is found to contain the t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3) translocations, as well as ESR1-NCOA2/3, GREB1-NCOA1/2 and GREB1-CTNNB1 fusions.	('GREB1', 'Gene', (129, 134))	('GREB1', 'Gene', '9687', (147, 152))	('ESR1', 'Gene', '2099', (115, 119))	('NCOA2/3', 'Gene', (120, 127))	('t(X;6)(p22.3;q23.1)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 62))	('NCOA2/3', 'Gene', '10499;8202', (120, 127))	('NCOA1/2', 'Gene', (135, 142))	('GREB1', 'Gene', '9687', (129, 134))	('CTNNB1', 'Gene', '1499', (153, 159))	('translocations', 'Var', (88, 102))	('GREB1', 'Gene', (147, 152))	('ESR1', 'Gene', (115, 119))	('t(4;18)(q21.1;q21.3)', 'STRUCTURAL_ABNORMALITY', 'None', (67, 87))	('CTNNB1', 'Gene', (153, 159))	('NCOA1/2', 'Gene', '8648;10499', (135, 142))
1339	31739799	The characteristic ESR1 or GREB1 rearrangement in UTROSCT might be more useful for pathological diagnosis.	('ESR1', 'Gene', '2099', (19, 23))	('GREB1', 'Gene', (27, 32))	('UTROSCT', 'Disease', (50, 57))	('ESR1', 'Gene', (19, 23))	('GREB1', 'Gene', '9687', (27, 32))	('rearrangement', 'Var', (33, 46))
1341	31739799	described four uterine sarcomas containing the GREB1 fusion genes.	('GREB1', 'Gene', (47, 52))	('GREB1', 'Gene', '9687', (47, 52))	('sarcomas', 'Disease', 'MESH:D012509', (23, 31))	('fusion genes', 'Var', (53, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcomas', 'Disease', (23, 31))
1349	31739799	Among these genes, PHF1 rearrangement has been found to be predominant in the sex cord variant of LGESS.	('PHF1', 'Gene', '5252', (19, 23))	('predominant', 'Reg', (59, 70))	('sex cord variant', 'Disease', (78, 94))	('rearrangement', 'Var', (24, 37))	('LGESS', 'Disease', (98, 103))	('PHF1', 'Gene', (19, 23))
1371	31739799	Molecularly, sequence analysis showed mutations in the exon 3 of beta-catenin gene in the areas of sex cord-like formations.	('mutations in', 'Var', (38, 50))	('beta-catenin', 'Gene', '1499', (65, 77))	('beta-catenin', 'Gene', (65, 77))
1387	31739799	Molecularly, KRAS, ARID1A, AKT1, CSF1R, GNAQ, NOTCH1, PTCH2, PTEN, ABL1, EPHB4, ATM, RET, CDH1, NF1, MET and ATRX mutations have been found in mesonephric adenocarcinomas.	('EPHB4', 'Gene', (73, 78))	('mesonephric adenocarcinomas', 'Disease', 'MESH:D000230', (143, 170))	('mutations', 'Var', (114, 123))	('ATRX', 'Gene', '546', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('ABL1', 'Gene', '25', (67, 71))	('ATM', 'Gene', '472', (80, 83))	('PTEN', 'Gene', (61, 65))	('ARID1A', 'Gene', (19, 25))	('AKT1', 'Gene', '207', (27, 31))	('NOTCH1', 'Gene', (46, 52))	('PTCH2', 'Gene', '8643', (54, 59))	('CSF1', 'molecular_function', 'GO:0005011', ('33', '37'))	('PTEN', 'Gene', '5728', (61, 65))	('CSF1R', 'Gene', '1436', (33, 38))	('RET', 'Gene', '5979', (85, 88))	('EPHB4', 'Gene', '2050', (73, 78))	('ARID1A', 'Gene', '8289', (19, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('PTCH2', 'Gene', (54, 59))	('ATM', 'Gene', (80, 83))	('NOTCH1', 'Gene', '4851', (46, 52))	('CSF1R', 'Gene', (33, 38))	('NF1', 'Gene', (96, 99))	('AKT1', 'Gene', (27, 31))	('found', 'Reg', (134, 139))	('CDH1', 'Gene', '999', (90, 94))	('GNAQ', 'Gene', '2776', (40, 44))	('MET', 'Gene', (101, 104))	('KRAS', 'Gene', '3845', (13, 17))	('NF1', 'Gene', '4763', (96, 99))	('GNAQ', 'Gene', (40, 44))	('RET', 'Gene', (85, 88))	('mesonephric adenocarcinomas', 'Disease', (143, 170))	('CDH1', 'Gene', (90, 94))	('KRAS', 'Gene', (13, 17))	('ABL1', 'Gene', (67, 71))	('ATRX', 'Gene', (109, 113))
1392	31739799	Genetically, KRAS and PIK3CA mutations have been detected in uterine mesonephric-like adenocarcinomas, while PTEN, TP53, ARID1A, ARID1B, or SMARCA4 alterations were not detected.	('ARID1B', 'Gene', '57492', (129, 135))	('ARID1A', 'Gene', (121, 127))	('PTEN', 'Gene', '5728', (109, 113))	('SMARCA4', 'Gene', '6597', (140, 147))	('ARID1A', 'Gene', '8289', (121, 127))	('TP53', 'Gene', (115, 119))	('detected', 'Reg', (49, 57))	('PIK3CA', 'Gene', '5290', (22, 28))	('mutations', 'Var', (29, 38))	('KRAS', 'Gene', '3845', (13, 17))	('SMARCA4', 'Gene', (140, 147))	('adenocarcinomas', 'Disease', 'MESH:D000230', (86, 101))	('TP53', 'Gene', '7157', (115, 119))	('PTEN', 'Gene', (109, 113))	('adenocarcinomas', 'Disease', (86, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('KRAS', 'Gene', (13, 17))	('ARID1B', 'Gene', (129, 135))	('PIK3CA', 'Gene', (22, 28))
1409	31739799	This research was funded by Science and Technology Development Project of Jilin Province (3D5177723429), Science and Technology of Jilin Province, Jilin Province Key Laboratory (3D517K363429), and The Role and Molecular Mechanism of EMT in the Resistance of ROS1-positive Lung Cancer (20180101014JC), Changchun, Jilin, China.	('Cancer', 'Disease', (277, 283))	('Cancer', 'Disease', 'MESH:D009369', (277, 283))	('Cancer', 'Phenotype', 'HP:0002664', (277, 283))	('EMT', 'biological_process', 'GO:0001837', ('233', '236'))	('ROS1', 'Gene', (258, 262))	('ROS1', 'Gene', '6098', (258, 262))	('20180101014JC', 'Var', (285, 298))	('Lung Cancer', 'Phenotype', 'HP:0100526', (272, 283))
1425	30356358	The level of tumor markers was not elevated: CA125, 17 U/ml; CA19-9, 9 U/ml; CA72-4, 2.9 U/ml; CEA, 1.1 ng/ml; and SCC, 0.9 ng/ml.	('CA72-4', 'Var', (77, 83))	('tumor', 'Disease', (13, 18))	('CA19-9', 'Var', (61, 67))	('CA125', 'Gene', '94025', (45, 50))	('CEA', 'Gene', (95, 98))	('SCC', 'Gene', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('CEA', 'Gene', '1084', (95, 98))	('CA72', 'Chemical', '-', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('SCC', 'Gene', '6317', (115, 118))	('CA125', 'Gene', (45, 50))
1545	29248205	Retained expression is expected in primary ovarian mucinous neoplasia and examples of pancreatobiliary and gastrointestinal carcinomas lacking SMAD4 mutation; in other words, retained expression is not diagnostically useful.	('primary ovarian mucinous neoplasia', 'Disease', 'MESH:D009369', (35, 69))	('SMAD4', 'Gene', '4089', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('mucinous neoplasia', 'Phenotype', 'HP:0031495', (51, 69))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (107, 134))	('pancreatobiliary and gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (86, 134))	('neoplasia', 'Phenotype', 'HP:0002664', (60, 69))	('primary ovarian mucinous neoplasia', 'Disease', (35, 69))	('SMAD4', 'Gene', (143, 148))	('ovarian mucinous neoplasia', 'Phenotype', 'HP:0031494', (43, 69))	('lacking', 'NegReg', (135, 142))	('mutation', 'Var', (149, 157))
1566	29248205	When the metastases exhibit the not uncommon pattern of flat architecture with high-grade cytologic atypia and aberrant P53 immunoexpression, their resemblance to STIC may be pronounced.	('metastases', 'Disease', (9, 19))	('P53', 'Gene', (120, 123))	('metastases', 'Disease', 'MESH:D009362', (9, 19))	('P53', 'Gene', '7157', (120, 123))	('aberrant', 'Var', (111, 119))
1585	29248205	Serous borderline tumors with BRAF mutations retain the expected borderline tumor architecture, but in addition feature polygonal eosinophilic cells that can become detached from the tumor's intracystic papillae (Fig.	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	("tumor's intracystic papillae", 'Disease', 'MESH:D010211', (183, 211))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Serous borderline tumors', 'Disease', (0, 24))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('Serous borderline tumors', 'Disease', 'MESH:D012569', (0, 24))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	("tumor's intracystic papillae", 'Disease', (183, 211))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('mutations', 'Var', (35, 44))
1605	29248205	De-differentiation in this context is an example of epithelial-to-mesenchymal transformation (EMT), which in the endometrium involves expression of EMT markers and epigenetic downregulation of e-cadherin via the miRNA200 series.	('EMT', 'biological_process', 'GO:0001837', ('94', '97'))	('EMT', 'biological_process', 'GO:0001837', ('148', '151'))	('cadherin', 'molecular_function', 'GO:0008014', ('195', '203'))	('e-cadherin', 'Gene', (193, 203))	('epigenetic', 'Var', (164, 174))	('epithelial-to-mesenchymal', 'Disease', (52, 77))	('e-cadherin', 'Gene', '999', (193, 203))
1613	29248205	With only occasional exceptions, de-differentiated endometrial carcinomas and the related undifferentiated endometrial carcinomas have a very poor prognosis that compares unfavorably with outcomes of patients with grade 3 endometrioid carcinoma.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('endometrioid carcinoma', 'Disease', (222, 244))	('patients', 'Species', '9606', (200, 208))	('de-differentiated', 'Var', (33, 50))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (107, 129))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (51, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (107, 129))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (51, 72))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (51, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (107, 128))	('endometrial carcinomas', 'Disease', (107, 129))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (222, 244))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (222, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('endometrial carcinomas', 'Disease', (51, 73))
1614	29248205	As these tumors may feature rhabdoid cells and have very frequent mutations in the SWI-SNF gene family, patients may theoretically benefit from certain forms of targeted therapy.	('mutations', 'Var', (66, 75))	('SWI-SNF', 'Gene', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('patients', 'Species', '9606', (104, 112))
1615	29248205	Furthermore, since approximately one-half of these tumors are mismatch repair-deficient or harbor hotspot mutations in the exonuclease domain of polymerase E, it is possible that they may be targeted effectively with immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (106, 115))	('mismatch repair', 'biological_process', 'GO:0006298', ('62', '77'))	('mismatch repair-deficient', 'Var', (62, 87))
1619	29248205	Interestingly, these tumors were highly likely to be mismatch repair deficient, both in the primary and metastatic sites.	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mismatch repair', 'Var', (53, 68))	('mismatch repair', 'biological_process', 'GO:0006298', ('53', '68'))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
1622	29248205	Encouragingly, there is evidence that microsatellite unstable endometrial carcinomas are associated with more favorable clinical outcomes than microsatellite stable carcinomas, particularly when adjuvant therapy is administered.	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (62, 84))	('carcinomas', 'Disease', 'MESH:D002277', (165, 175))	('carcinomas', 'Disease', (165, 175))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (62, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (62, 83))	('endometrial carcinomas', 'Disease', (62, 84))	('carcinomas', 'Disease', (74, 84))	('carcinomas', 'Disease', 'MESH:D002277', (74, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('microsatellite unstable', 'Var', (38, 61))
1643	29248205	Discussing a study reporting frequent CTNNB1 (beta-catenin) mutations in synchronous endometrial and ovarian carcinomas, Matias-Guiu noted that one case in the series had a shared CTNNB1 mutation, unlike the other cases that featured different CTNNB1 mutations in each site.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (101, 118))	('CTNNB1', 'Gene', '1499', (180, 186))	('CTNNB1', 'Gene', '1499', (244, 250))	('mutations', 'Var', (60, 69))	('CTNNB1', 'Gene', (38, 44))	('beta-catenin', 'Gene', (46, 58))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (101, 119))	('beta-catenin', 'Gene', '1499', (46, 58))	('CTNNB1', 'Gene', (244, 250))	('CTNNB1', 'Gene', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('synchronous endometrial and ovarian carcinomas', 'Disease', 'MESH:D009378', (73, 119))	('mutation', 'Var', (187, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('CTNNB1', 'Gene', '1499', (38, 44))
1644	29248205	To account for this, he hypothesized that a focus of non-neoplastic endometrium acquired a CTNNB1 mutation and, via trans-tubal spread, implanted into or onto the ovary in the form of endometriosis, which then acquired further mutations leading to the development of a CTNNB1-mutated endometrioid carcinoma in the ovary.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (284, 306))	('endometriosis', 'Phenotype', 'HP:0030127', (184, 197))	('CTNNB1', 'Gene', '1499', (269, 275))	('CTNNB1', 'Gene', (91, 97))	('mutation', 'Var', (98, 106))	('endometrioid carcinoma in the ovary', 'Disease', (284, 319))	('endometrioid carcinoma in the ovary', 'Disease', 'MESH:D016889', (284, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('CTNNB1', 'Gene', '1499', (91, 97))	('CTNNB1', 'Gene', (269, 275))	('endometriosis', 'Disease', 'MESH:D004715', (184, 197))	('endometriosis', 'Disease', (184, 197))	('leading to', 'Reg', (237, 247))	('mutations', 'Var', (227, 236))
1645	29248205	The focus that remained in the endometrium evolved into an endometrioid adenocarcinoma with the same CTNNB1 mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('CTNNB1', 'Gene', '1499', (101, 107))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (59, 86))	('endometrioid adenocarcinoma', 'Disease', (59, 86))	('mutation', 'Var', (108, 116))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (59, 86))	('CTNNB1', 'Gene', (101, 107))
1648	29248205	The authors showed that in every DNA mismatch repair-proficient endometrioid carcinoma studied, the endometrial and ovarian tumor in a given patient harbored a shared set of mutations that established the tumors as being clonally related.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (64, 86))	('endometrioid carcinoma', 'Disease', (64, 86))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('ovarian tumor', 'Disease', (116, 129))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('patient', 'Species', '9606', (141, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('ovarian tumor', 'Phenotype', 'HP:0100615', (116, 129))	('ovarian tumor', 'Disease', 'MESH:D010051', (116, 129))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mismatch repair', 'biological_process', 'GO:0006298', ('37', '52'))	('mutations', 'Var', (174, 183))	('tumors', 'Disease', (205, 211))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (64, 86))
1649	29248205	The tumors in each site subsequently acquired a further set of private mutations, supporting the idea that after tumor establishment at each respective site, the carcinomas underwent neoplastic progression independent of the other site.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (113, 118))	('neoplastic progression', 'CPA', (183, 205))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('carcinomas', 'Disease', (162, 172))	('carcinomas', 'Disease', 'MESH:D002277', (162, 172))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
1673	26673416	Recent studies on gene signature in EC cells have reported numerous genetic disorders that initiate carcinogenesis: for instance, PTEN, which regulates normal cell function, is highly mutated in type I EC, whereas p53, which prevents genome mutation, is altered by up to 80-90 % in type II EC.	('EC', 'Phenotype', 'HP:0012114', (290, 292))	('EC', 'Phenotype', 'HP:0012114', (202, 204))	('type I EC', 'Disease', (195, 204))	('numerous genetic disorders', 'Disease', (59, 85))	('mutated', 'Var', (184, 191))	('p53', 'Gene', (214, 217))	('numerous genetic disorders', 'Disease', 'MESH:D030342', (59, 85))	('PTEN', 'Gene', (130, 134))	('p53', 'Gene', '7157', (214, 217))	('EC', 'Phenotype', 'HP:0012114', (36, 38))	('PTEN', 'Gene', '5728', (130, 134))	('initiate carcinogenesis', 'Disease', (91, 114))	('initiate carcinogenesis', 'Disease', 'MESH:D063646', (91, 114))
1744	26673416	To investigate the significance of EGFR and HER-2 in the proliferation of endometrial cancer cells, all cells were transfected with siRNA to knock down EGFR or HER-2.	('endometrial cancer', 'Disease', 'MESH:D016889', (74, 92))	('knock down', 'Var', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('HER-2', 'Gene', (160, 165))	('EGFR', 'Gene', (152, 156))	('endometrial cancer', 'Disease', (74, 92))	('endometrial cancer', 'Phenotype', 'HP:0012114', (74, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))
1811	33260288	For example, TP53 mutations and CCNE1 locus amplification are common in serous carcinoma, but rare in endometrioid carcinoma.	('serous carcinoma', 'Disease', (72, 88))	('TP53', 'Gene', (13, 17))	('endometrioid carcinoma', 'Disease', (102, 124))	('CCNE1', 'Gene', (32, 37))	('CCNE1', 'Gene', '898', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('serous carcinoma', 'Disease', 'MESH:D018297', (72, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (102, 124))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (102, 124))	('TP53', 'Gene', '7157', (13, 17))	('common', 'Reg', (62, 68))	('mutations', 'Var', (18, 27))
1812	33260288	In contrast, most endometrioid carcinomas harbor ARID1A mutations, whereas serous carcinomas do not.	('serous carcinomas', 'Disease', (75, 92))	('mutations', 'Var', (56, 65))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (18, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('serous carcinomas', 'Disease', 'MESH:D018297', (75, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('endometrioid carcinomas', 'Disease', (18, 41))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (18, 41))	('ARID1A', 'Gene', '8289', (49, 55))	('ARID1A', 'Gene', (49, 55))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (18, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
1860	33260288	IHC staining showed positivity in GATA3 and TTF-1, negativity in CD10 and ER, and focal positivity in PR.	('GATA3', 'Gene', '2625', (34, 39))	('CD10', 'Gene', '4311', (65, 69))	('PR', 'Gene', '5241', (102, 104))	('positivity', 'Var', (20, 30))	('CD10', 'molecular_function', 'GO:0004245', ('65', '69'))	('TTF-1', 'Gene', '7270', (44, 49))	('GATA3', 'Gene', (34, 39))	('TTF-1', 'Gene', (44, 49))	('ER', 'Gene', '2099', (74, 76))	('CD10', 'Gene', (65, 69))
1866	33260288	The spindle cell component exhibited strong vimentin positivity and aberrant p53 expression, while CK expression was focal and weak.	('vimentin', 'cellular_component', 'GO:0045099', ('44', '52'))	('CK', 'Gene', '51727', (99, 101))	('spindle', 'cellular_component', 'GO:0005819', ('4', '11'))	('vimentin', 'Gene', '7431', (44, 52))	('p53', 'Gene', '7157', (77, 80))	('p53', 'Gene', (77, 80))	('vimentin', 'Gene', (44, 52))	('vimentin', 'cellular_component', 'GO:0045098', ('44', '52'))	('aberrant', 'Var', (68, 76))	('expression', 'MPA', (81, 91))
1888	33260288	NGS revealed mutations in TP53, PIK3CA, and NF1, and copy number variations (CNVs) in MYCL, FGFR3, CDK2, CDK4, ERBB2, and CCNE1.	('copy number variations', 'Var', (53, 75))	('CDK2', 'Gene', '1017', (99, 103))	('TP53', 'Gene', '7157', (26, 30))	('ERBB2', 'Gene', (111, 116))	('CDK2', 'Gene', (99, 103))	('PIK3CA', 'Gene', '5290', (32, 38))	('FGFR3', 'Gene', (92, 97))	('CDK4', 'Gene', (105, 109))	('NF1', 'Gene', '4763', (44, 47))	('CDK', 'molecular_function', 'GO:0004693', ('105', '108'))	('FGFR3', 'Gene', '2261', (92, 97))	('ERBB2', 'Gene', '2064', (111, 116))	('NF1', 'Gene', (44, 47))	('CCNE1', 'Gene', (122, 127))	('CDK4', 'Gene', '1019', (105, 109))	('MYCL', 'Gene', (86, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('mutations', 'Var', (13, 22))	('MYCL', 'Gene', '4610', (86, 90))	('TP53', 'Gene', (26, 30))	('PIK3CA', 'Gene', (32, 38))	('CCNE1', 'Gene', '898', (122, 127))	('CDK', 'molecular_function', 'GO:0004693', ('99', '102'))
1896	33260288	NGS analysis revealed mutations in TP53 and polymerase E (POLE) and CNVs involving ALK, ERBB2, CCNE1, AKT2, and AXL.	('ERBB2', 'Gene', (88, 93))	('ALK', 'Gene', '238', (83, 86))	('ERBB2', 'Gene', '2064', (88, 93))	('CCNE1', 'Gene', '898', (95, 100))	('CCNE1', 'Gene', (95, 100))	('polymerase E', 'Enzyme', (44, 56))	('AXL', 'Gene', '558', (112, 115))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('AKT2', 'Gene', (102, 106))	('AXL', 'Gene', (112, 115))	('mutations', 'Var', (22, 31))	('ALK', 'Gene', (83, 86))	('AKT2', 'Gene', '208', (102, 106))
1898	33260288	Since a significant number of CNVs were detected, the case was assigned to the copy-number high group, and a final diagnosis of serous carcinoma was made.	('CNVs', 'Var', (30, 34))	('serous carcinoma', 'Disease', (128, 144))	('serous carcinoma', 'Disease', 'MESH:D018297', (128, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))
1911	33260288	In a comprehensive genomic analysis of endometrioid and serous carcinoma based on the The Cancer Genome Atlas database, endometrioid and serous carcinomas were divided into four molecular subgroups, including POLE ultramutated, microsatellite instability-hypermutated, copy-number low, and copy-number high; serous carcinoma belongs only to the copy-number high group.	('copy-number low', 'Var', (269, 284))	('microsatellite instability-hypermutated', 'Var', (228, 267))	('serous carcinoma', 'Disease', (56, 72))	('serous carcinomas', 'Disease', (137, 154))	('serous carcinoma', 'Disease', 'MESH:D018297', (56, 72))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('serous carcinoma', 'Disease', 'MESH:D018297', (308, 324))	('serous carcinoma', 'Disease', (308, 324))	('copy-number high', 'Var', (290, 306))	('serous carcinoma', 'Disease', 'MESH:D018297', (137, 153))	('serous carcinomas', 'Disease', 'MESH:D018297', (137, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('Cancer', 'Disease', (90, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('Cancer', 'Disease', 'MESH:D009369', (90, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
1918	33260288	Tumors lacking aberrant p53 expression are unlikely to be serous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('serous carcinoma', 'Disease', (58, 74))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('expression', 'MPA', (28, 38))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('aberrant', 'Var', (15, 23))	('serous carcinoma', 'Disease', 'MESH:D018297', (58, 74))
1942	30550483	Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas.	('aberrant', 'Var', (119, 127))	('clear cell carcinomas', 'Disease', (145, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Napsin A', 'Gene', (39, 47))	('Napsin A', 'Gene', '9476', (39, 47))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (145, 166))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('expression', 'MPA', (105, 115))
1963	30550483	Nearly every case harbors a TP53 mutation, which is associated with aberrant immunohistochemical expression of p53.	('TP53', 'Gene', '7157', (28, 32))	('mutation', 'Var', (33, 41))	('TP53', 'Gene', (28, 32))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))
1986	30550483	ARID1A is a tumor suppressor gene mutated in ~50% of ovarian endometrioid and clear cell carcinomas, as well as a significant percentage of the corresponding uterine tumors, resulting in loss of immunoexpression of its protein product, BAF250a.	('loss', 'NegReg', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('BAF250a', 'Gene', (236, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('tumor', 'Disease', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('immunoexpression', 'MPA', (195, 211))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('12', '28'))	('tumors', 'Disease', (166, 172))	('ovarian endometrioid', 'Disease', (53, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('12', '28'))	('tumor', 'Disease', (166, 171))	('clear cell carcinomas', 'Disease', (78, 99))	('ovarian endometrioid', 'Disease', 'MESH:D016889', (53, 73))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('ARID1A', 'Gene', (0, 6))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (78, 99))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('BAF250a', 'Gene', '8289', (236, 243))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('uterine tumors', 'Phenotype', 'HP:0010784', (158, 172))	('mutated', 'Var', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('ARID1A', 'Gene', '8289', (0, 6))
1988	30550483	Aberrant p53 expression was found in 18% of grade 3 endometrioid carcinoma compared with 78% of serous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('Aberrant', 'Var', (0, 8))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('expression', 'MPA', (13, 23))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (52, 74))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (52, 74))	('p53', 'Gene', (9, 12))	('serous carcinomas', 'Disease', 'MESH:D018284', (96, 113))	('p53', 'Gene', '7157', (9, 12))	('serous carcinomas', 'Disease', (96, 113))	('found', 'Reg', (28, 33))	('endometrioid carcinoma', 'Disease', (52, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
2011	30550483	Insufficient evidence is available to support the use of vimentin, Ki-67, HNF1B, WT1 and IMP2, and monoclonal carcinoembryonic antigen may be safely omitted from the antibody panel.	('IMP', 'cellular_component', 'GO:0042720', ('89', '92'))	('antibody', 'cellular_component', 'GO:0019815', ('166', '174'))	('WT1', 'Gene', (81, 84))	('IMP', 'molecular_function', 'GO:0004244', ('89', '92'))	('IMP2', 'Gene', (89, 93))	('vimentin', 'Gene', '7431', (57, 65))	('vimentin', 'Gene', (57, 65))	('WT1', 'Gene', '7490', (81, 84))	('antibody', 'cellular_component', 'GO:0019814', ('166', '174'))	('vimentin', 'cellular_component', 'GO:0045098', ('57', '65'))	('monoclonal carcinoembryonic', 'Disease', 'MESH:D010265', (99, 126))	('monoclonal carcinoembryonic', 'Disease', (99, 126))	('IMP2', 'Gene', '10644', (89, 93))	('HNF1B', 'Gene', '6928', (74, 79))	('antibody', 'molecular_function', 'GO:0003823', ('166', '174'))	('HNF1B', 'Gene', (74, 79))	('antibody', 'cellular_component', 'GO:0042571', ('166', '174'))	('Ki-67', 'Var', (67, 72))	('vimentin', 'cellular_component', 'GO:0045099', ('57', '65'))
2042	30550483	Aberrant mutation-type p53 immunohistochemical expression is seen in up to one third of otherwise typical clear cell carcinomas (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('clear cell carcinomas', 'Disease', (106, 127))	('Aberrant mutation-type', 'Var', (0, 22))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (106, 127))
2044	30550483	Nevertheless, p53 immunohistochemistry can still provide useful information, as wild-type p53 staining minimizes the probability that the tumor is a true serous carcinoma, and mutation-type p53 expression is an adverse prognostic factor in histotypically ambiguous tumors.	('p53', 'Gene', (90, 93))	('tumor', 'Disease', (138, 143))	('serous carcinoma', 'Disease', (154, 170))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('minimizes', 'NegReg', (103, 112))	('tumor', 'Disease', (265, 270))	('p53', 'Gene', '7157', (190, 193))	('ambiguous tumors', 'Disease', (255, 271))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('serous carcinoma', 'Disease', 'MESH:D018284', (154, 170))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('mutation-type', 'Var', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (90, 93))	('ambiguous tumors', 'Disease', 'MESH:D012734', (255, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
2046	30550483	At the molecular level, ~14% of morphologically and immunophenotypically characteristic clear cell carcinomas display a profile of mutations (mutations in TP53 and PPP2R1A; wild-type PTEN, CTNNB1, and ARID1A) typically seen in serous carcinoma.	('mutations', 'Var', (142, 151))	('CTNNB1', 'Gene', '1499', (189, 195))	('PTEN', 'Gene', (183, 187))	('TP53', 'Gene', '7157', (155, 159))	('PTEN', 'Gene', '5728', (183, 187))	('serous carcinoma', 'Disease', 'MESH:D018284', (227, 243))	('clear cell carcinomas', 'Disease', (88, 109))	('PPP2R1A', 'Gene', '5518', (164, 171))	('TP53', 'Gene', (155, 159))	('CTNNB1', 'Gene', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('ARID1A', 'Gene', '8289', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('ARID1A', 'Gene', (201, 207))	('PPP2R1A', 'Gene', (164, 171))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (88, 109))	('serous carcinoma', 'Disease', (227, 243))
2050	30550483	Similarly, the diagnostic value of AMACR (alpha-methylacyl-coenzyme-A racemase or p504s), which has been reported to be frequently positive in clear cell carcinoma, requires further study.	('AMACR', 'Gene', '23600', (35, 40))	('AMACR', 'Gene', (35, 40))	('clear cell carcinoma', 'Disease', (143, 163))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (143, 163))	('p504s', 'Var', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
2089	30550483	The frequency of aberrant mutation-type p53 staining in these cases (36%) is comparable with that reported in conventional clear cell carcinoma (33%-38%), and substantially less than that expected in serous carcinoma.	('clear cell carcinoma', 'Disease', 'MESH:C538614', (123, 143))	('clear cell carcinoma', 'Disease', (123, 143))	('serous carcinoma', 'Disease', (200, 216))	('serous carcinoma', 'Disease', 'MESH:D018284', (200, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('p53', 'Gene', (40, 43))	('aberrant mutation-type', 'Var', (17, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('p53', 'Gene', '7157', (40, 43))
2122	30550483	Rare cases with germline DNA MMR gene mutations diagnostic of Lynch syndrome have been reported.	('Lynch syndrome', 'Disease', (62, 76))	('Lynch syndrome', 'Disease', 'MESH:D003123', (62, 76))	('MMR', 'biological_process', 'GO:0006298', ('29', '32'))	('mutations', 'Var', (38, 47))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))
2123	30550483	Possible mechanisms underlying the transition from differentiated to undifferentiated carcinoma include the acquisition of mutations in SMARCA4, ARID1B, CTNNB1, PPP2R1A or TP53 .	('PPP2R1A', 'Gene', (161, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('PPP2R1A', 'Gene', '5518', (161, 168))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('undifferentiated carcinoma', 'Disease', (69, 95))	('ARID1B', 'Gene', (145, 151))	('CTNNB1', 'Gene', (153, 159))	('CTNNB1', 'Gene', '1499', (153, 159))	('SMARCA4', 'Gene', '6597', (136, 143))	('ARID1B', 'Gene', '57492', (145, 151))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (69, 95))	('SMARCA4', 'Gene', (136, 143))	('mutations', 'Var', (123, 132))	('differentiated', 'Disease', (51, 65))
2144	30550483	Loss of BRG1 and/or INI1 expression has been reported in undifferentiated carcinoma and the undifferentiated component of dedifferentiated carcinomas; loss of another subunit of the SWI/SNF complex, BAF250a (the protein product of ARID1A) is common in both low-grade and high-grade endometrial carcinomas.	('BAF250a', 'Gene', (199, 206))	('undifferentiated carcinoma and the undifferentiated component of dedifferentiated carcinomas', 'Disease', 'MESH:D002277', (57, 149))	('INI1', 'Gene', (20, 24))	('INI1', 'Gene', '6598', (20, 24))	('endometrial carcinomas', 'Disease', (282, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (282, 303))	('carcinomas', 'Phenotype', 'HP:0030731', (294, 304))	('ARID1A', 'Gene', (231, 237))	('BAF250a', 'Gene', '8289', (199, 206))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (282, 304))	('BRG1', 'Gene', '6597', (8, 12))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('182', '197'))	('ARID1A', 'Gene', '8289', (231, 237))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (282, 304))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('BRG1', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('low-grade', 'Disease', (257, 266))	('loss', 'Var', (151, 155))
2172	30550483	A recent large-scale molecular genetic analysis of uterine carcinosarcomas by the Cancer Genome Atlas revealed extensive copy-number alterations and highly recurrent somatic mutations, most frequently in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS.	('carcinosarcomas', 'Disease', (59, 74))	('PPP2R1A', 'Gene', '5518', (224, 231))	('PIK3CA', 'Gene', '5290', (216, 222))	('TP53', 'Gene', (204, 208))	('PTEN', 'Gene', (210, 214))	('PPP2R1A', 'Gene', (224, 231))	('FBXW7', 'Gene', '55294', (233, 238))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PTEN', 'Gene', '5728', (210, 214))	('PIK3CA', 'Gene', (216, 222))	('Cancer', 'Disease', (82, 88))	('TP53', 'Gene', '7157', (204, 208))	('carcinosarcomas', 'Disease', 'MESH:D002296', (59, 74))	('KRAS', 'Gene', '3845', (244, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('copy-number alterations', 'Var', (121, 144))	('FBXW7', 'Gene', (233, 238))	('KRAS', 'Gene', (244, 248))
2189	29383036	Development of a personalized therapeutic strategy for ERBB-gene-mutated cancers The application of genomic technologies to patient tumor samples identified groups of signaling pathways which acquire activating mutations.	('signaling pathways', 'Pathway', (167, 185))	('cancers', 'Disease', (73, 80))	('signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ERBB', 'Gene', '1956', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutations', 'Var', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumor', 'Disease', (132, 137))	('patient', 'Species', '9606', (124, 131))	('activating', 'PosReg', (200, 210))	('ERBB', 'Gene', (55, 59))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
2190	29383036	Some cancers are dependent on these mutations and the aberrant proteins resulting from these mutations can be targeted by novel drugs which can eradicate the cancer.	('proteins', 'Protein', (63, 71))	('mutations', 'Var', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('aberrant proteins', 'Protein', (54, 71))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancer', 'Disease', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('mutations', 'Var', (36, 45))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('S', 'Chemical', 'MESH:D013455', (0, 1))
2191	29383036	We used www.cbioportal.org to determine the frequency of ERBB mutations in solid tumors.	('ERBB', 'Gene', (57, 61))	('solid tumors', 'Disease', 'MESH:D009369', (75, 87))	('ERBB', 'Gene', '1956', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (62, 71))	('solid tumors', 'Disease', (75, 87))
2195	29383036	In cancers not commonly associated with HER family protein overexpression, such as ovarian, endometrial, melanoma and head and neck cancers (n = 2116), we found that ERBB family mutations are enriched, occurring at rates from 14% to 34% and commonly co-occur with PIK3CA mutations.	('co-occur', 'Reg', (250, 258))	('mutations', 'Var', (178, 187))	('mutations', 'Var', (271, 280))	('PIK3CA', 'Gene', '5290', (264, 270))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('ovarian', 'Disease', (83, 90))	('ovarian', 'Disease', 'MESH:D010051', (83, 90))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('neck', 'cellular_component', 'GO:0044326', ('127', '131'))	('PIK3CA', 'Gene', (264, 270))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('ERBB', 'Gene', (166, 170))	('head and neck cancers', 'Phenotype', 'HP:0012288', (118, 139))	('cancers', 'Disease', (132, 139))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('ERBB', 'Gene', '1956', (166, 170))	('head and neck cancer', 'Phenotype', 'HP:0012288', (118, 138))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Disease', (3, 10))	('head and neck cancers', 'Disease', 'MESH:D006258', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
2196	29383036	Importantly, we demonstrate that ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors.	('P', 'Chemical', 'MESH:D010758', (92, 93))	('mutant', 'Var', (45, 51))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ERBB', 'Gene', (33, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('ERBB', 'Gene', '1956', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
2198	29383036	We demonstrate that ERBB family mutations are common in cancers not associated with overexpression or amplification of HER family proteins.	('cancers', 'Disease', (56, 63))	('ERBB', 'Gene', '1956', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('common', 'Reg', (46, 52))	('mutations', 'Var', (32, 41))	('ERBB', 'Gene', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
2199	29383036	These ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors, and when combined with pan-HER inhibitors have synergistic antiproliferative effects.	('ERBB', 'Gene', '1956', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('mutant', 'Var', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('ERBB', 'Gene', (6, 10))	('P', 'Chemical', 'MESH:D010758', (65, 66))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('antiproliferative effects', 'CPA', (141, 166))
2201	29383036	In some cases, cancers are dependent on these mutations and the resulting aberrant proteins can be targeted by novel drugs.	('targeted', 'Reg', (99, 107))	('proteins', 'Protein', (83, 91))	('mutations', 'Var', (46, 55))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('aberrant', 'Var', (74, 82))
2203	29383036	Some tumors thus contain mutations within oncogenes or tumor suppressor genes that predict responses to targeted anticancer therapies.	('tumors', 'Disease', (5, 11))	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('predict', 'Reg', (83, 90))	('cancer', 'Disease', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (55, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', (5, 10))	('oncogenes', 'Gene', (42, 51))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('S', 'Chemical', 'MESH:D013455', (0, 1))
2204	29383036	Examples include epidermal growth factor receptor (EGFR) mutations which are found in up to 15% of non-small cell lung cancers and are targetable by EGFR inhibitors (erlotinib and gefitinib).	('EGFR', 'Gene', (51, 55))	('mutations', 'Var', (57, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('lung cancers', 'Phenotype', 'HP:0100526', (114, 126))	('cell lung cancers', 'Disease', 'MESH:D008175', (109, 126))	('cell lung cancers', 'Disease', (109, 126))	('gefitinib', 'Chemical', 'MESH:D000077156', (180, 189))	('EGFR', 'Gene', '1956', (149, 153))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (99, 126))	('EGFR', 'Gene', '1956', (51, 55))	('erlotinib', 'Chemical', 'MESH:D000069347', (166, 175))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('17', '40'))	('epidermal growth factor receptor', 'Gene', (17, 49))	('epidermal growth factor receptor', 'Gene', '1956', (17, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('EGFR', 'Gene', (149, 153))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (103, 126))
2207	29383036	Dimerization results in activation of signal transduction pathways such as the PI3K/AKT and MAPK/ERK pathways, which are associated with oncogenesis and cancer therapy resistance.	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('ERK', 'Gene', '5594', (97, 100))	('AKT', 'Gene', (84, 87))	('ERK', 'molecular_function', 'GO:0004707', ('97', '100'))	('activation', 'PosReg', (24, 34))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('MAPK', 'molecular_function', 'GO:0004707', ('92', '96'))	('ERK', 'Gene', (97, 100))	('Dimerization', 'Var', (0, 12))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('activation of signal transduction', 'biological_process', 'GO:0009967', ('24', '57'))	('oncogenesis', 'Disease', 'MESH:D063646', (137, 148))	('oncogenesis', 'biological_process', 'GO:0007048', ('137', '148'))	('AKT', 'Gene', '207', (84, 87))	('signal transduction pathways', 'Pathway', (38, 66))	('oncogenesis', 'Disease', (137, 148))	('P', 'Chemical', 'MESH:D010758', (94, 95))
2208	29383036	Recent studies found that somatic ERBB2, ERBB3 and ERBB4 mutations occur in breast, colorectal and gastric cancers, with ERBB3 mutations being associated with an aggressive phenotype.	('associated', 'Reg', (143, 153))	('gastric cancers', 'Phenotype', 'HP:0012126', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast', 'Disease', (76, 82))	('ERBB3', 'Gene', '2065', (121, 126))	('ERBB2', 'Gene', (34, 39))	('ERBB3', 'Gene', (41, 46))	('ERBB2', 'Gene', '2064', (34, 39))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (84, 114))	('ERBB4', 'Gene', '2066', (51, 56))	('mutations', 'Var', (57, 66))	('ERBB3', 'Gene', (121, 126))	('ERBB3', 'Gene', '2065', (41, 46))	('occur', 'Reg', (67, 72))	('mutations', 'Var', (127, 136))	('ERBB4', 'Gene', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
2209	29383036	Modeling experiments of ERBB4 mutations have shown their ability to alter the signaling properties of the HER family members.	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('ERBB4', 'Gene', '2066', (24, 29))	('alter', 'Reg', (68, 73))	('ERBB4', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('signaling properties of', 'MPA', (78, 101))
2210	29383036	Our study identifies that ERBB family mutations which are commonly enriched in cancers which are not HER2 amplified are targetable with PI3K inhibitors.	('cancers', 'Disease', (79, 86))	('HER2', 'Gene', (101, 105))	('P', 'Chemical', 'MESH:D010758', (136, 137))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('HER2', 'Gene', '2064', (101, 105))	('ERBB', 'Gene', (26, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('136', '140'))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('mutations', 'Var', (38, 47))	('ERBB', 'Gene', '1956', (26, 30))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
2211	29383036	We also demonstrate that cancers which have both an ERBB family and PIK3CA mutation are most sensitive to the combination of the pan-HER kinase inhibitor afatinib and the PI3K inhibitor copanlisib, identifying a new therapeutic strategy for treating patients who harbor ERBB family mutations.	('ERBB', 'Gene', (270, 274))	('P', 'Chemical', 'MESH:D010758', (171, 172))	('afatinib', 'Chemical', 'MESH:D000077716', (154, 162))	('ERBB', 'Gene', '1956', (52, 56))	('PIK3CA', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('copanlisib', 'Chemical', 'MESH:C000589253', (186, 196))	('mutation', 'Var', (75, 83))	('patients', 'Species', '9606', (250, 258))	('PIK3CA', 'Gene', '5290', (68, 74))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('137', '153'))	('ERBB', 'Gene', '1956', (270, 274))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('171', '175'))	('ERBB', 'Gene', (52, 56))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
2212	29383036	Individual ERBB family (EGFR, ERBB2, ERBB3 and ERBB4) somatic mutations were detected in 12% of cancers identified from www.cbioportal.org.	('EGFR', 'Gene', '1956', (24, 28))	('ERBB', 'Gene', (37, 41))	('ERBB', 'Gene', (30, 34))	('ERBB', 'Gene', '1956', (37, 41))	('detected', 'Reg', (77, 85))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('ERBB3', 'Gene', '2065', (37, 42))	('ERBB4', 'Gene', '2066', (47, 52))	('cancers', 'Disease', (96, 103))	('ERBB', 'Gene', '1956', (30, 34))	('ERBB4', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ERBB', 'Gene', (11, 15))	('mutations', 'Var', (62, 71))	('ERBB', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (24, 28))	('ERBB2', 'Gene', (30, 35))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('ERBB3', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (30, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('ERBB', 'Gene', (47, 51))	('ERBB', 'Gene', '1956', (47, 51))
2213	29383036	Our analysis included 14,539 cases of cancer from 81 different datasets (Table 1), and found PIK3CA mutations occur in 13% of patient tumors, 14% have an ERBB family gene mutation, while 2% have a co-occurring PIK3CA and ERBB family gene mutation [Figure 1(a)].	('mutations', 'Var', (100, 109))	('tumors', 'Disease', (134, 140))	('PIK3CA', 'Gene', '5290', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('mutation', 'Var', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patient', 'Species', '9606', (126, 133))	('ERBB', 'Gene', (154, 158))	('ERBB', 'Gene', '1956', (221, 225))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('PIK3CA', 'Gene', (210, 216))	('PIK3CA', 'Gene', '5290', (210, 216))	('cancer', 'Disease', (38, 44))	('PIK3CA', 'Gene', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ERBB', 'Gene', '1956', (154, 158))	('ERBB', 'Gene', (221, 225))
2214	29383036	Mutations in the PIK3CA gene are some of the most commonly occurring targetable mutations detected in solid tumors.	('solid tumors', 'Disease', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('Mutations', 'Var', (0, 9))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
2216	29383036	In these studies we found somatic ERBB family mutations in 29% of cases (both alone and co-occurring with PIK3CA mutations), whilst PIK3CA mutations alone occur in 15% of cancers [Figure 1(b)].	('ERBB', 'Gene', '1956', (34, 38))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', (106, 112))	('PIK3CA', 'Gene', '5290', (106, 112))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('mutations', 'Var', (113, 122))	('cancers', 'Disease', (171, 178))	('ERBB', 'Gene', (34, 38))	('PIK3CA', 'Gene', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('PIK3CA', 'Gene', '5290', (132, 138))
2217	29383036	We also found that ERBB family mutations and PIK3CA mutations co-occur in 6% of these cancers.	('mutations', 'Var', (52, 61))	('mutations', 'Var', (31, 40))	('ERBB', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('PIK3CA', 'Gene', (45, 51))	('ERBB', 'Gene', '1956', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('PIK3CA', 'Gene', '5290', (45, 51))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
2218	29383036	Our findings demonstrate that even in cancer subtypes not commonly associated with HER family protein overexpression such as ovarian, endometrial, melanoma and head and neck cancer that ERBB family mutations are enriched and can co-occur with PIK3CA mutations.	('ovarian', 'Disease', (125, 132))	('ovarian', 'Disease', 'MESH:D010051', (125, 132))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('neck', 'cellular_component', 'GO:0044326', ('169', '173'))	('ERBB', 'Gene', (186, 190))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('PIK3CA', 'Gene', (243, 249))	('ERBB', 'Gene', '1956', (186, 190))	('cancer', 'Disease', (174, 180))	('mutations', 'Var', (198, 207))	('endometrial', 'Disease', (134, 145))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('neck cancer', 'Disease', 'MESH:D006258', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('neck cancer', 'Disease', (169, 180))	('head and neck cancer', 'Phenotype', 'HP:0012288', (160, 180))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('PIK3CA', 'Gene', '5290', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
2219	29383036	We selected datasets for further analysis which were enriched for ERBB family mutations (>12% ERBB family mutated, comparable to 13% of PIK3CA mutation rate) and included the largest numbers of patients (Table 2).	('PIK3CA', 'Gene', (136, 142))	('patients', 'Species', '9606', (194, 202))	('ERBB', 'Gene', '1956', (66, 70))	('ERBB', 'Gene', '1956', (94, 98))	('PIK3CA', 'Gene', '5290', (136, 142))	('mutations', 'Var', (78, 87))	('ERBB', 'Gene', (66, 70))	('ERBB', 'Gene', (94, 98))
2220	29383036	We found that somatic ERBB family mutations occur between a rate of 14.7% in head and neck squamous cell carcinoma and 27.7% in skin cutaneous melanoma.	('neck squamous cell carcinoma', 'Disease', (86, 114))	('ERBB', 'Gene', (22, 26))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (128, 151))	('neck', 'cellular_component', 'GO:0044326', ('86', '90'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (86, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (77, 114))	('ERBB', 'Gene', '1956', (22, 26))	('skin cutaneous melanoma', 'Disease', (128, 151))	('mutations', 'Var', (34, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))
2221	29383036	Analysis of ERBB family mutations reveals that over 20% of bladder urothelial carcinoma (n = 33/130), colorectal adenocarcinoma (n = 130/619), esophageal carcinoma (n = 38/185), pan-lung cancer (n = 271/1144), stomach adenocarcinoma (n = 98/289) and skin cutaneous melanomas (n = 101/366) have an ERBB family mutation which does not co-occur with a PI3KCA mutation.	('esophageal carcinoma', 'Disease', (143, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (255, 273))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (255, 274))	('skin cutaneous melanomas', 'Disease', 'MESH:C562393', (250, 274))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (210, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('ERBB', 'Gene', (12, 16))	('colorectal adenocarcinoma', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ERBB', 'Gene', (297, 301))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (143, 163))	('ERBB', 'Gene', '1956', (12, 16))	('ERBB', 'Gene', '1956', (297, 301))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (102, 127))	('pan-lung cancer', 'Disease', 'MESH:D008175', (178, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('mutation', 'Var', (309, 317))	('pan-lung cancer', 'Disease', (178, 193))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('stomach adenocarcinoma', 'Disease', (210, 232))	('skin cutaneous melanomas', 'Disease', (250, 274))	('melanomas', 'Phenotype', 'HP:0002861', (265, 274))	('bladder urothelial carcinoma', 'Disease', (59, 87))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (143, 163))	('P', 'Chemical', 'MESH:D010758', (349, 350))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (59, 87))
2222	29383036	Analysis of the datasets for which somatic ERBB family mutations are enriched (>12%) reveals that somatic PIK3CA mutation rates vary between 1.4% in melanoma and 41.7% in uterine corpus endometrioid carcinoma (Table 3).	('mutation', 'Var', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('PIK3CA', 'Gene', (106, 112))	('melanoma', 'Disease', (149, 157))	('ERBB', 'Gene', (43, 47))	('corpus endometrioid carcinoma', 'Disease', (179, 208))	('PIK3CA', 'Gene', '5290', (106, 112))	('corpus endometrioid carcinoma', 'Disease', 'MESH:D016889', (179, 208))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (186, 208))	('ERBB', 'Gene', '1956', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
2224	29383036	We finally found that co-occurring ERBB family and PIK3CA mutations can be identified in this subset of patient tumors at rates ranging between 1.5% in pan-lung cancer patients and 11.3% in uterine corpus endometrioid carcinomas.	('mutations', 'Var', (58, 67))	('pan-lung cancer', 'Disease', (152, 167))	('patient', 'Species', '9606', (168, 175))	('patient', 'Species', '9606', (104, 111))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (205, 228))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PIK3CA', 'Gene', (51, 57))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (205, 227))	('ERBB', 'Gene', (35, 39))	('ERBB', 'Gene', '1956', (35, 39))	('PIK3CA', 'Gene', '5290', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('corpus endometrioid carcinomas', 'Disease', (198, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('corpus endometrioid carcinomas', 'Disease', 'MESH:D016889', (198, 228))	('patients', 'Species', '9606', (168, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('pan-lung cancer', 'Disease', 'MESH:D008175', (152, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('tumors', 'Disease', (112, 118))
2225	29383036	Interestingly, in bladder urothelial carcinomas, stomach adenocarcinomas and uterine corpus endometrioid carcinomas more than 8% of patient tumors have a co-occurring PIK3CA and ERBB family mutation.	('PIK3CA', 'Gene', '5290', (167, 173))	('stomach adenocarcinomas', 'Disease', (49, 72))	('corpus endometrioid carcinomas', 'Disease', (85, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('corpus endometrioid carcinomas', 'Disease', 'MESH:D016889', (85, 115))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (49, 72))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('ERBB', 'Gene', (178, 182))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (92, 114))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('PIK3CA', 'Gene', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (92, 115))	('tumors', 'Disease', (140, 146))	('ERBB', 'Gene', '1956', (178, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('patient', 'Species', '9606', (132, 139))	('mutation', 'Var', (190, 198))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('bladder urothelial carcinomas', 'Disease', (18, 47))	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (18, 47))
2229	29383036	In patients with bladder urothelial carcinomas PIK3CA mutations significantly co-occur with ERBB3 (p = 0.035) and EGFR (p = 0.039), whilst in cervical squamous cell carcinomas and endocervical adenocarcinomas PIK3CA mutations significantly co-occur with ERBB2 (p = 0.027).	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (151, 175))	('ERBB2', 'Gene', (254, 259))	('ERBB3', 'Gene', '2065', (92, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('endocervical adenocarcinomas', 'Disease', (180, 208))	('PIK3CA', 'Gene', '5290', (47, 53))	('squamous cell carcinomas', 'Disease', (151, 175))	('PIK3CA', 'Gene', (209, 215))	('mutations', 'Var', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('ERBB2', 'Gene', '2064', (254, 259))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('co-occur', 'Reg', (78, 86))	('endocervical adenocarcinomas', 'Disease', 'MESH:D000230', (180, 208))	('patients', 'Species', '9606', (3, 11))	('ERBB3', 'Gene', (92, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('PIK3CA', 'Gene', (47, 53))	('bladder urothelial carcinomas', 'Disease', (17, 46))	('PIK3CA', 'Gene', '5290', (209, 215))	('EGFR', 'Gene', '1956', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (151, 175))	('bladder urothelial carcinomas', 'Disease', 'MESH:D001749', (17, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))
2231	29383036	Finally, in stomach adenocarcinomas there is a significant likelihood that tumors which have a PIK3CA mutation have a co-occurring mutation in ERBB3 (p = 0.008), EGFR (p = 0.014) and ERBB2 (p = 0.037) (Table 4).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('ERBB3', 'Gene', '2065', (143, 148))	('EGFR', 'Gene', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('ERBB2', 'Gene', (183, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))	('mutation', 'Var', (131, 139))	('PIK3CA', 'Gene', '5290', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('ERBB2', 'Gene', '2064', (183, 188))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('ERBB3', 'Gene', (143, 148))	('stomach adenocarcinomas', 'Disease', (12, 35))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (12, 35))	('PIK3CA', 'Gene', (95, 101))	('mutation', 'Var', (102, 110))
2232	29383036	Despite the obvious co-occurrence of mutations in these families of genes, little work to date has been performed to understand the functional and prognostic importance of co-occurring mutations in PIK3CA and ERBB family mutations in cancer.	('ERBB', 'Gene', '1956', (209, 213))	('PIK3CA', 'Gene', '5290', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('ERBB', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('PIK3CA', 'Gene', (198, 204))	('mutations', 'Var', (185, 194))	('cancer', 'Disease', (234, 240))
2235	29383036	In-vitro analysis of the antiproliferative effects of the PI3K inhibitors copanlisib (61 cell lines), pictilisib (23 cell lines) and gedatolisib (17 cell lines) representing multiple cancer types identified that cells with a PIK3CA mutation were 6.45 fold more sensitive to copanlisib (n = 8, p = 0.046), 2.14 fold more sensitive to pictilisib (n = 4, p = 0.025) and 6.27 fold more sensitive to gedatolisib (not significant, n = 5) than those cell lines which were wild type for PIK3CA (Table 5).	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('pictilisib', 'Chemical', 'MESH:C532162', (102, 112))	('PIK3CA', 'Gene', '5290', (225, 231))	('PIK3CA', 'Gene', '5290', (479, 485))	('PI3K', 'Gene', (58, 62))	('P', 'Chemical', 'MESH:D010758', (225, 226))	('P', 'Chemical', 'MESH:D010758', (479, 480))	('gedatolisib', 'Chemical', 'MESH:C549060', (133, 144))	('gedatolisib', 'Chemical', 'MESH:C549060', (395, 406))	('cancer', 'Disease', (183, 189))	('P', 'Chemical', 'MESH:D010758', (58, 59))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('PIK3CA', 'Gene', (225, 231))	('PIK3CA', 'Gene', (479, 485))	('mutation', 'Var', (232, 240))	('copanlisib', 'Chemical', 'MESH:C000589253', (274, 284))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('pictilisib', 'Chemical', 'MESH:C532162', (333, 343))	('copanlisib', 'Gene', (74, 84))	('copanlisib', 'Chemical', 'MESH:C000589253', (74, 84))
2236	29383036	This result demonstrates the importance of PIK3CA mutations as a biomarker of response to PI3K inhibitors.	('PIK3CA', 'Gene', '5290', (43, 49))	('mutations', 'Var', (50, 59))	('P', 'Chemical', 'MESH:D010758', (90, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('90', '94'))	('P', 'Chemical', 'MESH:D010758', (43, 44))	('PIK3CA', 'Gene', (43, 49))
2237	29383036	Interestingly, we also demonstrated that cell lines with only an ERBB family mutation are more sensitive to PI3K inhibition with copanlisib (p = 0.039) and gedatolisib (p = 0.002) relative to those cells which are WT for both PIK3CA and ERBB family genes (Figure 2).	('P', 'Chemical', 'MESH:D010758', (226, 227))	('ERBB', 'Gene', '1956', (65, 69))	('ERBB', 'Gene', '1956', (237, 241))	('mutation', 'Var', (77, 85))	('PIK3CA', 'Gene', (226, 232))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('sensitive', 'MPA', (95, 104))	('PI3K inhibition', 'Pathway', (108, 123))	('PIK3CA', 'Gene', '5290', (226, 232))	('ERBB', 'Gene', (65, 69))	('gedatolisib', 'Chemical', 'MESH:C549060', (156, 167))	('P', 'Chemical', 'MESH:D010758', (108, 109))	('copanlisib', 'Chemical', 'MESH:C000589253', (129, 139))	('ERBB', 'Gene', (237, 241))
2238	29383036	However, we also found cell lines with an ERBB family mutation (both ERBB family Mut and PIK3CA/ERBB family Mut cells) were 8.39 fold more sensitive to copanlisib (n = 22, p = 0.005), 2.86 fold more sensitive to pictilisib (n = 10, p = 3 x 10-4), and 6.33 fold more sensitive to gedatolisib (n = 5, p = 0.048) than cell lines which were ERBB family/PIK3CA WT (Table 6).	('sensitive', 'MPA', (139, 148))	('mutation', 'Var', (54, 62))	('ERBB', 'Gene', '1956', (96, 100))	('PIK3CA', 'Gene', (349, 355))	('pictilisib', 'Chemical', 'MESH:C532162', (212, 222))	('ERBB', 'Gene', '1956', (69, 73))	('ERBB', 'Gene', '1956', (42, 46))	('copanlisib', 'MPA', (152, 162))	('PIK3CA', 'Gene', (89, 95))	('gedatolisib', 'Chemical', 'MESH:C549060', (279, 290))	('ERBB', 'Gene', '1956', (337, 341))	('PIK3CA', 'Gene', '5290', (89, 95))	('copanlisib', 'Chemical', 'MESH:C000589253', (152, 162))	('PIK3CA', 'Gene', '5290', (349, 355))	('ERBB', 'Gene', (96, 100))	('ERBB', 'Gene', (69, 73))	('ERBB', 'Gene', (337, 341))	('ERBB', 'Gene', (42, 46))
2239	29383036	There were no significant differences between the copanlisib and pictilisib half-maximal inhibitory concentration IC50s in cells with only an ERBB family mutation versus either only PIK3CA-mutated cells or cell lines with both an ERBB family and a PIK3CA mutation.	('50s', 'Species', '1214577', (116, 119))	('ERBB', 'Gene', '1956', (142, 146))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', '5290', (248, 254))	('mutation', 'Var', (154, 162))	('pictilisib', 'Chemical', 'MESH:C532162', (65, 75))	('PIK3CA', 'Gene', '5290', (182, 188))	('ERBB', 'Gene', (230, 234))	('half-maximal inhibitory concentration', 'MPA', (76, 113))	('PIK3CA', 'Gene', (248, 254))	('copanlisib', 'Chemical', 'MESH:C000589253', (50, 60))	('ERBB', 'Gene', (142, 146))	('ERBB', 'Gene', '1956', (230, 234))
2244	29383036	SW620 and LoVo cell lines are both KRAS mutant whilst C2BBE1 cells have an Mammalian target of rapamycin (mTOR) mutation.	('BBE', 'molecular_function', 'GO:0050468', ('56', '59'))	('KRAS', 'Gene', (35, 39))	('mutation', 'Var', (112, 120))	('Mammalian target of rapamycin', 'Gene', '2475', (75, 104))	('SW620', 'CellLine', 'CVCL:0547', (0, 5))	('Mammalian target of rapamycin', 'Gene', (75, 104))	('KRAS', 'Gene', '3845', (35, 39))	('C2BBE1', 'CellLine', 'CVCL:1096', (54, 60))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', '2475', (106, 110))	('LoVo', 'CellLine', 'CVCL:0399', (10, 14))
2247	29383036	Copanlisib as a single agent induces significant inhibition of AKT phosphorylation (S473) in all cell lines regardless of mutational status and p70 S6K (T389) phosphorylation in all cells except KLE (WT/WT).	('phosphorylation', 'biological_process', 'GO:0016310', ('159', '174'))	('p70 S6K', 'Gene', (144, 151))	('AKT', 'Gene', (63, 66))	('S', 'Chemical', 'MESH:D013455', (84, 85))	('p70 S6K', 'Gene', '6198', (144, 151))	('Copanlisib', 'Gene', (0, 10))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('S', 'Chemical', 'MESH:D013455', (148, 149))	('AKT', 'Gene', '207', (63, 66))	('mutational', 'Var', (122, 132))	('inhibition', 'NegReg', (49, 59))	('Copanlisib', 'Chemical', 'MESH:C000589253', (0, 10))	('KLE', 'Chemical', '-', (195, 198))
2252	29383036	Treatment with the combination of afatinib and copanlisib significantly reduces the phosphorylation of AKT (S473, T308) and p70 S6K (T389) in all cell lines tested [Figure 4(c)].	('afatinib', 'Chemical', 'MESH:D000077716', (34, 42))	('AKT', 'Gene', '207', (103, 106))	('T308', 'Chemical', '-', (114, 118))	('S473', 'Var', (108, 112))	('p70 S6K', 'Gene', (124, 131))	('reduces', 'NegReg', (72, 79))	('T308', 'Var', (114, 118))	('S', 'Chemical', 'MESH:D013455', (108, 109))	('S', 'Chemical', 'MESH:D013455', (128, 129))	('AKT', 'Gene', (103, 106))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('p70 S6K', 'Gene', '6198', (124, 131))	('copanlisib', 'Chemical', 'MESH:C000589253', (47, 57))	('phosphorylation', 'MPA', (84, 99))
2253	29383036	Treatment with the combination of afatinib and copanlisib also significantly reduces MEK (S217/221) and MAPK (T202/Y204) phosphorylation in all cell lines apart from HT29 (PIK3CA Mut).	('copanlisib', 'Gene', (47, 57))	('MEK', 'Gene', '5609', (85, 88))	('afatinib', 'Chemical', 'MESH:D000077716', (34, 42))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('S', 'Chemical', 'MESH:D013455', (90, 91))	('P', 'Chemical', 'MESH:D010758', (106, 107))	('HT29', 'CellLine', 'CVCL:0320', (166, 170))	('P', 'Chemical', 'MESH:D010758', (172, 173))	('phosphorylation', 'MPA', (121, 136))	('PIK3CA', 'Gene', (172, 178))	('PIK3CA', 'Gene', '5290', (172, 178))	('MAPK', 'molecular_function', 'GO:0004707', ('104', '108'))	('MAPK', 'Protein', (104, 108))	('copanlisib', 'Chemical', 'MESH:C000589253', (47, 57))	('reduces', 'NegReg', (77, 84))	('T202/Y204', 'Var', (110, 119))	('MEK', 'Gene', (85, 88))
2257	29383036	In H1975 cells (ERBB family/PIK3CA Mut) the combination of copanlisib (120 nM) and afatinib (500 nM) was significantly more likely to increase apoptosis relative to the cell lines that are WT for both mutations (p = 0.006) or ERBB family mutant (p = 0.001) or PIK3CA mutant (p = 0.04).	('PIK3CA', 'Gene', (260, 266))	('PIK3CA', 'Gene', (28, 34))	('ERBB', 'Gene', (226, 230))	('apoptosis', 'CPA', (143, 152))	('increase', 'PosReg', (134, 142))	('ERBB', 'Gene', '1956', (226, 230))	('500 nM', 'Var', (93, 99))	('combination', 'Interaction', (44, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('H1975', 'Var', (3, 8))	('H1975', 'CellLine', 'CVCL:1511', (3, 8))	('afatinib', 'Chemical', 'MESH:D000077716', (83, 91))	('PIK3CA', 'Gene', '5290', (260, 266))	('120 nM', 'Var', (71, 77))	('PIK3CA', 'Gene', '5290', (28, 34))	('copanlisib', 'Gene', (59, 69))	('copanlisib', 'Chemical', 'MESH:C000589253', (59, 69))	('ERBB', 'Gene', (16, 20))	('ERBB', 'Gene', '1956', (16, 20))
2259	29383036	The combined evidence points towards the combination of afatinib and copanlisib producing a pro-apoptotic signal in H1975 cells, which is not observed in the remaining cell lines tested.	('combination', 'Var', (41, 52))	('copanlisib', 'Chemical', 'MESH:C000589253', (69, 79))	('afatinib', 'Gene', (56, 64))	('afatinib', 'Chemical', 'MESH:D000077716', (56, 64))	('copanlisib', 'Gene', (69, 79))	('pro-apoptotic signal', 'MPA', (92, 112))	('H1975', 'CellLine', 'CVCL:1511', (116, 121))	('producing', 'Reg', (80, 89))
2261	29383036	ERBB family mutations have been shown in our studies and by others to be enriched in classically non-ERBB-family amplified cancers.	('ERBB', 'Gene', '1956', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ERBB', 'Gene', '1956', (101, 105))	('mutations', 'Var', (12, 21))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('ERBB', 'Gene', (0, 4))	('cancers', 'Disease', (123, 130))	('ERBB', 'Gene', (101, 105))
2262	29383036	However, we also found that ERBB family mutations co-occur with PIK3CA mutations in endometrial, colorectal, ovarian and stomach cancers.	('stomach cancers', 'Phenotype', 'HP:0012126', (121, 136))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('PIK3CA', 'Gene', (64, 70))	('ERBB', 'Gene', '1956', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('colorectal, ovarian and stomach cancers', 'Disease', 'MESH:D015179', (97, 136))	('PIK3CA', 'Gene', '5290', (64, 70))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (71, 80))	('endometrial', 'Disease', (84, 95))	('ERBB', 'Gene', (28, 32))
2263	29383036	This therefore indicates that patients who have an ERBB family or PIK3CA mutation are significantly more likely to have an activated PI3K/AKT signaling pathway.	('ERBB', 'Gene', '1956', (51, 55))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('AKT', 'Gene', (138, 141))	('PIK3CA', 'Gene', (66, 72))	('P', 'Chemical', 'MESH:D010758', (66, 67))	('patients', 'Species', '9606', (30, 38))	('AKT signaling', 'biological_process', 'GO:0043491', ('138', '151'))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('ERBB', 'Gene', (51, 55))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutation', 'Var', (73, 81))	('signaling pathway', 'biological_process', 'GO:0007165', ('142', '159'))	('AKT', 'Gene', '207', (138, 141))
2268	29383036	In our study we wanted to test the antiproliferative impact of PI3K inhibition in a panel of cell lines that were selected based on their ERBB family and PIK3CA mutational status.	('PIK3CA', 'Gene', (154, 160))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('P', 'Chemical', 'MESH:D010758', (154, 155))	('P', 'Chemical', 'MESH:D010758', (63, 64))	('ERBB', 'Gene', '1956', (138, 142))	('antiproliferative', 'CPA', (35, 52))	('PIK3CA', 'Gene', '5290', (154, 160))	('inhibition', 'NegReg', (68, 78))	('ERBB', 'Gene', (138, 142))	('mutational', 'Var', (161, 171))
2269	29383036	The cell lines were also chosen to represent the solid tumors in which ERBB family and PIK3CA mutations are commonly found, such as colorectal, ovarian, endometrial and lung cancers.	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('colorectal', 'Disease', 'MESH:D015179', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PIK3CA', 'Gene', '5290', (87, 93))	('lung cancers', 'Phenotype', 'HP:0100526', (169, 181))	('mutations', 'Var', (94, 103))	('endometrial and lung cancers', 'Disease', 'MESH:D016889', (153, 181))	('solid tumors', 'Disease', (49, 61))	('found', 'Reg', (117, 122))	('ovarian', 'Disease', (144, 151))	('colorectal', 'Disease', (132, 142))	('ERBB', 'Gene', (71, 75))	('ovarian', 'Disease', 'MESH:D010051', (144, 151))	('ERBB', 'Gene', '1956', (71, 75))	('PIK3CA', 'Gene', (87, 93))	('solid tumors', 'Disease', 'MESH:D009369', (49, 61))
2270	29383036	Interestingly, in vitro analysis of the antiproliferative impact of the PI3K inhibitors in multiple cell lines of differing histologies found that cells which harbored an ERBB family mutation were as sensitive to PI3K inhibition as those cell lines which are PIK3CA mutated.	('PIK3CA', 'Gene', '5290', (259, 265))	('antiproliferative', 'MPA', (40, 57))	('P', 'Chemical', 'MESH:D010758', (213, 214))	('PI3K', 'molecular_function', 'GO:0016303', ('213', '217'))	('ERBB', 'Gene', (171, 175))	('P', 'Chemical', 'MESH:D010758', (72, 73))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('PIK3CA', 'Gene', (259, 265))	('mutation', 'Var', (183, 191))	('P', 'Chemical', 'MESH:D010758', (259, 260))	('ERBB', 'Gene', '1956', (171, 175))
2271	29383036	We therefore demonstrated that PI3K inhibitors could be effective for the treatment of patients who not only harbor PIK3CA mutations but also ERBB family mutations.	('PIK3CA', 'Gene', (116, 122))	('mutations', 'Var', (123, 132))	('ERBB', 'Gene', '1956', (142, 146))	('PIK3CA', 'Gene', '5290', (116, 122))	('P', 'Chemical', 'MESH:D010758', (31, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('ERBB', 'Gene', (142, 146))	('patients', 'Species', '9606', (87, 95))	('P', 'Chemical', 'MESH:D010758', (116, 117))
2273	29383036	Afatinib which has not been tested clinically in combination with PI3K inhibitors provides a rational approach for targeting cancers in which the PI3K pathway may be activated by ERBB family mutation.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('PI3K pathway', 'Pathway', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('66', '70'))	('targeting cancers', 'Disease', (115, 132))	('ERBB', 'Gene', (179, 183))	('P', 'Chemical', 'MESH:D010758', (66, 67))	('targeting cancers', 'Disease', 'MESH:D009369', (115, 132))	('P', 'Chemical', 'MESH:D010758', (146, 147))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('ERBB', 'Gene', '1956', (179, 183))	('mutation', 'Var', (191, 199))	('activated', 'PosReg', (166, 175))
2274	29383036	In fact when we combined afatinib and copanlisib together we found that cell lines which harbored both an ERBB family mutation and a PIK3CA mutation had the greatest antiproliferative response to the combination treatment.	('afatinib', 'Chemical', 'MESH:D000077716', (25, 33))	('copanlisib', 'Chemical', 'MESH:C000589253', (38, 48))	('PIK3CA', 'Gene', (133, 139))	('PIK3CA', 'Gene', '5290', (133, 139))	('mutation', 'Var', (140, 148))	('ERBB', 'Gene', (106, 110))	('antiproliferative response', 'CPA', (166, 192))	('mutation', 'Var', (118, 126))	('ERBB', 'Gene', '1956', (106, 110))
2275	29383036	We also demonstrated that two-thirds of cell lines that are ERBB family mutant, but were WT for PIK3CA, had synergistic inhibition of proliferation to the combination of afatinib and copanlisib.	('mutant', 'Var', (72, 78))	('ERBB', 'Gene', (60, 64))	('copanlisib', 'Chemical', 'MESH:C000589253', (183, 193))	('PIK3CA', 'Gene', (96, 102))	('inhibition', 'NegReg', (120, 130))	('afatinib', 'Chemical', 'MESH:D000077716', (170, 178))	('PIK3CA', 'Gene', '5290', (96, 102))	('ERBB', 'Gene', '1956', (60, 64))	('proliferation', 'CPA', (134, 147))
2282	29383036	This is an interesting observation as despite ERBB-family-mutant cell lines being sensitive to the combination of afatinib and copanlisib, it was only in the ERBB family/PIK3CA mutant cell lines that the combination produced a proapoptotic impact, likely indicating that the combination was cytostatic and not cytotoxic in cell lines which harbor an ERBB family mutation only.	('PIK3CA', 'Gene', '5290', (170, 176))	('proapoptotic impact', 'MPA', (227, 246))	('copanlisib', 'Chemical', 'MESH:C000589253', (127, 137))	('ERBB', 'Gene', (46, 50))	('ERBB', 'Gene', '1956', (158, 162))	('afatinib', 'Chemical', 'MESH:D000077716', (114, 122))	('ERBB', 'Gene', '1956', (46, 50))	('ERBB', 'Gene', (350, 354))	('ERBB', 'Gene', (158, 162))	('mutant', 'Var', (177, 183))	('PIK3CA', 'Gene', (170, 176))	('ERBB', 'Gene', '1956', (350, 354))
2287	29383036	However, our study clearly highlights the ability to identify and stratify patients based on the presence of ERBB family mutations, with patients whose tumors cofeature PIK3CA mutations the most likely to gain robust antitumor responses.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (176, 185))	('mutations', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('ERBB', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', (152, 157))	('gain', 'PosReg', (205, 209))	('patients', 'Species', '9606', (137, 145))	('ERBB', 'Gene', '1956', (109, 113))	('PIK3CA', 'Gene', '5290', (169, 175))	('tumors', 'Disease', (152, 158))	('PIK3CA', 'Gene', (169, 175))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
2305	29383036	Cells were then treated with the relevant drug and concentration KLE [WT/WT (group A), afat 125 nM, cop 8 nM or afat:cop 125:8 nM], H1975 [WT/Mut (group B), afat 30 nM, cop 8 nM or afat:cop 30:8 nM], C2BBE1 [Mut/WT (group C) afat 250 nM, cop 62.5 nM, afat:cop 250:62.5 nM], HT29 [Mut/Mut (group D) afat 125 nM, cop 30 nM or afat:cop 125:30 nM] or a similar concentration of DMSO/DMSO-TFA (vehicle control) in 5% FCS for 30 min.	('KLE', 'Chemical', '-', (65, 68))	('S', 'Chemical', 'MESH:D013455', (381, 382))	('S', 'Chemical', 'MESH:D013455', (376, 377))	('H1975 [', 'Var', (132, 139))	('C2BBE1 [Mut/WT', 'Var', (200, 214))	('S', 'Chemical', 'MESH:D013455', (414, 415))	('C2BBE1', 'CellLine', 'CVCL:1096', (200, 206))	('HT29', 'CellLine', 'CVCL:0320', (274, 278))	('DMSO', 'Chemical', 'MESH:D004121', (379, 383))	('H1975', 'CellLine', 'CVCL:1511', (132, 137))	('DMSO', 'Chemical', 'MESH:D004121', (374, 378))	('HT29 [Mut/Mut', 'Var', (274, 287))	('BBE', 'molecular_function', 'GO:0050468', ('202', '205'))
2323	25960768	Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('epigenetic silencing', 'Var', (168, 188))	('copy number variations', 'Var', (140, 162))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('CIMP', 'Chemical', '-', (27, 31))
2327	25960768	We present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors.	('hypermethylation', 'Var', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('CIMP', 'Chemical', '-', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (186, 192))	('CpG', 'Gene', (167, 170))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
2330	25960768	Recurrent patterns of aberrant DNA methylation are commonly observed in cancerous cells, implying that this epigenetic alteration is inherently linked to general mechanisms of oncogenesis and tumor progression.	('aberrant', 'Var', (22, 30))	('tumor', 'Disease', (192, 197))	('cancerous', 'Disease', (72, 81))	('DNA', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancerous', 'Disease', 'MESH:D009369', (72, 81))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('oncogenesis', 'biological_process', 'GO:0007048', ('176', '187'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('linked', 'Reg', (144, 150))
2332	25960768	Concurrent and widespread hypermethylation of CpG islands in clinically distinct cancer subtypes is known as CpG island methylator phenotype (CIMP).	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('hypermethylation', 'Var', (26, 42))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CIMP', 'Chemical', '-', (142, 146))
2337	25960768	For example, the inactivation of mismatch repair gene MLH1 correlates strongly with CIMP in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inactivation', 'Var', (17, 29))	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('CIMP', 'Chemical', '-', (84, 88))	('colon cancer', 'Disease', (92, 104))	('mismatch repair', 'biological_process', 'GO:0006298', ('33', '48'))	('CIMP', 'Disease', (84, 88))
2338	25960768	Glioblastoma exhibits mutations in epigenetic regulators such as IDH1/2 and in histone encoding genes such as H3F3A, whereas CIMP in leukemia is associated with TET2 mutations (for a review, see Witte et al.).	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('CIMP', 'Chemical', '-', (125, 129))	('Glioblastoma', 'Disease', (0, 12))	('epigenetic regulators', 'MPA', (35, 56))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('IDH1/2', 'Gene', '3417;3418', (65, 71))	('TET2', 'Gene', '54790', (161, 165))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('H3F3A', 'Gene', '3020', (110, 115))	('mutations', 'Var', (22, 31))	('TET2', 'Gene', (161, 165))	('H3F3A', 'Gene', (110, 115))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('IDH1/2', 'Gene', (65, 71))	('leukemia', 'Disease', (133, 141))
2381	25960768	An Ingenuity Pathway Analysis (IPA) evaluation of the genes associated with the differential methylation sites in individual cancers revealed a subset of canonical pathways that are collectively targeted in the CIMP probe sets (Figure 3A).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('CIMP', 'Chemical', '-', (211, 215))	('canonical pathways', 'Pathway', (154, 172))	('sites', 'Var', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('methylation sites', 'Var', (93, 110))
2385	25960768	Using the IPA tool, we also identified a set of recurrent upstream regulators for the differentially methylated probe set associated with each cancer type (Figure 3B).	('associated', 'Reg', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('differentially methylated', 'Var', (86, 111))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
2394	25960768	Also, we noted a strong correlation between the differentially methylated probe set and the set of 89 tumor-derived pan-cancer loci (Figure 4G), which supports the consistency of our findings between the cell lines and the tumor data.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('differentially methylated', 'Var', (48, 73))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
2409	25960768	Furthermore, less than half of the CIMP +  Hyper regions in the gene-associated set collocated with known transcription start sites annotated by Illumina (and a comparable number overlapped gene bodies), suggesting that aberrant hypermethylation in CIMP is not exclusive to gene promoters.	('CIMP', 'Gene', (249, 253))	('CIMP', 'Chemical', '-', (35, 39))	('CIMP', 'Chemical', '-', (249, 253))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('aberrant hypermethylation', 'Var', (220, 245))
2411	25960768	A subset of 121 regions associated with 93 genes exhibited significant levels of Spearman correlation between methylation and expression in all 12 cancer types, with varying magnitudes of effect in terms of actual differential expression (Figure 5B).	('methylation', 'biological_process', 'GO:0032259', ('110', '121'))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('expression', 'MPA', (126, 136))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('methylation', 'Var', (110, 121))	('cancer', 'Disease', (147, 153))
2413	25960768	Additionally, FLI1 (which had been identified in our selected differentially methylated probe sets for 8 of 14 cancer types), contained a combination of CIMP +  Hyper and CIMP +  Hypo regions, which occurred at the gene promoter and the first exon, respectively.	('FLI1', 'Gene', '2313', (14, 18))	('CIMP +  Hyper', 'Var', (153, 166))	('FLI1', 'Gene', (14, 18))	('CIMP', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CIMP', 'Chemical', '-', (171, 175))	('CIMP +  Hypo regions', 'Var', (171, 191))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
2417	25960768	To address commonalities, we used characterizations of TCGA data generated by Ciriello et al., which consisted of 479 selected functional events (SFEs) including 116 copy number gains, 151 copy number losses, mutation of 199 genes, and epigenetic silencing of 13 genes (requiring promoter methylation and decreased expression).	('copy number', 'Var', (166, 177))	('expression', 'MPA', (315, 325))	('losses', 'NegReg', (201, 207))	('methylation', 'biological_process', 'GO:0032259', ('289', '300'))	('SFE', 'Gene', '4311', (146, 149))	('mutation', 'Var', (209, 217))	('copy number', 'Var', (189, 200))	('SFE', 'Gene', (146, 149))	('epigenetic silencing', 'Var', (236, 256))	('gains', 'PosReg', (178, 183))
2421	25960768	Events with strong effects in more than one tumor type included MGMT and MLH1 promoter methylation, as well as mutation of ARID1A, KRAS, BRAF, and PTEN.	('ARID1A', 'Gene', (123, 129))	('KRAS', 'Gene', '3845', (131, 135))	('MGMT', 'Gene', '4255', (64, 68))	('PTEN', 'Gene', (147, 151))	('tumor', 'Disease', (44, 49))	('ARID1A', 'Gene', '8289', (123, 129))	('KRAS', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PTEN', 'Gene', '5728', (147, 151))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('MGMT', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('promoter methylation', 'MPA', (78, 98))	('mutation', 'Var', (111, 119))	('MLH1', 'Gene', (73, 77))	('MGMT', 'molecular_function', 'GO:0003908', ('64', '68'))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('MLH1', 'Gene', '4292', (73, 77))
2422	25960768	Events that were strong but gave mixed results towards the CIMP phenotype included mutation of TP53, PIK3CA, FBXW7, and several amplification and deletion regions.	('PIK3CA', 'Gene', '5290', (101, 107))	('FBXW7', 'Gene', '55294', (109, 114))	('FBXW7', 'Gene', (109, 114))	('TP53', 'Gene', (95, 99))	('mutation', 'Var', (83, 91))	('CIMP', 'Chemical', '-', (59, 63))	('TP53', 'Gene', '7157', (95, 99))	('PIK3CA', 'Gene', (101, 107))
2426	25960768	In contrast, mutations in six genes (BRAF, PTEN, KRAS, SETD2, PIK3R1, and PBRM1) and two gene silencing events (MLH1 and MGMT, for which the smallest FDRs were recorded) were more frequent in CIMP+ samples.	('silencing', 'NegReg', (94, 103))	('MGMT', 'Gene', '4255', (121, 125))	('MLH1', 'Gene', '4292', (112, 116))	('gene silencing', 'biological_process', 'GO:0016458', ('89', '103'))	('KRAS', 'Gene', '3845', (49, 53))	('PIK3R1', 'Gene', '5295', (62, 68))	('PTEN', 'Gene', (43, 47))	('CIMP+', 'Chemical', '-', (192, 197))	('KRAS', 'Gene', (49, 53))	('BRAF', 'Gene', '673', (37, 41))	('MGMT', 'Gene', (121, 125))	('BRAF', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (43, 47))	('MGMT', 'molecular_function', 'GO:0003908', ('121', '125'))	('mutations', 'Var', (13, 22))	('SETD2', 'Gene', (55, 60))	('frequent', 'Reg', (180, 188))	('PBRM1', 'Gene', '55193', (74, 79))	('PIK3R1', 'Gene', (62, 68))	('MLH1', 'Gene', (112, 116))	('SETD2', 'Gene', '29072', (55, 60))	('PBRM1', 'Gene', (74, 79))
2428	25960768	The remaining mutations are well known due to their involvement in the PI3K/PTEN/AKT/mTOR and the Ras/Raf/MEK/ERK pathways.	('ERK', 'Gene', (110, 113))	('AKT', 'Gene', '207', (81, 84))	('PTEN', 'Gene', (76, 80))	('MEK', 'Gene', (106, 109))	('MEK', 'Gene', '5609', (106, 109))	('PTEN', 'Gene', '5728', (76, 80))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('Raf', 'Gene', (102, 105))	('Raf', 'Gene', '22882', (102, 105))	('AKT', 'Gene', (81, 84))	('mTOR', 'Gene', '2475', (85, 89))	('ERK', 'Gene', '5594', (110, 113))	('mTOR', 'Gene', (85, 89))	('mutations', 'Var', (14, 23))	('involvement', 'Reg', (52, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
2429	25960768	In particular, both BRAF and KRAS mutations have been linked to CIMP status (high and low, respectively) in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('KRAS', 'Gene', (29, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('CIMP', 'Chemical', '-', (64, 68))	('BRAF', 'Gene', '673', (20, 24))	('KRAS', 'Gene', '3845', (29, 33))	('colorectal cancer', 'Disease', (108, 125))	('BRAF', 'Gene', (20, 24))	('linked', 'Reg', (54, 60))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
2432	25960768	CIMP+ samples for COAD, KIRC, LUSC, and READ exhibited a larger number of mutational events per sample than CIMP- samples, implicating impairment of DNA repair processes.	('CIMP-', 'Chemical', '-', (108, 113))	('DNA repair', 'biological_process', 'GO:0006281', ('149', '159'))	('COAD', 'Disease', (18, 22))	('mutational', 'Var', (74, 84))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('COAD', 'Disease', 'MESH:D029424', (18, 22))	('CIMP+', 'Chemical', '-', (0, 5))
2433	25960768	In contrast, copy number variation showed significant effects in CIMP- samples, where amplifications occurred more frequently in COAD and UCEC tumors, and deletions occurred more frequently in BRCA and UCEC tumors.	('UCEC tumors', 'Disease', 'MESH:D009369', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('amplifications', 'MPA', (86, 100))	('COAD', 'Disease', 'MESH:D029424', (129, 133))	('UCEC tumors', 'Disease', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('BRCA', 'Phenotype', 'HP:0003002', (193, 197))	('BRCA', 'Gene', '672', (193, 197))	('UCEC tumors', 'Disease', (138, 149))	('UCEC tumors', 'Disease', 'MESH:D009369', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('BRCA', 'Gene', (193, 197))	('deletions', 'Var', (155, 164))	('CIMP-', 'Chemical', '-', (65, 70))	('COAD', 'Disease', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
2434	25960768	However, these events are not always positively correlated, as shown by the reduction in deletions in COAD CIMP- samples.	('COAD', 'Disease', (102, 106))	('reduction', 'NegReg', (76, 85))	('deletions', 'Var', (89, 98))	('COAD', 'Disease', 'MESH:D029424', (102, 106))	('CIMP-', 'Chemical', '-', (107, 112))
2438	25960768	For example, MLH1 promoter methylation is observed in a subset of COAD and UCEC tumors with a very strong majority of CIMP+ labels.	('UCEC tumors', 'Disease', (75, 86))	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('MLH1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MLH1', 'Gene', '4292', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('COAD', 'Disease', (66, 70))	('CIMP+', 'Chemical', '-', (118, 123))	('methylation', 'Var', (27, 38))	('UCEC tumors', 'Disease', 'MESH:D009369', (75, 86))	('observed', 'Reg', (42, 50))	('COAD', 'Disease', 'MESH:D029424', (66, 70))
2439	25960768	Similarly, a high proportion of CIMP+ labels was observed in samples with MGMT promoter methylation, combined with either (a) FBXW7 mutations or (b) APC and KRAS mutations or (c) absence of FBXW7 and APC mutations (Figure 7).	('APC', 'Disease', (200, 203))	('APC', 'Disease', 'MESH:D011125', (149, 152))	('APC', 'Disease', (149, 152))	('FBXW7', 'Gene', (190, 195))	('FBXW7', 'Gene', (126, 131))	('MGMT', 'Gene', (74, 78))	('CIMP+', 'Chemical', '-', (32, 37))	('FBXW7', 'Gene', '55294', (190, 195))	('KRAS', 'Gene', '3845', (157, 161))	('mutations', 'Var', (162, 171))	('FBXW7', 'Gene', '55294', (126, 131))	('mutations', 'Var', (132, 141))	('MGMT', 'molecular_function', 'GO:0003908', ('74', '78'))	('APC', 'cellular_component', 'GO:0005680', ('200', '203'))	('MGMT', 'Gene', '4255', (74, 78))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('KRAS', 'Gene', (157, 161))	('APC', 'cellular_component', 'GO:0005680', ('149', '152'))	('APC', 'Disease', 'MESH:D011125', (200, 203))
2440	25960768	Of note, subgroups containing these alterations consisted entirely of tumors of the aero-digestive tract (HNSC, LUSC, COAD, and READ).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('COAD', 'Disease', 'MESH:D029424', (118, 122))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('COAD', 'Disease', (118, 122))	('alterations', 'Var', (36, 47))	('tumors of the aero-digestive tract', 'Phenotype', 'HP:0007378', (70, 104))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('LUSC', 'Disease', (112, 116))
2442	25960768	In our samples lacking MGMT and MLH1 promoter methylation, the highest proportions of CIMP+ samples were observed in a subgroup dominated by KIRC tumors that were characterized by a combination of SETD2 and PBRM1 mutations.	('MLH1', 'Gene', (32, 36))	('PBRM1', 'Gene', (207, 212))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('SETD2', 'Gene', '29072', (197, 202))	('PBRM1', 'Gene', '55193', (207, 212))	('CIMP+', 'Chemical', '-', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('SETD2', 'Gene', (197, 202))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('MGMT', 'Gene', '4255', (23, 27))	('MGMT', 'Gene', (23, 27))	('MGMT', 'molecular_function', 'GO:0003908', ('23', '27'))	('tumors', 'Disease', (146, 152))	('MLH1', 'Gene', '4292', (32, 36))	('mutations', 'Var', (213, 222))
2443	25960768	We found co-occurrence of CCNE1 amplification and TP53 mutations in a subgroup derived from a mixture of BLCA, BRCA, UCEC, and LUAD tumors where all the samples were labeled as CIMP-.	('mutations', 'Var', (55, 64))	('CCNE1', 'Gene', '898', (26, 31))	('CCNE1', 'Gene', (26, 31))	('BRCA', 'Phenotype', 'HP:0003002', (111, 115))	('BRCA', 'Gene', '672', (111, 115))	('CIMP-', 'Chemical', '-', (177, 182))	('amplification', 'Var', (32, 45))	('TP53', 'Gene', '7157', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Gene', (111, 115))	('LUAD tumors', 'Disease', (127, 138))	('LUAD tumors', 'Disease', 'MESH:D009369', (127, 138))	('TP53', 'Gene', (50, 54))	('BLCA', 'Chemical', '-', (105, 109))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
2445	25960768	Other copy number events, such as amplification of the region containing NKX2 and FOXA1 or deletion of HERC2 were observed in subgroups with a majority of CIMP+ samples and a large fraction of LUAD but also a few BRCA tumors.	('BRCA tumors', 'Disease', 'MESH:D009369', (213, 224))	('NKX2', 'Gene', (73, 77))	('HERC2', 'Gene', (103, 108))	('deletion', 'Var', (91, 99))	('FOXA1', 'Gene', (82, 87))	('BRCA', 'Phenotype', 'HP:0003002', (213, 217))	('CIMP+', 'Chemical', '-', (155, 160))	('FOXA1', 'Gene', '3169', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('BRCA tumors', 'Disease', (213, 224))	('amplification', 'Var', (34, 47))	('HERC2', 'Gene', '8924', (103, 108))	('observed', 'Reg', (114, 122))
2446	25960768	Deletion of a region containing GALR1 was observed in a subset with a majority of CIMP+ tumors that came primarily from the COAD and HNSC types.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('GALR1', 'Gene', '2587', (32, 37))	('HNSC', 'Phenotype', 'HP:0012288', (133, 137))	('COAD', 'Disease', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CIMP+', 'Chemical', '-', (82, 87))	('GALR1', 'Gene', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('Deletion', 'Var', (0, 8))
2447	25960768	Our pan-cancer regression tree shows that VHL mutations correlate with significant reductions in average levels of CGI methylation in KIRC tumors (Additional file 1: Figure S2).	('reductions', 'NegReg', (83, 93))	('cancer', 'Disease', (8, 14))	('CGI methylation', 'MPA', (115, 130))	('mutations', 'Var', (46, 55))	('VHL', 'Disease', (42, 45))	('VHL', 'Disease', 'MESH:D006623', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
2448	25960768	Similarly, amplification of two chromosomal regions in chromosome 17, including ERBB2 (a.k.a.	('ERBB2', 'Gene', '2064', (80, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('amplification', 'Var', (11, 24))	('ERBB2', 'Gene', (80, 85))
2452	25960768	For example, our classification tree for BLCA highlights alterations affecting RB1 and ARID1A in CIMP+ tumors (Additional file 1: Figure S3), consistent with previous independent analyses.	('BLCA', 'Chemical', '-', (41, 45))	('RB1', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('RB1', 'Gene', '5925', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('CIMP+', 'Chemical', '-', (97, 102))	('tumors', 'Disease', (103, 109))	('alterations', 'Var', (57, 68))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('ARID1A', 'Gene', '8289', (87, 93))	('ARID1A', 'Gene', (87, 93))
2453	25960768	In BRCA, we found a strong association between CCND1 amplification and CIMP status (Additional file 1: Figures S3 and S4).	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('amplification', 'Var', (53, 66))	('CIMP', 'Chemical', '-', (71, 75))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (47, 52))	('CIMP status', 'Disease', (71, 82))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
2454	25960768	Also, the presence of MYC amplifications delineated a subset of samples that consisted entirely of CIMP- tumors (Additional file 1: Figure S3).	('MYC', 'Gene', '4609', (22, 25))	('CIMP- tumors', 'Disease', 'MESH:D009369', (99, 111))	('CIMP- tumors', 'Disease', (99, 111))	('delineated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MYC', 'Gene', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('presence', 'Var', (10, 18))	('amplifications', 'Var', (26, 40))
2455	25960768	This is consistent with reports from TCGA identifying MYC amplification and high-expression in basal-like breast tumors, which tend to be hypomethylated.	('breast tumors', 'Phenotype', 'HP:0100013', (106, 119))	('MYC', 'Gene', '4609', (54, 57))	('breast tumors', 'Disease', 'MESH:D001943', (106, 119))	('breast tumors', 'Disease', (106, 119))	('MYC', 'Gene', (54, 57))	('high-expression', 'Var', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
2456	25960768	In KIRC, the presence of either mutations or deletions affecting gene SETD2 and methylation of the GSTP1 promoter correlate with an important increase in the frequency of CIMP+ cases (Additional file 1: Figures S3 and S4).	('GSTP1', 'Gene', (99, 104))	('increase', 'PosReg', (142, 150))	('methylation', 'MPA', (80, 91))	('GSTP1', 'Gene', '2950', (99, 104))	('mutations', 'Var', (32, 41))	('CIMP+ cases', 'Disease', (171, 182))	('deletions', 'Var', (45, 54))	('SETD2', 'Gene', '29072', (70, 75))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))	('SETD2', 'Gene', (70, 75))	('CIMP+', 'Chemical', '-', (171, 176))
2457	25960768	Also in KIRC, we found that deletion of a genomic region containing CDKN2A and CDKN2B on chromosome 9 is associated with increased levels of CGI methylation (Additional file 1: Figure S4).	('CDKN2B', 'Gene', '1030', (79, 85))	('increased', 'PosReg', (121, 130))	('CDKN2A', 'Gene', (68, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('89', '99'))	('CDKN2A', 'Gene', '1029', (68, 74))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('deletion', 'Var', (28, 36))	('CGI methylation', 'MPA', (141, 156))	('CDKN2B', 'Gene', (79, 85))
2458	25960768	This kind of deletion has been linked to a more aggressive phenotype of clear cell carcinoma.	('linked to', 'Reg', (31, 40))	('deletion', 'Var', (13, 21))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (72, 92))	('clear cell carcinoma', 'Disease', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
2459	25960768	In LUSC, methylation of the RBP1 promoter and amplification of a region containing KDM5A correlate with an increase in average CGI methylation (Additional file 1: Figure S4).	('KDM5A', 'Gene', (83, 88))	('methylation', 'Var', (9, 20))	('RBP1', 'Gene', (28, 32))	('increase', 'PosReg', (107, 115))	('KDM5A', 'Gene', '5927', (83, 88))	('RBP1', 'Gene', '5947', (28, 32))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('CGI methylation', 'MPA', (127, 142))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))
2460	25960768	In UCEC, our data show that methylation of the MLH1 promoter results in a very high probability of CIMP+ status.	('MLH1', 'Gene', '4292', (47, 51))	('CIMP+ status', 'Disease', (99, 111))	('MLH1', 'Gene', (47, 51))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('CIMP+', 'Chemical', '-', (99, 104))
2461	25960768	For samples that do not exhibit this trait, the presence of TP53 mutations is associated with the opposite outcome.	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('presence', 'Var', (48, 56))	('mutations', 'Var', (65, 74))
2462	25960768	Among the remaining samples, PIK3R1 mutations are linked to increased CIMP+ rates (Additional file 1: Figure S3).	('CIMP+ rates', 'MPA', (70, 81))	('CIMP+', 'Chemical', '-', (70, 75))	('mutations', 'Var', (36, 45))	('PIK3R1', 'Gene', '5295', (29, 35))	('PIK3R1', 'Gene', (29, 35))	('increased', 'PosReg', (60, 69))
2463	25960768	Thus, the presence of tumor-specific mutations provides a potential link to predicting methylation status.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', (22, 27))
2469	25960768	For these three types, the median age of CIMP+ patients is higher than the median age in CIMP- (consistent with an independent study of CIMP+ status in COAD).	('COAD', 'Disease', 'MESH:D029424', (152, 156))	('CIMP+', 'Chemical', '-', (41, 46))	('patients', 'Species', '9606', (47, 55))	('CIMP+', 'Var', (41, 46))	('COAD', 'Disease', (152, 156))	('CIMP-', 'Chemical', '-', (89, 94))	('higher', 'PosReg', (59, 65))	('CIMP+', 'Chemical', '-', (136, 141))
2470	25960768	We found no statistical association between CIMP status and gender in any cancer type, except KIRC (P = 0.025, Fisher's exact test with Holm's correction), where we observed a significantly higher frequency of CIMP+ labels in male samples (45%, 58 of 128) than in female samples (22%, 15 of 66).	('CIMP+', 'Chemical', '-', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('CIMP+ labels', 'Var', (210, 222))	('cancer', 'Disease', (74, 80))	('CIMP', 'Chemical', '-', (44, 48))	('CIMP', 'Chemical', '-', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('higher', 'PosReg', (190, 196))
2477	25960768	These results are consistent with independent reports of MSI in CIMP-high colorectal tumors and also with the division between UCEC serous and endometrioid samples (largely CIMP- and CIMP+ in our analysis, respectively), where endometrioid tumors carry microsatellite instability and serous tumors do not.	('serous tumors', 'Disease', 'MESH:D018284', (284, 297))	('MSI', 'Disease', (57, 60))	('CIMP-', 'Chemical', '-', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('endometrioid tumors', 'Disease', (227, 246))	('serous tumors', 'Disease', (284, 297))	('microsatellite instability', 'Var', (253, 279))	('colorectal tumors', 'Disease', 'MESH:D015179', (74, 91))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('CIMP+', 'Chemical', '-', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('colorectal tumors', 'Disease', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('endometrioid tumors', 'Disease', 'MESH:D016889', (227, 246))	('CIMP-', 'Chemical', '-', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MSI', 'Disease', 'None', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
2478	25960768	Thus, the MSI characteristic appears to be associated with CIMP+ status and mutually exclusive with TP53 mutations and copy number variation.	('CIMP+', 'Chemical', '-', (59, 64))	('TP53', 'Gene', '7157', (100, 104))	('copy number variation', 'Var', (119, 140))	('MSI', 'Disease', 'None', (10, 13))	('TP53', 'Gene', (100, 104))	('MSI', 'Disease', (10, 13))	('associated', 'Reg', (43, 53))	('CIMP+ status', 'Var', (59, 71))
2481	25960768	This conclusion is consistent with trends reported by TCGA, where many luminal B samples showed a hypermethylator phenotype while basal-like samples were hypomethylated and associated with very high rates of TP53 mutations.	('mutations', 'Var', (213, 222))	('hypermethylator phenotype', 'MPA', (98, 123))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))
2488	25960768	This variation appears to be proportional to distance along the intestinal tract and is consistent with a previous study of colorectal cancer samples collected from three anatomic locations and assessed at eight CIMP-specific promoters using MethyLight technology, as well as independent reports of a gradual decrease in the frequency of BRAF mutations and microsatellite instability within this same region of the intestinal tract.	('BRAF', 'Gene', '673', (338, 342))	('microsatellite instability', 'MPA', (357, 383))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('colorectal cancer', 'Disease', (124, 141))	('CIMP-', 'Chemical', '-', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('decrease', 'NegReg', (309, 317))	('mutations', 'Var', (343, 352))	('BRAF', 'Gene', (338, 342))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
2491	25960768	Also in HNSC, CIMP- samples exhibited significantly better survival curves for recurrence free status than CIMP+ samples (Additional file 1: Figure S5B).	('CIMP- samples', 'Var', (14, 27))	('HNSC', 'Phenotype', 'HP:0012288', (8, 12))	('CIMP+', 'Chemical', '-', (107, 112))	('better', 'PosReg', (52, 58))	('HNSC', 'Disease', (8, 12))	('CIMP-', 'Chemical', '-', (14, 19))	('S5B', 'Gene', '5711', (148, 151))	('recurrence free status', 'MPA', (79, 101))	('S5B', 'Gene', (148, 151))
2495	25960768	This is consistent with our finding of recurrent CDKN2A and CDKN2B deletions in CIMP+ samples from KIRC patients mentioned earlier (Additional file 1: Figure S4), which were independently linked to a more clinically aggressive phenotype of kidney clear cell carcinoma.	('kidney clear cell carcinoma', 'Disease', (240, 267))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (240, 267))	('CDKN2A', 'Gene', '1029', (49, 55))	('deletions', 'Var', (67, 76))	('CIMP+', 'Chemical', '-', (80, 85))	('CDKN2B', 'Gene', (60, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('CDKN2B', 'Gene', '1030', (60, 66))	('linked to', 'Reg', (188, 197))	('CDKN2A', 'Gene', (49, 55))	('patients', 'Species', '9606', (104, 112))
2498	25960768	In fact, the association between CIMP status and histological subtype extends to tumor grade (an indicator of how quickly a tumor is likely to grow and spread based on microscopic appearance), where CIMP- samples exhibit higher grades than CIMP+ samples (Additional file 1: Figure S6B, P = 9.6 x 10-4, Fisher's exact test, Bonferroni correction).	('CIMP+', 'Chemical', '-', (240, 245))	('higher', 'PosReg', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CIMP', 'Chemical', '-', (33, 37))	('tumor', 'Disease', (124, 129))	('CIMP-', 'Var', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CIMP-', 'Chemical', '-', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CIMP', 'Chemical', '-', (240, 244))	('CIMP', 'Chemical', '-', (199, 203))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
2500	25960768	Overall, our results support the existence of both commonalities and tissue-specific differences in CGI hypermethylation patterns across tumors.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('hypermethylation', 'Var', (104, 120))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
2501	25960768	The most important similarity found in our analysis is the existence of consistent levels of average CGI hypermethylation that correlate with CIMP status and are independent of cancer type (Figure 2B,C).	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('CGI', 'Protein', (101, 104))	('hypermethylation', 'Var', (105, 121))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('CIMP', 'Chemical', '-', (142, 146))
2503	25960768	Our genome-wide analyses (Additional file 1: Figure S1) show that much of the focal, cancer-related CGI hypermethylation occurs at loci that exhibit consistently baseline levels of methylation in control samples.	('hypermethylation', 'Var', (104, 120))	('CGI', 'Disease', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('methylation', 'biological_process', 'GO:0032259', ('181', '192'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
2507	25960768	For example, significantly recurrent functional events in CIMP+ samples correspond to mutated genes or silencing of MLH1 and MGMT, while recurrent events in CIMP- consist primarily of chromosomal amplifications and TP53 mutations (Table 2).	('MGMT', 'molecular_function', 'GO:0003908', ('125', '129'))	('CIMP+', 'Chemical', '-', (58, 63))	('MGMT', 'Gene', (125, 129))	('mutated genes', 'Var', (86, 99))	('MLH1', 'Gene', (116, 120))	('MGMT', 'Gene', '4255', (125, 129))	('MLH1', 'Gene', '4292', (116, 120))	('TP53', 'Gene', '7157', (215, 219))	('CIMP-', 'Chemical', '-', (157, 162))	('mutations', 'Var', (220, 229))	('TP53', 'Gene', (215, 219))	('silencing', 'NegReg', (103, 112))
2512	25960768	While mutations in gene H3F3A, which encodes histone variant H3.3, have been correlated with specific DNA methylation subgroups in pediatric glioblastoma, our analysis of upstream regulators implicates involvement in most of the cancer types that we evaluated, with the exception of LUAD and BLCA (Figure 3B).	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('cancer', 'Disease', (229, 235))	('H3F3A', 'Gene', '3020', (24, 29))	('BLCA', 'Chemical', '-', (292, 296))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (131, 153))	('correlated', 'Reg', (77, 87))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('H3F3A', 'Gene', (24, 29))	('involvement', 'Reg', (202, 213))	('LUAD', 'Phenotype', 'HP:0030078', (283, 287))	('LUAD', 'Disease', (283, 287))	('BLCA', 'Disease', (292, 296))	('pediatric glioblastoma', 'Disease', (131, 153))	('mutations', 'Var', (6, 15))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
2514	25960768	Loss-of-function mutations in the demethylating enzyme TET2 have been previously associated to CIMP in leukemia, and our results reveal recurrence of this mutation in CIMP+ for other types such as UCEC and READ (Figure 6A).	('Loss-of-function', 'NegReg', (0, 16))	('CIMP', 'Disease', (95, 99))	('TET2', 'Gene', (55, 59))	('UCEC', 'Disease', (197, 201))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('CIMP', 'Chemical', '-', (167, 171))	('CIMP', 'Chemical', '-', (95, 99))	('leukemia', 'Disease', (103, 111))	('READ', 'Disease', (206, 210))	('TET2', 'Gene', '54790', (55, 59))	('CIMP+', 'Chemical', '-', (167, 172))	('mutations', 'Var', (17, 26))
2515	25960768	Also, mutations of ARID1A have been linked to MSI and CIMP in gastrointestinal cancers, and our results indicate importance in UCEC and BLCA.	('MSI', 'Disease', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CIMP', 'Chemical', '-', (54, 58))	('BLCA', 'Disease', (136, 140))	('ARID1A', 'Gene', (19, 25))	('MSI', 'Disease', 'None', (46, 49))	('UCEC', 'Disease', (127, 131))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (62, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('linked', 'Reg', (36, 42))	('gastrointestinal cancers', 'Disease', (62, 86))	('ARID1A', 'Gene', '8289', (19, 25))	('BLCA', 'Chemical', '-', (136, 140))	('mutations', 'Var', (6, 15))
2516	25960768	BRAF mutations, which are perhaps one of the most commonly accepted indicator events for CIMP in colorectal cancers, also appear to be relevant in LUAD, but not the other tumor types.	('colorectal cancers', 'Disease', (97, 115))	('LUAD', 'Disease', (147, 151))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mutations', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('BRAF', 'Gene', '673', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colorectal cancers', 'Disease', 'MESH:D015179', (97, 115))	('CIMP', 'Chemical', '-', (89, 93))	('BRAF', 'Gene', (0, 4))	('tumor', 'Disease', (171, 176))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
2517	25960768	For example, amplification of genes PIK3CA and CCNE1 occur significantly more frequently in CIMP- samples.	('CCNE1', 'Gene', '898', (47, 52))	('PIK3CA', 'Gene', '5290', (36, 42))	('CCNE1', 'Gene', (47, 52))	('CIMP-', 'Chemical', '-', (92, 97))	('CIMP- samples', 'Disease', (92, 105))	('amplification', 'Var', (13, 26))	('PIK3CA', 'Gene', (36, 42))
2519	25960768	Our pan-cancer regression tree revealed global CGI hypomethylation in samples with mutated NSD1, which came primarily from the HNSC data set (Additional file 1: Figure S2).	('NSD1', 'Gene', (91, 95))	('mutated', 'Var', (83, 90))	('cancer', 'Disease', (8, 14))	('hypomethylation', 'Var', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('HNSC', 'Phenotype', 'HP:0012288', (127, 131))	('NSD1', 'Gene', '64324', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
2521	25960768	Our results also linked mutations in KDM6A, a H3K27me3 demethylase, to decreased CpG island methylation (Additional file 1: Figure S2).	('KDM6A', 'Gene', '7403', (37, 42))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('KDM6A', 'Gene', (37, 42))	('CpG island methylation', 'MPA', (81, 103))	('mutations', 'Var', (24, 33))	('decreased', 'NegReg', (71, 80))
2527	25960768	Our results help to clarify this apparent contradiction by showing that poor survival could be associated with luminal B patients with CIMP+ status and that luminal B patients with CIMP- can have good survival outcomes (Figure 8B).	('CIMP+ status', 'Var', (135, 147))	('patients', 'Species', '9606', (167, 175))	('CIMP+', 'Chemical', '-', (135, 140))	('CIMP-', 'Chemical', '-', (181, 186))	('patients', 'Species', '9606', (121, 129))	('poor', 'NegReg', (72, 76))
2528	25960768	Interestingly, the situation is reversed in luminal A tumors, where CIMP+ status is associated to good survival and CIMP- status is associated with poor survival (as originally reported by Fang et al.).	('poor', 'NegReg', (148, 152))	('luminal A tumors', 'Disease', 'MESH:D009369', (44, 60))	('CIMP-', 'Chemical', '-', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('luminal A tumors', 'Disease', (44, 60))	('CIMP+', 'Chemical', '-', (68, 73))	('CIMP- status', 'Var', (116, 128))
2545	25960768	In the case of the KIRP dataset, we excluded nine tumor samples that behaved as outliers based on PCA plots computed over variably methylated probes (these tumor samples clustered together with each other, away from the rest of tumors and closer to the set of controls; the actual sample IDs were TCGA-A4-7915-01, TCGA-F9-A4JJ-01, TCGA-G7-6793-01, TCGA-GL-7966-01, TCGA-P4-A5E8-01, TCGA-P4-A5EA-01, TCGA-BQ-5879-01, TCGA-BQ-5893-01, TCGA-BQ-5894-01).	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (156, 161))	('TCGA-G7-6793-01', 'CellLine', 'CVCL:4V47', (331, 346))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('TCGA-BQ-5893-01', 'Var', (416, 431))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('TCGA-G7-6793-01', 'Var', (331, 346))	('tumors', 'Disease', (228, 234))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TCGA-F9-A4JJ-01', 'Var', (314, 329))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('TCGA-BQ-5893-01', 'CellLine', 'CVCL:6383', (416, 431))	('TCGA-P4-A5EA-01', 'Var', (382, 397))	('TCGA-GL-7966-01', 'CellLine', 'CVCL:Y146', (348, 363))	('EA-01', 'CellLine', 'CVCL:E575', (392, 397))	('TCGA-BQ-5879-01', 'CellLine', 'CVCL:6383', (399, 414))	('TCGA-BQ-5894-01', 'CellLine', 'CVCL:6383', (433, 448))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TCGA-F9-A4JJ-01', 'CellLine', 'CVCL:D605', (314, 329))
2564	25960768	For every cancer type, we observe differences in beta values of at least 0.1 and 0.3 when the variably methylated set and the differentially methylated set, respectively, are used to estimate average per-probe methylation in the CIMP+ and CIMP- subsets of samples.	('CIMP-', 'Chemical', '-', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('CIMP+', 'Chemical', '-', (229, 234))	('methylation', 'Var', (210, 221))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('methylation', 'biological_process', 'GO:0032259', ('210', '221'))
2588	25960768	For the comparison of the average number of mutation, amplification and deletion events per sample shown in Figure 6B, we provide a bar plot showing mean number of events of each category for each individual cancer type.	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('deletion', 'Var', (72, 80))	('amplification', 'MPA', (54, 67))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
2604	24478461	Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers.	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('found', 'Reg', (99, 104))	('BRCA', 'Phenotype', 'HP:0003002', (34, 38))	('BRCA1', 'Gene', '672', (34, 39))	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Phenotype', 'HP:0003002', (152, 156))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('BRCA1', 'Gene', '672', (152, 157))	('BECN1', 'Gene', (44, 49))	('BRCA1', 'Gene', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('BRCA1', 'Gene', (152, 157))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRCA1 loss', 'Disease', 'MESH:D015431', (152, 162))	('ovarian cancers', 'Phenotype', 'HP:0100615', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRCA1', 'Gene', '672', (73, 78))	('BRCA1', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (108, 134))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('deletions', 'Var', (55, 64))	('BRCA1 loss', 'Disease', (152, 162))
2605	24478461	Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers.	('tumor', 'Disease', (119, 124))	('BECN1', 'Gene', (39, 44))	('human', 'Species', '9606', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('cancer', 'Disease', (150, 156))	('mutation', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('loss', 'NegReg', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
2608	24478461	Monoallelic disruption of BECN1 on chromosome 17q21 has been reported in 40 to 75% of human breast, ovarian, and prostate tumors, suggesting that autophagy is a tumor suppression mechanism.	('prostate tumors', 'Disease', (113, 128))	('ovarian', 'Disease', (100, 107))	('breast', 'Disease', (92, 98))	('prostate tumors', 'Disease', 'MESH:D011471', (113, 128))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('autophagy', 'biological_process', 'GO:0016236', ('146', '155'))	('BECN1', 'Gene', (26, 31))	('autophagy', 'CPA', (146, 155))	('human', 'Species', '9606', (86, 91))	('Monoallelic disruption', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('autophagy', 'biological_process', 'GO:0006914', ('146', '155'))	('reported', 'Reg', (61, 69))
2609	24478461	BECN1 allelic loss was also found in 9 out of 22 breast cancer cell lines by fluorescence in situ hybridization (FISH) analysis, although no coding or splice site mutations were found.	('BECN1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('allelic', 'Var', (6, 13))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('loss', 'NegReg', (14, 18))
2612	24478461	BRCA1 is a critical regulator of DNA repair by homologous recombination (HR) and its loss causes DNA repair defects and cancer predisposition.	('loss', 'Var', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('DNA repair', 'biological_process', 'GO:0006281', ('33', '43'))	('BRCA1', 'Gene', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('DNA repair', 'biological_process', 'GO:0006281', ('97', '107'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('homologous recombination', 'biological_process', 'GO:0035825', ('47', '71'))	('causes', 'Reg', (90, 96))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('DNA repair', 'MPA', (97, 107))
2615	24478461	In support of the concept that autophagy is a tumor suppression mechanism and that allelic loss of BECN1 promotes cancer, Beclin1+/- mice are prone to mammary hyperplasia, liver and lung carcinomas and lymphomas.	('hyperplasia', 'Disease', (159, 170))	('liver and lung carcinomas and lymphomas', 'Disease', 'MESH:D006528', (172, 211))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('hyperplasia', 'Disease', 'MESH:D006965', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Beclin1', 'Gene', '56208', (122, 129))	('autophagy', 'biological_process', 'GO:0016236', ('31', '40'))	('Beclin1', 'Gene', (122, 129))	('BECN1', 'Gene', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('promotes', 'PosReg', (105, 113))	('autophagy', 'biological_process', 'GO:0006914', ('31', '40'))	('mammary hyperplasia', 'Phenotype', 'HP:0010313', (151, 170))	('tumor', 'Disease', (46, 51))	('lymphomas', 'Phenotype', 'HP:0002665', (202, 211))	('loss', 'Var', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('prone', 'Reg', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (202, 210))	('cancer', 'Disease', (114, 120))
2616	24478461	However, mosaic whole body knock out of the essential autophagy gene Atg5, or liver-specific knock out of the essential autophagy gene Atg7, produces only benign liver hepatomas and no other neoplasms.	('autophagy', 'biological_process', 'GO:0006914', ('120', '129'))	('autophagy', 'biological_process', 'GO:0006914', ('54', '63'))	('benign liver hepatomas', 'Disease', (155, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (191, 200))	('Atg5', 'Gene', (69, 73))	('Atg7', 'Gene', (135, 139))	('benign liver hepatomas', 'Disease', 'MESH:D018248', (155, 177))	('knock out', 'Var', (27, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (191, 199))	('neoplasms', 'Disease', 'MESH:D009369', (191, 200))	('neoplasms', 'Disease', (191, 200))	('knock out', 'Var', (93, 102))	('autophagy', 'biological_process', 'GO:0016236', ('120', '129'))	('autophagy', 'biological_process', 'GO:0016236', ('54', '63'))
2619	24478461	The vast majority of germline mutations in BRCA1 are loss-of-function mutations (frameshift, indels, nonsense mutations, or missense), or focal deletions, not gross deletions in the BRCA1 locus at 17q21 that extend to encompass BECN1.	('BRCA1', 'Gene', (43, 48))	('BRCA1', 'Gene', '672', (182, 187))	('deletions', 'Var', (144, 153))	('missense', 'Var', (124, 132))	('BRCA1', 'Gene', (182, 187))	('frameshift', 'Var', (81, 91))	('nonsense mutations', 'Var', (101, 119))	('germline mutations', 'Var', (21, 39))	('BRCA', 'Phenotype', 'HP:0003002', (43, 47))	('BRCA1', 'Gene', '672', (43, 48))	('BRCA', 'Phenotype', 'HP:0003002', (182, 186))	('loss-of-function', 'NegReg', (53, 69))
2623	24478461	Without autophagy tumors accumulate defective mitochondria, have growth and metabolic defects, and progresses to a more benign fate.	('defective', 'Var', (36, 45))	('progresses', 'PosReg', (99, 109))	('growth', 'CPA', (65, 71))	('metabolic defects', 'Disease', (76, 93))	('autophagy tumors', 'Disease', (8, 24))	('more benign fate', 'CPA', (115, 131))	('autophagy tumors', 'Disease', 'MESH:C564093', (8, 24))	('metabolic defects', 'Disease', 'MESH:D008659', (76, 93))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('autophagy', 'biological_process', 'GO:0016236', ('8', '17'))	('mitochondria', 'cellular_component', 'GO:0005739', ('46', '58'))	('autophagy', 'biological_process', 'GO:0006914', ('8', '17'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
2625	24478461	Germline mutations in BRCA1, BRCA2, and PALB2, predispose to hereditary breast cancer and the three proteins function together to maintain genome stability by promoting faithful repair of double strand breaks by HR.	('Germline mutations', 'Var', (0, 18))	('PALB2', 'Gene', (40, 45))	('PALB2', 'Gene', '79728', (40, 45))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (61, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('genome', 'MPA', (139, 145))	('maintain', 'PosReg', (130, 138))	('faithful repair', 'MPA', (169, 184))	('BRCA2', 'Gene', (29, 34))	('predispose', 'Reg', (47, 57))	('hereditary breast cancer', 'Disease', (61, 85))	('promoting', 'PosReg', (159, 168))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('function', 'Reg', (109, 117))	('BRCA1', 'Gene', '672', (22, 27))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA', 'Phenotype', 'HP:0003002', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('BRCA1', 'Gene', (22, 27))
2626	24478461	Mammary epithelial cell-specific knockout of Palb2 causes mammary tumorigenesis with long latency that is suppressed by allelic loss of Becnl, suggesting that autophagy is tumor-promoting.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('knockout', 'Var', (33, 41))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (172, 177))	('autophagy', 'biological_process', 'GO:0016236', ('159', '168'))	('Palb2', 'Gene', '79728', (45, 50))	('causes', 'Reg', (51, 57))	('autophagy', 'biological_process', 'GO:0006914', ('159', '168'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('Palb2', 'Gene', (45, 50))
2627	24478461	Deletion of Trp53 abrogates tumorigenesis impairment upon allelic loss of Becnl in Pa/fr2-deficient mammary tumors, thus the combination of autophagy defect and loss of a critical DNA repair mechanism augments the p53 anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('Pa/fr2-deficient mammary tumors', 'Disease', (83, 114))	('autophagy', 'biological_process', 'GO:0016236', ('140', '149'))	('impairment', 'NegReg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Pa/fr2-deficient mammary tumors', 'Disease', 'MESH:D015674', (83, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('p53', 'Gene', '7157', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('augments', 'PosReg', (201, 209))	('abrogates', 'NegReg', (18, 27))	('Deletion', 'Var', (0, 8))	('autophagy', 'biological_process', 'GO:0006914', ('140', '149'))	('tumor', 'Disease', (223, 228))	('p53', 'Gene', '7157', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p53', 'Gene', (214, 217))	('Trp53', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('Trp53', 'Gene', '7157', (12, 17))	('p53', 'Gene', (14, 17))	('DNA repair', 'biological_process', 'GO:0006281', ('180', '190'))	('autophagy defect and loss', 'Disease', 'MESH:C564093', (140, 165))
2628	24478461	Since loss of both Palb2 and autophagy promote DNA damage and p53 activation,, this explains enhanced p53 activity and why autophagy suppresses the p53 response and mammary tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('p53', 'Gene', '7157', (62, 65))	('activation', 'PosReg', (66, 76))	('loss', 'Var', (6, 10))	('autophagy', 'CPA', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (62, 65))	('autophagy', 'biological_process', 'GO:0016236', ('123', '132'))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('autophagy', 'biological_process', 'GO:0016236', ('29', '38'))	('promote', 'PosReg', (39, 46))	('Palb2', 'Gene', (19, 24))	('p53', 'Gene', '7157', (148, 151))	('DNA damage', 'MPA', (47, 57))	('enhanced', 'PosReg', (93, 101))	('Palb2', 'Gene', '79728', (19, 24))	('p53', 'Gene', (102, 105))	('p53', 'Gene', (148, 151))	('autophagy', 'biological_process', 'GO:0006914', ('123', '132'))	('autophagy', 'biological_process', 'GO:0006914', ('29', '38'))	('suppresses', 'NegReg', (133, 143))	('tumor', 'Disease', (173, 178))	('activity', 'MPA', (106, 114))
2629	24478461	The important unanswered question here is whether mutations in essential autophagy genes are found in human cancers using current genomic information, and if they are found, are they loss- or gain-of-function mutations?	('loss-', 'NegReg', (183, 188))	('mutations', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('gain-of-function', 'PosReg', (192, 208))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('autophagy', 'biological_process', 'GO:0006914', ('73', '82'))	('autophagy', 'biological_process', 'GO:0016236', ('73', '82'))	('autophagy genes', 'Gene', (73, 88))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
2632	24478461	We first assessed BECN1 for single nucleotide variations (SNVs) and copy number variations (CNVs) in human breast, ovarian and prostate cancer genome sequences.	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('human', 'Species', '9606', (101, 106))	('single nucleotide variations', 'Var', (28, 56))	('copy number variations', 'Var', (68, 90))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (115, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
2633	24478461	Since BECN1 is adjacent to BRCA1, we specifically looked for deletions of BECN1 that do not encompass BRCA1.	('BRCA1', 'Gene', (102, 107))	('BECN1', 'Gene', (74, 79))	('deletions', 'Var', (61, 70))	('BRCA1', 'Gene', '672', (27, 32))	('BRCA1', 'Gene', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (102, 106))	('BRCA1', 'Gene', '672', (102, 107))	('BRCA', 'Phenotype', 'HP:0003002', (27, 31))
2634	24478461	We found enrichment for truncating mutations of BRCA1, deletion of the chromosomal region that included BRCA1 only, and deletions affecting both BRCA1 and BECN1, but not truncating mutations of BECN1 or deletions of only BECN1.	('BRCA1', 'Gene', '672', (48, 53))	('deletions', 'Var', (120, 129))	('BRCA', 'Phenotype', 'HP:0003002', (48, 52))	('BRCA1', 'Gene', '672', (104, 109))	('BRCA', 'Phenotype', 'HP:0003002', (145, 149))	('BRCA1', 'Gene', (48, 53))	('BRCA1', 'Gene', '672', (145, 150))	('BRCA1', 'Gene', (104, 109))	('chromosomal region', 'cellular_component', 'GO:0098687', ('71', '89'))	('BRCA1', 'Gene', (145, 150))	('deletion', 'Var', (55, 63))	('truncating', 'MPA', (24, 34))	('BECN1', 'Gene', (155, 160))	('BRCA', 'Phenotype', 'HP:0003002', (104, 108))
2635	24478461	Analysis of all other cancers that lack BRCA1 deletion indicated no significant recurrence of SNVs or CNVs in BECN1.	('deletion', 'Var', (46, 54))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('BRCA', 'Phenotype', 'HP:0003002', (40, 44))	('BRCA1', 'Gene', '672', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('SNVs', 'Disease', (94, 98))	('BRCA1', 'Gene', (40, 45))
2642	24478461	We test the sensitivity of our method by finding the previously reported CNV (amplifications in PIK3CA, EGFR, FOXA1 and HER2; de/etions in MLL3, PTEN, RB1 and MAP2K4) in breast invasive cancer.	('MAP2K4', 'Gene', '6416', (159, 165))	('MAP2K4', 'Gene', (159, 165))	('HER2', 'Gene', '2064', (120, 124))	('PIK3CA', 'Gene', '5290', (96, 102))	('FOXA1', 'Gene', '3169', (110, 115))	('EGFR', 'Gene', (104, 108))	('RB1', 'Gene', '5925', (151, 154))	('MAP2K', 'molecular_function', 'GO:0004708', ('159', '164'))	('MLL3', 'Gene', '58508', (139, 143))	('FOXA1', 'Gene', (110, 115))	('de/etions', 'Var', (126, 135))	('PTEN', 'Gene', (145, 149))	('HER2', 'Gene', (120, 124))	('PIK3CA', 'Gene', (96, 102))	('EGFR', 'Gene', '1956', (104, 108))	('MLL3', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('breast invasive cancer', 'Disease', 'MESH:D001943', (170, 192))	('breast invasive cancer', 'Disease', (170, 192))	('RB1', 'Gene', (151, 154))
2647	24478461	We extracted the somatic mutations for BECN1 and BRCA1 and indicated their type as missense, nonsense, silent, splice site, and insertion or deletion resulting in frame shift or in frame (Table S3 and Table S4).	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('nonsense', 'Var', (93, 101))	('deletion', 'Var', (141, 149))	('BECN1', 'Gene', (39, 44))	('missense', 'Var', (83, 91))	('BRCA1', 'Gene', '672', (49, 54))	('frame', 'MPA', (163, 168))	('BRCA1', 'Gene', (49, 54))	('insertion', 'Var', (128, 137))
2651	24478461	CNVs were classified into three groups defined by whether the CNV overlapped with BECN1 but not BRCA1, overlapped with BRCA1 but not BECN1, or overlapped with both BECN1 and BRCA1 (Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (96, 100))	('BRCA1', 'Gene', (174, 179))	('BRCA1', 'Gene', (119, 124))	('BRCA1', 'Gene', '672', (96, 101))	('BRCA1', 'Gene', (96, 101))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('BRCA', 'Phenotype', 'HP:0003002', (174, 178))	('BRCA1', 'Gene', '672', (174, 179))	('BRCA1', 'Gene', '672', (119, 124))	('overlapped', 'Var', (103, 113))
2653	24478461	As expected, breast and ovarian tumors were significantly enriched for having deletions in the locus containing both BECN1 and BRCA1 (Table 1).	('BRCA1', 'Gene', '672', (127, 132))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (13, 38))	('BRCA1', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('BRCA', 'Phenotype', 'HP:0003002', (127, 131))	('ovarian tumor', 'Phenotype', 'HP:0100615', (24, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('BECN1', 'Gene', (117, 122))	('ovarian tumors', 'Phenotype', 'HP:0100615', (24, 38))	('deletions', 'Var', (78, 87))
2654	24478461	Other tumor types that exhibited significant enrichment for deletions in both BECN1 and BRCA1 include kidney chromophobe and uterine corpus endometrioid carcinoma (Table 1).	('BRCA1', 'Gene', (88, 93))	('kidney chromophobe', 'Disease', 'MESH:D000238', (102, 120))	('corpus endometrioid carcinoma', 'Disease', (133, 162))	('corpus endometrioid carcinoma', 'Disease', 'MESH:D016889', (133, 162))	('BECN1', 'Gene', (78, 83))	('deletions', 'Var', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('kidney chromophobe', 'Disease', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BRCA1', 'Gene', '672', (88, 93))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (140, 162))	('tumor', 'Disease', (6, 11))
2656	24478461	Closer examination found that the CNVs in kidney chromophobe and kidney renal papillary cell carcinoma are whole chromosome deletions and amplifications, respectively, which are consistent with known loss and gain of chromosome 17 for these two types of tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumors', 'Disease', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('chromosome', 'cellular_component', 'GO:0005694', ('217', '227'))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (72, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('CNVs', 'Var', (34, 38))	('kidney chromophobe and kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007674', (42, 102))
2657	24478461	CNVs that overlap BRCA1 but not BECN1 were enriched for deletions in breast and ovarian tumors, while CNVs that overlap BECN1 but not BRCA1 were not enriched for deletions in any tumor (Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (134, 139))	('ovarian tumors', 'Phenotype', 'HP:0100615', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('ovarian tumor', 'Phenotype', 'HP:0100615', (80, 93))	('BECN1', 'Gene', (120, 125))	('BRCA1', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('deletions', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('BRCA', 'Phenotype', 'HP:0003002', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (69, 94))	('BRCA1', 'Gene', '672', (134, 139))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (179, 184))
2658	24478461	These results are consistent with the loss of BRCA1 being the driver mutation in breast and ovarian tumors.	('loss', 'Var', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BRCA1', 'Gene', '672', (46, 51))	('ovarian tumors', 'Phenotype', 'HP:0100615', (92, 106))	('ovarian tumor', 'Phenotype', 'HP:0100615', (92, 105))	('BRCA', 'Phenotype', 'HP:0003002', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (81, 106))	('BRCA1', 'Gene', (46, 51))
2660	24478461	Loss of chromosome 17q21 and BRCA1 has been reported in prostate cancer only very infrequently (0.45%).	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA1', 'Gene', '672', (29, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('BRCA1', 'Gene', (29, 34))	('Loss', 'Var', (0, 4))	('prostate cancer', 'Disease', (56, 71))
2661	24478461	For prostate adenocarcinoma, we found 9 deletions (covering both BECN1 and BRCA1) and no amplifications (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('BRCA1', 'Gene', (75, 80))	('prostate adenocarcinoma', 'Disease', (4, 27))	('deletions', 'Var', (40, 49))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (4, 27))	('BECN1', 'Gene', (65, 70))	('BRCA', 'Phenotype', 'HP:0003002', (75, 79))	('BRCA1', 'Gene', '672', (75, 80))
2662	24478461	Prostate adenocarcinoma is a heterogeneous disease and the fraction of this disease where loss of 17q21 is a driver mutation is small compared to breast or ovarian cancer.	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (146, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (0, 23))	('17q21', 'Gene', (98, 103))	('breast or ovarian cancer', 'Disease', (146, 170))	('Prostate adenocarcinoma', 'Disease', (0, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('loss of', 'Var', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
2663	24478461	It is clear, however, that in contrast to previous reports, BECN1 deletions do not significantly occur in the absence of BRCA1 deletion.	('BRCA', 'Phenotype', 'HP:0003002', (121, 125))	('BECN1', 'Gene', (60, 65))	('BRCA1', 'Gene', '672', (121, 126))	('BRCA1', 'Gene', (121, 126))	('deletions', 'Var', (66, 75))
2664	24478461	There are 169 and 32 (ratio of 5.28) mutations found in BRCA1 and BECN1 respectively across all tumor samples (6632) and the numbers are 137 and 31 (ratio of 4.42) if we exclude breast and ovarian tumors where BRCA1 is known to be a tumor suppressor (Table S2).	('BRCA', 'Phenotype', 'HP:0003002', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('ovarian tumor', 'Phenotype', 'HP:0100615', (189, 202))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('ovarian tumors', 'Phenotype', 'HP:0100615', (189, 203))	('tumor', 'Disease', (233, 238))	('BRCA1', 'Gene', '672', (210, 215))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('233', '249'))	('BRCA1', 'Gene', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('BECN1', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA', 'Phenotype', 'HP:0003002', (56, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('233', '249'))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (37, 46))	('BRCA1', 'Gene', (56, 61))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (178, 203))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (197, 202))
2666	24478461	None of the mutations found in BECN1 were nonsense or splice site mutations (Table S3) with the potential to alter function and that are frequently found tumor suppressor mutations.	('mutations', 'Var', (12, 21))	('alter', 'Reg', (109, 114))	('tumor suppressor', 'biological_process', 'GO:0051726', ('154', '170'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('154', '170'))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('BECN1', 'Gene', (31, 36))	('function', 'MPA', (115, 123))	('tumor', 'Disease', (154, 159))
2667	24478461	If we restrict analysis to breast and ovarian cancer, there is only one mutation found in BECN1 and it is a missense mutation in an ovarian tumor.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (27, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('ovarian tumor', 'Phenotype', 'HP:0100615', (132, 145))	('ovarian tumor', 'Disease', 'MESH:D010051', (132, 145))	('missense mutation', 'Var', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('BECN1', 'Gene', (90, 95))	('ovarian tumor', 'Disease', (132, 145))
2668	24478461	In contrast, there are 32 mutations in BRCA1 of which 23 are nonsense, splice site or frame shift mutations all of which lead to truncation of BRCA1 (Table S4).	('BRCA1', 'Gene', '672', (143, 148))	('truncation', 'MPA', (129, 139))	('BRCA1', 'Gene', (143, 148))	('BRCA', 'Phenotype', 'HP:0003002', (143, 147))	('BRCA', 'Phenotype', 'HP:0003002', (39, 43))	('mutations', 'Var', (26, 35))	('BRCA1', 'Gene', '672', (39, 44))	('lead to', 'Reg', (121, 128))	('frame shift', 'Var', (86, 97))	('BRCA1', 'Gene', (39, 44))
2669	24478461	Across all cancer data from TCGA, there are 30 missense, 0 nonsense, 0 splice site and 11 silent mutations for BECN1 and 135 missense, 20 nonsense, 12 splice site and 39 silent mutations for BRCA1.	('BRCA1', 'Gene', (191, 196))	('missense', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA', 'Phenotype', 'HP:0003002', (191, 195))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('missense', 'Var', (125, 133))	('BRCA1', 'Gene', '672', (191, 196))	('cancer', 'Disease', (11, 17))	('BECN1', 'Gene', (111, 116))
2670	24478461	To find statistical enrichment of missense, nonsense or splice site mutations compared to silent mutations, we use as null model the aggregate of mutations across all samples in breast cancer (778 tumors) yielding 31861 missense, 2339 nonsense, 1075 splice site and 11677 silent mutations.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('missense', 'Var', (220, 228))	('nonsense', 'Var', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (178, 191))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))
2671	24478461	Since the vast majority of mutations detected in tumors are passenger mutations with little or no selective advantage to the tumors, the ratio of missense to silent mutations (2.73), nonsense to silent mutations (0.20), and splice site to silent mutations (0.09) are good approximations for little or no selection of missense, nonsense or splice site over silent mutations.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))
2673	24478461	There is statistically significant enrichment for ratio of nonsense to silent and splice site to silent mutations for BRCA1 (2.6 and 3.4 fold enrichment with p-value of 0.0008 and 0.0003 using two-tailed Chi-square test with Yate's correction).	('BRCA1', 'Gene', (118, 123))	('nonsense', 'Var', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('BRCA1', 'Gene', '672', (118, 123))
2674	24478461	There is no significant enrichment for missense over silent mutations for BRCA1 and BECN1, and no enrichment of nonsense and splice site over silent mutations in BECN1.	('BECN1', 'Gene', (84, 89))	('BRCA1', 'Gene', '672', (74, 79))	('BRCA', 'Phenotype', 'HP:0003002', (74, 78))	('BRCA1', 'Gene', (74, 79))	('missense', 'Var', (39, 47))	('BECN1', 'Gene', (162, 167))
2678	24478461	Despite reports indicating allelic loss of BECN1 in some human cancers, this appears to be explained solely by the proximity of BECN1 to BRCA1.	('BRCA1', 'Gene', '672', (137, 142))	('BECN1', 'Gene', (43, 48))	('loss', 'NegReg', (35, 39))	('BRCA1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('allelic', 'Var', (27, 34))	('BRCA', 'Phenotype', 'HP:0003002', (137, 141))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('human', 'Species', '9606', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
2681	24478461	Furthermore, there is no finding of nonsense or splice site mutations in BECN1 in any other cancers.	('nonsense or splice site mutations', 'Var', (36, 69))	('BECN1', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
2683	24478461	In these cancers, the majority of the deletions are large and take out both genes and a hundred others.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('deletions', 'Var', (38, 47))
2684	24478461	While focal deletions and somatic, predicted loss of function mutations (missense, nonsense, frame shift and splice site mutations) are found in BRCA1, they are not found in BECN1.	('BRCA', 'Phenotype', 'HP:0003002', (145, 149))	('BRCA1', 'Gene', '672', (145, 150))	('loss of function', 'NegReg', (45, 61))	('BRCA1', 'Gene', (145, 150))	('nonsense', 'Var', (83, 91))	('frame shift', 'Var', (93, 104))
2685	24478461	Furthermore, there are no significant germline mutation or allelic loss of BECN1 in breast and ovarian cancer patients, nor are there inactivating mutations in the absence of BRCA1 mutation or loss.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA1', 'Gene', (175, 180))	('BECN1', 'Gene', (75, 80))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))	('loss', 'NegReg', (67, 71))	('mutation', 'Var', (181, 189))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (84, 109))	('BRCA', 'Phenotype', 'HP:0003002', (175, 179))	('patients', 'Species', '9606', (110, 118))	('BRCA1', 'Gene', '672', (175, 180))
2687	24478461	Indeed, allelic loss of Becnl suppresses rather than promotes mammary tumorgenesis mediated by Palb2 deficiency.	('promotes', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Palb2', 'Gene', '79728', (95, 100))	('Becnl', 'Gene', (24, 29))	('suppresses', 'NegReg', (30, 40))	('tumor', 'Disease', (70, 75))	('Palb2', 'Gene', (95, 100))	('deficiency', 'Var', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
2690	24478461	Mice with allelic loss of Becnl, or bi-allelic deletion of Atg5 or Atg7 in liver are prone to liver tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('loss', 'NegReg', (18, 22))	('bi-allelic deletion', 'Var', (36, 55))	('Atg5', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Atg7', 'Gene', (67, 71))	('Mice', 'Species', '10090', (0, 4))	('liver tumors', 'Disease', 'MESH:D008113', (94, 106))	('prone', 'Reg', (85, 90))	('liver tumors', 'Phenotype', 'HP:0002896', (94, 106))	('liver tumors', 'Disease', (94, 106))
2692	24478461	Indeed, deletion of Atg7 diverts progression of lung adenocarcinomas to benign oncocytomas.	('lung adenocarcinomas to benign oncocytomas', 'Disease', (48, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('progression', 'MPA', (33, 44))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (48, 68))	('diverts', 'NegReg', (25, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinomas to benign oncocytomas', 'Disease', 'MESH:D018249', (48, 90))	('deletion', 'Var', (8, 16))	('Atg7', 'Gene', (20, 24))
2721	22784357	With regard to CD44 and its variants, several studies have investigated its expressions in endometrial pathologies, including adenocarcinomas, yielding different results.	('CD44', 'Gene', '960', (15, 19))	('adenocarcinomas', 'Disease', 'MESH:D000230', (126, 141))	('CD44', 'Gene', (15, 19))	('endometrial pathologies', 'Disease', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('variants', 'Var', (28, 36))	('adenocarcinomas', 'Disease', (126, 141))
2791	27499902	We identified non-synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations.	('non-synonymous', 'Var', (14, 28))	('alterations', 'Var', (110, 121))	('harbouring', 'Reg', (94, 104))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))
2792	27499902	The PI3K pathway was the most commonly mutated signalling pathway with mutations identified in PIK3CA, PTEN, PIK3R1, and/or PIK3R2 in two-thirds of the cases.	('mutated', 'Reg', (39, 46))	('PTEN', 'Gene', (103, 107))	('PIK3CA', 'Gene', (95, 101))	('PTEN', 'Gene', '5728', (103, 107))	('PIK3CA', 'Gene', '5290', (95, 101))	('PIK3R2', 'Gene', (124, 130))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('signalling pathway', 'biological_process', 'GO:0007165', ('47', '65'))	('PIK3R2', 'Gene', '5296', (124, 130))	('mutations', 'Var', (71, 80))	('PI3K pathway', 'Pathway', (4, 16))	('PIK3R1', 'Gene', (109, 115))	('PIK3R1', 'Gene', '5295', (109, 115))
2793	27499902	Mutations in FBXW7, PPP2R1A, ARID1A and KRAS were demonstrated in a minority of cases.	('PPP2R1A', 'Gene', (20, 27))	('FBXW7', 'Gene', '55294', (13, 18))	('PPP2R1A', 'Gene', '5518', (20, 27))	('KRAS', 'Gene', (40, 44))	('FBXW7', 'Gene', (13, 18))	('ARID1A', 'Gene', '8289', (29, 35))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (40, 44))	('ARID1A', 'Gene', (29, 35))
2795	27499902	Furthermore, the same TP53 alterations and/or PI3K pathway mutations seen in the primary tumours were also identified in the metastatic sites.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('primary tumours', 'Disease', (81, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('PI3K pathway', 'Pathway', (46, 58))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('TP53', 'Gene', '7157', (22, 26))	('mutations', 'Var', (59, 68))	('primary tumours', 'Disease', 'MESH:D009369', (81, 96))	('TP53', 'Gene', (22, 26))	('alterations', 'Var', (27, 38))
2798	27499902	Our results provide insights into the oncogenesis of uterine carcinosarcoma and identify targetable mutations that represent early oncogenic events.	('mutations', 'Var', (100, 109))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (53, 75))	('oncogenesis', 'biological_process', 'GO:0007048', ('38', '49'))	('carcinosarcoma', 'Disease', (61, 75))	('carcinosarcoma', 'Disease', 'MESH:D002296', (61, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
2808	27499902	A number of prior studies compared patterns of X-chromosome inactivation, microsatellite instability (MSI), types of TP53 and KRAS mutations and loss of heterozygosity (LOH) status between the carcinoma and sarcoma elements and demonstrated shared molecular features in the majority of cases 12, 13, 14, 15.	('KRAS', 'Gene', '3845', (126, 130))	('mutations', 'Var', (131, 140))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (193, 214))	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('47', '72'))	('MSI', 'Disease', (102, 105))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('X-chromosome', 'cellular_component', 'GO:0000805', ('47', '59'))	('loss', 'Var', (145, 149))	('microsatellite instability', 'MPA', (74, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('KRAS', 'Gene', (126, 130))	('MSI', 'Disease', 'None', (102, 105))
2824	27499902	In brief, primer sets were designed using Primer 3 to amplify the specific mutations, tagged with CS1 (5'-ACACTGACGACATGGTTCTACA-3') and CS2 (5'-TACGGTAGCAGAGACTTGGTCT-3') sequencing tags, and synthesized by IDT Technologies (Coralville, IA, USA).	('CS2', 'Gene', (137, 140))	('CS1', 'Gene', '6744', (98, 101))	('CS1', 'Gene', (98, 101))	('mutations', 'Var', (75, 84))	('CS2', 'Gene', '1443', (137, 140))
2845	27499902	Overall, there appeared to be good concordance in the detection of mutations in FFPE tumour tissue.	('FFPE tumour', 'Disease', (80, 91))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('FFPE tumour', 'Disease', 'MESH:D009369', (80, 91))	('mutations', 'Var', (67, 76))
2846	27499902	TP53 mutations were present in the majority of carcinosarcoma (24 of 30) (80%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('carcinosarcoma', 'Disease', (47, 61))	('mutations', 'Var', (5, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('carcinosarcoma', 'Disease', 'MESH:D002296', (47, 61))
2847	27499902	Most of the tumours harbouring missense TP53 mutations showed diffuse nuclear p53 immunostaining, with the exception of two cases (7 and 21) that harboured TP53 deletions and showed diffuse nuclear p53 immunostaining (Table 2).	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('mutations', 'Var', (45, 54))	('missense', 'Var', (31, 39))	('tumours', 'Disease', (12, 19))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('TP53', 'Gene', '7157', (40, 44))	('p53', 'Gene', (78, 81))	('p53', 'Gene', (198, 201))	('TP53', 'Gene', (40, 44))	('showed', 'Reg', (55, 61))	('p53', 'Gene', '7157', (198, 201))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('p53', 'Gene', '7157', (78, 81))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))
2848	27499902	Cases 19 and 30 both demonstrated TP53 mutations (frameshift and nonsense) in the sarcoma component but not the carcinoma component of the tumour, and both displayed a wild-type pattern of p53 immunostaining in both components of the tumour.	('tumour', 'Disease', (139, 145))	('carcinoma component of the tumour', 'Disease', (112, 145))	('TP53', 'Gene', (34, 38))	('p53', 'Gene', '7157', (189, 192))	('tumour', 'Disease', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('frameshift', 'Var', (50, 60))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcoma component', 'Disease', 'MESH:D012509', (82, 99))	('carcinoma component of the tumour', 'Disease', 'MESH:D009369', (112, 145))	('nonsense', 'Var', (65, 73))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('sarcoma component', 'Disease', (82, 99))	('TP53', 'Gene', '7157', (34, 38))	('p53', 'Gene', (189, 192))
2849	27499902	Loss of nuclear p53 immunohistochemistry was detected in 5 cases with indel or nonsense mutations, and 3 additional tumours (cases 17, 18 and 29) displayed abnormal patterns of staining with no detectable mutations (Table 2 and supplementary material Table 2).	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('indel', 'Var', (70, 75))	('p53', 'Gene', (16, 19))	('Loss', 'NegReg', (0, 4))	('additional tumours', 'Disease', 'MESH:D009369', (105, 123))	('p53', 'Gene', '7157', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('nonsense mutations', 'Var', (79, 97))	('additional tumours', 'Disease', (105, 123))
2851	27499902	In the primary tumours, mutations involving genes that encode the kinase or regulatory proteins of the PI3K pathway were identified in 20 of 30 tumours (67%), where multiple PI3K pathway proteins were mutated in 6 tumours.	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('identified', 'Reg', (121, 131))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('PI3K', 'molecular_function', 'GO:0016303', ('174', '178'))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumours', 'Disease', (15, 22))	('primary tumours', 'Disease', (7, 22))	('tumours', 'Disease', 'MESH:D009369', (214, 221))	('tumours', 'Disease', (214, 221))	('primary tumours', 'Disease', 'MESH:D009369', (7, 22))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('mutations', 'Var', (24, 33))	('tumours', 'Disease', (144, 151))	('PI3K', 'molecular_function', 'GO:0016303', ('103', '107'))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
2852	27499902	PIK3CA mutations were found in 12 of 30 (40%) tumours, which were scattered throughout the different functional domains of PIK3CA (Figure 3).	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('PIK3CA', 'Gene', (123, 129))	('tumours', 'Disease', (46, 53))	('found', 'Reg', (22, 27))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (123, 129))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (7, 16))
2853	27499902	PTEN mutations, most commonly missense in type, were observed in eight tumours (27%).	('missense', 'Var', (30, 38))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('observed', 'Reg', (53, 61))	('tumours', 'Disease', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
2854	27499902	PIK3R1 mutations were found in five tumours (17%), while only one tumour demonstrated a PIK3R2 mutation.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('tumour', 'Disease', (36, 42))	('PIK3R1', 'Gene', '5295', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('PIK3R1', 'Gene', (0, 6))	('found', 'Reg', (22, 27))	('tumours', 'Disease', (36, 43))	('PIK3R2', 'Gene', (88, 94))	('PIK3R2', 'Gene', '5296', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', (66, 72))	('mutations', 'Var', (7, 16))
2855	27499902	Of note in this cohort, PIK3CA mutations were rarely found with concurrent PIK3R1 or PIK3R2 mutations.	('PIK3R1', 'Gene', (75, 81))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('mutations', 'Var', (92, 101))	('PIK3CA', 'Gene', '5290', (24, 30))	('PIK3R2', 'Gene', (85, 91))	('PIK3R1', 'Gene', '5295', (75, 81))	('PIK3R2', 'Gene', '5296', (85, 91))
2856	27499902	One tumour (case 20) with a PIK3CA mutation also harboured an AKT3 (E167D) mutation, while case 18 harboured an AKT3 (M336I) mutation at low frequency (5%) without concurrent PI3K pathway mutations.	('AKT3', 'Gene', (62, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('175', '179'))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('PIK3CA', 'Gene', (28, 34))	('AKT3', 'Gene', '10000', (62, 66))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('AKT3', 'Gene', (112, 116))	('M336I', 'Mutation', 'rs773792621', (118, 123))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutation', 'Var', (35, 43))	('tumour', 'Disease', (4, 10))	('E167D', 'Mutation', 'rs755369410', (68, 73))	('AKT3', 'Gene', '10000', (112, 116))
2859	27499902	By immunohistochemistry, only two cases showed loss of BAF250 (ARID1A), which corresponded to the presence of frameshift and nonsense mutations (Table 2).	('BAF250', 'Gene', (55, 61))	('frameshift', 'Var', (110, 120))	('nonsense mutations', 'Var', (125, 143))	('ARID1A', 'Gene', '8289', (63, 69))	('ARID1A', 'Gene', (63, 69))	('loss', 'NegReg', (47, 51))	('BAF250', 'Gene', '8289', (55, 61))
2861	27499902	A somatic MED12 mutation (D23Y) was identified in one tumour, which has been previously documented in a case of endometrial carcinoma 27; however, it was not the typical hotspot MED12 mutation found in uterine smooth muscle tumours 20, 21.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('D23Y', 'Var', (26, 30))	('muscle tumours', 'Disease', 'MESH:D009217', (217, 231))	('muscle tumours', 'Disease', (217, 231))	('MED12', 'Gene', (10, 15))	('MED12', 'Gene', (178, 183))	('tumours', 'Phenotype', 'HP:0002664', (224, 231))	('endometrial carcinoma', 'Disease', (112, 133))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('tumour', 'Disease', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (112, 133))	('D23Y', 'Mutation', 'p.D23Y', (26, 30))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (112, 133))	('MED12', 'Gene', '9968', (178, 183))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('MED12', 'Gene', '9968', (10, 15))
2864	27499902	A somatic POLE exonuclease domain mutation (M444K) was identified in one tumour (case 30), which was reported in an ultra-mutated endometrial carcinoma in a prior study 17.	('endometrial carcinoma', 'Disease', (130, 151))	('tumour', 'Disease', (73, 79))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (130, 151))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('M444K', 'Var', (44, 49))	('M444K', 'Mutation', 'p.M444K', (44, 49))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (130, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
2865	27499902	In keeping with the ultra-mutator phenotype, this tumour also possessed 11 point mutations involving eight other genes.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('point mutations', 'Var', (75, 90))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', (50, 56))
2870	27499902	Two cases exhibited additional mutation(s) in the sarcoma component compared to the carcinoma component: case 19 with a TP53 missense mutation, and case 27 with PIK3R2, CHD4 mutations, and a POLE non-exonuclease domain mutation.	('carcinoma component', 'Disease', (84, 103))	('CHD4', 'Gene', (169, 173))	('PIK3R2', 'Gene', '5296', (161, 167))	('missense mutation', 'Var', (125, 142))	('mutation', 'Var', (31, 39))	('sarcoma component', 'Disease', 'MESH:D012509', (50, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('carcinoma component', 'Disease', 'MESH:C562869', (84, 103))	('mutations', 'Var', (174, 183))	('CHD4', 'Gene', '1108', (169, 173))	('sarcoma component', 'Disease', (50, 67))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))	('PIK3R2', 'Gene', (161, 167))
2871	27499902	In contrast, two cases displayed additional mutation(s) in the carcinoma component compared to the sarcoma component: case 8 with an ARID1A mutation, and case 14 with PPP2R1A, FBXW7 and SPOP mutations.	('ARID1A', 'Gene', '8289', (133, 139))	('ARID1A', 'Gene', (133, 139))	('sarcoma component', 'Disease', (99, 116))	('mutation', 'Var', (44, 52))	('carcinoma component', 'Disease', 'MESH:C562869', (63, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('SPOP', 'Gene', '8405', (186, 190))	('mutation', 'Var', (140, 148))	('FBXW7', 'Gene', '55294', (176, 181))	('SPOP', 'Gene', (186, 190))	('carcinoma component', 'Disease', (63, 82))	('FBXW7', 'Gene', (176, 181))	('sarcoma component', 'Disease', 'MESH:D012509', (99, 116))	('PPP2R1A', 'Gene', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('PPP2R1A', 'Gene', '5518', (167, 174))
2872	27499902	Overall, there was complete concordance or partial overlap in mutations identified in the carcinoma and the sarcoma components in 11 of 12 cases, hence indicating clonal relatedness between the carcinoma and the sarcoma components.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcoma component', 'Disease', (212, 229))	('carcinoma', 'Disease', 'MESH:D002277', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Disease', 'MESH:D002277', (194, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma component', 'Disease', 'MESH:D012509', (108, 125))	('carcinoma', 'Disease', (90, 99))	('sarcoma component', 'Disease', (108, 125))	('carcinoma', 'Disease', (194, 203))	('sarcoma component', 'Disease', 'MESH:D012509', (212, 229))	('mutations', 'Var', (62, 71))
2876	27499902	For case 22, the carcinoma and the sarcoma components of the uterine primary all harboured the same PTEN, PIK3R1 and TP53 (frameshift) mutations with loss of p53 immunostaining.	('PTEN', 'Gene', (100, 104))	('PIK3R1', 'Gene', '5295', (106, 112))	('sarcoma component', 'Disease', 'MESH:D012509', (35, 52))	('p53', 'Gene', '7157', (158, 161))	('carcinoma', 'Disease', (17, 26))	('PIK3R1', 'Gene', (106, 112))	('PTEN', 'Gene', '5728', (100, 104))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mutations', 'Var', (135, 144))	('frameshift) mutations', 'Var', (123, 144))	('sarcoma components of the uterine', 'Phenotype', 'HP:0010784', (35, 68))	('sarcoma component', 'Disease', (35, 52))	('carcinoma', 'Disease', 'MESH:D002277', (17, 26))	('loss', 'NegReg', (150, 154))	('p53', 'Gene', (158, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
2877	27499902	In contrast, the metastatic tumour (bilateral ovaries and peritoneal deposits) displayed no evidence of PTEN, PIK3R1 mutations, and harboured a different TP53 missense mutation with diffuse nuclear p53 immunostaining (Figure 2E-F).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('TP53', 'Gene', (154, 158))	('missense mutation', 'Var', (159, 176))	('PIK3R1', 'Gene', (110, 116))	('bilateral ovaries', 'Disease', (36, 53))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('PIK3R1', 'Gene', '5295', (110, 116))	('p53', 'Gene', (198, 201))	('tumour', 'Disease', (28, 34))	('bilateral ovaries', 'Disease', 'MESH:D010051', (36, 53))	('p53', 'Gene', '7157', (198, 201))	('bilateral ovaries', 'Phenotype', 'HP:0010463', (36, 53))	('PTEN', 'Gene', (104, 108))	('TP53', 'Gene', '7157', (154, 158))	('PTEN', 'Gene', '5728', (104, 108))
2880	27499902	Additional immunohistochemistry analysis demonstrated nuclear WT1 positivity in the ovarian tumour but not the uterine tumour (Figure 2E-F) 28.	('uterine tumour', 'Phenotype', 'HP:0010784', (111, 125))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian tumour', 'Disease', (84, 98))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', (92, 98))	('WT1', 'Gene', '7490', (62, 65))	('WT1', 'Gene', (62, 65))	('ovarian tumour', 'Phenotype', 'HP:0100615', (84, 98))	('positivity', 'Var', (66, 76))	('tumour', 'Disease', (119, 125))	('ovarian tumour', 'Disease', 'MESH:D010051', (84, 98))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
2883	27499902	We have previously identified different molecular types of uterine carcinosarcomas with some tumours showing endometrial serous carcinoma-like mutation profiles (characterized by the presence of TP53 mutation with PPP2R1A and/or FBXW7 mutations and in the absence of PTEN, CTNNB1, KRAS or ARID1A mutations) and other tumours showing endometrioid carcinoma-like mutation profiles (characterized by the presence of PTEN, CTNNB1, KRAS and/or ARID1A mutations) 16.	('ARID1A', 'Gene', (439, 445))	('KRAS', 'Gene', (427, 431))	('CTNNB1', 'Gene', (419, 425))	('PTEN', 'Gene', (267, 271))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('ARID1A', 'Gene', (289, 295))	('KRAS', 'Gene', '3845', (281, 285))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (333, 355))	('CTNNB1', 'Gene', (273, 279))	('FBXW7', 'Gene', (229, 234))	('TP53', 'Gene', (195, 199))	('ARID1A', 'Gene', '8289', (439, 445))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('KRAS', 'Gene', (281, 285))	('ARID1A', 'Gene', '8289', (289, 295))	('PTEN', 'Gene', '5728', (267, 271))	('PPP2R1A', 'Gene', '5518', (214, 221))	('mutation', 'Var', (200, 208))	('carcinosarcomas', 'Disease', 'MESH:D002296', (67, 82))	('tumours', 'Disease', (317, 324))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (333, 355))	('PTEN', 'Gene', (413, 417))	('mutations', 'Var', (235, 244))	('endometrial serous carcinoma', 'Disease', (109, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('tumours', 'Phenotype', 'HP:0002664', (317, 324))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('FBXW7', 'Gene', '55294', (229, 234))	('PPP2R1A', 'Gene', (214, 221))	('TP53', 'Gene', '7157', (195, 199))	('tumours', 'Disease', 'MESH:D009369', (317, 324))	('CTNNB1', 'Gene', '1499', (419, 425))	('tumours', 'Disease', (93, 100))	('endometrioid carcinoma', 'Disease', (333, 355))	('PTEN', 'Gene', '5728', (413, 417))	('carcinosarcomas', 'Disease', (67, 82))	('CTNNB1', 'Gene', '1499', (273, 279))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (109, 137))	('tumour', 'Phenotype', 'HP:0002664', (317, 323))	('KRAS', 'Gene', '3845', (427, 431))	('mutations', 'Var', (446, 455))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
2892	27499902	This is evident in the cases where the two histologic components were separately analysed; all cases with detectable mutations shared at least one somatic mutation in common between the carcinoma and the sarcoma components.	('carcinoma', 'Disease', 'MESH:D002277', (186, 195))	('mutations', 'Var', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('sarcoma component', 'Disease', 'MESH:D012509', (204, 221))	('carcinoma', 'Disease', (186, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('sarcoma component', 'Disease', (204, 221))
2895	27499902	There were four tumours that showed differences in mutations in additional to shared mutations between the two components.	('mutations', 'Var', (51, 60))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
2896	27499902	These included two cases with additional mutations found in the sarcoma component and two cases with additional mutations found in the carcinoma component.	('mutations', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinoma component', 'Disease', 'MESH:C562869', (135, 154))	('sarcoma component', 'Disease', 'MESH:D012509', (64, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcoma component', 'Disease', (64, 81))	('carcinoma component', 'Disease', (135, 154))
2903	27499902	We have identified mutations involving PI3K pathway in two-thirds of uterine carcinosarcoma examined, most commonly involving PIK3CA and PTEN.	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('PIK3CA', 'Gene', (126, 132))	('carcinosarcoma', 'Disease', (77, 91))	('mutations', 'Var', (19, 28))	('PI3K pathway', 'Pathway', (39, 51))	('PIK3CA', 'Gene', '5290', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('PTEN', 'Gene', (137, 141))	('carcinosarcoma', 'Disease', 'MESH:D002296', (77, 91))	('PTEN', 'Gene', '5728', (137, 141))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (69, 91))
2904	27499902	In contrast to prior studies on uterine carcinosarcomas 29, 30, our present analyses identified both traditional PIK3CA hotspots (exons 9 and 20) mutations as well as mutations in the adaptor binding domain, helical domain, and C2 domain which can also enhance kinase enzymatic activity 31, 32.	('mutations', 'Var', (146, 155))	('PIK3CA', 'Gene', (113, 119))	('carcinosarcomas', 'Disease', 'MESH:D002296', (40, 55))	('PIK3CA', 'Gene', '5290', (113, 119))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (32, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('mutations', 'Var', (167, 176))	('carcinosarcomas', 'Disease', (40, 55))	('binding', 'molecular_function', 'GO:0005488', ('192', '199'))	('enhance', 'PosReg', (253, 260))	('kinase enzymatic activity', 'MPA', (261, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
2905	27499902	When present, these PI3K pathway mutations were found in the carcinoma and sarcoma components of the primary tumour, as well as in the metastatic tumour.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('20', '24'))	('mutations', 'Var', (33, 42))	('tumour', 'Disease', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('found', 'Reg', (48, 53))	('PI3K pathway', 'Pathway', (20, 32))	('carcinoma and sarcoma components of the primary tumour', 'Disease', 'MESH:D012509', (61, 115))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
2906	27499902	This indicates that these PI3K pathway mutations occur relatively early in the tumourigenesis of carcinosarcoma and likely represent important oncogenic driver events that could be targeted with PIK3CA/mTOR inhibitors 33, 34, 35.	('carcinosarcoma', 'Disease', (97, 111))	('PIK3CA', 'Gene', (195, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('PIK3CA', 'Gene', '5290', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (39, 48))	('carcinosarcoma', 'Disease', 'MESH:D002296', (97, 111))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('mTOR', 'Gene', '2475', (202, 206))	('PI3K pathway', 'Pathway', (26, 38))	('mTOR', 'Gene', (202, 206))	('tumour', 'Disease', (79, 85))
2907	27499902	We also observed a very high frequency of TP53 alterations (90%) in this series of uterine carcinosarcomas, which is supported by previous literature 5, 12, 16.	('TP53', 'Gene', '7157', (42, 46))	('carcinosarcomas', 'Disease', 'MESH:D002296', (91, 106))	('TP53', 'Gene', (42, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('carcinosarcomas', 'Disease', (91, 106))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (83, 105))	('alterations', 'Var', (47, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
2909	27499902	In keeping with prior studies, MMR protein deficiency that suggests underlying microsatellite instability was rarely observed in our present series of uterine carcinosarcoma 12, 24.	('carcinosarcoma', 'Disease', (159, 173))	('carcinosarcoma', 'Disease', 'MESH:D002296', (159, 173))	('MMR', 'biological_process', 'GO:0006298', ('31', '34'))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (151, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('MMR protein deficiency', 'Disease', (31, 53))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('MMR protein deficiency', 'Disease', 'MESH:C536143', (31, 53))	('microsatellite', 'Var', (79, 93))
2910	27499902	A recent study demonstrated frequent mutations in chromatin remodelling genes (ARID1A, ARID1B, MLL3, SPOP) with the identification of 4 mismatch repair deficient tumour in a cohort of 17 uterine and five ovarian carcinosarcomas 36.	('mismatch', 'Var', (136, 144))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('50', '71'))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (204, 227))	('mismatch repair', 'biological_process', 'GO:0006298', ('136', '151'))	('SPOP', 'Gene', (101, 105))	('MLL3', 'Gene', (95, 99))	('deficient tumour', 'Disease', (152, 168))	('ARID1B', 'Gene', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('ovarian carcinosarcomas', 'Disease', (204, 227))	('chromatin', 'cellular_component', 'GO:0000785', ('50', '59'))	('ARID1B', 'Gene', '57492', (87, 93))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (204, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('mutations', 'Var', (37, 46))	('ARID1A', 'Gene', (79, 85))	('SPOP', 'Gene', '8405', (101, 105))	('ARID1A', 'Gene', '8289', (79, 85))	('deficient tumour', 'Disease', 'MESH:D009369', (152, 168))	('MLL3', 'Gene', '58508', (95, 99))
2911	27499902	While these results are overall different from our present cohort, a closer examination reveals that nearly all of the identified ARID1A, ARID1B and MLL3 mutations were found in the four MMR-deficient uterine carcinosarcomas and in four of the five ovarian carcinosarcomas.	('ARID1A', 'Gene', (130, 136))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (249, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('MLL3', 'Gene', '58508', (149, 153))	('ARID1A', 'Gene', '8289', (130, 136))	('found', 'Reg', (169, 174))	('MLL3', 'Gene', (149, 153))	('carcinosarcomas', 'Disease', 'MESH:D002296', (209, 224))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (249, 272))	('carcinosarcomas', 'Disease', 'MESH:D002296', (257, 272))	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('MMR', 'biological_process', 'GO:0006298', ('187', '190'))	('deficient uterine', 'Phenotype', 'HP:0000013', (191, 208))	('ARID1B', 'Gene', (138, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (264, 272))	('carcinosarcomas', 'Disease', (209, 224))	('mutations', 'Var', (154, 163))	('ARID1B', 'Gene', '57492', (138, 144))	('carcinosarcomas', 'Disease', (257, 272))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (201, 223))	('ovarian carcinosarcomas', 'Disease', (249, 272))
2912	27499902	We did, however, identify a few cases in our cohort with ARID1A mutations and one with an SPOP mutation.	('SPOP', 'Gene', '8405', (90, 94))	('SPOP', 'Gene', (90, 94))	('mutations', 'Var', (64, 73))	('ARID1A', 'Gene', '8289', (57, 63))	('ARID1A', 'Gene', (57, 63))
2925	27499902	Further studies are needed to investigate whether there is increased propensity for POLE-mutated endometrioid carcinoma to display spindle cell elements.	('POLE-mutated', 'Var', (84, 96))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (97, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (97, 119))	('endometrioid carcinoma', 'Disease', (97, 119))	('spindle', 'cellular_component', 'GO:0005819', ('131', '138'))
2940	31578148	Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation, we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PGK', 'molecular_function', 'GO:0004618', ('34', '37'))	('PDHK1', 'Gene', '5163', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('S203', 'Var', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('PDHK', 'molecular_function', 'GO:0004740', ('48', '52'))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('PGK1', 'Gene', (34, 38))	('PDHK1', 'Gene', (48, 53))	('PGK1', 'Gene', '5230', (34, 38))
2941	31578148	The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types, respectively.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('TNM', 'Gene', '10178', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PGK', 'molecular_function', 'GO:0004618', ('4', '7'))	('mRNA level', 'MPA', (9, 19))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('hypomethylation', 'Var', (52, 67))	('elevated', 'PosReg', (38, 46))	('PGK1', 'Gene', '5230', (4, 8))	('associated', 'Reg', (92, 102))	('PGK1', 'Gene', (4, 8))	('TNM', 'Gene', (117, 120))	('cancer', 'Disease', (142, 148))
2943	31578148	Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival (OS) in cancers of the breast, liver, lung, stomach, and esophagus and with advanced TNM stage in breast and esophageal cancers.	('short', 'NegReg', (105, 110))	('associated', 'Reg', (89, 99))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PDHK', 'molecular_function', 'GO:0004740', ('36', '40'))	('PDHK1', 'Gene', (36, 41))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cancers of the breast', 'Phenotype', 'HP:0100013', (136, 157))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung', 'Disease', (166, 170))	('S203', 'Var', (27, 31))	('PDHK1', 'Gene', '5163', (36, 41))	('cancers of the breast', 'Disease', 'MESH:D001943', (136, 157))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('PGK1', 'Gene', '5230', (22, 26))	('breast and esophageal cancers', 'Disease', 'MESH:D001943', (226, 255))	('TNM', 'Gene', '10178', (213, 216))	('PGK', 'molecular_function', 'GO:0004618', ('22', '25'))	('phosphorylation levels', 'MPA', (47, 69))	('TNM', 'Gene', (213, 216))	('PGK1', 'Gene', (22, 26))	('stomach', 'Disease', (172, 179))	('T338', 'Var', (42, 46))	('liver', 'Disease', (159, 164))	('esophagus', 'Disease', (185, 194))	('cancers of the breast', 'Disease', (136, 157))
2944	31578148	PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver, lung, and stomach cancer.	('lung', 'Disease', (82, 86))	('liver', 'Disease', (75, 80))	('pS203', 'Var', (5, 10))	('short OS', 'Disease', (63, 71))	('stomach cancer', 'Disease', 'MESH:D013274', (92, 106))	('PDHK1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PDHK', 'molecular_function', 'GO:0004740', ('15', '19'))	('PDHK1', 'Gene', '5163', (15, 20))	('stomach cancer', 'Phenotype', 'HP:0012126', (92, 106))	('PGK', 'molecular_function', 'GO:0004618', ('0', '3'))	('stomach cancer', 'Disease', (92, 106))	('PGK1', 'Gene', (0, 4))	('PGK1', 'Gene', '5230', (0, 4))
2954	31578148	In response to receptor tyrosine kinase activation, the expression of K-Ras G12V and B-Raf V600E, hypoxia, pyruvate metabolism in mitochondria is suppressed.	('G12V', 'Mutation', 'p.G12V', (76, 80))	('hypoxia', 'Disease', (98, 105))	('V600E', 'Mutation', 'p.V600E', (91, 96))	('B-Raf V600E', 'Var', (85, 96))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('pyruvate metabolism', 'biological_process', 'GO:0006090', ('107', '126'))	('mitochondria', 'cellular_component', 'GO:0005739', ('130', '142'))	('activation', 'PosReg', (40, 50))	('pyruvate', 'Chemical', 'MESH:D011773', (107, 115))	('pyruvate metabolism in mitochondria', 'MPA', (107, 142))	('V600E', 'Var', (91, 96))	('K-Ras G12V', 'Var', (70, 80))	('tyrosine', 'Chemical', 'None', (24, 32))	('suppressed', 'NegReg', (146, 156))
2958	31578148	In addition, PGK1 S203 and PDHK1 T338 phosphorylation levels were found to be positively correlated with each other, and both were correlated with PDH S293 inactivating phosphorylation levels and poor prognosis in patients with glioblastoma (GBM).	('correlated', 'Interaction', (89, 99))	('correlated', 'Reg', (131, 141))	('patients', 'Species', '9606', (214, 222))	('glioblastoma', 'Disease', 'MESH:D005909', (228, 240))	('PDHK1', 'Gene', '5163', (27, 32))	('PDH', 'Gene', '54704', (27, 30))	('PDH', 'Gene', '54704', (147, 150))	('PDH', 'molecular_function', 'GO:0004246', ('147', '150'))	('GBM', 'Phenotype', 'HP:0012174', (242, 245))	('PDHK1', 'Gene', (27, 32))	('glioblastoma', 'Disease', (228, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (228, 240))	('PDH', 'molecular_function', 'GO:0033718', ('147', '150'))	('PGK', 'molecular_function', 'GO:0004618', ('13', '16'))	('PGK1', 'Gene', '5230', (13, 17))	('inactivating', 'NegReg', (156, 168))	('PDH', 'molecular_function', 'GO:0004739', ('147', '150'))	('PDH', 'Gene', (27, 30))	('PDH', 'Gene', (147, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('169', '184'))	('PGK1', 'Gene', (13, 17))	('S203', 'Var', (18, 22))	('PDHK', 'molecular_function', 'GO:0004740', ('27', '31'))	('GBM', 'Disease', (242, 245))	('phosphorylation levels', 'MPA', (38, 60))	('GBM', 'Disease', 'MESH:D005909', (242, 245))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))
2961	31578148	We also analyzed the clinical relevance of PGK1 S203 and PDHK1 T338 phosphorylation levels by conducting immunohistochemical experiments in an additional 818 independent cancer cases (including 619 with paired normal tissues).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('PGK', 'molecular_function', 'GO:0004618', ('43', '46'))	('cancer', 'Disease', (170, 176))	('PGK1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PDHK1', 'Gene', (57, 62))	('PGK1', 'Gene', '5230', (43, 47))	('PDHK', 'molecular_function', 'GO:0004740', ('57', '61'))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('PDHK1', 'Gene', '5163', (57, 62))	('clinical', 'Species', '191496', (21, 29))	('S203', 'Var', (48, 52))
2972	31578148	Rabbit polyclonal antibodies recognizing phospho-PGK1 S203 and phospho-PDHK1 T338 were obtained from Signalway Antibody (College Park, MD, USA).	('PGK1', 'Gene', '5230', (49, 53))	('PDHK', 'molecular_function', 'GO:0004740', ('71', '75'))	('S203', 'Var', (54, 58))	('PDHK1', 'Gene', (71, 76))	('PDHK1', 'Gene', '5163', (71, 76))	('PGK', 'molecular_function', 'GO:0004618', ('49', '52'))	('PGK1', 'Gene', (49, 53))	('Rabbit', 'Species', '9986', (0, 6))
3000	31578148	DNA methylation regulates gene expression and is implicated in tumor progression and therapeutic response.	('tumor', 'Disease', (63, 68))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('regulates', 'Reg', (16, 25))	('gene expression', 'MPA', (26, 41))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('gene expression', 'biological_process', 'GO:0010467', ('26', '41'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('implicated', 'Reg', (49, 59))
3008	31578148	3b; Additional file 1: Table S4), suggesting promoter hypomethylation as a mechanism promoting PGK1 expression.	('PGK', 'molecular_function', 'GO:0004618', ('95', '98'))	('promoter hypomethylation', 'Var', (45, 69))	('expression', 'MPA', (100, 110))	('PGK1', 'Gene', (95, 99))	('PGK1', 'Gene', '5230', (95, 99))	('promoting', 'PosReg', (85, 94))
3010	31578148	We next analyzed the association between PGK1 promoter hypomethylation and the survival of patients with STAD, BLCA, ESCA, LIHC, and BRCA, and found that only in BRCA, hypomethylation of cg13203541 was associated with short OS (HR = 0.551, 95% CI 0.361-0.841, P = 0.005; Additional file 1: Table S5; Fig.	('BRCA', 'Phenotype', 'HP:0003002', (162, 166))	('BRCA', 'Disease', (133, 137))	('ESCA', 'Phenotype', 'HP:0011459', (117, 121))	('BLCA', 'Disease', 'MESH:D001749', (111, 115))	('LIHC', 'Disease', 'MESH:D006528', (123, 127))	('BRCA', 'Disease', 'MESH:D001943', (133, 137))	('PGK1', 'Gene', (41, 45))	('STAD', 'Disease', (105, 109))	('cg13203541', 'Var', (187, 197))	('patients', 'Species', '9606', (91, 99))	('BRCA', 'Disease', (162, 166))	('short OS', 'Disease', (218, 226))	('PGK', 'molecular_function', 'GO:0004618', ('41', '44'))	('BRCA', 'Disease', 'MESH:D001943', (162, 166))	('hypomethylation', 'Var', (168, 183))	('ESCA', 'Disease', (117, 121))	('BRCA', 'Phenotype', 'HP:0003002', (133, 137))	('STAD', 'Disease', 'MESH:D013274', (105, 109))	('ESCA', 'Disease', 'MESH:D004938', (117, 121))	('associated', 'Reg', (202, 212))	('LIHC', 'Disease', (123, 127))	('BLCA', 'Disease', (111, 115))	('PGK1', 'Gene', '5230', (41, 45))
3011	31578148	A multivariate Cox regression model showed that cg13203541 methylation was an independent predictor of prolonged OS in BRCA (HR = 0.599, 95% CI 0.382-0.939, P = 0.026; Additional file 1: Table S5).	('BRCA', 'Disease', (119, 123))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('BRCA', 'Disease', 'MESH:D001943', (119, 123))	('cg13203541 methylation', 'Var', (48, 70))
3016	31578148	We found that in all five cancer types, PGK1 pS203 and PDHK1 pT338 levels were higher in most tumor tissues than in their matched normal tissues (Additional file 1: Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('pT338 levels', 'MPA', (61, 73))	('PGK', 'molecular_function', 'GO:0004618', ('40', '43'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PGK1', 'Gene', (40, 44))	('cancer', 'Disease', (26, 32))	('PDHK1', 'Gene', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('PGK1', 'Gene', '5230', (40, 44))	('PDHK1', 'Gene', '5163', (55, 60))	('tumor', 'Disease', (94, 99))	('PDHK', 'molecular_function', 'GO:0004740', ('55', '59'))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('higher', 'PosReg', (79, 85))	('pS203', 'Var', (45, 50))
3019	31578148	Kaplan-Meier analysis showed that higher levels of both PGK1 pS203 and PDHK1 pT338 were associated with shorter OS in patients with these five cancer types (all P < 0.05) (Fig.	('shorter OS', 'Disease', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PDHK', 'molecular_function', 'GO:0004740', ('71', '75'))	('PGK1', 'Gene', '5230', (56, 60))	('PGK1', 'Gene', (56, 60))	('higher', 'PosReg', (34, 40))	('pS203', 'Var', (61, 66))	('PDHK1', 'Gene', (71, 76))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('PDHK1', 'Gene', '5163', (71, 76))	('PGK', 'molecular_function', 'GO:0004618', ('56', '59'))	('patients', 'Species', '9606', (118, 126))
3020	31578148	An independent variable t test showed that both PGK1 pS203 and PDHK1 pT338 were associated with advanced TNM stage in patients with BRCA and ESCA (all P < 0.05) (Table 1).	('TNM', 'Gene', (105, 108))	('PGK1', 'Gene', (48, 52))	('PDHK', 'molecular_function', 'GO:0004740', ('63', '67'))	('PGK1', 'Gene', '5230', (48, 52))	('BRCA', 'Disease', 'MESH:D001943', (132, 136))	('pS203', 'Var', (53, 58))	('PDHK1', 'Gene', '5163', (63, 68))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('patients', 'Species', '9606', (118, 126))	('ESCA', 'Phenotype', 'HP:0011459', (141, 145))	('associated', 'Reg', (80, 90))	('ESCA', 'Disease', (141, 145))	('TNM', 'Gene', '10178', (105, 108))	('PGK', 'molecular_function', 'GO:0004618', ('48', '51'))	('PDHK1', 'Gene', (63, 68))	('BRCA', 'Disease', (132, 136))	('ESCA', 'Disease', 'MESH:D004938', (141, 145))
3023	31578148	Additional analyses of a cohort of 818 cases revealed that the phosphorylation levels of PGK1 S203 and PDHK1 T338 were independent prognostic biomarkers for LIHC, LUAD, and STAD.	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('PDHK1', 'Gene', (103, 108))	('PDHK', 'molecular_function', 'GO:0004740', ('103', '107'))	('T338', 'Var', (109, 113))	('PDHK1', 'Gene', '5163', (103, 108))	('phosphorylation levels', 'MPA', (63, 85))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('PGK', 'molecular_function', 'GO:0004618', ('89', '92'))	('LIHC', 'Disease', (157, 161))	('LUAD', 'Disease', (163, 167))	('STAD', 'Disease', 'MESH:D013274', (173, 177))	('LUAD', 'Disease', 'MESH:C538231', (163, 167))	('PGK1', 'Gene', (89, 93))	('STAD', 'Disease', (173, 177))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('PGK1', 'Gene', '5230', (89, 93))	('S203', 'Var', (94, 98))
3024	31578148	All these findings suggest that PGK1 gene modification and PGK1-mitochondrial function were significantly associated with clinical behaviors of cancer patients.	('clinical behaviors', 'Disease', (122, 140))	('associated', 'Reg', (106, 116))	('PGK1', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PGK1', 'Gene', '5230', (32, 36))	('patients', 'Species', '9606', (151, 159))	('PGK', 'molecular_function', 'GO:0004618', ('59', '62'))	('gene modification', 'Var', (37, 54))	('cancer', 'Disease', (144, 150))	('PGK1', 'Gene', (59, 63))	('clinical', 'Species', '191496', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PGK', 'molecular_function', 'GO:0004618', ('32', '35'))	('PGK1', 'Gene', '5230', (59, 63))
3034	31578148	Therefore, in the present study, we analyzed the DNA methylation data for 14 cancer types from TCGA datasets and identified hypomethylation of the PGK1 promoter (cg13203541) as an independent prognostic biomarker in BRCA patients (Additional file 1: Table S5).	('patients', 'Species', '9606', (221, 229))	('DNA methylation', 'biological_process', 'GO:0006306', ('49', '64'))	('PGK', 'molecular_function', 'GO:0004618', ('147', '150'))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('hypomethylation', 'Var', (124, 139))	('BRCA', 'Disease', (216, 220))	('cg13203541', 'Var', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PGK1', 'Gene', (147, 151))	('BRCA', 'Phenotype', 'HP:0003002', (216, 220))	('BRCA', 'Disease', 'MESH:D001943', (216, 220))	('PGK1', 'Gene', '5230', (147, 151))
3035	31578148	We also detected mitochondrial PGK1-dependent PDHK1 T338 phosphorylation in additional cases of five cancer types and demonstrated that mitochondrial function of PGK1 significantly affected the clinical behaviors of patients with these cancers.	('PGK1', 'Gene', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mitochondrial function', 'MPA', (136, 158))	('PDHK1', 'Gene', '5163', (46, 51))	('affected', 'Reg', (181, 189))	('PDHK', 'molecular_function', 'GO:0004740', ('46', '50'))	('PGK1', 'Gene', '5230', (31, 35))	('PDHK1', 'Gene', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('PGK', 'molecular_function', 'GO:0004618', ('31', '34'))	('cancers', 'Disease', (236, 243))	('cancer', 'Disease', (236, 242))	('patients', 'Species', '9606', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('PGK', 'molecular_function', 'GO:0004618', ('162', '165'))	('T338', 'Var', (52, 56))	('PGK1', 'Gene', (31, 35))	('PGK1', 'Gene', '5230', (162, 166))	('cancer', 'Disease', (101, 107))	('clinical behaviors', 'CPA', (194, 212))	('clinical', 'Species', '191496', (194, 202))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('phosphorylation', 'MPA', (57, 72))
3037	31578148	One important example is isocitrate dehydrogenase 1 (IDH1) mutation, which has important clinical significance and was found in GBM and myeloid malignancies, such as acute myelocytic leukaemia (AML) and myelodysplastic syndromes (MDS).	('AML', 'Disease', 'MESH:D015470', (194, 197))	('myeloid malignancies', 'Disease', (136, 156))	('acute myelocytic leukaemia', 'Disease', 'MESH:D015470', (166, 192))	('isocitrate', 'Chemical', 'MESH:D007523', (25, 35))	('AML', 'Disease', (194, 197))	('mutation', 'Var', (59, 67))	('AML', 'Phenotype', 'HP:0004808', (194, 197))	('acute myelocytic leukaemia', 'Phenotype', 'HP:0004808', (166, 192))	('MDS', 'Phenotype', 'HP:0002863', (230, 233))	('clinical', 'Species', '191496', (89, 97))	('GBM', 'Disease', (128, 131))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (203, 228))	('myeloid malignancies', 'Disease', 'OMIM:601308', (136, 156))	('GBM', 'Disease', 'MESH:D005909', (128, 131))	('myelodysplastic syndromes', 'Disease', (203, 228))	('MDS', 'Disease', 'MESH:D009190', (230, 233))	('IDH1', 'Gene', (53, 57))	('found', 'Reg', (119, 124))	('acute myelocytic leukaemia', 'Disease', (166, 192))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (203, 228))	('MDS', 'Disease', (230, 233))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('IDH1', 'Gene', '3417', (53, 57))	('myelocytic leukaemia', 'Phenotype', 'HP:0012324', (172, 192))
3038	31578148	A clinical study suggested that IDH1 mutation was an independent, favorable prognostic marker in grade 2-4 glioma.	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('IDH1', 'Gene', '3417', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('clinical', 'Species', '191496', (2, 10))	('glioma', 'Disease', (107, 113))
3195	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))
3212	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))	('colon cancers', 'Disease', 'MESH:D015179', (150, 163))	('WISP2', 'Gene', '8839', (99, 104))	('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))
3223	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', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (117, 138))	('cancer', 'Disease', (117, 123))	('aggressiveness', 'Phenotype', 'HP:0000718', (124, 138))
3228	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))
3247	27847479	Lynch Syndrome (LS) is a hereditary cancer syndrome caused by germline alterations in the DNA mismatch repair (MMR) genes.	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('MMR', 'Gene', (111, 114))	('Lynch Syndrome', 'Disease', (0, 14))	('mismatch repair', 'biological_process', 'GO:0006298', ('94', '109'))	('hereditary cancer syndrome', 'Disease', (25, 51))	('alterations', 'Var', (71, 82))	('DNA', 'Gene', (90, 93))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (25, 51))	('caused by', 'Reg', (52, 61))	('MMR', 'biological_process', 'GO:0006298', ('111', '114'))
3251	27847479	Whole genome sequencing provides a comprehensive view of the cancer genome including all types of somatic/germline mutations, nucleotide substitutions, small insertions and deletions, copy number variations, chromosomal rearrangements, as well as analysis of the non-coding regions.	('copy number variations', 'Var', (184, 206))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('small insertions', 'Var', (152, 168))	('cancer', 'Disease', (61, 67))	('nucleotide substitutions', 'Var', (126, 150))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('deletions', 'Var', (173, 182))
3253	27847479	Besides, WGS and WES are unsuitable for clinical application because of relatively lower read depth and this later limit the identification of low-allelic-fraction single nucleotide polymorphisms (SNPs) which is important for early diagnosis, prevention of drug resistance and residual tumor detection.	('drug resistance', 'Phenotype', 'HP:0020174', (257, 272))	('tumor', 'Disease', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('drug resistance', 'biological_process', 'GO:0009315', ('257', '272'))	('lower', 'NegReg', (83, 88))	('limit', 'NegReg', (115, 120))	('drug resistance', 'biological_process', 'GO:0042493', ('257', '272'))	('read depth', 'MPA', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('single nucleotide polymorphisms', 'Var', (164, 195))
3257	27847479	Recurrent translocations of genes in important cancer pathways including WNT, EGFR-RAS-MAPK, PI3K, protein kinase A, retinoblastoma and apoptosis were identified.	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (117, 131))	('EGFR', 'Gene', '1956', (78, 82))	('retinoblastoma', 'Disease', (117, 131))	('translocations', 'Var', (10, 24))	('cancer', 'Disease', (47, 53))	('apoptosis', 'Disease', (136, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('WNT', 'Gene', (73, 76))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('EGFR', 'Gene', (78, 82))	('PI3K', 'Gene', (93, 97))	('retinoblastoma', 'Disease', 'MESH:D012175', (117, 131))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('protein kinase', 'Enzyme', (99, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))
3258	27847479	The most frequent translocations were discovered in a member of the BCL family which were BCL2, BCL7A, BCL9, and BCL2L11.	('BCL2', 'molecular_function', 'GO:0015283', ('90', '94'))	('BCL2', 'molecular_function', 'GO:0015283', ('113', '117'))	('BCL7A', 'Gene', '605', (96, 101))	('translocations', 'Var', (18, 32))	('BCL9', 'Gene', (103, 107))	('BCL7A', 'Gene', (96, 101))	('BCL9', 'Gene', '607', (103, 107))	('BCL2', 'Gene', '596', (90, 94))	('BCL2', 'Gene', '596', (113, 117))	('BCL2', 'Gene', (90, 94))	('BCL2L11', 'Gene', '10018', (113, 120))	('BCL2', 'Gene', (113, 117))	('BCL2L11', 'Gene', (113, 120))
3259	27847479	This large-scale consortium also performedWES on 248 ECs and identified novel POLE hotspot mutations (Pro286Arg and Val411Leu) in 13 of the 17 ultra-mutated samples.	('Pro286Arg', 'SUBSTITUTION', 'None', (102, 111))	('Val411Leu', 'Var', (116, 125))	('Pro286Arg', 'Var', (102, 111))	('Val411Leu', 'SUBSTITUTION', 'None', (116, 125))	('EC', 'Phenotype', 'HP:0012114', (53, 55))
3266	27847479	In addition to confirming the existence of alterations in TP53, PIK3CA and PPP2R1A, they also identified high frequency of somatic alterations in novel genes involved in serous ECs which were FBXW7, CHD4, SPOP, MAP3K4, ABCC9, and CYP4X1.	('ABCC9', 'Gene', (219, 224))	('TP53', 'Gene', '7157', (58, 62))	('FBXW7', 'Gene', (192, 197))	('MAP3K4', 'Gene', '4216', (211, 217))	('alterations', 'Var', (131, 142))	('PIK3CA', 'Gene', '5290', (64, 70))	('MAP3K', 'molecular_function', 'GO:0004709', ('211', '216'))	('alterations', 'Var', (43, 54))	('CYP4X1', 'Gene', (230, 236))	('ABCC9', 'Gene', '10060', (219, 224))	('MAP3K4', 'Gene', (211, 217))	('FBXW7', 'Gene', '55294', (192, 197))	('TP53', 'Gene', (58, 62))	('SPOP', 'Gene', '8405', (205, 209))	('serous EC', 'Chemical', '-', (170, 179))	('EC', 'Phenotype', 'HP:0012114', (177, 179))	('PPP2R1A', 'Gene', '5518', (75, 82))	('CHD4', 'Gene', (199, 203))	('PIK3CA', 'Gene', (64, 70))	('CYP4X1', 'Gene', '260293', (230, 236))	('SPOP', 'Gene', (205, 209))	('CHD4', 'Gene', '1108', (199, 203))	('PPP2R1A', 'Gene', (75, 82))
3270	27847479	DNA copy number analysis revealed concurrent frequent genomic amplification of the CCNE1 with FBXW7 mutations, suggesting that these genes are involved in same signaling pathway.	('mutations', 'Var', (100, 109))	('signaling pathway', 'biological_process', 'GO:0007165', ('160', '177'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('involved', 'Reg', (143, 151))	('CCNE1', 'Gene', '898', (83, 88))	('CCNE1', 'Gene', (83, 88))	('genomic amplification', 'Var', (54, 75))	('FBXW7', 'Gene', '55294', (94, 99))	('FBXW7', 'Gene', (94, 99))
3271	27847479	They also proposed the role of endometrial intraepithelial carcinoma as a precursor to serous carcinoma whereby nine cases of serous carcinoma with an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PP2R1A, and TP53 mutations.	('serous carcinoma', 'Disease', 'MESH:D018284', (126, 142))	('endometrial intraepithelial carcinoma', 'Disease', 'MESH:D016889', (169, 206))	('mutations', 'Var', (247, 256))	('endometrial intraepithelial carcinoma', 'Disease', (31, 68))	('PIK3CA', 'Gene', '5290', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('TP53', 'Gene', (242, 246))	('serous carcinoma', 'Disease', (87, 103))	('serous endometrial intraepithelial carcinoma', 'Disease', (162, 206))	('endometrial intraepithelial carcinoma', 'Disease', 'MESH:D016889', (31, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('serous endometrial intraepithelial carcinoma', 'Phenotype', 'HP:0012887', (162, 206))	('PP2R1A', 'Gene', (230, 236))	('serous carcinoma', 'Disease', (126, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('PIK3CA', 'Gene', (222, 228))	('serous carcinoma', 'Disease', 'MESH:D018284', (87, 103))	('serous endometrial intraepithelial carcinoma', 'Disease', 'MESH:D016889', (162, 206))	('TP53', 'Gene', '7157', (242, 246))
3272	27847479	Taken together, the authors presented molecular genetic alterations involving the p53, cyclin E-FBXW7 and PI3K pathways as the major mechanisms in the uterine serous carcinoma progression.	('serous carcinoma', 'Disease', 'MESH:D018284', (159, 175))	('alterations', 'Var', (56, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('FBXW7', 'Gene', '55294', (96, 101))	('PI3K', 'molecular_function', 'GO:0016303', ('106', '110'))	('PI3K', 'Pathway', (106, 110))	('cyclin', 'molecular_function', 'GO:0016538', ('87', '93'))	('mechanisms', 'Reg', (133, 143))	('p53', 'Gene', (82, 85))	('FBXW7', 'Gene', (96, 101))	('p53', 'Gene', '7157', (82, 85))	('serous carcinoma', 'Disease', (159, 175))
3274	27847479	In addition to earlier published studies which identified frequent alterations in TP53, PIK3CA, PPPR1A, and FBXW7, also discovered high frequency mutations of the SPOP gene which targets the protein for ubiquitination.	('TP53', 'Gene', (82, 86))	('PIK3CA', 'Gene', '5290', (88, 94))	('mutations', 'Var', (146, 155))	('ubiquitination', 'MPA', (203, 217))	('FBXW7', 'Gene', (108, 113))	('SPOP', 'Gene', '8405', (163, 167))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('protein', 'Protein', (191, 198))	('SPOP', 'Gene', (163, 167))	('FBXW7', 'Gene', '55294', (108, 113))	('TP53', 'Gene', '7157', (82, 86))	('PIK3CA', 'Gene', (88, 94))
3275	27847479	Frequent TP53 deletions and amplifications of chromosome segments containing PIK3CA and CCNE1 are known to be targets of FBXW7.	('PIK3CA', 'Gene', (77, 83))	('CCNE1', 'Gene', '898', (88, 93))	('CCNE1', 'Gene', (88, 93))	('amplifications', 'Var', (28, 42))	('PIK3CA', 'Gene', '5290', (77, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('TP53', 'Gene', '7157', (9, 13))	('deletions', 'Var', (14, 23))	('TP53', 'Gene', (9, 13))	('FBXW7', 'Gene', '55294', (121, 126))	('FBXW7', 'Gene', (121, 126))
3276	27847479	This study also discovered overexpression of ERBB2 which act as an upstream regulator of PIK3CA/AKT/mTOR signaling pathway and loss of MBD3 gene function, a member of the NuRD-chromatin-modification complex.	('MBD3', 'Gene', (135, 139))	('MBD3', 'Gene', '53615', (135, 139))	('AKT', 'Gene', (96, 99))	('loss', 'Var', (127, 131))	('PIK3CA', 'Gene', (89, 95))	('chromatin-modification', 'biological_process', 'GO:0016569', ('176', '198'))	('signaling pathway', 'biological_process', 'GO:0007165', ('105', '122'))	('PIK3CA', 'Gene', '5290', (89, 95))	('ERBB2', 'Gene', '2064', (45, 50))	('AKT', 'Gene', '207', (96, 99))	('function', 'MPA', (145, 153))	('ERBB2', 'Gene', (45, 50))	('chromatin-modification', 'biological_process', 'GO:0006325', ('176', '198'))	('mTOR', 'Gene', (100, 104))	('chromatin', 'cellular_component', 'GO:0000785', ('176', '185'))	('mTOR', 'Gene', '2475', (100, 104))
3279	27847479	Both low-grade and grade 3 endometrioid EC demonstrated a similar pattern of high frequency of mutations in PTEN, PIK3CA, ARID1A, KRAS, and CTNNB1.	('PIK3CA', 'Gene', '5290', (114, 120))	('ARID1A', 'Gene', '8289', (122, 128))	('ARID1A', 'Gene', (122, 128))	('PTEN', 'Gene', (108, 112))	('PTEN', 'Gene', '5728', (108, 112))	('CTNNB1', 'Gene', (140, 146))	('EC', 'Phenotype', 'HP:0012114', (40, 42))	('KRAS', 'Gene', (130, 134))	('PIK3CA', 'Gene', (114, 120))	('mutations', 'Var', (95, 104))	('CTNNB1', 'Gene', '1499', (140, 146))	('KRAS', 'Gene', '3845', (130, 134))
3280	27847479	There is a significant increase in TP53 mutation frequency in grade 3 endometrioid EC when compared to low-grade EC.	('mutation', 'Var', (40, 48))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('increase', 'PosReg', (23, 31))	('grade 3 endometrioid EC', 'Disease', (62, 85))	('EC', 'Phenotype', 'HP:0012114', (83, 85))	('EC', 'Phenotype', 'HP:0012114', (113, 115))
3281	27847479	ARID1A mutation was significantly associated with concurrent PTEN and PIK3CA mutations in both low-grade endometrioid EC and grade 3 endometrioid ECs, suggesting a cooperative role in endometrioid carcinogenesis.	('associated', 'Reg', (34, 44))	('endometrioid carcinogenesis', 'Disease', 'MESH:D063646', (184, 211))	('ARID1A', 'Gene', '8289', (0, 6))	('low-grade endometrioid EC', 'Disease', (95, 120))	('PIK3CA', 'Gene', (70, 76))	('endometrioid carcinogenesis', 'Disease', (184, 211))	('ARID1A', 'Gene', (0, 6))	('mutations', 'Var', (77, 86))	('PTEN', 'Gene', (61, 65))	('mutation', 'Var', (7, 15))	('PTEN', 'Gene', '5728', (61, 65))	('EC', 'Phenotype', 'HP:0012114', (146, 148))	('EC', 'Phenotype', 'HP:0012114', (118, 120))	('PIK3CA', 'Gene', '5290', (70, 76))
3282	27847479	However, this phenomenon was not observed in endometrial serous carcinomas which have frequent mutations in TP53 and PPP2R1A but lack mutations in PTEN, ARID1A, and CTNBB1.	('endometrial serous carcinomas', 'Disease', (45, 74))	('TP53', 'Gene', '7157', (108, 112))	('PPP2R1A', 'Gene', (117, 124))	('TP53', 'Gene', (108, 112))	('PPP2R1A', 'Gene', '5518', (117, 124))	('lack', 'NegReg', (129, 133))	('ARID1A', 'Gene', '8289', (153, 159))	('mutations', 'Var', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('ARID1A', 'Gene', (153, 159))	('PTEN', 'Gene', (147, 151))	('endometrial serous carcinomas', 'Disease', 'MESH:D016889', (45, 74))	('PTEN', 'Gene', '5728', (147, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
3285	27847479	Higher frequency of mutations was discovered in low-grade endometrial endometrioid carcinoma (67%) compared to low-grade ovarian endometrioid carcinoma (17%).	('ovarian endometrioid carcinoma', 'Disease', (121, 151))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (58, 92))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (70, 92))	('endometrial endometrioid carcinoma', 'Disease', (58, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (129, 151))	('ovarian endometrioid carcinoma', 'Disease', 'MESH:D016889', (121, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('mutations', 'Var', (20, 29))
3286	27847479	The frequency of CTNNB1 mutation was significantly higher in ovarian endometrioid cancer (53%) when compared to endometrioid EC (28%).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('higher', 'Reg', (51, 57))	('CTNNB1', 'Gene', (17, 23))	('ovarian endometrioid cancer', 'Disease', (61, 88))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (69, 88))	('EC', 'Phenotype', 'HP:0012114', (125, 127))	('ovarian endometrioid cancer', 'Disease', 'MESH:D010051', (61, 88))	('mutation', 'Var', (24, 32))	('CTNNB1', 'Gene', '1499', (17, 23))
3291	27847479	This study revealed 120 variants in 99 genes, with 50% of the ECs harboring mutations in the PTEN.	('PTEN', 'Gene', (93, 97))	('mutations', 'Var', (76, 85))	('PTEN', 'Gene', '5728', (93, 97))	('variants', 'Var', (24, 32))	('harboring', 'Reg', (66, 75))	('EC', 'Phenotype', 'HP:0012114', (62, 64))
3292	27847479	Molecular aberrations in PIK3R1, AKT2 and FOXO1 that could led to putative activation of the IL-7 signaling pathway and which has not been previously linked with EC, are also reported.	('IL-7', 'molecular_function', 'GO:0005139', ('93', '97'))	('aberrations', 'Var', (10, 21))	('IL-7', 'Gene', '3574', (93, 97))	('PIK3R1', 'Gene', '5295', (25, 31))	('IL-7', 'Gene', (93, 97))	('AKT2', 'Gene', (33, 37))	('PIK3R1', 'Gene', (25, 31))	('activation', 'PosReg', (75, 85))	('FOXO1', 'Gene', (42, 47))	('FOXO1', 'Gene', '2308', (42, 47))	('AKT2', 'Gene', '208', (33, 37))	('signaling pathway', 'biological_process', 'GO:0007165', ('98', '115'))	('EC', 'Phenotype', 'HP:0012114', (162, 164))
3305	27847479	Dysregulation of TSNAX is presumed to be associated with cancer and the authors proposed the potential of TSNAX-DISC1 as an EC biomarker.	('TSNAX', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('TSNAX-DISC1', 'Gene', (106, 117))	('associated', 'Reg', (41, 51))	('TSNAX-DISC1', 'Gene', '100303453;7257;27185', (106, 117))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (57, 63))	('TSNAX', 'Gene', '7257', (106, 111))	('TSNAX', 'Gene', '7257', (17, 22))	('DISC', 'cellular_component', 'GO:0031264', ('112', '116'))	('EC', 'Phenotype', 'HP:0012114', (124, 126))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TSNAX', 'Gene', (106, 111))
3310	26629914	Differences in DNA methylation (DNAm) levels are amongst the earliest changes in human carcinogenesis and are a hallmark of cancer, offering the potential for novel strategies to predict cancer biology and outcome.	('Differences', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (187, 193))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinogenesis', 'Disease', (87, 101))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('human', 'Species', '9606', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('DNA methylation', 'MPA', (15, 30))
3349	26629914	As the genes comprising cluster hyper 2 seem to show the same IGV in most cells of the tumour, but the high IGV of the cluster hyper 2 genes is associated with poor prognosis, we deem the cluster hyper 2 IGV to be a 'consistent tumour-cell inherent phenomenon', which is likely to be regulated by differential binding of transcription factors (TF).	('transcription', 'biological_process', 'GO:0006351', ('321', '334'))	('tumour', 'Disease', (87, 93))	('binding', 'molecular_function', 'GO:0005488', ('310', '317'))	('cluster hyper', 'Var', (188, 201))	('tumour', 'Disease', (228, 234))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))
3455	21272308	On one hand the molecular changes in two major subtypes of endometrial cancer are well known: the estrogen-related type I shows defects in DNA-mismatch repair, mutations in PTEN, beta-catenin, and k-ras, while type II, nonendometrioid such as papillary serous and clear cell shows aneuploidy and p53 mutations.	('p53', 'Gene', (296, 299))	('defects', 'NegReg', (128, 135))	('mutations', 'Var', (160, 169))	('PTEN', 'Gene', (173, 177))	('aneuploidy', 'Disease', (281, 291))	('k-ras', 'Protein', (197, 202))	('PTEN', 'Gene', '5728', (173, 177))	('mismatch repair', 'biological_process', 'GO:0006298', ('143', '158'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (300, 309))	('DNA-mismatch repair', 'MPA', (139, 158))	('endometrial cancer', 'Phenotype', 'HP:0012114', (59, 77))	('beta-catenin', 'Gene', (179, 191))	('p53', 'Gene', '7157', (296, 299))	('beta-catenin', 'Gene', '1499', (179, 191))	('aneuploidy', 'Disease', 'MESH:D000782', (281, 291))	('endometrial cancer', 'Disease', (59, 77))	('endometrial cancer', 'Disease', 'MESH:D016889', (59, 77))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))
3468	26166718	The genomic heterogeneity of FIGO grade 3 endometrioid carcinoma: impacts on diagnostic accuracy and reproducibility The Cancer Genome Atlas (TCGA) identified 4 groups of endometrial carcinomas based on an integrated genomic characterization: POLE ultramutated (POLE), microsatellite instability-high (MSI-H), copy number-low (CN-L), and copy number-high (CN-H).	('endometrial carcinomas', 'Disease', 'MESH:D016889', (171, 193))	('MSI-H', 'Disease', 'MESH:D000848', (302, 307))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (42, 64))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (42, 64))	('copy number-high', 'Var', (338, 354))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (171, 192))	('endometrial carcinomas', 'Disease', (171, 193))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (171, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('copy number-low', 'Var', (310, 325))	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('MSI-H', 'Disease', (302, 307))	('endometrioid carcinoma', 'Disease', (42, 64))	('Cancer Genome Atlas', 'Disease', (121, 140))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (121, 140))
3473	26166718	The interobserver agreement rate was highest in the CN-L group (90%; kappa 0.9), compared to the other genomic groups (POLE: 62%, kappa 0.55; MSI-H: 78%, kappa 0.74; and CN-H: 53%, kappa 0.48).	('CN-L', 'Var', (52, 56))	('highest', 'Reg', (37, 44))	('MSI-H', 'Disease', (142, 147))	('MSI-H', 'Disease', 'MESH:D000848', (142, 147))
3479	26166718	Endometrioid carcinoma is characterized by frequent mutations in PTEN, ARID1A, DNA mismatch repair genes, KRAS, and PIK3CA.	('mutations', 'Var', (52, 61))	('PIK3CA', 'Gene', (116, 122))	('KRAS', 'Gene', '3845', (106, 110))	('PTEN', 'Gene', (65, 69))	('PTEN', 'Gene', '5728', (65, 69))	('Endometrioid carcinoma', 'Disease', 'MESH:D016889', (0, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('PIK3CA', 'Gene', '5290', (116, 122))	('Endometrioid carcinoma', 'Phenotype', 'HP:0012114', (0, 22))	('mismatch repair', 'biological_process', 'GO:0006298', ('83', '98'))	('KRAS', 'Gene', (106, 110))	('Endometrioid carcinoma', 'Disease', (0, 22))	('ARID1A', 'Gene', '8289', (71, 77))	('ARID1A', 'Gene', (71, 77))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
3480	26166718	Additionally, a subset of high-grade and even rare low-grade endometrioid carcinomas harbors mutations in TP53.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (61, 84))	('mutations', 'Var', (93, 102))	('harbors', 'Reg', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('endometrioid carcinomas', 'Disease', (61, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
3481	26166718	In contrast, serous carcinoma is characterized by frequent mutations in TP53 and PPP2R1A, while mutations involving PTEN, ARID1A, DNA mismatch repair genes, and KRAS are very infrequent.	('ARID1A', 'Gene', '8289', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('ARID1A', 'Gene', (122, 128))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('TP53', 'Gene', '7157', (72, 76))	('mismatch repair', 'biological_process', 'GO:0006298', ('134', '149'))	('TP53', 'Gene', (72, 76))	('serous carcinoma', 'Disease', (13, 29))	('PPP2R1A', 'Gene', (81, 88))	('mutations', 'Var', (59, 68))	('PTEN', 'Gene', (116, 120))	('PPP2R1A', 'Gene', '5518', (81, 88))	('KRAS', 'Gene', (161, 165))	('PTEN', 'Gene', '5728', (116, 120))	('serous carcinoma', 'Disease', 'MESH:D018284', (13, 29))	('KRAS', 'Gene', '3845', (161, 165))
3484	26166718	Based on the integration of the somatic gene mutations, microsatellite instability, and somatic copy-number alterations results, endometrial carcinomas were categorized into 4 genomic groups: 1) An "ultramutated" group harboring mutations in the exonuclease domain of the polymerase epsilon (POLE) gene, and characterized by very high mutation rates; 2) A "hypermutated" group characterized by microsatellite instability (MSI) due to MLH1 promoter methylation, with high mutation rates and few copy number alterations; 3) A "copy number-low (CN-low)" group, composed of most of the microsatellite-stable grade 1 and grade 2 endometrioid carcinomas, which demonstrated low mutation rates; and 4) A "copy number-high" (CN-high) group with extensive copy number aberrations, low mutation rates, and recurrent TP53 mutations, composed of all of the serous carcinomas in the study and 25% of all FIGO grade 3 endometrioid carcinomas.	('endometrioid carcinomas', 'Disease', (624, 647))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (129, 151))	('serous carcinomas', 'Disease', 'MESH:D018284', (845, 862))	('mutations', 'Var', (811, 820))	('carcinoma', 'Phenotype', 'HP:0030731', (637, 646))	('carcinomas', 'Phenotype', 'HP:0030731', (637, 647))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (904, 927))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (129, 151))	('TP53', 'Gene', (806, 810))	('MLH1', 'Gene', (434, 438))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (624, 647))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (904, 926))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (904, 927))	('MLH1', 'Gene', '4292', (434, 438))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (129, 150))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (624, 646))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('serous carcinomas', 'Disease', (845, 862))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (624, 647))	('endometrial carcinomas', 'Disease', (129, 151))	('TP53', 'Gene', '7157', (806, 810))	('carcinoma', 'Phenotype', 'HP:0030731', (917, 926))	('carcinomas', 'Phenotype', 'HP:0030731', (917, 927))	('endometrioid carcinomas', 'Disease', (904, 927))	('carcinoma', 'Phenotype', 'HP:0030731', (852, 861))	('carcinomas', 'Phenotype', 'HP:0030731', (852, 862))
3489	26166718	The TCGA study showed that CN-high endometrial carcinomas had the worst progression-free survival of the 4 TCGA genomic groups.	('endometrial carcinomas', 'Disease', (35, 57))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (35, 57))	('worst', 'NegReg', (66, 71))	('CN-high', 'Var', (27, 34))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (35, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('progression-free survival', 'CPA', (72, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (35, 56))
3490	26166718	In contrast, despite their high-grade morphology, POLE-mutated high-grade endometrioid carcinoma had the best progression-free survival of the 4 molecular categories.	('POLE-mutated', 'Var', (50, 62))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (74, 96))	('endometrioid carcinoma', 'Disease', (74, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
3493	26166718	The primary aim of this study was to determine whether the subset of CN-high Gr3-EMC identified in the TCGA study would have histologic features of serous carcinoma on retrospective histologic review by 2 experienced gynecologic pathologists.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('serous carcinoma', 'Disease', (148, 164))	('serous carcinoma', 'Disease', 'MESH:D018284', (148, 164))	('CN-high', 'Var', (69, 76))	('EMC', 'cellular_component', 'GO:0072546', ('81', '84'))	('Gr3-EMC', 'Gene', (77, 84))
3499	26166718	Using the criteria from Hoang et al's study, cases were defined genotypically as endometrioid carcinoma when they had PTEN and/or ARID1A mutations, with or without TP53 mutation, or as serous carcinoma if the tumor harbored a TP53 mutation in the absence of PTEN and ARID1A.	('ARID1A', 'Gene', (130, 136))	('PTEN', 'Gene', (118, 122))	('serous carcinoma', 'Disease', (185, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('TP53', 'Gene', (226, 230))	('PTEN', 'Gene', (258, 262))	('ARID1A', 'Gene', '8289', (130, 136))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (81, 103))	('TP53', 'Gene', (164, 168))	('tumor', 'Disease', (209, 214))	('PTEN', 'Gene', '5728', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('serous carcinoma', 'Disease', 'MESH:D018284', (185, 201))	('PTEN', 'Gene', '5728', (258, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrioid carcinoma', 'Disease', (81, 103))	('TP53', 'Gene', '7157', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('ARID1A', 'Gene', (267, 273))	('TP53', 'Gene', '7157', (164, 168))	('mutations', 'Var', (137, 146))	('ARID1A', 'Gene', '8289', (267, 273))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (81, 103))
3509	26166718	Despite the fact that these 6 cases were interpreted as serous carcinoma by both reviewers, only 2 of the 6 cases had a serous carcinoma genotype (i.e., harboring TP53 mutation in the absence of PTEN and/or ARID1A mutation), which were among the CN-high group (TCGA-AP-A053 and TCGA-AP-AOLF).	('serous carcinoma', 'Disease', (56, 72))	('PTEN', 'Gene', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('TP53', 'Gene', '7157', (163, 167))	('serous carcinoma', 'Disease', 'MESH:D018284', (56, 72))	('mutation', 'Var', (168, 176))	('TP53', 'Gene', (163, 167))	('serous carcinoma', 'Disease', (120, 136))	('ARID1A', 'Gene', '8289', (207, 213))	('serous carcinoma', 'Disease', 'MESH:D018284', (120, 136))	('ARID1A', 'Gene', (207, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('PTEN', 'Gene', '5728', (195, 199))
3513	26166718	The single CN-high case was classified histologically as FIGO grade 3 endometrioid carcinoma, despite having a serous carcinoma genomic signature.	('serous carcinoma', 'Disease', (111, 127))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (70, 92))	('CN-high', 'Var', (11, 18))	('serous carcinoma', 'Disease', 'MESH:D018284', (111, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (70, 92))	('endometrioid carcinoma', 'Disease', (70, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
3521	26166718	Endometrioid carcinoma is characterized by frequent mutations in PTEN and/or ARID1A, with a subset harboring mutations in TP53 (especially FIGO grade 3 tumors).	('mutations', 'Var', (52, 61))	('ARID1A', 'Gene', '8289', (77, 83))	('ARID1A', 'Gene', (77, 83))	('TP53', 'Gene', (122, 126))	('PTEN', 'Gene', (65, 69))	('PTEN', 'Gene', '5728', (65, 69))	('Endometrioid carcinoma', 'Disease', 'MESH:D016889', (0, 22))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('FIGO grade 3', 'Disease', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Endometrioid carcinoma', 'Phenotype', 'HP:0012114', (0, 22))	('mutations', 'Var', (109, 118))	('Endometrioid carcinoma', 'Disease', (0, 22))	('tumors', 'Disease', (152, 158))	('TP53', 'Gene', '7157', (122, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
3522	26166718	Mutation of PPP2R1A is infrequent in endometrioid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (37, 60))	('Mutation', 'Var', (0, 8))	('PPP2R1A', 'Gene', (12, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('PPP2R1A', 'Gene', '5518', (12, 19))	('endometrioid carcinomas', 'Disease', (37, 60))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (37, 59))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (37, 60))
3523	26166718	In contrast, serous carcinoma is characterized by frequent mutations in TP53 and PPP2R1A, whereas mutations involving PTEN and/or ARID1A are very infrequent.	('ARID1A', 'Gene', '8289', (130, 136))	('ARID1A', 'Gene', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('TP53', 'Gene', '7157', (72, 76))	('PTEN', 'Gene', '5728', (118, 122))	('TP53', 'Gene', (72, 76))	('PTEN', 'Gene', (118, 122))	('serous carcinoma', 'Disease', (13, 29))	('PPP2R1A', 'Gene', (81, 88))	('mutations', 'Var', (59, 68))	('serous carcinoma', 'Disease', 'MESH:D018284', (13, 29))	('PPP2R1A', 'Gene', '5518', (81, 88))
3528	26166718	High nuclear grade distributed diffusely in the setting of glandular or papillary tumor was equated with a serous carcinoma genotype.	('serous carcinoma', 'Disease', (107, 123))	('serous carcinoma', 'Disease', 'MESH:D018284', (107, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('High nuclear', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('papillary tumor', 'Disease', (72, 87))	('glandular', 'Disease', (59, 68))	('papillary tumor', 'Disease', 'MESH:D002291', (72, 87))
3532	26166718	Aberrant p53 immunohistochemical expression without abnormalities in ARID1A or DNA mismatch repair proteins, as well as PTEN, should be sufficient to confirm a serous carcinoma diagnosis if suspected on routine morphological examination.	('confirm', 'Reg', (150, 157))	('serous carcinoma', 'Disease', (160, 176))	('Aberrant', 'Var', (0, 8))	('ARID1A', 'Gene', '8289', (69, 75))	('p53', 'Gene', (9, 12))	('PTEN', 'Gene', '5728', (120, 124))	('serous carcinoma', 'Disease', 'MESH:D018284', (160, 176))	('p53', 'Gene', '7157', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('mismatch repair', 'biological_process', 'GO:0006298', ('83', '98'))	('PTEN', 'Gene', (120, 124))	('ARID1A', 'Gene', (69, 75))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
3533	26166718	Conversely, aberrant p53 expression along with alteration of one or more of the previously mentioned markers supports endometrioid differentiation, whereas tumors lacking aberrant p53 expression are not likely to be serous carcinoma (Figure 5).	('p53', 'Gene', (180, 183))	('expression', 'MPA', (25, 35))	('p53', 'Gene', '7157', (180, 183))	('endometrioid differentiation', 'Disease', (118, 146))	('p53', 'Gene', '7157', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('serous carcinoma', 'Disease', (216, 232))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('aberrant', 'Var', (12, 20))	('serous carcinoma', 'Disease', 'MESH:D018284', (216, 232))	('tumors', 'Disease', (156, 162))	('p53', 'Gene', (21, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
3537	26166718	A panel of immunohistochemical stains such as p53, PTEN, ARID1A, and p16 may be used to discriminate serous carcinomas from FIGO grade 3 endometrioid carcinoma; however, currently the only definite way to detect EC-POLE tumors is by sequencing the POLE gene.	('EC-POLE tumors', 'Disease', 'MESH:D009369', (212, 226))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (137, 159))	('ARID1A', 'Gene', (57, 63))	('PTEN', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (137, 159))	('EC-POLE tumors', 'Disease', (212, 226))	('p53', 'Gene', '7157', (46, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('serous carcinomas', 'Disease', (101, 118))	('ARID1A', 'Gene', '8289', (57, 63))	('PTEN', 'Gene', '5728', (51, 55))	('sequencing', 'Var', (233, 243))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('p53', 'Gene', (46, 49))	('endometrioid carcinoma', 'Disease', (137, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('p16', 'Gene', (69, 72))	('serous carcinomas', 'Disease', 'MESH:D018284', (101, 118))	('p16', 'Gene', '1029', (69, 72))
3550	26166718	Nevertheless, approximately 25% of FIGO grade 3 endometrioid carcinomas cluster with serous carcinoma by virtue of TP53 mutation and high copy number alterations as shown by the TCGA.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (48, 70))	('high copy number alterations', 'Var', (133, 161))	('TP53', 'Gene', '7157', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutation', 'Var', (120, 128))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (48, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('serous carcinoma', 'Disease', (85, 101))	('TP53', 'Gene', (115, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('endometrioid carcinomas cluster', 'Disease', (48, 79))	('serous carcinoma', 'Disease', 'MESH:D018284', (85, 101))	('FIGO', 'Disease', (35, 39))	('endometrioid carcinomas cluster', 'Disease', 'MESH:D016889', (48, 79))
3553	31672974	We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes.	('endometrial carcinoma', 'Disease', (68, 89))	('POLE-mutated', 'Var', (91, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('copy number high', 'Var', (133, 149))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('microsatellite instability', 'MPA', (105, 131))	('copy number low', 'Var', (155, 170))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (68, 89))
3554	31672974	These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes.	('linked', 'Reg', (29, 35))	('deficiencies', 'Var', (52, 64))	('DNA repair', 'biological_process', 'GO:0006281', ('41', '51'))	('DNA', 'Disease', (41, 44))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('patient', 'Species', '9606', (153, 160))
3570	31672974	Microsatellite instability, caused by defective mismatch repair, is observed in 20-40% of endometrial endometrioid carcinoma and is associated with higher histological grade and more lymphovascular space invasion but better prognosis.	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (90, 124))	('mismatch repair', 'Protein', (48, 63))	('defective', 'Var', (38, 47))	('observed', 'Reg', (68, 76))	('Microsatellite instability', 'Disease', (0, 26))	('lymphovascular space invasion', 'CPA', (183, 212))	('endometrial endometrioid carcinoma', 'Disease', (90, 124))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (102, 124))	('mismatch repair', 'biological_process', 'GO:0006298', ('48', '63'))
3571	31672974	The ultramutated phenotype, resulting from mutations in the exonuclease domain of DNA polymerase epsilon (POLE), is present in several cancer types, including endometrial cancer, and linked with diseases at an earlier stage and with a more favorable prognosis.	('linked with', 'Reg', (183, 194))	('cancer', 'Disease', (135, 141))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations in', 'Var', (43, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('POLE', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('present', 'Reg', (116, 123))
3572	31672974	Copy number aberration is a dominant characteristic of the genome in endometrial and ovarian serous carcinoma, and is associated with a more advanced disease and poor patient outcomes.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('patient', 'Species', '9606', (167, 174))	('Copy number aberration', 'Var', (0, 22))	('endometrial and ovarian serous carcinoma', 'Disease', 'MESH:D010051', (69, 109))	('advanced disease', 'Disease', (141, 157))	('associated', 'Reg', (118, 128))	('advanced disease', 'Disease', 'MESH:D020178', (141, 157))
3579	31672974	We used a modified version of the molecular subtyping method based on genomic aberration profiling (described in the Methods) on 109 uterine and ovarian CS samples, and then used a decision tree to classify samples into four molecular subtypes: POLE-mutated (POLE), microsatellite instability (MSI), copy number high (CNH), and copy number low (CNL) subtypes.	('ovarian CS', 'Disease', (145, 155))	('copy number', 'Var', (328, 339))	('ovarian CS', 'Disease', 'MESH:D010049', (145, 155))	('microsatellite', 'MPA', (266, 280))	('copy', 'Var', (300, 304))
3581	31672974	MSI tumors exhibited numerous indels (range: 10-63, median: 27) and a moderately increased number of SNVs (range: 8-207, median: 55) but fewer CNVs (range: 0-7, median: 2).	('MSI tumors', 'Disease', (0, 10))	('indels', 'Var', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SNVs', 'MPA', (101, 105))	('CNVs', 'MPA', (143, 147))	('MSI tumors', 'Disease', 'MESH:D009369', (0, 10))
3582	31672974	The remaining tumors were assigned as CNL subtype, with few SNVs, indels, or CNVs (Fig.	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('CNVs', 'Var', (77, 81))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('indels', 'Var', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
3590	31672974	The ovarian CS and endometrial carcinoma share a subset of SNVs/indels, including the POLE p.P286R mutation.	('ovarian CS', 'Disease', (4, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('p.P286R', 'Var', (91, 98))	('ovarian CS', 'Disease', 'MESH:D010049', (4, 14))	('endometrial carcinoma', 'Disease', (19, 40))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (19, 40))	('p.P286R', 'Mutation', 'p.P286R', (91, 98))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (19, 40))
3594	31672974	Moreover, the multivariate Cox regression analysis with FIGO stage, tumor size, and primary tumor anatomical site confirmed that each of these genomic aberration subtypes was independent (POLE: p = 0.9985 and 0.9987, HR = 0.0000 and 0.0000; MSI: p = 0.0068 and 0.0205, HR = 0.1937 and 0.0937; CNH: p = 0.0007 and 0.0296, HR = 3.9048 and 2.6047; CNL: p = 0.1782 and 0.0025, HR = 1.9214 and 4.1512).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('0.0937', 'Var', (285, 291))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
3597	31672974	We curated gene sets for mismatch repair (MMR) and homologous recombination (HR) pathways that were relevant for hereditary breast, endometrial, and ovarian cancer, and subsequently assessed whether a tumor retained a germline and/or somatic mutation or CpG-site hypermethylation in the selected genes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ovarian cancer', 'Disease', (149, 163))	('mismatch repair', 'biological_process', 'GO:0006298', ('25', '40'))	('endometrial', 'Disease', (132, 143))	('hereditary breast', 'Disease', (113, 130))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('endometrial', 'Disease', 'MESH:D016889', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('homologous recombination', 'biological_process', 'GO:0035825', ('51', '75'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('tumor', 'Disease', (201, 206))	('hereditary breast', 'Disease', 'MESH:D061325', (113, 130))	('MMR', 'biological_process', 'GO:0006298', ('42', '45'))	('CpG-site hypermethylation', 'Var', (254, 279))
3600	31672974	Defective MMR was observed in the MSI subtype, including MLH1 promoter hypermethylation and germline/somatic mutations in MLH1, MSH2, MSH6, or PMS2 loci.	('MLH1', 'Gene', '4292', (57, 61))	('PMS2', 'Gene', '5395', (143, 147))	('MLH1', 'Gene', (57, 61))	('MSH6', 'Gene', '2956', (134, 138))	('MLH1', 'Gene', (122, 126))	('MMR', 'biological_process', 'GO:0006298', ('10', '13'))	('MLH1', 'Gene', '4292', (122, 126))	('MSH2', 'Gene', (128, 132))	('MSH2', 'Gene', '4436', (128, 132))	('hypermethylation', 'Var', (71, 87))	('MSH6', 'Gene', (134, 138))	('PMS2', 'Gene', (143, 147))
3601	31672974	HR deficiency was a distinctive feature of the CNH subtype, as exemplified by (1) BRCA1 and RAD51C promoter hypermethylation; (2) germline inactivation plus loss of heterozygosity (LOH) in the loci of BRCA1/2, ATM, RAD50, and BLM; and (3) somatic mutation of the PTEN gene.	('BRCA1/2', 'Gene', (201, 208))	('RAD', 'biological_process', 'GO:1990116', ('215', '218'))	('BRCA1', 'Gene', '672', (82, 87))	('BRCA1', 'Gene', (82, 87))	('HR deficiency', 'Disease', (0, 13))	('BRCA1/2', 'Gene', '672;675', (201, 208))	('RAD51C', 'Gene', '5889', (92, 98))	('BRCA1', 'Gene', '672', (201, 206))	('HR deficiency', 'Disease', 'MESH:D001919', (0, 13))	('loss of', 'NegReg', (157, 164))	('inactivation', 'Var', (139, 151))	('RAD', 'biological_process', 'GO:1990116', ('92', '95'))	('RAD50', 'Gene', (215, 220))	('BRCA1', 'Gene', (201, 206))	('ATM', 'Gene', '472', (210, 213))	('PTEN', 'Gene', (263, 267))	('RAD51C', 'Gene', (92, 98))	('RAD50', 'Gene', '10111', (215, 220))	('PTEN', 'Gene', '5728', (263, 267))	('ATM', 'Gene', (210, 213))
3603	31672974	CCNE1 amplification and homozygous deletions of RB1 and NF1 loci were previously reported to be involved in chromosomal instability through a distinct mechanism not involving HR deficiency (non-HRD).	('chromosomal instability', 'MPA', (108, 131))	('RB1', 'Gene', (48, 51))	('HRD', 'Disease', 'MESH:C537157', (194, 197))	('NF1', 'Gene', '4763', (56, 59))	('CCNE1', 'Gene', '898', (0, 5))	('HR deficiency', 'Disease', (175, 188))	('involved', 'Reg', (96, 104))	('HRD', 'Disease', (194, 197))	('CCNE1', 'Gene', (0, 5))	('RB1', 'Gene', '5925', (48, 51))	('HR deficiency', 'Disease', 'MESH:D001919', (175, 188))	('chromosomal instability', 'Phenotype', 'HP:0040012', (108, 131))	('amplification', 'Var', (6, 19))	('NF1', 'Gene', (56, 59))	('homozygous deletions', 'Var', (24, 44))
3604	31672974	Within the CNH subtype, 17 (26.6%) of 64 CNH tumors (15 CCNE1 amplification and 2 RB1 deletion) exhibited this non-HRD-type chromosomal instability.	('RB1', 'Gene', '5925', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('exhibited', 'Reg', (96, 105))	('HRD', 'Disease', (115, 118))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('CNH tumors', 'Disease', 'MESH:D009369', (41, 51))	('chromosomal instability', 'Phenotype', 'HP:0040012', (124, 147))	('CCNE1', 'Gene', '898', (56, 61))	('CCNE1', 'Gene', (56, 61))	('RB1', 'Gene', (82, 85))	('amplification', 'Var', (62, 75))	('HRD', 'Disease', 'MESH:C537157', (115, 118))	('CNH tumors', 'Disease', (41, 51))	('deletion', 'Var', (86, 94))
3609	31672974	Also, by GISTIC analysis of SNP6 data, copy number amplification was highly significant for MECOM, MYC, and CCNE1.	('MECOM', 'Gene', (92, 97))	('CCNE1', 'Gene', (108, 113))	('MYC', 'Disease', (99, 102))	('MECOM', 'Gene', '2122', (92, 97))	('CCNE1', 'Gene', '898', (108, 113))	('copy number amplification', 'Var', (39, 64))
3627	31672974	The phylogenetic trees of the CNL and CNH subtype tumors had a high proportion of trunks: the carcinoma and sarcoma components shared most of the SNVs/indels of the 596 genes (Fig.	('CNH subtype tumors', 'Disease', 'MESH:C535673', (38, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('CNH subtype tumors', 'Disease', (38, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('SNVs/indels', 'Var', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (94, 115))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
3629	31672974	Whereas none of the 26 (0%) and only 2 of the 12 (16.7%) drivers on the carcinoma- or sarcoma-branches were clonal among the POLE and MSI subtypes, 21 of 43 (48.8%) and 9 of 12 (75.0%) driver mutations on the trunk were clonal, respectively (Fig.	('carcinoma- or sarcoma-branches', 'Disease', (72, 102))	('carcinoma- or sarcoma-branches', 'Disease', 'MESH:D012509', (72, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('trunk', 'cellular_component', 'GO:0043198', ('209', '214'))	('mutations', 'Var', (192, 201))
3631	31672974	CS tumors of the CNH subtype frequently had longer trunks with shorter branches for both carcinoma and sarcoma components, and this branching pattern was also confirmed with tree analyses with SNVs/indels from the exome data (when available) and with CNVs of the target panel or exome data (Supplementary Fig.	('CS tumors', 'Disease', 'MESH:D006223', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('longer', 'PosReg', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (89, 110))	('CS tumors', 'Disease', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('shorter', 'NegReg', (63, 70))	('SNVs/indels', 'Var', (193, 204))	('CNH', 'Disease', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
3637	31672974	However, in the CNH subtype (GY030 tumor), similarities between T2 (carcinoma-dominant) and T3 (sarcoma-dominant), and between T4 (carcinoma-dominant) and T6 (sarcoma-dominant) suggest parallel evolution of the bimodal T2/T3 and T4/T6 regions.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('carcinoma-dominant', 'Disease', 'MESH:D002277', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinoma-dominant', 'Disease', (68, 86))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('sarcoma-dominant', 'Disease', (96, 112))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (159, 175))	('CNH', 'Disease', (16, 19))	('sarcoma-dominant', 'Disease', (159, 175))	('tumor', 'Disease', (35, 40))	('carcinoma-dominant', 'Disease', 'MESH:D002277', (131, 149))	('carcinoma-dominant', 'Disease', (131, 149))	('GY030', 'Var', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (96, 112))
3641	31672974	No recurrent genetic mutations in SNVs/indels or CNVs were differentially detected between carcinoma- and sarcoma-dominant regions with multi-regional sequenced data of 3 cases (EN676, GY030, and EN558; the data from EN482 were not used for this purpose since sarcoma-dominant region sequenced data was not available for the case; also described in Supplementary Note 3).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('sarcoma-dominant', 'Disease', (106, 122))	('EN558', 'Var', (196, 201))	('sarcoma-dominant', 'Disease', (260, 276))	('carcinoma- and sarcoma-dominant regions', 'Disease', 'MESH:D012509', (91, 130))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (106, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('EN676', 'Var', (178, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('GY030', 'Var', (185, 190))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (260, 276))
3669	31672974	ARID1A mutation was correlated with better patient outcomes when all cases were included in the analysis, because it was more frequently mutated in POLE and MSI subtypes, which show an intrinsically more favorable prognosis.	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('patient', 'Species', '9606', (43, 50))
3670	31672974	On the contrary, in the CNH subgroup, patients with ARID1A mutant tumors showed substantially poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutant', 'Var', (59, 65))	('tumors', 'Disease', (66, 72))	('ARID1A', 'Gene', '8289', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('ARID1A', 'Gene', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (38, 46))	('poor', 'NegReg', (94, 98))
3677	31672974	Whereas CTNNB1-activating mutations have long been recognized as a driving mechanism of EMT in multiple cancer types, including uterine endometrioid carcinoma, in the current CS cohort and contrary to our expectations, the mutational status was independent of the EMT score but, instead, associated with hypomethylation of the miR-200a/200b/429 and miR-141/200c promotors.	('mutations', 'Var', (26, 35))	('miR-200a', 'Gene', '406983', (327, 335))	('endometrioid carcinoma', 'Disease', 'MESH:D018269', (136, 158))	('cancer', 'Disease', (104, 110))	('associated with', 'Reg', (288, 303))	('hypomethylation', 'MPA', (304, 319))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CTNNB1', 'Gene', '1499', (8, 14))	('EMT', 'biological_process', 'GO:0001837', ('88', '91'))	('miR-141', 'Gene', '406933', (349, 356))	('mutational', 'Var', (223, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('endometrioid carcinoma', 'Disease', (136, 158))	('miR-141', 'Gene', (349, 356))	('EMT', 'biological_process', 'GO:0001837', ('264', '267'))	('miR-200a', 'Gene', (327, 335))	('CTNNB1', 'Gene', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (136, 158))
3683	31672974	In the current cohort, 2 cases (OV594 and OV343) had synchronous endometrial and ovarian carcinomas (SEOC) and were associated with endometriosis in the ovary.	('associated with', 'Reg', (116, 131))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('endometriosis', 'Phenotype', 'HP:0030127', (132, 145))	('OV594', 'Var', (32, 37))	('OV343', 'Var', (42, 47))	('synchronous endometrial', 'Disease', 'MESH:D016889', (53, 76))	('endometriosis', 'Disease', (132, 145))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (81, 99))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (81, 98))	('endometriosis', 'Disease', 'MESH:D004715', (132, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('ovarian carcinomas', 'Disease', (81, 99))	('synchronous endometrial', 'Disease', (53, 76))
3717	31672974	Loss of heterozygosity (LOH) in copy number was determined by the number of variant sequence reads compared with the wildtype in the tumor DNA.	('variant', 'Var', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Loss', 'NegReg', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('tumor', 'Disease', (133, 138))
3723	31672974	The timing of a driver event is inferred from the cancer cell fraction calculated from the mutant allele frequency of a SNV/indel and the copy number state where the SNV/indel resides.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cell fraction', 'cellular_component', 'GO:0000267', ('57', '70'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutant', 'Var', (91, 97))
3727	31672974	Samples were first categorized by POLE hotspot mutations in the exonuclease domain (POLE mutated; POLE) and then by MSI-high status (microsatellite instability; MSI), which was determined by deviations from paired normal control in electropherograms of 2 or more among 6 DNA markers (BAT25, BAT26, D2S123, D5S346, D17S250, and BAT40), as previously described.	('D17S250', 'Var', (314, 321))	('D2S123', 'Chemical', 'MESH:C492712', (298, 304))	('BAT25', 'Var', (284, 289))	('BAT40', 'Var', (327, 332))	('D2S123', 'Var', (298, 304))	('DNA', 'cellular_component', 'GO:0005574', ('271', '274'))	('D5S346', 'Var', (306, 312))	('BAT26', 'Var', (291, 296))
3729	31672974	We used another molecular subtyping method based on major driver mutations observed in carcinomas with endometrioid or serous histology.	('endometrioid', 'Disease', (103, 115))	('carcinomas', 'Disease', 'MESH:D002277', (87, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('carcinomas', 'Disease', (87, 97))	('mutations', 'Var', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
3730	31672974	For this analysis, samples with PTEN or ARID1A mutations were assigned as endometrioid-like, samples with TP53 or PPP2R1A mutations were classified as serous-like, and the remaining samples lacking any mutation in these four genes were assigned to the unclassified group.	('ARID1A', 'Gene', (40, 46))	('ARID1A', 'Gene', '8289', (40, 46))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('mutations', 'Var', (47, 56))	('PPP2R1A', 'Gene', (114, 121))	('PPP2R1A', 'Gene', '5518', (114, 121))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('endometrioid-like', 'Disease', (74, 91))
3734	25504438	DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC).	('ZNF677', 'Gene', (166, 172))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (176, 203))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (100, 123))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (96, 123))	('regulates', 'Reg', (34, 43))	('NSCLC', 'Disease', (205, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('tumor', 'Disease', (57, 62))	('non-small cell lung cancers', 'Disease', (176, 203))	('lung cancers', 'Phenotype', 'HP:0100526', (191, 203))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('methylation', 'Var', (4, 15))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (176, 203))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('non-small cell lung cancers', 'Disease', (96, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('lung cancers', 'Phenotype', 'HP:0100526', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cell growth', 'biological_process', 'GO:0016049', ('63', '74'))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (96, 123))	('ZNF677', 'Gene', '342926', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ZNF677', 'Gene', (86, 92))	('ZNF677', 'Gene', '342926', (166, 172))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (180, 203))
3736	25504438	We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001).	('ZNF677', 'Gene', (116, 122))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('methylation', 'MPA', (123, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('downregulation', 'NegReg', (55, 69))	('methylation', 'biological_process', 'GO:0032259', ('123', '134'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('methylation', 'Var', (14, 25))	('NSCLC', 'Disease', (138, 143))	('ZNF677', 'Gene', '342926', (48, 54))	('ZNF677', 'Gene', (48, 54))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('tumor', 'Disease', (101, 106))	('patients', 'Species', '9606', (144, 152))	('ZNF677', 'Gene', '342926', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
3737	25504438	In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression.	('expression', 'MPA', (78, 88))	('ZNF677', 'Gene', '342926', (24, 30))	('ZNF677', 'Gene', (71, 77))	('TU', 'Phenotype', 'HP:0002664', (19, 21))	('ZNF677', 'Gene', (24, 30))	('TUs', 'Chemical', '-', (19, 22))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'Var', (31, 42))	('ZNF677', 'Gene', '342926', (71, 77))	('loss', 'NegReg', (63, 67))
3742	25504438	Gene expression in malignant tumors may be affected by genetic and epigenetic changes.	('epigenetic changes', 'Var', (67, 85))	('malignant tumors', 'Disease', (19, 35))	('affected', 'Reg', (43, 51))	('malignant tumors', 'Disease', 'MESH:D018198', (19, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('genetic', 'Var', (55, 62))	('Gene expression', 'MPA', (0, 15))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))
3746	25504438	So far, many genes were found which are transcriptionally inactivated by methylation in NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('methylation', 'Var', (73, 84))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
3756	25504438	Overall, our results indicate that ZNF677 is frequently transcriptionally silenced by methylation in NSCLCs and they suggest that ZNF677 has tumor cell growth suppressing properties.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('ZNF677', 'Gene', (130, 136))	('ZNF677', 'Gene', '342926', (35, 41))	('NSCLC', 'Disease', (101, 106))	('silenced', 'NegReg', (74, 82))	('tumor', 'Disease', (141, 146))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('methylation', 'Var', (86, 97))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('cell growth', 'biological_process', 'GO:0016049', ('147', '158'))	('ZNF677', 'Gene', '342926', (130, 136))	('ZNF677', 'Gene', (35, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
3757	25504438	Moreover, ZNF677 methylation might be of prognostic relevance for NSCLC patients.	('NSCLC', 'Disease', (66, 71))	('ZNF677', 'Gene', '342926', (10, 16))	('methylation', 'Var', (17, 28))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('ZNF677', 'Gene', (10, 16))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
3760	25504438	A statistically significant downregulation of ZNF677 expression in TU compared to NL samples was observed in dataset E-GEOD-18842 (Bonferroni adjusted p-value = 0.00003) and similar results were seen in dataset E-GEOD-19188 (Bonferroni adjusted p-value = 0.0007).	('TU', 'Phenotype', 'HP:0002664', (67, 69))	('ZNF677', 'Gene', (46, 52))	('downregulation', 'NegReg', (28, 42))	('E-GEOD-18842', 'Var', (117, 129))	('ZNF677', 'Gene', '342926', (46, 52))	('expression', 'MPA', (53, 63))
3780	25504438	In addition, we analysed ZNF677 methylation in cell lines of other tumor entities including breast cancer (N = 5), colon cancer (N = 2), ovarian cancer (N = 2), pancreatic cancer (N = 2) and head and neck cancer (N = 2) by MS-HRM (supplementary Figure S2).	('head and neck cancer', 'Disease', 'MESH:D006258', (191, 211))	('methylation', 'Var', (32, 43))	('analysed', 'Reg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (67, 72))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('ovarian cancer', 'Disease', 'MESH:D010051', (137, 151))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('pancreatic cancer', 'Disease', 'MESH:D010190', (161, 178))	('breast cancer', 'Disease', (92, 105))	('ZNF677', 'Gene', '342926', (25, 31))	('colon cancer', 'Disease', (115, 127))	('head and neck cancer', 'Phenotype', 'HP:0012288', (191, 211))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('neck', 'cellular_component', 'GO:0044326', ('200', '204'))	('ovarian cancer', 'Disease', (137, 151))	('ZNF677', 'Gene', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('pancreatic cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
3781	25504438	All these tumor cell lines except 1 breast cancer (MDA-MB-468) and 1 ovarian cancer (SCOV3) cell line were found to be ZNF677 methylated.	('ovarian cancer', 'Disease', (69, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('methylated', 'Var', (126, 136))	('breast cancer', 'Disease', (36, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('tumor', 'Disease', (10, 15))	('ZNF677', 'Gene', (119, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('ZNF677', 'Gene', '342926', (119, 125))
3782	25504438	By comparing methylation values of these cell lines with ZNF677 mRNA expression values from the TCGA Cancer Cell Line Encyclopedia, a strong negative correlation between ZNF677 methylation and ZNF677 expression in these cell lines was observed (R = -0.889, p < 0.0001; supplementary Figure S2).	('methylation', 'biological_process', 'GO:0032259', ('177', '188'))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('ZNF677', 'Gene', (170, 176))	('ZNF677', 'Gene', (57, 63))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (101, 130))	('negative', 'NegReg', (141, 149))	('ZNF677', 'Gene', '342926', (170, 176))	('ZNF677', 'Gene', '342926', (193, 199))	('expression', 'MPA', (200, 210))	('Cancer Cell Line Encyclopedia', 'Disease', (101, 130))	('ZNF677', 'Gene', '342926', (57, 63))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('methylation', 'Var', (177, 188))	('ZNF677', 'Gene', (193, 199))
3783	25504438	Overall, these results suggest that methylation of the 5  region of ZNF677 is responsible for ZNF677 silencing in many tumor cell lines of different entities including NSCLC, breast cancer, colon cancer, ovarian cancer, pancreatic cancer and head and neck cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('ovarian cancer', 'Disease', (204, 218))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('silencing', 'NegReg', (101, 110))	('breast cancer', 'Disease', (175, 188))	('responsible', 'Reg', (78, 89))	('colon cancer', 'Disease', (190, 202))	('head and neck cancer', 'Phenotype', 'HP:0012288', (242, 262))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('pancreatic cancer', 'Disease', (220, 237))	('ZNF677', 'Gene', '342926', (68, 74))	('ZNF677', 'Gene', (68, 74))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('methylation', 'Var', (36, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('head and neck cancer', 'Disease', 'MESH:D006258', (242, 262))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (119, 124))	('colon cancer', 'Disease', 'MESH:D015179', (190, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('neck', 'cellular_component', 'GO:0044326', ('251', '255'))	('ZNF677', 'Gene', '342926', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('ZNF677', 'Gene', (94, 100))	('NSCLC', 'Disease', (168, 173))
3787	25504438	In addition, ROC curve analyses revealed that methylation of ZNF677 statistically significant distinguishes TU from NL samples (p = 1.1 * 10-23; area under the curve: 0.838; 95% CI: 0.792 - 0.885; Figure 3B).	('distinguishes', 'Reg', (94, 107))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('ZNF677', 'Gene', (61, 67))	('ZNF677', 'Gene', '342926', (61, 67))	('TU', 'Phenotype', 'HP:0002664', (108, 110))
3788	25504438	For comparison of ZNF677 methylation data with clinico-pathological characteristics of the NSCLC patients, patients were grouped into "high ZNF677 TU methylation" and "low ZNF677 TU methylation" using the mean % of ZNF677 methylation in TU samples as cut-off level.	('ZNF677', 'Gene', '342926', (140, 146))	('methylation', 'Var', (150, 161))	('ZNF677', 'Gene', '342926', (172, 178))	('ZNF677', 'Gene', (140, 146))	('low', 'NegReg', (168, 171))	('TU', 'Phenotype', 'HP:0002664', (237, 239))	('ZNF677', 'Gene', (172, 178))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('patients', 'Species', '9606', (107, 115))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('TU', 'Phenotype', 'HP:0002664', (179, 181))	('ZNF677', 'Gene', '342926', (18, 24))	('TU', 'Phenotype', 'HP:0002664', (147, 149))	('ZNF677', 'Gene', (18, 24))	('NSCLC', 'Disease', (91, 96))	('ZNF677', 'Gene', '342926', (215, 221))	('patients', 'Species', '9606', (97, 105))	('ZNF677', 'Gene', (215, 221))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))
3791	25504438	In addition, multivariate analyses identified ZNF677 TU methylation as independent prognostic factor for shorter OS of NSCLC patients (hazard ratio [HR] = 1.8, 95% confidence interval [CI] = 1 to 3.1, p = 0.046).	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('TU', 'Phenotype', 'HP:0002664', (53, 55))	('ZNF677', 'Gene', (46, 52))	('TU methylation', 'Var', (53, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('shorter OS', 'Disease', (105, 115))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('ZNF677', 'Gene', '342926', (46, 52))	('NSCLC', 'Disease', (119, 124))	('patients', 'Species', '9606', (125, 133))
3792	25504438	No other statistically significant associations between ZNF677 methylation and clinico-pathological characteristics of the patients were observed.	('patients', 'Species', '9606', (123, 131))	('ZNF677', 'Gene', '342926', (56, 62))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('methylation', 'Var', (63, 74))	('ZNF677', 'Gene', (56, 62))
3796	25504438	Moreover, they suggest that ZNF677 methylation and ZNF677 mRNA expression might be of prognostic impact for certain NSCLC patients, however, additional studies are necessary to determine the potential clinical relevance.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('prognostic', 'Reg', (86, 96))	('ZNF677', 'Gene', '342926', (28, 34))	('clinical', 'Species', '191496', (201, 209))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('mRNA expression', 'MPA', (58, 73))	('ZNF677', 'Gene', (28, 34))	('ZNF677', 'Gene', '342926', (51, 57))	('patients', 'Species', '9606', (122, 130))	('methylation', 'Var', (35, 46))	('ZNF677', 'Gene', (51, 57))	('NSCLC', 'Disease', (116, 121))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('impact', 'Reg', (97, 103))
3801	25504438	In the majority of TU samples the detection of ZNF677 methylation was associated with downregulated ZNF677 protein expression.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('TU', 'Phenotype', 'HP:0002664', (19, 21))	('methylation', 'Var', (54, 65))	('ZNF677', 'Gene', (47, 53))	('ZNF677', 'Gene', '342926', (100, 106))	('downregulated', 'NegReg', (86, 99))	('protein', 'Protein', (107, 114))	('ZNF677', 'Gene', (100, 106))	('ZNF677', 'Gene', '342926', (47, 53))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
3803	25504438	Thus, we compared methylation and expression data from LUAD and LUSC datasets and we found a strong negative correlation between ZNF677 methylation and ZNF677 expression in both datasets (R = -0.673 and R = -0.654, respectively; p < 0.000001, respectively; supplementary Figure S2C).	('ZNF677', 'Gene', (152, 158))	('ZNF677', 'Gene', '342926', (129, 135))	('methylation', 'Var', (136, 147))	('negative', 'NegReg', (100, 108))	('ZNF677', 'Gene', (129, 135))	('expression', 'MPA', (159, 169))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('ZNF677', 'Gene', '342926', (152, 158))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))
3804	25504438	Moreover, we were interested if besides methylation also mutations or copy number changes might be responsible for downregulated ZNF677 expression in NSCLC patients.	('patients', 'Species', '9606', (156, 164))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('ZNF677', 'Gene', '342926', (129, 135))	('expression', 'MPA', (136, 146))	('ZNF677', 'Gene', (129, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('mutations', 'Var', (57, 66))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('copy number changes', 'Var', (70, 89))	('downregulated', 'NegReg', (115, 128))	('NSCLC', 'Disease', (150, 155))
3805	25504438	Thus, we searched for ZNF677 mutations in LUAD and LUSC datasets.	('ZNF677', 'Gene', '342926', (22, 28))	('ZNF677', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))
3806	25504438	ZNF677 mutations including 1 splice variant and 6 missense mutations (C232S, H477N, G254W, C492F, H281Y and P514T) were found only in 2% of both ADC and SCC patients and their localisation is shown in supplementary Figures S3A and S3B.	('C232S', 'Mutation', 'rs765013733', (70, 75))	('G254W', 'Mutation', 'p.G254W', (84, 89))	('patients', 'Species', '9606', (157, 165))	('H281Y', 'Var', (98, 103))	('G254W', 'Var', (84, 89))	('C492F', 'Mutation', 'p.C492F', (91, 96))	('C492F', 'Var', (91, 96))	('H477N', 'Mutation', 'p.H477N', (77, 82))	('H477N', 'Var', (77, 82))	('SCC', 'Gene', '6317', (153, 156))	('H281Y', 'Mutation', 'p.H281Y', (98, 103))	('P514T', 'Mutation', 'p.P514T', (108, 113))	('localisation', 'biological_process', 'GO:0051179', ('176', '188'))	('SCC', 'Gene', (153, 156))	('C232S', 'Var', (70, 75))	('ZNF677', 'Gene', '342926', (0, 6))	('ADC', 'Disease', (145, 148))	('ZNF677', 'Gene', (0, 6))	('P514T', 'Var', (108, 113))
3807	25504438	All ZNF677 mutations were mutually exclusive.	('ZNF677', 'Gene', (4, 10))	('ZNF677', 'Gene', '342926', (4, 10))	('mutations', 'Var', (11, 20))
3808	25504438	Mutations H477N and C492F were predicted to have a high functional impact (supplementary Figure S3C).	('C492F', 'Var', (20, 25))	('H477N', 'Mutation', 'p.H477N', (10, 15))	('C492F', 'Mutation', 'p.C492F', (20, 25))	('H477N', 'Var', (10, 15))
3809	25504438	In addition, we searched for ZNF677 copy number changes in LUAD and LUSC TCGA aCGH datasets of 983 NSCLC patients.	('ZNF677', 'Gene', (29, 35))	('patients', 'Species', '9606', (105, 113))	('copy number changes', 'Var', (36, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('ZNF677', 'Gene', '342926', (29, 35))	('NSCLC', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
3810	25504438	A homozygous ZNF677 deletion was detected only in 1 ADC patient (supplementary Figures S3D and S3E), however, heterozygous ZNF677 deletions were found in 34% of ADC patients and in 25% of SCC patients.	('ZNF677', 'Gene', '342926', (123, 129))	('deletions', 'Var', (130, 139))	('patient', 'Species', '9606', (192, 199))	('ZNF677', 'Gene', '342926', (13, 19))	('SCC', 'Gene', '6317', (188, 191))	('ADC', 'Disease', (161, 164))	('ZNF677', 'Gene', (123, 129))	('patient', 'Species', '9606', (165, 172))	('ZNF677', 'Gene', (13, 19))	('patients', 'Species', '9606', (192, 200))	('deletion', 'Var', (20, 28))	('patients', 'Species', '9606', (165, 173))	('patient', 'Species', '9606', (56, 63))	('SCC', 'Gene', (188, 191))
3814	25504438	These results demonstrate that heterozygous ZNF677 deletions but not ZNF677 mutations occur frequently in NSCLCs indicating that ZNF677 mutations do not play a role in inactivation of ZNF677 in NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('ZNF677', 'Gene', '342926', (129, 135))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('ZNF677', 'Gene', (184, 190))	('ZNF677', 'Gene', (44, 50))	('ZNF677', 'Gene', (129, 135))	('ZNF677', 'Gene', '342926', (69, 75))	('NSCLC', 'Disease', (194, 199))	('ZNF677', 'Gene', '342926', (184, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('deletions', 'Var', (51, 60))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('ZNF677', 'Gene', (69, 75))	('NSCLC', 'Disease', (106, 111))	('ZNF677', 'Gene', '342926', (44, 50))
3818	25504438	Reduced cell growth (1.4 to 3.6-fold, mean 2.7-fold) of pCMV6-ZNF677 transfected A549, NCI-H2073 and NCI-H1993 cells was confirmed using a cell viability assay (Figure 4D).	('cell growth', 'CPA', (8, 19))	('transfected', 'Var', (69, 80))	('ZNF677', 'Gene', '342926', (62, 68))	('NCI-H1993', 'CellLine', 'CVCL:1512', (101, 110))	('Reduced', 'NegReg', (0, 7))	('cell growth', 'biological_process', 'GO:0016049', ('8', '19'))	('ZNF677', 'Gene', (62, 68))	('NCI-H2073', 'CellLine', 'CVCL:1521', (87, 96))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
3821	25504438	However, we observed a reduced migration capacity of pCMV6-ZNF677 transfected cells compared to cells transfected with the empty control vector by using a scratch assay (Figure 4F).	('transfected', 'Var', (66, 77))	('migration capacity', 'CPA', (31, 49))	('ZNF677', 'Gene', '342926', (59, 65))	('ZNF677', 'Gene', (59, 65))	('reduced', 'NegReg', (23, 30))
3825	25504438	We identified 198, 71 and 83 differentially expressed genes in pCMV6-ZNF677 transfected A549, NCI-H1993 and NCI-H2073 cells compared to control cells, respectively (Figure 5B, supplementary Table S1).	('ZNF677', 'Gene', '342926', (69, 75))	('transfected', 'Var', (76, 87))	('NCI-H1993', 'CellLine', 'CVCL:1512', (94, 103))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('differentially expressed genes', 'MPA', (29, 59))	('NCI-H2073', 'CellLine', 'CVCL:1521', (108, 117))	('ZNF677', 'Gene', (69, 75))
3830	25504438	In a recent genome-wide search for CGI methylation in a large number of NSCLC patients, we identified 477 tumor-specifically methylated genes and from the majority of them regulation by methylation and/or an involvement in the pathogenesis of NSCLCs was unknown so far.	('methylated genes', 'Var', (125, 141))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('NSCLC', 'Disease', (72, 77))	('NSCLC', 'Disease', (243, 248))	('regulation', 'biological_process', 'GO:0065007', ('172', '182'))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (243, 248))	('methylation', 'biological_process', 'GO:0032259', ('186', '197'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('pathogenesis', 'biological_process', 'GO:0009405', ('227', '239'))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('tumor', 'Disease', (106, 111))
3842	25504438	ZNF677 mutations were found in only 2% of the tumors using TCGA datasets.	('mutations', 'Var', (7, 16))	('ZNF677', 'Gene', '342926', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('ZNF677', 'Gene', (0, 6))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
3843	25504438	In addition, we observed an association between ZNF677 methylation and loss of ZNF677 expression for the majority of TU samples analysed while ZNF677 not methylated TU samples mostly expressed ZNF677.	('ZNF677', 'Gene', '342926', (143, 149))	('ZNF677', 'Gene', '342926', (48, 54))	('TU', 'Phenotype', 'HP:0002664', (117, 119))	('ZNF677', 'Gene', '342926', (79, 85))	('expression', 'MPA', (86, 96))	('ZNF677', 'Gene', (48, 54))	('ZNF677', 'Gene', (143, 149))	('TU', 'Phenotype', 'HP:0002664', (165, 167))	('loss', 'NegReg', (71, 75))	('ZNF677', 'Gene', '342926', (193, 199))	('methylation', 'Var', (55, 66))	('ZNF677', 'Gene', (79, 85))	('ZNF677', 'Gene', (193, 199))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
3850	25504438	These results suggest that ZNF677 methylation might be of potential prognostic relevance, however, additional studies are necessary to confirm our results.	('ZNF677', 'Gene', '342926', (27, 33))	('ZNF677', 'Gene', (27, 33))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('methylation', 'Var', (34, 45))
3853	25504438	Certain characteristics of tumor suppressor genes (TSG) include that they are often located in chromosomal regions with frequent loss of heterozygosity (LOH), that they may become inactivated by genetic or epigenetic mechanisms and that they may inhibit tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (254, 259))	('inhibit', 'NegReg', (246, 253))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('tumor', 'Disease', (27, 32))	('loss', 'NegReg', (129, 133))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))	('inactivated', 'NegReg', (180, 191))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('epigenetic', 'Var', (206, 216))	('cell growth', 'biological_process', 'GO:0016049', ('260', '271'))
3869	25504438	ZNF677 methylation occurs tumor-specific in NSCLC patients and might be of potential prognostic impact for these patients.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('ZNF677', 'Gene', '342926', (0, 6))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('methylation', 'Var', (7, 18))	('ZNF677', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('NSCLC', 'Disease', (44, 49))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
3885	25504438	ZNF677 expression was determined by RT-PCR using Taqman Gene Expression Assays (Applied Biosystems) Hs00737026_m1 (ZNF677) and Hs03929097_g1 (GAPDH).	('ZNF677', 'Gene', '342926', (0, 6))	('Hs00737026_m1', 'Var', (100, 113))	('GAPDH', 'Gene', '2597', (142, 147))	('GAPDH', 'Gene', (142, 147))	('ZNF677', 'Gene', '342926', (115, 121))	('Hs03929097_g1', 'Var', (127, 140))	('ZNF677', 'Gene', (0, 6))	('ZNF677', 'Gene', (115, 121))	('Gene Expression', 'biological_process', 'GO:0010467', ('56', '71'))
3898	25504438	Membranes were blocked followed by incubation with primary antibodies anti-ZNF677 (1:100, Abcam), anti-IRF9 (1:50, Santa Cruz Biotechnology), anti-ISG15 (1:1000, Cell Signaling), anti-CSH1 (1:375, Thermo Scientific), anti-ACTB (1:200, Abcam) and anti-GAPDH (0.05mg/ml, Sigma Aldrich).	('ISG15', 'Gene', '9636', (147, 152))	('1:200', 'Var', (228, 233))	('GAPDH', 'Gene', '2597', (251, 256))	('GAPDH', 'Gene', (251, 256))	('IRF9', 'Gene', (103, 107))	('ZNF677', 'Gene', (75, 81))	('ISG15', 'Gene', (147, 152))	('Signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('CSH1', 'Gene', (184, 188))	('0.05mg/ml', 'Var', (258, 267))	('CSH1', 'Gene', '1442', (184, 188))	('ZNF677', 'Gene', '342926', (75, 81))	('IRF9', 'Gene', '10379', (103, 107))
3906	25504438	Galaxy platform and TopHat2 were used to align raw RNA-seq data (fastq files) of ZNF677 transfected NSCLC cells and of control cells to hg19.	('NSCLC', 'Disease', (100, 105))	('ZNF677', 'Gene', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('transfected', 'Var', (88, 99))	('ZNF677', 'Gene', '342926', (81, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
3907	23947899	CyclinD1, a prominent prognostic marker for endometrial diseases Alteration of CyclinD1 was suggested to relate with development of endometrial carcinogenesis before, however CyclinD1 expression is not well defined in endometrial hyperplasia lesions.	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (218, 241))	('CyclinD1', 'Gene', '595', (0, 8))	('CyclinD1', 'Gene', '595', (79, 87))	('endometrial diseases', 'Disease', 'MESH:D014591', (44, 64))	('Alteration', 'Var', (65, 75))	('endometrial hyperplasia lesions', 'Disease', 'MESH:D004714', (218, 249))	('CyclinD1', 'Gene', (175, 183))	('endometrial carcinogenesis', 'Disease', (132, 158))	('relate with', 'Reg', (105, 116))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (132, 158))	('CyclinD1', 'Gene', (0, 8))	('endometrial diseases', 'Disease', (44, 64))	('CyclinD1', 'Gene', (79, 87))	('endometrial hyperplasia lesions', 'Disease', (218, 249))	('CyclinD1', 'Gene', '595', (175, 183))
3915	23947899	Kaplan Meier analysis demonstrated that patients with high CyclinD1 expression had an obviously poor prognosis than patients without CyclinD1 staining (p < 0.05).	('CyclinD1', 'Gene', '595', (59, 67))	('expression', 'MPA', (68, 78))	('high', 'Var', (54, 58))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (116, 124))	('CyclinD1', 'Gene', (133, 141))	('CyclinD1', 'Gene', (59, 67))	('CyclinD1', 'Gene', '595', (133, 141))
3923	23947899	Mutations, amplification and over-expression of CCND1 gene, which can alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis .	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('contribute', 'Reg', (156, 166))	('CCND1', 'Gene', '595', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (170, 175))	('Mutations', 'Var', (0, 9))	('alters', 'Reg', (70, 76))	('cell cycle progression', 'CPA', (77, 99))	('over-expression', 'PosReg', (29, 44))	('CCND1', 'Gene', (48, 53))	('amplification', 'Var', (11, 24))
4017	30550482	In those cases where there is morphologic doubt and where further confirmation is required, the best marker is p53; aberrant (mutation-type) staining (either the overexpression pattern or null pattern) favors serous carcinoma, whereas wild-type staining favors endometrioid carcinoma.	('p53', 'Gene', (111, 114))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (261, 283))	('p53', 'Gene', '7157', (111, 114))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (261, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('favors', 'PosReg', (202, 208))	('serous carcinoma', 'Disease', (209, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('endometrioid carcinoma', 'Disease', (261, 283))	('serous carcinoma', 'Disease', 'MESH:D018284', (209, 225))	('aberrant', 'Var', (116, 124))
4041	30550482	Aberrant (mutation-type) staining is present in virtually all serous carcinomas, whereas wild-type staining is present in almost all low-grade endometrioid carcinomas, although a small proportion of the latter exhibit mutation-type immunoreactivity.	('endometrioid carcinomas', 'Disease', (143, 166))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (143, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Aberrant', 'Var', (0, 8))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (143, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (143, 166))	('serous carcinomas', 'Disease', 'MESH:D018284', (62, 79))	('serous carcinomas', 'Disease', (62, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
4053	30550482	p53 immunohistochemistry may be of value to help confirm a diagnosis of carcinosarcoma as both the epithelial and mesenchymal components often exhibit mutation-type immunoreactivity, in contrast to wild-type staining in most cases of low-grade endometrioid carcinoma.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (244, 266))	('carcinosarcoma', 'Disease', 'MESH:D002296', (72, 86))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (244, 266))	('endometrioid carcinoma', 'Disease', (244, 266))	('carcinosarcoma', 'Disease', (72, 86))	('mutation-type', 'Var', (151, 164))	('exhibit', 'Reg', (143, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
4108	30550482	Mismatch repair gene defects and mutations of the switch/sucrose non-fermentable chromatin remodeling complex are common.	('Mismatch repair gene', 'Gene', (0, 20))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('mutations', 'Var', (33, 42))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('81', '101'))	('defects', 'Var', (21, 28))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('81', '109'))	('sucrose', 'Chemical', 'MESH:D013395', (57, 64))
4120	29190668	The disease-free survival of patients who were double-positive for p53-stained and high-ERbeta was significantly shorter than that in other patients.	('patients', 'Species', '9606', (29, 37))	('p53', 'Gene', (67, 70))	('disease-free survival', 'CPA', (4, 25))	('p53', 'Gene', '7157', (67, 70))	('patients', 'Species', '9606', (140, 148))	('shorter', 'NegReg', (113, 120))	('high-ERbeta', 'Var', (83, 94))
4129	29190668	In type-I endometrial endometrioid carcinoma, dysfunction of DNA mismatch repair genes and gene mutations in phosphatase and tensin homolog deleted from chromosome 10 (PTEN) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) have been shown to be associated with carcinogenesis of the endometrium, whereas gene mutations in TP53 have been reported to be associated with high-level invasive and metastatic properties of cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('associated', 'Reg', (367, 377))	('carcinogenesis', 'Disease', (276, 290))	('cancer', 'Phenotype', 'HP:0002664', (432, 438))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('KRAS', 'Gene', '24525', (232, 236))	('mutations', 'Var', (96, 105))	('carcinogenesis', 'Disease', 'MESH:D063646', (276, 290))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('109', '139'))	('phosphatase', 'molecular_function', 'GO:0016791', ('109', '120'))	('TP53', 'Gene', (337, 341))	('cancer', 'Disease', 'MESH:D009369', (432, 438))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (22, 44))	('rat', 'Species', '10116', (196, 199))	('KRAS', 'Gene', (232, 236))	('associated with', 'Reg', (260, 275))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (10, 44))	('PTEN', 'Gene', (168, 172))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('endometrial endometrioid carcinoma', 'Disease', (10, 44))	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('sarcoma', 'Disease', (200, 207))	('mismatch repair', 'biological_process', 'GO:0006298', ('65', '80'))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('cancer', 'Disease', (432, 438))	('PTEN', 'Gene', '50557', (168, 172))
4160	29190668	DNA was extracted from frozen tumor samples for TP53 mutation screening using a QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions.	('mutation', 'Var', (53, 61))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('TP53', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
4161	29190668	Following DNA extraction, the samples were evaluated for mutations in exons 5-8 of the TP53 gene because almost all TP53 gene mutations in various cancers have been found in these exons.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('TP53 gene', 'Gene', (116, 125))	('TP53', 'Gene', (87, 91))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('mutations', 'Var', (126, 135))	('cancers', 'Disease', (147, 154))
4171	29190668	The pathological data showed that histological grade 2/3, deep myometrial invasion (>= 1/2), lymph-vascular space invasion (LVSI), detection of immunoreactive p53 (p53-stained), and high-ERbeta were significantly correlated with the incidences of regional lymph node metastasis and/or postoperative recurrence by univariate analysis of metastatic factors (Table 3).	('detection', 'Var', (131, 140))	('lymph-vascular', 'Disease', (93, 107))	('deep myometrial invasion', 'CPA', (58, 82))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('p53', 'Gene', (164, 167))	('high-ERbeta', 'Var', (182, 193))	('regional lymph node metastasis', 'CPA', (247, 277))	('correlated', 'Reg', (213, 223))	('rat', 'Species', '10116', (292, 295))	('p53', 'Gene', '7157', (164, 167))
4179	29190668	Next, we examined mutations in the TP53 gene, which can affect the immunohistochemical detection of p53 protein.	('affect', 'Reg', (56, 62))	('mutations', 'Var', (18, 27))	('TP53', 'Gene', (35, 39))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('p53', 'Gene', (100, 103))	('p53', 'Gene', '7157', (100, 103))
4182	29190668	From this analysis, TP53 gene mutations were observed in 13 (32.5%) of 40 endometrioid carcinoma cases.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('TP53 gene', 'Gene', (20, 29))	('mutations', 'Var', (30, 39))	('observed', 'Reg', (45, 53))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (74, 96))	('endometrioid carcinoma', 'Disease', (74, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
4183	29190668	Among them, the positive rates were 27.3% in G1 (3/11), 31.3% in G2 (5/16), and 38.5% in G3 (5/13), indicating that TP53 gene mutations were not significantly correlated with the histological grade in endometrioid carcinoma.	('endometrioid carcinoma', 'Disease', (201, 223))	('TP53', 'Gene', (116, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (201, 223))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (201, 223))	('rat', 'Species', '10116', (25, 28))	('mutations', 'Var', (126, 135))
4184	29190668	In addition, there were no significant differences in the incidences of metastatic and/or recurrent disease between patients with and without TP53 gene mutation.	('recurrent disease', 'CPA', (90, 107))	('metastatic', 'CPA', (72, 82))	('TP53', 'Gene', (142, 146))	('patients', 'Species', '9606', (116, 124))	('mutation', 'Var', (152, 160))
4186	29190668	High-positive groups (50-79 and 80-100%) showed high rates of p53 mutation (44.4 and 83.3%, respectively), while low-positive groups (10-19 and 20-49%) demonstrated low rates of p53 mutation (16.7 and 14.3%, respectively).	('rat', 'Species', '10116', (169, 172))	('p53', 'Gene', '7157', (62, 65))	('rat', 'Species', '10116', (53, 56))	('mutation', 'Var', (66, 74))	('p53', 'Gene', (178, 181))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (178, 181))	('rat', 'Species', '10116', (159, 162))
4190	29190668	The sensitivity and negative predictive values of high expression of ERbeta for regional lymph node metastasis and/or postoperative recurrence were both 100% (29/29 and 86/86, respectively), whereas the specificity and positive predictive values were 68.8% (86/125) and 42.6% (29/68), respectively (Table 4).	('regional lymph node metastasis', 'CPA', (80, 110))	('high expression', 'Var', (50, 65))	('rat', 'Species', '10116', (125, 128))	('ERbeta', 'Gene', (69, 75))
4194	29190668	Kaplan-Meier survival analysis showed that disease-free survival in patients with p53-stained and high-ERbeta (p53+/ERbetahigh) was significantly shorter than that in other patient groups (Fig 3).	('disease-free survival', 'CPA', (43, 64))	('patient', 'Species', '9606', (68, 75))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('patients', 'Species', '9606', (68, 76))	('high-ERbeta', 'Var', (98, 109))	('shorter', 'NegReg', (146, 153))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('patient', 'Species', '9606', (173, 180))
4199	29190668	Previous reports showed that positive immunostaining for p53 is associated with an increased risk of relapse in patients with low-risk stage I endometrioid endometrial carcinoma.	('positive immunostaining', 'Var', (29, 52))	('associated', 'Reg', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('patients', 'Species', '9606', (112, 120))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (156, 177))	('relapse', 'Disease', (101, 108))	('p53', 'Gene', (57, 60))	('endometrial carcinoma', 'Disease', (156, 177))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('p53', 'Gene', '7157', (57, 60))
4200	29190668	Moreover, p53 mutation is associated with a poor prognosis in patients with endometrial cancer.	('p53', 'Gene', '7157', (10, 13))	('endometrial cancer', 'Disease', (76, 94))	('endometrial cancer', 'Phenotype', 'HP:0012114', (76, 94))	('mutation', 'Var', (14, 22))	('endometrial cancer', 'Disease', 'MESH:D016889', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (62, 70))	('p53', 'Gene', (10, 13))
4202	29190668	To confirm the correlation between the immunohistochemical expression of p53 protein and TP53 gene mutations, we analyzed the sequences of the established hot-spot areas of the TP53 gene in patients with p53-stained.	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('TP53', 'Gene', (89, 93))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('patients', 'Species', '9606', (190, 198))	('p53', 'Gene', (204, 207))	('p53', 'Gene', '7157', (204, 207))	('mutations', 'Var', (99, 108))	('TP53', 'Gene', (177, 181))
4203	29190668	However, unexpectedly, our analysis confirmed genetic alterations in TP53 in only 30% of cases with p53-stained.	('TP53', 'Gene', (69, 73))	('genetic alterations', 'Var', (46, 65))	('rat', 'Species', '10116', (58, 61))	('p53', 'Gene', (100, 103))	('p53', 'Gene', '7157', (100, 103))
4204	29190668	In addition, there were no significant correlations between TP53 gene mutations and the incidence of regional lymph node metastasis and/or postoperative recurrence in our cases.	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (70, 79))	('regional lymph node metastasis', 'CPA', (101, 131))	('rat', 'Species', '10116', (146, 149))
4206	29190668	Theoretically, the accumulation of p53 protein in cancer cells can be explained by not only gene mutations but also dysregulation of the factors that mediate metabolic or functional cascades involving p53 protein.	('mutations', 'Var', (97, 106))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('p53', 'Gene', (35, 38))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('p53', 'Gene', (201, 204))	('p53', 'Gene', '7157', (35, 38))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('p53', 'Gene', '7157', (201, 204))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('protein', 'Protein', (39, 46))	('accumulation', 'PosReg', (19, 31))
4207	29190668	To support this speculation, when we further classified the p53-stained group into a low-positive group (10-49%) and high-positive group (50-100%), the low-positive group had a low rate of TP53 gene mutation in spite of a high incidence rate of regional lymph node metastasis and/or postoperative recurrence (Table 5).	('regional lymph node metastasis', 'CPA', (245, 275))	('TP53', 'Gene', (189, 193))	('rat', 'Species', '10116', (290, 293))	('mutation', 'Var', (199, 207))	('p53', 'Gene', (60, 63))	('rat', 'Species', '10116', (181, 184))	('p53', 'Gene', '7157', (60, 63))	('rat', 'Species', '10116', (237, 240))	('low', 'NegReg', (177, 180))
4211	29190668	Considering that TP53 gene mutant tumors also show the null phenotype of immunoreactive p53 expression, it should be noted that the immunohistochemical detection of p53 protein alone may not be sufficient to predict the risk of regional lymph node metastasis and/or postoperative recurrence.	('p53', 'Gene', (165, 168))	('tumors', 'Disease', (34, 40))	('p53', 'Gene', '7157', (165, 168))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('regional lymph node metastasis', 'CPA', (228, 258))	('mutant', 'Var', (27, 33))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('p53', 'Gene', (88, 91))	('rat', 'Species', '10116', (273, 276))	('TP53 gene', 'Gene', (17, 26))	('p53', 'Gene', '7157', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
4219	29190668	Based on the assessment criteria reported by Konstantinopoulos et al., our study showed that high expression of ERbeta was significantly correlated with the incidence of regional lymph node metastasis and/or postoperative recurrence.	('regional lymph node metastasis', 'CPA', (170, 200))	('postoperative recurrence', 'CPA', (208, 232))	('ERbeta', 'Protein', (112, 118))	('rat', 'Species', '10116', (215, 218))	('correlated', 'Reg', (137, 147))	('high', 'Var', (93, 97))
4224	29190668	Although the number of samples is limited, the calculated sensitivity (100%) and negative predictive value of high expression of ERbeta for regional lymph node metastasis and/or postoperative recurrence are very promising.	('high expression', 'Var', (110, 125))	('rat', 'Species', '10116', (185, 188))	('ERbeta', 'Gene', (129, 135))	('regional lymph node metastasis', 'CPA', (140, 170))
4225	29190668	In the population with high ERbeta expression, the positive rates of regional lymph node metastasis and/or postoperative recurrence were 61.1% in the p53-positive group and 21.9% in the p53-negative group (Table 4).	('rat', 'Species', '10116', (114, 117))	('high', 'Var', (23, 27))	('rat', 'Species', '10116', (60, 63))	('p53', 'Gene', (186, 189))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (186, 189))	('ERbeta', 'Protein', (28, 34))	('p53', 'Gene', '7157', (150, 153))	('regional lymph node metastasis', 'CPA', (69, 99))
4229	29190668	In contrast, other studies have reported that mutant p53 is strongly induced in p53-mutated colon cancer SW480 cells, whereas wild-type p53 is strongly downregulated in p53 wild-type colon cancer HCT116 cells in response to ERbeta expression.	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('p53', 'Gene', (169, 172))	('colon cancer', 'Phenotype', 'HP:0003003', (183, 195))	('p53', 'Gene', '7157', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colon cancer', 'Disease', (92, 104))	('p53', 'Gene', '7157', (80, 83))	('colon cancer', 'Disease', 'MESH:D015179', (183, 195))	('p53', 'Gene', (136, 139))	('p53', 'Gene', (80, 83))	('mutant', 'Var', (46, 52))	('p53', 'Gene', '7157', (53, 56))	('induced', 'Reg', (69, 76))	('colon cancer', 'Disease', (183, 195))	('SW480', 'CellLine', 'CVCL:0546', (105, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('p53', 'Gene', '7157', (169, 172))	('HCT116', 'CellLine', 'CVCL:0291', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('p53', 'Gene', (53, 56))
4235	29190668	Although the number of samples was small, the double-positive expression of immunoreactive ERbeta and p53 proteins may become a promising clinical parameter to predict the risk of lymph node metastasis and postoperative relapse.	('lymph node metastasis', 'CPA', (180, 201))	('p53', 'Gene', '7157', (102, 105))	('ERbeta', 'Protein', (91, 97))	('rat', 'Species', '10116', (213, 216))	('double-positive', 'Var', (46, 61))	('p53', 'Gene', (102, 105))	('proteins', 'Protein', (106, 114))
4241	32850338	The IIIC category was subdivided into three subcategories based on the tumor (T) and nodes (N) stage, including IIICa (T1N1 and T1N2), IIICb (T2N1 and T2N2), and IIICc (T2N1 and T2N2).	('T2N2', 'Var', (151, 155))	('T1N1', 'Var', (119, 123))	('T2N1', 'Var', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('T2N1', 'Var', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('T1N2', 'Var', (128, 132))	('tumor', 'Disease', (71, 76))
4275	32850338	Regarding the classification method of the new subdivision of the IIIC category, the total patients in the training set were firstly divided into six subgroups (T1N1, T1N2, T2N1, T2N2, T3N1, and T3N2) according to the AJCC T and N stage.	('T2N2', 'Var', (179, 183))	('T2N1', 'Var', (173, 177))	('patients', 'Species', '9606', (91, 99))	('T3N1', 'Var', (185, 189))
4277	32850338	On the contrary, patients with T2N1 had significantly poor prognosis compared with patients with T1N1 or T1N2.	('patients', 'Species', '9606', (83, 91))	('poor', 'NegReg', (54, 58))	('patients', 'Species', '9606', (17, 25))	('T2N1', 'Var', (31, 35))
4283	32850338	Consequently, based on the independent prognostic factors obtained from multivariate analysis, patients with IIIC stage endometrioid cancer were subdivided into three new categories: IIICa, patients with T1N1 or T1N2; IIICb, patients with T2N1 or T2N2; and IIICc, patients with T3N1 or T3N2.	('patients', 'Species', '9606', (225, 233))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (190, 198))	('IIIC stage endometrioid cancer', 'Disease', 'MESH:D009369', (109, 139))	('T1N2', 'Var', (212, 216))	('IIIC stage endometrioid cancer', 'Disease', (109, 139))	('patients', 'Species', '9606', (264, 272))	('T2N1', 'Var', (239, 243))	('T1N1', 'Var', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('T2N2', 'Var', (247, 251))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (120, 139))
4302	32850338	A recent study based on the SEER database showed that endometrioid tumors with stage IIIC2 were associated with higher all-cause and CSM compared with those with IIIC1 stage.	('higher', 'PosReg', (112, 118))	('endometrioid tumors', 'Disease', 'MESH:D016889', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CSM', 'Disease', (133, 136))	('all-cause', 'MPA', (119, 128))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('stage IIIC2', 'Var', (79, 90))	('endometrioid tumors', 'Disease', (54, 73))
4311	32850338	Although regional lymph node metastasis has occurred in all patients, the prognosis of patients with T3 stage was significantly worse than that of patients with T1 stage (HR = 2.64, p < 0.001).	('patients', 'Species', '9606', (60, 68))	('T3 stage', 'Var', (101, 109))	('patients', 'Species', '9606', (147, 155))	('worse', 'NegReg', (128, 133))	('patients', 'Species', '9606', (87, 95))
4318	32850338	Due to the relatively poor prognostic value of FIGO IIIC staging, especially in patients with endometrioid type, we established a new IIIC subdivision system and divided patients with T1N1 or T1N2 into IIICa due to the relatively similar prognosis.	('T1N1', 'Var', (184, 188))	('endometrioid type', 'Disease', (94, 111))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (170, 178))
4319	32850338	Those with T2N1 or T2N2 were categorized as IIICb, whereas the rest of the IIIC patients with T3N1 or T3N2 were staged as IIICc.	('T2N2', 'Var', (19, 23))	('patients', 'Species', '9606', (80, 88))	('T2N1', 'Var', (11, 15))
4350	31638937	In addition, two microsatellite stable (MSS) tumors were hypermutated, which was explained by a dominant POLE signature and pathogenic POLE mutations (p.Pro286Arg and p.Ser459Phe).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('p.Pro286Arg', 'Var', (151, 162))	('p.Ser459Phe', 'Mutation', 'p.S459F', (167, 178))	('Ser', 'cellular_component', 'GO:0005790', ('169', '172'))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('p.Pro286Arg', 'Mutation', 'p.P286R', (151, 162))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('p.Ser459Phe', 'Var', (167, 178))
4402	31638937	In agreement, we found significantly higher mutational load in MSI tumors classified by MSIsensor (median 90.1 mutations/Mb; range 69.2-217.8) as compared to MSS tumors (median 6.1 mutations/Mb; range 2.6-294.8) (p = 1.09 * 10- 11, Wilcoxon rank sum test) (Fig.	('MSI', 'Disease', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutational load', 'MPA', (44, 59))	('higher', 'PosReg', (37, 43))	('mutations/Mb', 'Var', (111, 123))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MSI', 'Disease', 'MESH:D053842', (63, 66))	('MSI', 'Disease', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', (67, 73))	('MSI', 'Disease', 'MESH:D053842', (88, 91))
4406	31638937	Mutational analysis of the exome data confirmed that both tumors had pathogenic POLE mutations (patient 1: p.Pro286Arg, patient 4: p.Ser459Phe, Additional file 1: Table S5) located in the exonuclease domain of POLE, which are known to cause a hypermutated phenotype.	('p.Ser459Phe', 'Mutation', 'p.S459F', (131, 142))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('p.Pro286Arg', 'Mutation', 'p.P286R', (107, 118))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('p.Pro286Arg', 'Var', (107, 118))	('patient', 'Species', '9606', (120, 127))	('p.Ser459Phe', 'Var', (131, 142))	('patient', 'Species', '9606', (96, 103))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mutations', 'Var', (85, 94))	('Ser', 'cellular_component', 'GO:0005790', ('133', '136'))	('pathogenic', 'Reg', (69, 79))
4409	31638937	We identified additional 12 tumors with potential pathogenic somatic POLE mutations (Additional file 1: Table S5).	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (74, 83))	('pathogenic', 'Reg', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
4410	31638937	However, these mutations were all located outside the exonuclease domain and the tumors did not show any signs of a POLE signature.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
4413	31638937	In addition to MSI status, mutational load is also being investigated as a biomarker for immunotherapy.	('mutational load', 'Var', (27, 42))	('MSI', 'Disease', 'MESH:D053842', (15, 18))	('MSI', 'Disease', (15, 18))
4414	31638937	Thus, MSI status as well as mutational load is likely to improve treatment stratification of cancer patients.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('improve', 'PosReg', (57, 64))	('mutational load', 'Var', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MSI', 'Disease', 'MESH:D053842', (6, 9))	('MSI', 'Disease', (6, 9))	('patients', 'Species', '9606', (100, 108))
4415	31638937	The increasing use of NGS in the diagnostic work-up of cancer patients offers a great potential for assessing both MSI status as well as mutational load.	('mutational load', 'Var', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('assessing', 'Reg', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (62, 70))	('MSI', 'Disease', 'MESH:D053842', (115, 118))	('cancer', 'Disease', (55, 61))	('MSI', 'Disease', (115, 118))
4435	31638937	Homopolymeric loci are especially vulnerable in this regard, thus increasing the chance of obtaining significantly different length distributions between tumor and germline samples.	('Homopolymeric', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('different', 'Reg', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('increasing', 'PosReg', (66, 76))	('length distributions', 'MPA', (125, 145))	('tumor', 'Disease', (154, 159))
4445	31638937	Currently, clinical trials are enrolling patients with mutations in genes, POLE and POLD1, to determine the effectiveness of immunotherapy in these patients (ClinicalTrials.gov Identifier: NCT03461952).	('patients', 'Species', '9606', (148, 156))	('POLD1', 'Gene', '5424', (84, 89))	('mutations', 'Var', (55, 64))	('POLD1', 'Gene', (84, 89))	('patients', 'Species', '9606', (41, 49))	('POLE', 'Gene', (75, 79))
4454	31638937	Grants from the Danish Cancer Society (R107-A7935, R133-A8520-00-S41, R146-A9466-16-S2) and the Novo Nordisk Foundation (NNF14OC0012747, NNF17OC0025052).	('R133-A8520-00-S41, R146-A9466-16-S2', 'Chemical', 'MESH:C448629', (51, 86))	('R133-A8520-00-S41', 'Var', (51, 68))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('R107-A7935', 'Var', (39, 49))	('R146-A9466-16-S2', 'Var', (70, 86))
4484	26945341	In a subset of cases that demonstrated mismatch repair (MMR) protein expression abnormalities, the H&E stained slides were re-reviewed to assess for the presence or absence of tumor-infiltrating lymphocytes.	('H&E', 'Chemical', '-', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('abnormalities', 'Var', (80, 93))	('MMR', 'biological_process', 'GO:0006298', ('56', '59'))	('tumor', 'Disease', (176, 181))	('mismatch repair', 'biological_process', 'GO:0006298', ('39', '54'))	('protein', 'Protein', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('mismatch', 'Var', (39, 47))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
4542	26945341	Enthusiasm for detection of CD117 overexpression by IHC has waned somewhat since clinical trials have failed to demonstrate a benefit for imatinib therapy in pulmonary SCNECa with CD117 overexpression by IHC .	('overexpression', 'PosReg', (186, 200))	('CD117', 'Var', (180, 185))	('imatinib', 'Chemical', 'MESH:D000068877', (138, 146))	('pulmonary SCNECa', 'Disease', (158, 174))
4543	26945341	Although MLH1/PMS2 loss may be attributable to sporadic MLH1 promoter hypermethylation, the latter two staining patterns are suggestive of Lynch syndrome.	('Lynch syndrome', 'Disease', (139, 153))	('hypermethylation', 'Var', (70, 86))	('loss', 'NegReg', (19, 23))	('Lynch syndrome', 'Disease', 'MESH:D003123', (139, 153))	('MLH1/PMS2', 'Gene', (9, 18))	('MLH1', 'Gene', (56, 60))
4578	27322142	Our approach revealed several dysregulated L-FFL motifs common across different cancers or specific to particular cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('motifs', 'Var', (49, 55))	('cancers', 'Disease', (114, 121))	('L-FFL', 'Chemical', '-', (43, 48))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('L-FFL', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('particular cancers', 'Disease', (103, 121))	('particular cancers', 'Disease', 'MESH:D009369', (103, 121))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
4579	27322142	We also found that L-FFL motifs can take part in other types of regulatory networks, such as mRNA-mediated FFLs and ceRNA networks, and form the more complex networks in human cancers.	('cancers', 'Disease', (176, 183))	('L-FFL', 'Var', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('take', 'Reg', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('regulatory', 'MPA', (64, 74))	('human', 'Species', '9606', (170, 175))	('L-FFL', 'Chemical', '-', (19, 24))	('form', 'Reg', (136, 140))
4582	27322142	Long non-coding RNAs (lncRNAs, > 200 nucleotides in length) are pervasive across the genome and dysregulation of their expression is associated with many human diseases, including cancer.	('expression', 'MPA', (119, 129))	('human', 'Species', '9606', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Long', 'Protein', (0, 4))	('dysregulation', 'Var', (96, 109))	('cancer', 'Disease', (180, 186))	('associated', 'Reg', (133, 143))
4598	27322142	More importantly, we found that some L-FFL motifs provide novel information on cancer regulation.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('L-FFL', 'Gene', (37, 42))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('motifs', 'Var', (43, 49))	('information', 'Reg', (64, 75))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('L-FFL', 'Chemical', '-', (37, 42))
4603	27322142	Our L-FFL network is composed of L-FFL motifs in lung cancer, which may represent a new mechanism in cancer (Figure 1F).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('L-FFL', 'Chemical', '-', (4, 9))	('cancer', 'Disease', (54, 60))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('L-FFL', 'Chemical', '-', (33, 38))	('L-FFL motifs', 'Var', (33, 45))
4617	27322142	Here, L-FFL motifs dysregulated in at least two cancer types are designated as "common", while those dysregulated in only one cancer type are considered "specific".	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('L-FFL', 'Chemical', '-', (6, 11))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('motifs', 'Var', (12, 18))	('cancer', 'Disease', (48, 54))	('L-FFL', 'Gene', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
4634	27322142	These results suggest that L-FFL motifs may serve as prognostic biomarkers for different cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('L-FFL', 'Chemical', '-', (27, 32))	('motifs', 'Var', (33, 39))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
4636	27322142	First, we identified dysregulated mRNA-mediated FFL (M-FFL) motifs in different types of cancers by following the same pipeline as with the L-FFL motif identification.	('L-FFL', 'Chemical', '-', (140, 145))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('motifs', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
4638	27322142	For example, we found that an L-FFL motif constituted by SNHG12, E2F1, and miR-16, and an M-FFL motif constituted by E2F1, miR-16 and AURKB could form a complex regulation motif by sharing common TF E2F1 and miRNA miR-16, which were highly dysregulated in breast and bladder cancers (Figure 5A, Supplementary Table S6).	('E2F1', 'Gene', (65, 69))	('miR-16', 'Gene', '51573', (214, 220))	('E2F1', 'Gene', '1869', (65, 69))	('E2F1', 'Gene', (199, 203))	('breast and bladder cancers', 'Disease', 'MESH:D001749', (256, 282))	('miR-16', 'Gene', (75, 81))	('E2F1', 'Gene', '1869', (199, 203))	('miR-16', 'Gene', (123, 129))	('AURKB', 'Gene', (134, 139))	('E2F1', 'Gene', (117, 121))	('L-FFL', 'Chemical', '-', (30, 35))	('regulation', 'biological_process', 'GO:0065007', ('161', '171'))	('SNHG12', 'Gene', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('E2F1', 'Gene', '1869', (117, 121))	('miR-16', 'Gene', '51573', (75, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (267, 281))	('miR-16', 'Gene', '51573', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('miR-16', 'Gene', (214, 220))	('miRNA', 'Var', (208, 213))	('SNHG12', 'Gene', '85028', (57, 63))	('bladder cancers', 'Phenotype', 'HP:0009725', (267, 282))	('AURKB', 'Gene', '9212', (134, 139))
4653	27322142	In this study, we also identified dysregulated L-FFL motifs that were common and specific to several cancers, consistent with previous studies on the tissue specificity of miRNA and lncRNA.	('dysregulated', 'Var', (34, 46))	('L-FFL', 'Chemical', '-', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('L-FFL', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
4655	27322142	Our functional and survival analyses suggest that L-FFL motifs may serve as prognostic biomarkers for cancer.	('motifs', 'Var', (56, 62))	('L-FFL', 'Chemical', '-', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('L-FFL', 'Protein', (50, 55))
4693	26343160	Silencing IAMC1 expression by siRNAs in a high-grade endometrioid carcinoma cell line did not affect its proliferative activity but significantly suppressed cell motility and invasion in vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('suppressed', 'NegReg', (146, 156))	('cell motility', 'biological_process', 'GO:0048870', ('157', '170'))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (53, 75))	('IAMC1', 'Gene', (10, 15))	('Silencing', 'Var', (0, 9))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (53, 75))	('endometrioid carcinoma', 'Disease', (53, 75))
4702	26343160	Endometrioid carcinoma is characterized by frequent somatic mutations in PTEN, ARID1A and CTNNB1, in addition to mutations in POLE and mismatch repair genes in a subset of tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('PTEN', 'Gene', (73, 77))	('CTNNB1', 'Gene', '1499', (90, 96))	('mismatch repair', 'biological_process', 'GO:0006298', ('135', '150'))	('PTEN', 'Gene', '5728', (73, 77))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('Endometrioid carcinoma', 'Disease', 'MESH:D016889', (0, 22))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Endometrioid carcinoma', 'Phenotype', 'HP:0012114', (0, 22))	('ARID1A', 'Gene', '8289', (79, 85))	('ARID1A', 'Gene', (79, 85))	('Endometrioid carcinoma', 'Disease', (0, 22))	('CTNNB1', 'Gene', (90, 96))	('mutations', 'Var', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))
4703	26343160	In contrast, serous carcinomas harbor somatic TP53, PIK3CA, PPP2R1A and FBXW7 mutations but not those commonly detected in the endometrioid type.	('serous carcinomas', 'Disease', 'MESH:D018284', (13, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('TP53', 'Gene', '7157', (46, 50))	('serous carcinomas', 'Disease', (13, 30))	('PIK3CA', 'Gene', (52, 58))	('mutations', 'Var', (78, 87))	('FBXW7', 'Gene', '55294', (72, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (20, 30))	('TP53', 'Gene', (46, 50))	('PPP2R1A', 'Gene', '5518', (60, 67))	('PIK3CA', 'Gene', '5290', (52, 58))	('PPP2R1A', 'Gene', (60, 67))	('FBXW7', 'Gene', (72, 77))
4704	26343160	Serous carcinomas also exhibit gene amplification involving HER2 and CCNE1.	('carcinomas', 'Phenotype', 'HP:0030731', (7, 17))	('gene amplification', 'Var', (31, 49))	('HER2', 'Gene', (60, 64))	('Serous carcinomas', 'Disease', 'MESH:D018284', (0, 17))	('CCNE1', 'Gene', '898', (69, 74))	('CCNE1', 'Gene', (69, 74))	('HER2', 'Gene', '2064', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('Serous carcinomas', 'Disease', (0, 17))
4720	26343160	Log-rank test was used to compare the survival between patients with high LAMC1 expression (> median) and low LAMC1 expression (<= median) in endometrioid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('LAMC1', 'Gene', '3915', (110, 115))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (142, 164))	('LAMC1', 'Gene', '3915', (74, 79))	('LAMC1', 'Gene', (110, 115))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (142, 164))	('endometrioid carcinoma', 'Disease', (142, 164))	('LAMC1', 'Gene', (74, 79))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (55, 63))
4723	26343160	Cells were transfected with two different LAMC1-specific short interfering RNA (siRNAs) (Ambion, cat #439240, ID # s8077 and s8078) and scramble siRNA (Ambion, cat # 4390849) as the control, with Lipofectamine RNAiMAX Transfection Reagent (Life technology, cat # 13778100).	('LAMC1', 'Gene', (42, 47))	('ID # s8077', 'Var', (110, 120))	('cat', 'molecular_function', 'GO:0004096', ('160', '163'))	('s8078', 'Var', (125, 130))	('cat', 'molecular_function', 'GO:0004096', ('257', '260'))	('RNA', 'cellular_component', 'GO:0005562', ('75', '78'))	('cat', 'molecular_function', 'GO:0004096', ('97', '100'))	('LAMC1', 'Gene', '3915', (42, 47))	('Lipofectamine', 'Chemical', 'MESH:C086724', (196, 209))
4748	26343160	Thus, we selected a high-grade endometrioid carcinoma cell line, HEC1B, and determined the effect of silencing LAMC1 expression on cell motility and invasion using in vitro assays.	('LAMC1', 'Gene', '3915', (111, 116))	('silencing', 'Var', (101, 110))	('LAMC1', 'Gene', (111, 116))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (31, 53))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (31, 53))	('cell motility', 'biological_process', 'GO:0048870', ('131', '144'))	('endometrioid carcinoma', 'Disease', (31, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('HEC1B', 'CellLine', 'CVCL:0294', (65, 70))	('cell motility', 'CPA', (131, 144))
4760	26343160	The results of these studies not only validate those molecular genetic changes previously reported in uterine endometrioid and serous carcinoma, but also provide new insight into its pathogenesis by demonstrating aberrations in several tumor-associated genes and pathways that may potentially participate in tumor initiation and progression.	('tumor', 'Disease', (308, 313))	('participate', 'Reg', (293, 304))	('changes', 'Var', (71, 78))	('pathogenesis', 'biological_process', 'GO:0009405', ('183', '195'))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('uterine endometrioid', 'Disease', (102, 122))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor initiation', 'Disease', 'MESH:D009369', (308, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('serous carcinoma', 'Disease', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('serous carcinoma', 'Disease', 'MESH:D018284', (127, 143))	('tumor initiation', 'Disease', (308, 324))	('tumor', 'Disease', (236, 241))	('aberrations', 'Var', (213, 224))
4771	26343160	For example, miR-22 and miR-29a have been recently reported to target LAMC1, and transfection of miRNA mimics in prostate cancer cells induced apoptosis and diminished cell migration and viability.	('miR-22', 'Gene', (13, 19))	('LAMC1', 'Gene', '3915', (70, 75))	('cell migration', 'biological_process', 'GO:0016477', ('168', '182'))	('transfection', 'Var', (81, 93))	('miR-29a', 'Gene', (24, 31))	('LAMC1', 'Gene', (70, 75))	('miR-29a', 'Gene', '407021', (24, 31))	('prostate cancer', 'Disease', (113, 128))	('diminished', 'NegReg', (157, 167))	('apoptosis', 'CPA', (143, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('induced', 'PosReg', (135, 142))	('miR-22', 'Gene', '407004', (13, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
4781	26343160	It is possible that advanced endometrioid carcinomas with either high or low LAMC1 expression respond similarly to the standard chemotherapy after surgery and LAMC1 upregulation alone is insufficient to promote tumor recurrence.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('LAMC1', 'Gene', '3915', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('LAMC1', 'Gene', (159, 164))	('endometrioid carcinomas', 'Disease', (29, 52))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (29, 51))	('LAMC1', 'Gene', '3915', (77, 82))	('high', 'Var', (65, 69))	('insufficient', 'Disease', 'MESH:D000309', (187, 199))	('tumor', 'Disease', (211, 216))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('low', 'NegReg', (73, 76))	('insufficient', 'Disease', (187, 199))	('LAMC1', 'Gene', (77, 82))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (29, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (29, 52))
4788	26343160	Silencing LAMC1 expression significantly suppressed endometrioid carcinoma cell motility and invasion in vitro.	('endometrioid carcinoma cell motility', 'Disease', 'MESH:D016889', (52, 88))	('LAMC1', 'Gene', '3915', (10, 15))	('LAMC1', 'Gene', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('endometrioid carcinoma cell motility', 'Disease', (52, 88))	('suppressed', 'NegReg', (41, 51))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (52, 74))	('invasion', 'CPA', (93, 101))	('Silencing', 'Var', (0, 9))	('cell motility', 'biological_process', 'GO:0048870', ('75', '88'))
4793	32599890	Gene mutation analyses identified oncogenic mutations in endometriosis and normal endometrium and revealed that the same mutations were present at different endometriotic lesions.	('endometriosis', 'Disease', (57, 70))	('mutations', 'Var', (44, 53))	('endometriosis', 'Phenotype', 'HP:0030127', (57, 70))	('endometriosis', 'Disease', 'MESH:D004715', (57, 70))
4794	32599890	It was also shown that most of the gene mutations found in endometriosis occurred in normal endometrium.	('occurred', 'Reg', (73, 81))	('endometriosis', 'Disease', 'MESH:D004715', (59, 72))	('endometriosis', 'Phenotype', 'HP:0030127', (59, 72))	('endometriosis', 'Disease', (59, 72))	('mutations', 'Var', (40, 49))
4817	32599890	ROS causes not only gene mutations but also epigenetic alterations, such as DNA methylation.	('DNA methylation', 'biological_process', 'GO:0006306', ('76', '91'))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('causes', 'Reg', (4, 10))	('ROS', 'Gene', (0, 3))	('epigenetic alterations', 'MPA', (44, 66))	('DNA methylation', 'Disease', (76, 91))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('gene mutations', 'Var', (20, 34))
4876	32599890	It has been suggested that EAOC arises from endometriosis because EAOC exhibits mutations in ARID1A, PIK3CA, and PTEN as well as loss of heterozygosity at a high frequency, which is also common in coexisting endometriosis.	('endometriosis', 'Disease', (44, 57))	('PIK3CA', 'Gene', (101, 107))	('mutations', 'Var', (80, 89))	('endometriosis', 'Disease', 'MESH:D004715', (44, 57))	('endometriosis', 'Phenotype', 'HP:0030127', (44, 57))	('EAOC', 'Disease', (27, 31))	('PTEN', 'Gene', (113, 117))	('PTEN', 'Gene', '5728', (113, 117))	('EAOC', 'Disease', (66, 70))	('endometriosis', 'Disease', 'MESH:D004715', (208, 221))	('endometriosis', 'Phenotype', 'HP:0030127', (208, 221))	('ARID1A', 'Gene', (93, 99))	('endometriosis', 'Disease', (208, 221))
4878	32599890	In reports examining deep endometriosis, which is not usually associated with carcinogenesis, 19 of 24 patients had gene mutations and 5 had oncogenic mutations.	('endometriosis', 'Disease', (26, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('endometriosis', 'Phenotype', 'HP:0030127', (26, 39))	('carcinogenesis', 'Disease', (78, 92))	('gene mutations', 'Var', (116, 130))	('patients', 'Species', '9606', (103, 111))	('endometriosis', 'Disease', 'MESH:D004715', (26, 39))
4879	32599890	reported numerous KRAS and PIK3CA mutations in both endometriosis and normal endometrial glandular epithelium, and the same mutations were observed even at different sites of endometriosis.	('endometriosis', 'Disease', (175, 188))	('KRAS', 'Gene', (18, 22))	('endometriosis', 'Disease', 'MESH:D004715', (175, 188))	('KRAS', 'Gene', '3845', (18, 22))	('endometriosis', 'Disease', 'MESH:D004715', (52, 65))	('PIK3CA', 'Gene', (27, 33))	('endometriosis', 'Phenotype', 'HP:0030127', (175, 188))	('endometriosis', 'Disease', (52, 65))	('endometriosis', 'Phenotype', 'HP:0030127', (52, 65))	('mutations', 'Var', (34, 43))
4881	32599890	In mouse models of ARID1A and PIK3CA mutations in the endometrium, it was reported that endometriosis occurred when the endometrial glands were easily regurgitated into the peritoneal cavity by salpingectomy.	('PIK3CA', 'Gene', (30, 36))	('endometriosis', 'Phenotype', 'HP:0030127', (88, 101))	('mouse', 'Species', '10090', (3, 8))	('ARID1A', 'Gene', (19, 25))	('occurred', 'Reg', (102, 110))	('mutations', 'Var', (37, 46))	('endometriosis', 'Disease', 'MESH:D004715', (88, 101))	('endometriosis', 'Disease', (88, 101))
4890	32599890	Many driver gene mutations are common to endometrium, endometriosis, and EAOC.	('endometriosis', 'Phenotype', 'HP:0030127', (54, 67))	('driver gene', 'Gene', (5, 16))	('mutations', 'Var', (17, 26))	('EAOC', 'Disease', (73, 77))	('endometriosis', 'Disease', (54, 67))	('endometriosis', 'Disease', 'MESH:D004715', (54, 67))	('endometrium', 'Disease', (41, 52))
4891	32599890	In addition, when comparing these with endometrial cancer gene mutations from The Cancer Genome Atlas, a significant number of them are consistent with endometrium, endometriosis, and EAOC gene mutations.	('endometriosis', 'Disease', 'MESH:D004715', (165, 178))	('endometriosis', 'Disease', (165, 178))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('endometrial cancer', 'Disease', (39, 57))	('Cancer', 'Disease', (82, 88))	('mutations', 'Var', (194, 203))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('endometriosis', 'Phenotype', 'HP:0030127', (165, 178))	('endometrium', 'Disease', (152, 163))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('endometrial cancer', 'Phenotype', 'HP:0012114', (39, 57))	('EAOC', 'Disease', (184, 188))	('endometrial cancer', 'Disease', 'MESH:D016889', (39, 57))
4895	32599890	Nonetheless, eutopic endometrial glandular epithelial cells with sufficient gene mutations, when engrafted in the ovaries by menstrual blood reflux, cause carcinogenesis through the effect of the cancer-promoting ovarian microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ovaries', 'Disease', 'MESH:D010051', (114, 121))	('carcinogenesis', 'Disease', (155, 169))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('cancer-promoting ovarian', 'Disease', (196, 220))	('cancer-promoting ovarian', 'Disease', 'MESH:D010051', (196, 220))	('iron', 'Chemical', 'MESH:D007501', (229, 233))	('mutations', 'Var', (81, 90))	('blood reflux', 'Phenotype', 'HP:0002020', (135, 147))	('ovaries', 'Disease', (114, 121))	('cause', 'Reg', (149, 154))
4896	32599890	However, cells with an initiator mutation may not always cause carcinogenesis, which is similar to the fact that inoculating immunodeficient mice with cancer cells does not result in 100% tumor formation.	('tumor', 'Disease', (188, 193))	('mutation', 'Var', (33, 41))	('cause', 'Reg', (57, 62))	('formation', 'biological_process', 'GO:0009058', ('194', '203'))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('immunodeficient', 'Disease', 'MESH:D007153', (125, 140))	('cancer', 'Disease', (151, 157))	('immunodeficient', 'Disease', (125, 140))	('mice', 'Species', '10090', (141, 145))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('carcinogenesis', 'Disease', (63, 77))
4902	32599890	Although many of the gene mutations in the glands of endometriosis tissue were also found in normal eutopic endometrium by exome sequencing, the study did not look for mutations at each gland.	('endometriosis', 'Disease', (53, 66))	('mutations', 'Var', (26, 35))	('endometriosis', 'Disease', 'MESH:D004715', (53, 66))	('endometriosis', 'Phenotype', 'HP:0030127', (53, 66))
4903	32599890	Endometrial glands are known to be monoclonal; therefore, to prove that endometriosis or EAOC is caused by the regurgitation of endometrial gland ducts with genetic mutations, it is necessary to analyze each gene mutation in the glands and to identify the glands that are the same clones as endometriosis and EAOC.	('endometriosis', 'Disease', (291, 304))	('endometriosis', 'Disease', 'MESH:D004715', (291, 304))	('endometriosis', 'Phenotype', 'HP:0030127', (291, 304))	('mutation', 'Var', (213, 221))	('endometriosis', 'Phenotype', 'HP:0030127', (72, 85))	('endometriosis', 'Disease', 'MESH:D004715', (72, 85))	('EAOC', 'Disease', (309, 313))	('endometriosis', 'Disease', (72, 85))
4905	32599890	To prove that eutopic endometrium with genetic mutations causes endometriosis and EAOC, it is necessary to further advance the sequencing technology in addition to meticulous sectioning of the endometrium.	('endometriosis', 'Disease', (64, 77))	('endometriosis', 'Phenotype', 'HP:0030127', (64, 77))	('genetic mutations', 'Var', (39, 56))	('EAOC', 'Disease', (82, 86))	('endometriosis', 'Disease', 'MESH:D004715', (64, 77))	('causes', 'Reg', (57, 63))
4930	32599890	It has been reported that many ovarian cancer cases have gene mutations and chromosome number abnormalities (copy number increases of chromosome 7q and 8q) in cervical Pap smear samples or endometrial Tao brush samples.	('Pap', 'molecular_function', 'GO:0043751', ('168', '171'))	('increases', 'PosReg', (121, 130))	('ovarian cancer', 'Phenotype', 'HP:0100615', (31, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('gene mutations', 'Var', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (31, 45))	('chromosome number abnormalities', 'Disease', (76, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	('chromosome number abnormalities', 'Phenotype', 'HP:0031411', (76, 107))	('ovarian cancer', 'Disease', (31, 45))	('chromosome number abnormalities', 'Disease', 'MESH:D007674', (76, 107))
4933	32599890	In OCCC, PIK3CA mutations are found in 33-40% of cases, activating the PI3K/AKT/mTOR pathway.	('AKT', 'Gene', '207', (76, 79))	('mTOR', 'Gene', (80, 84))	('activating', 'PosReg', (56, 66))	('mTOR', 'Gene', '2475', (80, 84))	('mutations', 'Var', (16, 25))	('AKT', 'Gene', (76, 79))	('PIK3CA', 'Gene', (9, 15))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))	('OCCC', 'Disease', (3, 7))
4936	32599890	Poly (ADP-ribose) polymerase (PARP) inhibitors have been shown to be effective against ovarian cancer, with BRCA1/BRCA2 gene mutations resulting in homologous recombination deficiency.	('mutations', 'Var', (125, 134))	('homologous recombination', 'biological_process', 'GO:0035825', ('148', '172'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('PARP', 'Gene', (30, 34))	('BRCA2', 'Gene', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Poly (ADP-ribose) polymerase', 'Gene', '142', (0, 28))	('BRCA1', 'Gene', '672', (108, 113))	('BRCA2', 'Gene', '675', (114, 119))	('deficiency', 'Disease', (173, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('deficiency', 'Disease', 'MESH:D007153', (173, 183))	('PARP', 'Gene', '142', (30, 34))	('BRCA1', 'Gene', (108, 113))	('resulting in', 'Reg', (135, 147))	('Poly (ADP-ribose) polymerase', 'Gene', (0, 28))	('ovarian cancer', 'Disease', (87, 101))
4937	32599890	Although BRCA1/2 gene mutations resulting in homologous recombination deficiency are found in only 6-8% of EAOCs, PARP inhibitors may be effective in cases with mutations.	('deficiency', 'Disease', (70, 80))	('PARP', 'Gene', '142', (114, 118))	('BRCA1/2', 'Gene', (9, 16))	('deficiency', 'Disease', 'MESH:D007153', (70, 80))	('BRCA1/2', 'Gene', '672;675', (9, 16))	('mutations', 'Var', (22, 31))	('homologous recombination', 'biological_process', 'GO:0035825', ('45', '69'))	('PARP', 'Gene', (114, 118))
4940	32599890	Although there are no data showing that anti-VEGF antibodies are more likely to be effective in EAOC than other histology types, it is possible that they may be shown to be effective for EAOC in combination with other drugs in the future.	('antibodies', 'Var', (50, 60))	('VEGF', 'Gene', '7422', (45, 49))	('EAOC', 'Disease', (96, 100))	('effective', 'Reg', (83, 92))	('VEGF', 'Gene', (45, 49))	('EAOC', 'Disease', (187, 191))
4945	32599890	In addition, in Lynch syndrome, germline mutations are found in MLH1, MSH2, MSH6, and PMS2 and their associated parts among mismatch repair genes, and the cumulative morbidity rate of ovarian cancer is higher (10-12%) compared with the general population.	('ovarian cancer', 'Disease', (184, 198))	('MLH1', 'Gene', (64, 68))	('germline mutations', 'Var', (32, 50))	('MLH1', 'Gene', '4292', (64, 68))	('MSH6', 'Gene', (76, 80))	('Lynch syndrome', 'Disease', (16, 30))	('PMS2', 'Gene', (86, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (184, 198))	('Lynch syndrome', 'Disease', 'MESH:D003123', (16, 30))	('PMS2', 'Gene', '5395', (86, 90))	('MSH6', 'Gene', '2956', (76, 80))	('MSH2', 'Gene', (70, 74))	('mismatch repair', 'biological_process', 'GO:0006298', ('124', '139'))	('MSH2', 'Gene', '4436', (70, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
4946	32599890	In a study that performed whole exome sequencing of OCCC, there were 3 (6%) of 48 suspected cases of Lynch syndrome, suggesting that Lynch syndrome may be associated with a certain frequency in OCCC, in which mismatch repair gene mutations lead to high frequency microsatellite instability, a susceptibility biomarker for immune checkpoint inhibitors.	('Lynch syndrome', 'Disease', 'MESH:D003123', (133, 147))	('high frequency microsatellite instability', 'MPA', (248, 289))	('Lynch syndrome', 'Disease', (101, 115))	('mutations', 'Var', (230, 239))	('mismatch repair gene', 'Gene', (209, 229))	('mismatch repair', 'biological_process', 'GO:0006298', ('209', '224'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (101, 115))	('lead to', 'Reg', (240, 247))	('Lynch syndrome', 'Disease', (133, 147))
4948	32599890	It was also reported that administration of an anti-IL-6 antibody to an OCCC mouse model improved prognosis, indicating the potential for future clinical applications.	('improved', 'PosReg', (89, 97))	('antibody', 'cellular_component', 'GO:0042571', ('57', '65'))	('antibody', 'cellular_component', 'GO:0019815', ('57', '65'))	('IL-6', 'molecular_function', 'GO:0005138', ('52', '56'))	('antibody', 'cellular_component', 'GO:0019814', ('57', '65'))	('prognosis', 'CPA', (98, 107))	('anti-IL-6', 'Var', (47, 56))	('antibody', 'molecular_function', 'GO:0003823', ('57', '65'))	('mouse', 'Species', '10090', (77, 82))
4949	32599890	The activity of histone deacetylase 6 (HDAC6) has been shown to be closely associated with ovarian cancer with ARID1A mutations, and the efficacy of HDAC6 inhibitors and combination therapy with anti-PD-L1 antibodies has been demonstrated in an OCCC mouse model lacking the ARID1A gene, which may also have future clinical applications.	('PD-L1', 'Gene', (200, 205))	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('mutations', 'Var', (118, 127))	('ovarian cancer', 'Disease', (91, 105))	('PD-L1', 'Gene', '60533', (200, 205))	('ARID1A', 'Gene', (111, 117))	('histone deacetylase 6', 'Gene', '15185', (16, 37))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('HDAC6', 'Gene', '15185', (149, 154))	('HDAC6', 'Gene', '15185', (39, 44))	('associated', 'Reg', (75, 85))	('activity', 'MPA', (4, 12))	('HDAC6', 'Gene', (149, 154))	('mouse', 'Species', '10090', (250, 255))	('histone deacetylase 6', 'Gene', (16, 37))	('HDAC6', 'Gene', (39, 44))
4953	29854314	Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer Foretinib (GSK1363089 or XL880), which is an oral multikinase inhibitor developed to primarily target the hepatocyte growth factor (HGF)/Met signaling pathway, has shown anti-tumor effects against some cancers in preclinical and clinical studies.	('GSK', 'molecular_function', 'GO:0050321', ('88', '91'))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('XL880', 'Chemical', 'MESH:C544831', (102, 107))	('cancers', 'Disease', (279, 286))	('p53', 'Gene', '7157', (31, 34))	('factor ', 'Gene', '7422', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('Met signaling pathway', 'biological_process', 'GO:0048012', ('214', '235'))	('p53', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('GSK', 'molecular_function', 'GO:0050321', ('11', '14'))	('GSK1363089', 'Chemical', 'MESH:C544831', (11, 21))	('endometrial cancer', 'Phenotype', 'HP:0012114', (58, 76))	('GSK1363089', 'Chemical', 'MESH:C544831', (88, 98))	('factor ', 'Gene', (201, 208))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('endometrial cancer', 'Disease', (58, 76))	('GSK1363089', 'Var', (11, 21))	('endometrial cancer', 'Disease', 'MESH:D016889', (58, 76))	('Foretinib', 'Chemical', 'MESH:C544831', (77, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('tumor', 'Disease', (252, 257))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('183', '207'))
4957	29854314	p53 mutations were observed in 37 (10.8%) of 344 endometrial cancer specimens.	('p53', 'Gene', (0, 3))	('endometrial cancer', 'Disease', (49, 67))	('observed', 'Reg', (19, 27))	('endometrial cancer', 'Phenotype', 'HP:0012114', (49, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('endometrial cancer', 'Disease', 'MESH:D016889', (49, 67))	('mutations', 'Var', (4, 13))
4959	29854314	Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib was found to exert greater anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations.	('cancer', 'Disease', (26, 32))	('anti-phosphorylation', 'MPA', (52, 72))	('foretinib', 'Gene', (140, 149))	('endometrial cancer', 'Disease', 'MESH:D016889', (201, 219))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('nde', 'Gene', '54820', (123, 126))	('ter', 'Gene', '9524', (173, 176))	('wild-type', 'Var', (235, 244))	('nde', 'Gene', (123, 126))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('ter', 'Gene', (173, 176))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('endometrial cancer', 'Phenotype', 'HP:0012114', (201, 219))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('endometrial cancer', 'Disease', (201, 219))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('foretinib', 'Chemical', 'MESH:C544831', (140, 149))
4975	29854314	In several epithelial and mesenchymal cancers, the high expression of the Met protein has been reported to be an independent predictor of an adverse outcome, and Met was reported to activate cancer cell dissemination.	('high expression', 'MPA', (51, 66))	('mesenchymal cancers', 'Disease', (26, 45))	('activate', 'PosReg', (182, 190))	('epithelial', 'Disease', (11, 21))	('mesenchymal cancers', 'Disease', 'MESH:C535700', (26, 45))	('cancer', 'Disease', (191, 197))	('nde', 'Gene', '54820', (114, 117))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', (38, 44))	('protein', 'Protein', (78, 85))	('nde', 'Gene', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('nde', 'Gene', '54820', (119, 122))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('Met', 'Gene', (74, 77))	('Met', 'Var', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('nde', 'Gene', (119, 122))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
4993	29854314	It has been well documented that the activation of PI3K signaling increases the translocation of the mouse double minute 2 homolog (MDM2) from the cytoplasm to the nucleus, allowing p53 to be degraded by proteasomes.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('PI3K', 'Var', (51, 55))	('increases', 'PosReg', (66, 75))	('mouse', 'Species', '10090', (101, 106))	('nucleus', 'cellular_component', 'GO:0005634', ('164', '171'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('147', '156'))	('homolog (MDM2', 'Gene', '17246', (123, 136))	('translocation', 'MPA', (80, 93))	('PI3K signaling', 'biological_process', 'GO:0014065', ('51', '65'))	('p53', 'Protein', (182, 185))	('degraded', 'MPA', (192, 200))
5002	29854314	Figure 3D shows that the anti-proliferation effect of foretinib was reduced in p53 siRNA-transfected cells.	('foretinib', 'Gene', (54, 63))	('foretinib', 'Chemical', 'MESH:C544831', (54, 63))	('anti-proliferation effect', 'CPA', (25, 50))	('p53', 'Var', (79, 82))	('reduced', 'NegReg', (68, 75))
5005	29854314	As shown in Figure 5A, the HGF siRNA-transfected EC cells showed significant growth inhibition, which occurred in a time-dependent manner, in comparison to the scrambled siRNA-transfected cells.	('growth inhibition', 'CPA', (77, 94))	('HGF siRNA-transfected', 'Var', (27, 48))	('nde', 'Gene', '54820', (125, 128))	('nde', 'Gene', (125, 128))
5006	29854314	Moreover, HGF siRNA transfection induced a significantly greater level of apoptosis in comparison to the scrambled siRNA-transfected cells (Figure 5B and 5C).	('apoptosis', 'MPA', (74, 83))	('HGF siRNA transfection', 'Var', (10, 32))	('transfection', 'Var', (20, 32))	('ter', 'Gene', '9524', (61, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('ter', 'Gene', (61, 64))
5007	29854314	In order to assess whether the p53-dependent apoptosis was induced via the inhibition of autocrine HGF/Met signaling, we examined the expression of p-Akt, p-MDM2, p53 and PUMA in HGF siRNA-transfected EC cells by Western blotting.	('ste', 'Gene', (215, 218))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('ste', 'Gene', '6783', (215, 218))	('nde', 'Gene', (39, 42))	('ter', 'Gene', '9524', (216, 219))	('p-MDM2', 'Var', (155, 161))	('nde', 'Gene', '54820', (39, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('ter', 'Gene', (216, 219))
5009	29854314	These data suggest that autocrine HGF/Met signaling interferes with the p53 activity in EC cells, and that inhibiting autocrine HGF/Met signaling restores the p53 function.	('ter', 'Gene', '9524', (54, 57))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('p53', 'Protein', (72, 75))	('activity', 'MPA', (76, 84))	('inhibiting', 'Var', (107, 117))	('p53 function', 'MPA', (159, 171))	('ter', 'Gene', (54, 57))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('restores', 'PosReg', (146, 154))
5022	29854314	Table 2 shows the association between the malignant potential of the tumor and the p53 status (determined by immunochemical staining).	('ter', 'Gene', '9524', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ter', 'Gene', (97, 100))	('tumor', 'Disease', (69, 74))	('association', 'Interaction', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('p53 status', 'Var', (83, 93))
5024	29854314	Thirty-seven (10.8%) patients were positive for p53 and 307 (89.2%) were negative for p53.	('patients', 'Species', '9606', (21, 29))	('positive', 'Reg', (35, 43))	('p53', 'Var', (48, 51))
5025	29854314	The rate of p53 positivity in the high-grade tumor group (24.0%) was significantly higher than that in the low-grade tumor group (6.0%).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('p53', 'Protein', (12, 15))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('positivity', 'Var', (16, 26))	('higher', 'PosReg', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
5028	29854314	Foretinib was found to induce anti-cancer effects by the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib had more anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('wild-type', 'Var', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('endometrial cancer', 'Phenotype', 'HP:0012114', (188, 206))	('foretinib', 'Chemical', 'MESH:C544831', (145, 154))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('endometrial cancer', 'Disease', (188, 206))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('more', 'PosReg', (159, 163))	('foretinib', 'Gene', (145, 154))	('nde', 'Gene', '54820', (128, 131))	('endometrial cancer', 'Disease', 'MESH:D016889', (188, 206))	('nde', 'Gene', (128, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (200, 206))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
5034	29854314	Although the full spectrum of activity is still being uncovered, mutant p53 has been found in various cancers and involvement in the development and progression of cancer has been clarified.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('found', 'Reg', (85, 90))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
5035	29854314	Mutant p53 has been found in approximately 10-20% of uterine endometrioid carcinomas and >90% of uterine serous or clear cell carcinomas.	('ter', 'Gene', '9524', (54, 57))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (61, 84))	('clear cell carcinomas', 'Disease', (115, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('ter', 'Gene', '9524', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ter', 'Gene', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (115, 136))	('found', 'Reg', (20, 25))	('ter', 'Gene', (98, 101))	('Mutant', 'Var', (0, 6))	('endometrioid carcinomas', 'Disease', (61, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('p53', 'Gene', (7, 10))
5036	29854314	In addition, there is a trend toward a higher frequency of p53 mutations with increasing histopathological grades in uterine endometrioid carcinomas.	('mutations', 'Var', (63, 72))	('p53', 'Gene', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('ter', 'Gene', (118, 121))	('endometrioid carcinomas', 'Disease', (125, 148))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (125, 148))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (125, 147))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (125, 148))	('ter', 'Gene', '9524', (118, 121))
5037	29854314	reported that mutant p53 was found in 43% of Grade 3 uterine endometrioid carcinomas, while it was not detected in Grade 1 endometrioid carcinomas.	('ter', 'Gene', '9524', (54, 57))	('endometrioid carcinomas', 'Disease', (123, 146))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (61, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (123, 146))	('found', 'Reg', (29, 34))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (123, 145))	('mutant', 'Var', (14, 20))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (123, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ter', 'Gene', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('endometrioid carcinomas', 'Disease', (61, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('p53', 'Gene', (21, 24))
5038	29854314	It also reported that p53 mutations are detected in 24-36% of clear cell carcinomas.	('p53', 'Gene', (22, 25))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (62, 83))	('detected', 'Reg', (40, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('mutations', 'Var', (26, 35))	('clear cell carcinomas', 'Disease', (62, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
5039	29854314	Mutations in p53 are not a simple phenomenon because some tumors harbor mutations in p53 that allow the protein to retain its functions.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('protein', 'Protein', (104, 111))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('p53', 'Gene', (85, 88))	('functions', 'MPA', (126, 135))
5046	29854314	This also suggests that foretinib would be effective for treating high-grade endometrial cancer, which causes p53 mutations.	('p53', 'Gene', (110, 113))	('endometrial cancer', 'Disease', 'MESH:D016889', (77, 95))	('mutations', 'Var', (114, 123))	('endometrial cancer', 'Disease', (77, 95))	('foretinib', 'Chemical', 'MESH:C544831', (24, 33))	('endometrial cancer', 'Phenotype', 'HP:0012114', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
5187	29805391	Positivity of HER-2/neu has been seen previously in high grade Endometrioid carcinoma and serous carcinoma.	('Endometrioid carcinoma', 'Disease', (63, 85))	('serous carcinoma', 'Disease', 'MESH:D018284', (90, 106))	('Endometrioid carcinoma', 'Phenotype', 'HP:0012114', (63, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('HER-2/neu', 'Gene', (14, 23))	('seen', 'Reg', (33, 37))	('HER-2/neu', 'Gene', '2064', (14, 23))	('Positivity', 'Var', (0, 10))	('Endometrioid carcinoma', 'Disease', 'MESH:D016889', (63, 85))	('serous carcinoma', 'Disease', (90, 106))
5233	28748640	We used qRT-PCR to validate differential endometrial gene expression identified by RNAseq in a subset of Nottingham cohort of PCOS, EC and control patients for whom mRNA and cDNA were available as previously described.10 The hydrolysis probe PCR reagents employed were as follows: beta-actin: Hs01060665_g1; NQO1: Hs02512143_s1.	('gene expression', 'biological_process', 'GO:0010467', ('53', '68'))	('Hs01060665_g1', 'Var', (293, 306))	('beta-actin', 'Gene', '728378', (281, 291))	('PCOS', 'Disease', (126, 130))	('beta-actin', 'Gene', (281, 291))	('PCOS', 'Disease', 'MESH:D011085', (126, 130))	('patients', 'Species', '9606', (147, 155))	('EC', 'Phenotype', 'HP:0012114', (132, 134))	('Hs02512143_s1', 'Var', (314, 327))	('NQO1', 'molecular_function', 'GO:0003955', ('308', '312'))
5241	28748640	The score range was 0-300, and tumours were then dichotomised into low expression (score < 200) and high expression (score > 200).	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('tumours', 'Disease', (31, 38))	('score < 200', 'Var', (83, 94))
5265	28748640	Progesterone protects the endometrium from the mitogenic effects of oestrogen and withdrawal of progesterone triggers endometrial sloughing (menstruation), which allows the natural shedding of abnormal endometrial cells.	('withdrawal', 'Var', (82, 92))	('triggers', 'Reg', (109, 117))	('endometrial', 'Disease', (118, 129))	('menstruation', 'biological_process', 'GO:0042703', ('141', '153'))	('progesterone', 'Chemical', 'MESH:D011374', (96, 108))
5266	28748640	A common systemic pathway such as an aberrant insulin signalling pathway may cause oligo/amenorrhoea as well as endometrial hyperplasia and EC independent of body mass index (BMI).	('amenorrhoea', 'Disease', (89, 100))	('insulin', 'Gene', (46, 53))	('EC', 'Phenotype', 'HP:0012114', (140, 142))	('cause', 'Reg', (77, 82))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (112, 135))	('insulin', 'Gene', '3630', (46, 53))	('amenorrhoea', 'Disease', 'MESH:C537962', (89, 100))	('insulin', 'molecular_function', 'GO:0016088', ('46', '53'))	('signalling pathway', 'biological_process', 'GO:0007165', ('54', '72'))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (112, 135))	('endometrial hyperplasia', 'Disease', (112, 135))	('aberrant', 'Var', (37, 45))
5267	28748640	In such a scenario, aberrant systemic signalling programs pro-oncogenic transcriptional networks in the endometrium of women with PCOS that may predispose to EC.	('PCOS', 'Disease', 'MESH:D011085', (130, 134))	('predispose', 'Reg', (144, 154))	('EC', 'Phenotype', 'HP:0012114', (158, 160))	('systemic signalling', 'MPA', (29, 48))	('aberrant', 'Var', (20, 28))	('pro-oncogenic transcriptional networks', 'Pathway', (58, 96))	('women', 'Species', '9606', (119, 124))	('signalling', 'biological_process', 'GO:0023052', ('38', '48'))	('PCOS', 'Disease', (130, 134))
5273	28748640	NQO1 has an established role in the endometrium.26 NQO1 encodes NAD(P)H:quinone oxidoreductase 1 in detoxification pathways27, 28, 29 and has been reported to activate specific quinone-derived pharmaceuticals including mitomycin C and apaziquone.30, 31 NQO1 also acts to protect the p53 tumour suppressor protein, and many other proteins involved in proliferation from proteasomal degradation.32 Interestingly, missense variants in NQO1 are implicated in many cancer types33, 34, 35 and more recently, increased NQO1 expression is associated with poor prognosis in ovarian36 and lung37 cancers.	('NQO1', 'molecular_function', 'GO:0003955', ('253', '257'))	('missense variants', 'Var', (411, 428))	('lung37 cancers', 'Disease', 'MESH:D009369', (579, 593))	('expression', 'MPA', (517, 527))	('lung37 cancers', 'Disease', (579, 593))	('NQO1', 'molecular_function', 'GO:0003955', ('512', '516'))	('cancer', 'Disease', (586, 592))	('NQO1', 'Gene', (432, 436))	('NQO1', 'Gene', (512, 516))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', (460, 466))	('cancer', 'Phenotype', 'HP:0002664', (586, 592))	('tumour', 'Disease', 'MESH:D009369', (287, 293))	('NQO1', 'molecular_function', 'GO:0003955', ('51', '55'))	('NQO1', 'molecular_function', 'GO:0003955', ('0', '4'))	('cancer', 'Phenotype', 'HP:0002664', (460, 466))	('NQO1', 'molecular_function', 'GO:0003955', ('432', '436'))	('increased', 'PosReg', (502, 511))	('tumour', 'Disease', (287, 293))	('cancers', 'Phenotype', 'HP:0002664', (586, 593))	('p53', 'Gene', '7157', (283, 286))	('degradation', 'biological_process', 'GO:0009056', ('381', '392'))	('p53', 'Gene', (283, 286))	('cancer', 'Disease', 'MESH:D009369', (586, 592))	('NAD(P)H:quinone oxidoreductase 1', 'Gene', '1728', (64, 96))	('cancer', 'Disease', 'MESH:D009369', (460, 466))	('protein', 'cellular_component', 'GO:0003675', ('305', '312'))	('ovarian36', 'Disease', (565, 574))	('detoxification', 'biological_process', 'GO:0098754', ('100', '114'))
5277	28748640	NQO1 expression is regulated by the oestrogen receptor-alpha (ERalpha/NR3A1) and oestrogen receptor-beta (ERbeta/NR3A2)40 and by progesterone.41 As outlined above, aberrant oestrogen and progesterone signalling contributes to EC risk.	('NQO1', 'molecular_function', 'GO:0003955', ('0', '4'))	('NR3A2', 'Gene', '2100', (113, 118))	('NR3A2', 'Gene', (113, 118))	('EC', 'Phenotype', 'HP:0012114', (226, 228))	('ERalpha', 'Gene', (62, 69))	('progesterone', 'Chemical', 'MESH:D011374', (187, 199))	('signalling', 'biological_process', 'GO:0023052', ('200', '210'))	('ERbeta', 'Gene', '2100', (106, 112))	('aberrant', 'Var', (164, 172))	('ERalpha', 'Gene', '2099', (62, 69))	('progesterone', 'Chemical', 'MESH:D011374', (129, 141))	('NQO1', 'Gene', (0, 4))	('EC risk', 'Disease', (226, 233))	('ERbeta', 'Gene', (106, 112))	('NR3A1', 'Gene', (70, 75))	('NR3A1', 'Gene', '2099', (70, 75))	('contributes', 'Reg', (211, 222))
5279	28748640	In conclusion, we have used a preliminary RNAseq analysis to identify aberrant gene expression in EC and endometrium from women with PCOS.	('aberrant gene', 'Var', (70, 83))	('EC', 'Phenotype', 'HP:0012114', (98, 100))	('PCOS', 'Disease', 'MESH:D011085', (133, 137))	('gene expression', 'biological_process', 'GO:0010467', ('79', '94'))	('women', 'Species', '9606', (122, 127))	('PCOS', 'Disease', (133, 137))
5297	28358054	ASS1 epigenetically enhanced DEPTOR expression by altering the histone methylation.	('DEPTOR', 'Gene', (29, 35))	('epigenetically', 'Var', (5, 19))	('enhanced', 'PosReg', (20, 28))	('DEPTOR', 'Gene', '64798', (29, 35))	('histone methylation', 'biological_process', 'GO:0016571', ('63', '82'))	('histone methylation', 'MPA', (63, 82))	('ASS1', 'Gene', '445', (0, 4))	('altering', 'Reg', (50, 58))	('ASS1', 'Gene', (0, 4))
5315	28358054	It is known that amino acids, particularly arginine, leucine, and glutamine, activate mTORC1.	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('activate', 'PosReg', (77, 85))	('glutamine', 'Var', (66, 75))	('glutamine', 'Chemical', 'MESH:D005973', (66, 75))	('leucine', 'Var', (53, 60))	('mTORC1', 'Gene', '382056', (86, 92))	('leucine', 'Chemical', 'MESH:D007930', (53, 60))	('arginine', 'Var', (43, 51))	('mTORC1', 'cellular_component', 'GO:0031931', ('86', '92'))	('mTORC1', 'Gene', (86, 92))
5316	28358054	It has recently been reported that arginine regulates mTORC1 activity by inducing its recruitment to lysosomal membranes.	('recruitment to lysosomal membranes', 'MPA', (86, 120))	('mTORC1', 'cellular_component', 'GO:0031931', ('54', '60'))	('arginine', 'Var', (35, 43))	('inducing', 'Reg', (73, 81))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))	('mTORC1', 'Gene', (54, 60))	('activity', 'MPA', (61, 69))	('mTORC1', 'Gene', '382056', (54, 60))
5318	28358054	Although it is well known that arginine stimulates mTORC1 activity, the involvement of ASS1 and arginine that has been endogenously synthesized by ASS1 in the mTORC1 signaling pathway has not been elucidated.	('mTORC1', 'Gene', (159, 165))	('arginine', 'Var', (31, 39))	('ASS1', 'Gene', '445', (87, 91))	('mTORC1', 'cellular_component', 'GO:0031931', ('159', '165'))	('stimulates', 'PosReg', (40, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('166', '183'))	('arginine', 'Chemical', 'MESH:D001120', (31, 39))	('mTORC1', 'cellular_component', 'GO:0031931', ('51', '57'))	('arginine', 'Chemical', 'MESH:D001120', (96, 104))	('mTORC1', 'Gene', '382056', (159, 165))	('mTORC1', 'Gene', '382056', (51, 57))	('ASS1', 'Gene', (147, 151))	('ASS1', 'Gene', '445', (147, 151))	('mTORC1', 'Gene', (51, 57))	('ASS1', 'Gene', (87, 91))
5327	28358054	To examine the significance of ASS1 in endometrial cancer cells, we disrupted the ASS1 gene in HEC1B and AN3CA cells, which showed ASS1 expression among the endometrial cancer cell lines, using the CRISPR/Cas9 system and successfully established ASS1-knockout (ASS1-KO) HEC1B and AN3CA cells (Fig.	('endometrial cancer', 'Disease', (39, 57))	('ASS1', 'Gene', '445', (246, 250))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ASS1', 'Gene', (246, 250))	('endometrial cancer', 'Disease', 'MESH:D016889', (39, 57))	('ASS1', 'Gene', '445', (31, 35))	('ASS1', 'Gene', (261, 265))	('ASS1', 'Gene', (31, 35))	('ASS1', 'Gene', '445', (261, 265))	('endometrial cancer', 'Phenotype', 'HP:0012114', (157, 175))	('disrupted', 'Var', (68, 77))	('endometrial cancer', 'Disease', (157, 175))	('HEC1B', 'Gene', (95, 100))	('ASS1', 'Gene', '445', (131, 135))	('ASS1', 'Gene', (131, 135))	('HEC1B', 'CellLine', 'CVCL:0294', (270, 275))	('HEC1B', 'CellLine', 'CVCL:0294', (95, 100))	('endometrial cancer', 'Disease', 'MESH:D016889', (157, 175))	('ASS1', 'Gene', (82, 86))	('ASS1', 'Gene', '445', (82, 86))	('Cas', 'cellular_component', 'GO:0005650', ('205', '208'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (39, 57))
5329	28358054	In addition, an in vitro scratch assay and an invasion assay using the Transwell filter system with Matrigel demonstrated that depletion of ASS1 in HEC1B and AN3CA cells did not affect their motility and invasion capability (Fig.	('invasion capability', 'CPA', (204, 223))	('depletion', 'Var', (127, 136))	('HEC1B', 'Gene', (148, 153))	('ASS1', 'Gene', (140, 144))	('ASS1', 'Gene', '445', (140, 144))	('HEC1B', 'CellLine', 'CVCL:0294', (148, 153))
5344	28358054	These results indicate that, under arginine-depleted conditions, the absence of ASS1 enhances cell motility and invasion capability in response to re-supplementation with arginine.	('ASS1', 'Gene', '445', (80, 84))	('arginine', 'Chemical', 'MESH:D001120', (171, 179))	('ASS1', 'Gene', (80, 84))	('response to re-supplementation with arginine', 'MPA', (135, 179))	('invasion capability', 'CPA', (112, 131))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))	('cell motility', 'biological_process', 'GO:0048870', ('94', '107'))	('enhances', 'PosReg', (85, 93))	('cell motility', 'CPA', (94, 107))	('absence', 'Var', (69, 76))
5347	28358054	3(a), ASS1-KO HEC1B cells had lower DEPTOR transcript abundance than EV HEC1B cells, while no significant difference was observed in the expression levels of genes coding for other mTOR complex components such as mTOR, RAPTOR, or RICTOR.	('mTOR', 'Gene', (213, 217))	('HEC1B', 'Var', (14, 19))	('lower', 'NegReg', (30, 35))	('RICTOR', 'Gene', '253260', (230, 236))	('RAPTOR', 'Gene', '57521', (219, 225))	('EV', 'Chemical', '-', (69, 71))	('mTOR', 'Gene', '2475', (181, 185))	('mTOR complex', 'cellular_component', 'GO:0038201', ('181', '193'))	('mTOR', 'Gene', (181, 185))	('DEPTOR', 'Gene', (36, 42))	('DEPTOR', 'Gene', '64798', (36, 42))	('HEC1B', 'CellLine', 'CVCL:0294', (14, 19))	('RICTOR', 'Gene', (230, 236))	('HEC1B', 'CellLine', 'CVCL:0294', (72, 77))	('RAPTOR', 'Gene', (219, 225))	('ASS1', 'Gene', '445', (6, 10))	('mTOR', 'Gene', '2475', (213, 217))	('ASS1', 'Gene', (6, 10))
5365	28358054	Taken together, these results show that ASS1 is a positive regulator of DEPTOR expression, and that the absence of ASS1 causes faster and higher mTORC1 activation, resulting in enhanced motility and invasion capability in endometrial cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('endometrial cancer', 'Disease', (222, 240))	('absence', 'Var', (104, 111))	('enhanced', 'PosReg', (177, 185))	('endometrial cancer', 'Disease', 'MESH:D016889', (222, 240))	('mTORC1', 'Gene', (145, 151))	('DEPTOR', 'Gene', '64798', (72, 78))	('mTORC1', 'Gene', '382056', (145, 151))	('mTORC1', 'cellular_component', 'GO:0031931', ('145', '151'))	('ASS1', 'Gene', (115, 119))	('ASS1', 'Gene', '445', (115, 119))	('invasion capability', 'CPA', (199, 218))	('higher', 'PosReg', (138, 144))	('DEPTOR', 'Gene', (72, 78))	('ASS1', 'Gene', '445', (40, 44))	('motility', 'CPA', (186, 194))	('ASS1', 'Gene', (40, 44))	('activation', 'MPA', (152, 162))	('endometrial cancer', 'Phenotype', 'HP:0012114', (222, 240))
5373	28358054	H3K27me3 in the DEPTOR promoter region of ASS1-KO AN3CA cells was also increased (see Supplementary Fig.	('ASS1', 'Gene', '445', (42, 46))	('DEPTOR', 'Gene', (16, 22))	('H3K27me3', 'Var', (0, 8))	('increased', 'PosReg', (71, 80))	('DEPTOR', 'Gene', '64798', (16, 22))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('ASS1', 'Gene', (42, 46))
5386	28358054	These results suggested that, even in vivo, absence of ASS1 may enhance cell motility and invasion capability through decreased DEPTOR expression.	('DEPTOR', 'Gene', (128, 134))	('enhance', 'PosReg', (64, 71))	('invasion capability', 'CPA', (90, 109))	('ASS1', 'Gene', (55, 59))	('absence', 'Var', (44, 51))	('cell motility', 'CPA', (72, 85))	('DEPTOR', 'Gene', '64798', (128, 134))	('cell motility', 'biological_process', 'GO:0048870', ('72', '85'))	('decreased', 'NegReg', (118, 127))	('ASS1', 'Gene', '445', (55, 59))
5402	28358054	The amounts of H3K9me2 and H3K27me3, which are repressive chromatin marks, at the DEPTOR promoter region were augmented in ASS1-KO cells compared with those in EV cells (Fig.	('DEPTOR', 'Gene', '64798', (82, 88))	('H3K9me2', 'Var', (15, 22))	('EV', 'Chemical', '-', (160, 162))	('H3', 'Chemical', 'MESH:C012616', (15, 17))	('augmented', 'PosReg', (110, 119))	('chromatin', 'cellular_component', 'GO:0000785', ('58', '67'))	('ASS1', 'Gene', (123, 127))	('H3K27me3', 'Var', (27, 35))	('ASS1', 'Gene', '445', (123, 127))	('H3', 'Chemical', 'MESH:C012616', (27, 29))	('DEPTOR', 'Gene', (82, 88))
5407	28358054	Thus, it is well known that arginine, which is transported into cells from the extracellular environment, stimulates mTORC1 activity.	('mTORC1', 'cellular_component', 'GO:0031931', ('117', '123'))	('extracellular', 'cellular_component', 'GO:0005576', ('79', '92'))	('arginine', 'Var', (28, 36))	('mTORC1', 'Gene', '382056', (117, 123))	('stimulates', 'PosReg', (106, 116))	('arginine', 'Chemical', 'MESH:D001120', (28, 36))	('mTORC1', 'Gene', (117, 123))
5414	28358054	Our study showed that the amounts of H3K9me2 and H3K27me3 at the DEPTOR promoter region were reduced in EV cells compared with those in ASS1-KO cells (Fig.	('EV', 'Chemical', '-', (104, 106))	('amounts', 'MPA', (26, 33))	('H3K9me2', 'Var', (37, 44))	('ASS1', 'Gene', '445', (136, 140))	('H3', 'Chemical', 'MESH:C012616', (37, 39))	('reduced', 'NegReg', (93, 100))	('DEPTOR', 'Gene', '64798', (65, 71))	('ASS1', 'Gene', (136, 140))	('H3K27me3', 'Var', (49, 57))	('DEPTOR', 'Gene', (65, 71))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
5417	28358054	It has been reported that ASS1 knockdown in bladder cancer and myxofibrosarcoma cell lines and DEPTOR knockout in esophageal squamous cell carcinoma and lung adenocarcinoma cell lines showed increased cell motility and invasion ability, respectively.	('bladder cancer', 'Phenotype', 'HP:0009725', (44, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('cell motility', 'biological_process', 'GO:0048870', ('201', '214'))	('cell motility', 'CPA', (201, 214))	('DEPTOR', 'Gene', '64798', (95, 101))	('myxofibrosarcoma cell lines', 'Disease', 'MESH:C538614', (63, 90))	('esophageal squamous cell carcinoma and lung adenocarcinoma', 'Disease', 'MESH:D000077277', (114, 172))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (153, 172))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('DEPTOR', 'Gene', (95, 101))	('invasion ability', 'CPA', (219, 235))	('bladder cancer', 'Disease', (44, 58))	('ASS1', 'Gene', (26, 30))	('increased', 'PosReg', (191, 200))	('bladder cancer', 'Disease', 'MESH:D001749', (44, 58))	('ASS1', 'Gene', '445', (26, 30))	('myxofibrosarcoma cell lines', 'Disease', (63, 90))	('knockdown', 'Var', (31, 40))
5424	28358054	Antibodies were obtained from the following sources: rabbit polyclonal antibody to ASS1 (HPA020896) was from Sigma-Aldrich (Milwaukee, WI); mouse monoclonal antibodies to ASS1 (ab124465), H3K9me2 (ab1220), and H3K27me3 (ab6002) were from Abcam (Cambridge, UK); rabbit monoclonal antibodies to p70 S6 Kinase (#2708), Phospho-p70 S6 Kinase (Thr389) (#9234), Phospho-S6 Ribosomal Protein (Ser240/244) (#5364), Akt (#4691), Phospho-Akt (Ser473) (#4060), DEPTOR/DEPDC6 (#11816), H3K4me3 (#9751), Histone H3 (#4620 and #4499) and beta-Actin (HRP-conjugated) (#5125) were from Cell Signaling Technology (Danvers, MA); and anti-mouse (#330) and anti-rabbit (#458) secondary antibodies were from Medical & Biological Laboratories (Nagoya, Japan).	('antibody', 'cellular_component', 'GO:0019815', ('71', '79'))	('Akt', 'Gene', (428, 431))	('Ser', 'cellular_component', 'GO:0005790', ('433', '436'))	('mouse', 'Species', '10090', (620, 625))	('H3', 'Chemical', 'MESH:C012616', (210, 212))	('Ser', 'cellular_component', 'GO:0005790', ('386', '389'))	('DEPTOR', 'Gene', (450, 456))	('antibody', 'cellular_component', 'GO:0019814', ('71', '79'))	('Akt', 'Gene', '207', (428, 431))	('Ser240', 'Chemical', '-', (386, 392))	('ASS1', 'Gene', '445', (171, 175))	('ASS1', 'Gene', (171, 175))	('ASS1', 'Gene', (83, 87))	('ASS1', 'Gene', '445', (83, 87))	('Ribosomal Protein', 'molecular_function', 'GO:0003735', ('367', '384'))	('mouse', 'Species', '10090', (140, 145))	('Akt', 'Gene', (407, 410))	('antibody', 'molecular_function', 'GO:0003823', ('71', '79'))	('rabbit', 'Species', '9986', (642, 648))	('#9751', 'Var', (483, 488))	('Signaling', 'biological_process', 'GO:0023052', ('575', '584'))	('beta-Actin', 'Gene', (524, 534))	('antibody', 'cellular_component', 'GO:0042571', ('71', '79'))	('beta-Actin', 'Gene', '728378', (524, 534))	('rabbit', 'Species', '9986', (261, 267))	('Akt', 'Gene', '207', (407, 410))	('H3', 'Chemical', 'MESH:C012616', (499, 501))	('DEPTOR', 'Gene', '64798', (450, 456))	('rabbit', 'Species', '9986', (53, 59))	('#4620', 'Var', (503, 508))	('H3', 'Chemical', 'MESH:C012616', (188, 190))	('#330', 'Var', (627, 631))	('DEPDC6', 'Gene', (457, 463))	('#11816', 'Var', (465, 471))	('H3', 'Chemical', 'MESH:C012616', (474, 476))	('DEPDC6', 'Gene', '64798', (457, 463))
5443	28358054	Proteins were analyzed by SDS gel electrophoresis and immunoblotting following standard protocols using the anti-ASS1 antibody (1:200 dilution), anti-p70 S6 Kinase antibody (1:1000 dilution), anti-Phospho-p70 S6 Kinase (Thr389) antibody (1:1000 dilution), anti-DEPTOR/DEPDC6 antibody (1:1000 dilution), anti-Akt antibody (1:1000 dilution), anti-Phospho-Akt (Ser473) antibody (1:2000 dilution), anti-H3K27me3 antibody (1:1000 dilution), anti-Histone H3 antibody (1:1000 dilution), and anti-beta-Actin antibody (HRP-conjugated) (1:1000 dilution).	('antibody', 'cellular_component', 'GO:0042571', ('452', '460'))	('antibody', 'cellular_component', 'GO:0019814', ('408', '416'))	('antibody', 'cellular_component', 'GO:0042571', ('312', '320'))	('DEPDC6', 'Gene', '64798', (268, 274))	('antibody', 'cellular_component', 'GO:0019814', ('366', '374'))	('antibody', 'molecular_function', 'GO:0003823', ('228', '236'))	('H3', 'Chemical', 'MESH:C012616', (449, 451))	('antibody', 'molecular_function', 'GO:0003823', ('164', '172'))	('Akt', 'Gene', (308, 311))	('antibody', 'cellular_component', 'GO:0019814', ('118', '126'))	('antibody', 'cellular_component', 'GO:0042571', ('228', '236'))	('antibody', 'molecular_function', 'GO:0003823', ('118', '126'))	('anti-H3K27me3', 'Var', (394, 407))	('antibody', 'cellular_component', 'GO:0042571', ('164', '172'))	('antibody', 'molecular_function', 'GO:0003823', ('275', '283'))	('H3', 'Chemical', 'MESH:C012616', (399, 401))	('antibody', 'cellular_component', 'GO:0019814', ('500', '508'))	('antibody', 'cellular_component', 'GO:0042571', ('118', '126'))	('Akt', 'Gene', '207', (308, 311))	('antibody', 'molecular_function', 'GO:0003823', ('408', '416'))	('antibody', 'cellular_component', 'GO:0042571', ('275', '283'))	('antibody', 'molecular_function', 'GO:0003823', ('366', '374'))	('antibody', 'cellular_component', 'GO:0019815', ('312', '320'))	('antibody', 'cellular_component', 'GO:0019815', ('452', '460'))	('antibody', 'cellular_component', 'GO:0042571', ('408', '416'))	('Akt', 'Gene', (353, 356))	('antibody', 'cellular_component', 'GO:0042571', ('366', '374'))	('antibody', 'cellular_component', 'GO:0019815', ('164', '172'))	('antibody', 'molecular_function', 'GO:0003823', ('500', '508'))	('antibody', 'cellular_component', 'GO:0019815', ('228', '236'))	('Akt', 'Gene', '207', (353, 356))	('DEPTOR', 'Gene', '64798', (261, 267))	('ASS1', 'Gene', (113, 117))	('ASS1', 'Gene', '445', (113, 117))	('antibody', 'cellular_component', 'GO:0042571', ('500', '508'))	('antibody', 'cellular_component', 'GO:0019815', ('118', '126'))	('antibody', 'cellular_component', 'GO:0019814', ('312', '320'))	('antibody', 'cellular_component', 'GO:0019814', ('452', '460'))	('antibody', 'cellular_component', 'GO:0019815', ('275', '283'))	('antibody', 'cellular_component', 'GO:0019815', ('408', '416'))	('antibody', 'cellular_component', 'GO:0019815', ('366', '374'))	('antibody', 'cellular_component', 'GO:0019814', ('164', '172'))	('beta-Actin', 'Gene', (489, 499))	('beta-Actin', 'Gene', '728378', (489, 499))	('antibody', 'cellular_component', 'GO:0019814', ('228', '236'))	('antibody', 'cellular_component', 'GO:0019815', ('500', '508'))	('antibody', 'molecular_function', 'GO:0003823', ('452', '460'))	('DEPTOR', 'Gene', (261, 267))	('Ser', 'cellular_component', 'GO:0005790', ('358', '361'))	('DEPDC6', 'Gene', (268, 274))	('antibody', 'cellular_component', 'GO:0019814', ('275', '283'))	('antibody', 'molecular_function', 'GO:0003823', ('312', '320'))
5446	28358054	Two dye-swapped experiments were performed by hybridizing two cRNAs labeled with either Cy-3 or Cy-5 onto a Whole Human Genome Oligo Microarray ver.	('Cy-3', 'Var', (88, 92))	('Cy-5', 'Chemical', 'MESH:C085321', (96, 100))	('Cy-5', 'Var', (96, 100))	('Human', 'Species', '9606', (114, 119))	('Cy-3', 'Chemical', '-', (88, 92))
5450	28358054	Human DEPTOR Taqman probe and primers (Applied Biosystems, Hs00961900_m1) and human ACTB Taqman probe and primers (Applied Biosystems, Hs01060665_g1) were used.	('Human', 'Species', '9606', (0, 5))	('DEPTOR', 'Gene', '64798', (6, 12))	('ACTB', 'Gene', (84, 88))	('ACTB', 'Gene', '60', (84, 88))	('human', 'Species', '9606', (78, 83))	('DEPTOR', 'Gene', (6, 12))	('Hs01060665_g1', 'Var', (135, 148))
5451	28358054	The ASS1 gene in HEC1B and AN3CA was disrupted using the CRISPR/Cas9 system.	('Cas', 'cellular_component', 'GO:0005650', ('64', '67'))	('disrupted', 'Var', (37, 46))	('HEC1B', 'Gene', (17, 22))	('HEC1B', 'CellLine', 'CVCL:0294', (17, 22))	('ASS1', 'Gene', (4, 8))	('ASS1', 'Gene', '445', (4, 8))
5456	28358054	The CRISPR targeting sequences used in this study were as follows: Human ASS1: exon 3: 5'-CACCGACACCTCGTGCATCCTCGTG-3' exon 5 #1: 5'-CACCGTATGAGGACCGCTACCTCCT-3' exon 5 #2: 5'-CACCGCTGCATCGCCCGCAAACAAG-3' The following primers were used to screen for the disrupted alleles: Human ASS1: exon 3: (Forward) 5'-TTTGGCGCGCCTGTCTCAGGGTCACTCAGGT-3' (Reverse) 5'-TTTGCGGCCGCTGGGAAGACTGTGTGCCTTC-3' exon 5: (Forward) 5'-TTTGGCGCGCCCCCCTGTCCTTGCCTACTTC-3' (Reverse) 5'-TTTGCGGCCGCCTCAGAATGGGCGTTCAGGT-3' Similarly, we transfected the pX330-U6-Chimeric_BBCBh-hSpCas9 empty vector into HEC-1B and AN3CA cells with a linear puromycin marker and constructed a stable cell line, which was used as a control (EV).	('ASS1', 'Gene', '445', (73, 77))	('pX330-U6-Chimeric_BBCBh-hSpCas9', 'Var', (524, 555))	('Human', 'Species', '9606', (274, 279))	('ASS1', 'Gene', (280, 284))	('HEC-1', 'CellLine', 'CVCL:1274', (574, 579))	('puromycin', 'Chemical', 'MESH:D011691', (611, 620))	('ASS1', 'Gene', '445', (280, 284))	('EV', 'Chemical', '-', (693, 695))	('Human', 'Species', '9606', (67, 72))	('ASS1', 'Gene', (73, 77))
5637	30675285	Two patients carried germline pathogenic mutation in cancer-predisposing genes BRCA1 or BARD1.	('BARD1', 'Gene', '580', (88, 93))	('BRCA1', 'Gene', '672', (79, 84))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('BRCA1', 'Gene', (79, 84))	('BARD1', 'Gene', (88, 93))	('mutation', 'Var', (41, 49))	('pathogenic', 'Reg', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('patients', 'Species', '9606', (4, 12))
5658	30675285	Nonsynonymous variants in exons and adjacent intronic regions with frequency >=10% in at least one tumor were evaluated and manually controlled using an IGV viewer (Broad Institute).	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Nonsynonymous variants', 'Var', (0, 22))
5661	30675285	False calls of detected mutation in PIK3CA evaluated by NextGENe: p.(R524K), p.(Y644H), p.(E707K) were filtered out.	('p.(Y644H)', 'Mutation', 'rs17849072', (77, 86))	('p.(Y644H', 'Var', (77, 85))	('PIK3CA', 'Gene', '5290', (36, 42))	('p.(R524K', 'Var', (66, 74))	('p.(R524K)', 'Mutation', 'rs104885999', (66, 75))	('p.(E707K)', 'Mutation', 'rs3729687', (88, 97))	('p.(E707K', 'Var', (88, 96))	('PIK3CA', 'Gene', (36, 42))
5664	30675285	Germline variants possibly associated with cancer predisposing syndromes were selected according to the following rules: i) VAF >40% in both tumors; ii) variants are not described as SNPs; and iii) clinical significance of the variant was assessed to be pathogenic and/or of uncertain significance according to the ClinVar database.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Disease', (43, 49))	('associated', 'Reg', (27, 37))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('VAF', 'Chemical', '-', (124, 127))	('variant', 'Var', (227, 234))
5665	30675285	These variants were confirmed as germline mutations by Sanger sequencing of DNA isolated from non-tumor tissue.	('variants', 'Var', (6, 14))	('non-tumor', 'Disease', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('non-tumor', 'Disease', 'MESH:D009369', (94, 103))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))
5668	30675285	Microsatellite stable (MSS) tumors showed no instability.	('Microsatellite', 'Var', (0, 14))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('MSS', 'Chemical', '-', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
5684	30675285	Two SEOs (9%, 2/22) carried mutations in ARID1A, AKT1 and PIK3CA while PTEN was a wild-type.	('AKT1', 'Gene', '207', (49, 53))	('ARID1A', 'Gene', '8289', (41, 47))	('PIK3CA', 'Gene', (58, 64))	('ARID1A', 'Gene', (41, 47))	('AKT1', 'Gene', (49, 53))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('PIK3CA', 'Gene', '5290', (58, 64))	('SEOs', 'Chemical', '-', (4, 8))	('mutations', 'Var', (28, 37))
5685	30675285	Another two cases carried only AKT1 mutation, which is a known pathogenic hot-spot p.(E17K) variant.	('carried', 'Reg', (18, 25))	('AKT1', 'Gene', '207', (31, 35))	('AKT1', 'Gene', (31, 35))	('p.(E17K)', 'SUBSTITUTION', 'None', (83, 91))	('p.(E17K', 'Var', (83, 90))	('mutation', 'Var', (36, 44))
5686	30675285	Interestingly, one microsatellite instable SEO (CS15, both tumors of grade 2) shared pathogenic somatic mutation in HNF1B NM_000458.2: c.1561_1562insC, p.(Q521Pfs*30), both tumors carried mutations in MLH3, MLH1 and also further mutations in PTEN NM_000314.4: c.955_958del, p.(T319X), ARID1A NM_006015.4: c.5981delT, p.(V1994Gfs*21) and c.3667C>T, p.(R1223C), KRAS NM_004985.3: c.35G>A, p.(G12D) and TP53 NM_001126112.2: c.960_961del, p.(K321Tfs*15).	('c.35G>A', 'Var', (378, 385))	('p.(Q521Pfs*30)', 'Mutation', 'rs764042837', (152, 166))	('p.(G12D)', 'Mutation', 'rs121913529', (387, 395))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('c.960_961del', 'Var', (421, 433))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('c.1561_1562insC', 'Var', (135, 150))	('KRAS', 'Gene', '3845', (360, 364))	('c.1561_1562insC', 'INSERTION', 'None', (135, 150))	('c.5981delT', 'DELETION', 'None', (305, 315))	('c.5981delT', 'Var', (305, 315))	('PTEN', 'Gene', (242, 246))	('p.(V1994Gfs*21)', 'Mutation', 'p.V1994GfsX21', (317, 332))	('p.(T319X)', 'Mutation', 'p.T319X', (274, 283))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('TP53', 'Gene', (400, 404))	('tumors', 'Disease', (173, 179))	('c.3667C>T', 'Mutation', 'rs1227227387', (337, 346))	('KRAS', 'Gene', (360, 364))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('c.3667C>T', 'Var', (337, 346))	('p.(R1223C)', 'Mutation', 'rs1227227387', (348, 358))	('c.955_958del', 'Var', (260, 272))	('c.955_958del', 'DELETION', 'None', (260, 272))	('PTEN', 'Gene', '5728', (242, 246))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('HNF1B', 'Gene', '6928', (116, 121))	('ARID1A', 'Gene', (285, 291))	('HNF1B', 'Gene', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('mutations', 'Var', (188, 197))	('p.(K321Tfs*15)', 'Mutation', 'p.K321TfsX15', (435, 449))	('c.35G>A', 'SUBSTITUTION', 'None', (378, 385))	('CS', 'Chemical', 'MESH:D002586', (48, 50))	('SEO', 'Chemical', '-', (43, 46))	('MLH1', 'Gene', (207, 211))	('carried', 'Reg', (180, 187))	('TP53', 'Gene', '7157', (400, 404))	('tumors', 'Disease', (59, 65))	('ARID1A', 'Gene', '8289', (285, 291))	('c.960_961del', 'DELETION', 'None', (421, 433))	('MLH3', 'Gene', '27030', (201, 205))	('MLH3', 'Gene', (201, 205))	('MLH1', 'Gene', '4292', (207, 211))
5689	30675285	Moreover, in one patient (54-year-old patient-CS22) a germline PTEN mutation NM_000314.4: c.389G>A, rs121909229, p.(R130Q) was detected.	('PTEN', 'Gene', '5728', (63, 67))	('rs121909229', 'Mutation', 'rs121909229', (100, 111))	('CS', 'Chemical', 'MESH:D002586', (46, 48))	('patient', 'Species', '9606', (17, 24))	('patient', 'Species', '9606', (38, 45))	('rs121909229', 'Var', (100, 111))	('p.(R130Q)', 'Mutation', 'rs121909229', (113, 122))	('c.389G>A', 'SUBSTITUTION', 'None', (90, 98))	('p.(R130Q', 'Var', (113, 121))	('c.389G>A', 'Var', (90, 98))	('PTEN', 'Gene', (63, 67))
5690	30675285	Germline pathogenic PTEN mutations are usually associated with Cowden syndrome (PTEN hamartoma tumor syndrome).	('mutations', 'Var', (25, 34))	('hamartoma', 'Phenotype', 'HP:0010566', (85, 94))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('PTEN hamartoma tumor syndrome', 'Disease', 'MESH:D006223', (80, 109))	('Cowden syndrome', 'Disease', 'MESH:D006223', (63, 78))	('PTEN hamartoma tumor syndrome', 'Disease', (80, 109))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Cowden syndrome', 'Disease', (63, 78))	('associated', 'Reg', (47, 57))	('PTEN', 'Gene', (20, 24))	('PTEN', 'Gene', '5728', (20, 24))
5693	30675285	Fragment analysis showed microsatellite instable phenotype in 22.7% (5/22) of cases, including the above-mentioned case which was microsatellite instable only in the endometrial tumor.	('endometrial tumor', 'Disease', (166, 183))	('microsatellite', 'Var', (25, 39))	('endometrial tumor', 'Disease', 'MESH:D016889', (166, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
5696	30675285	The tumors of a 29-year-old patient (CS01) shared pathogenic nonsense germline mutation in BARD1 NM_000465.2: c.1690C>T, rs587780021, p.(Q564X) together with shared somatic PTEN mutation.	('c.1690C>T', 'Var', (110, 119))	('p.(Q564X)', 'Mutation', 'rs587780021', (134, 143))	('rs587780021', 'Mutation', 'rs587780021', (121, 132))	('BARD1', 'Gene', '580', (91, 96))	('CS', 'Chemical', 'MESH:D002586', (37, 39))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('PTEN', 'Gene', (173, 177))	('BARD1', 'Gene', (91, 96))	('rs587780021', 'Var', (121, 132))	('patient', 'Species', '9606', (28, 35))	('PTEN', 'Gene', '5728', (173, 177))	('p.(Q564X', 'Var', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('c.1690C>T', 'SUBSTITUTION', 'None', (110, 119))
5697	30675285	Another (32-year old patient-CS16) shared pathogenic frameshift germline mutation in BRCA1 NM_007294.3: c.5266_5267insC, rs80357906, p.(Q1756Pfs*73) together with somatic TP53 mutation.	('p.(Q1756Pfs*73', 'Var', (133, 147))	('TP53', 'Gene', (171, 175))	('CS', 'Chemical', 'MESH:D002586', (29, 31))	('BRCA1', 'Gene', (85, 90))	('patient', 'Species', '9606', (21, 28))	('p.(Q1756Pfs*73)', 'Mutation', 'rs80357906', (133, 148))	('TP53', 'Gene', '7157', (171, 175))	('c.5266_5267insC', 'Var', (104, 119))	('rs80357906', 'Mutation', 'rs80357906', (121, 131))	('rs80357906', 'Var', (121, 131))	('BRCA1', 'Gene', '672', (85, 90))	('c.5266_5267insC', 'INSERTION', 'None', (104, 119))
5700	30675285	The SEO shared common mutation in PTEN and KRAS, which was absent in CCCO, while the MSH6 mutation NM_000179.2: c.2873_2874del, p.(Q958Pfs*7) was detected only in CCCO.	('p.(Q958Pfs*7)', 'Mutation', 'p.Q958PfsX7', (128, 141))	('MSH6', 'Gene', '2956', (85, 89))	('SEO', 'Chemical', '-', (4, 7))	('c.2873_2874del', 'Var', (112, 126))	('c.2873_2874del', 'DELETION', 'None', (112, 126))	('KRAS', 'Gene', (43, 47))	('MSH6', 'Gene', (85, 89))	('PTEN', 'Gene', (34, 38))	('KRAS', 'Gene', '3845', (43, 47))	('PTEN', 'Gene', '5728', (34, 38))
5707	30675285	One such study assessed the expression of cytokeratins, vimentin, CEA, Ca125 and Ca19.9.	('cytokeratins', 'Protein', (42, 54))	('CEA', 'Gene', '5670', (66, 69))	('vimentin', 'Gene', '7431', (56, 64))	('expression', 'MPA', (28, 38))	('vimentin', 'Gene', (56, 64))	('Ca19.9', 'CellLine', 'CVCL:X558', (81, 87))	('vimentin', 'cellular_component', 'GO:0045098', ('56', '64'))	('Ca19.9', 'Var', (81, 87))	('vimentin', 'cellular_component', 'GO:0045099', ('56', '64'))	('Ca125', 'Gene', (71, 76))	('CEA', 'Gene', (66, 69))
5709	30675285	In another study, the authors used different antibodies including ER, PR, HER2, p53, and Ki-67.	('Ki-67', 'Var', (89, 94))	('p53', 'Gene', (80, 83))	('HER2', 'Gene', (74, 78))	('HER2', 'Gene', '2064', (74, 78))	('p53', 'Gene', '7157', (80, 83))
5716	30675285	Molecular studies used variable approaches, including the assessing of microsatellite instability (MSI), the pattern of X chromosome inactivation, loss of heterozygosity (LOH), and mutation of single or small group of genes, especially PTEN and CTNNB1.	('CTNNB1', 'Gene', (245, 251))	('X chromosome', 'cellular_component', 'GO:0000805', ('120', '132'))	('X chromosome inactivation', 'biological_process', 'GO:0009048', ('120', '145'))	('mutation', 'Var', (181, 189))	('PTEN', 'Gene', (236, 240))	('CTNNB1', 'Gene', '1499', (245, 251))	('microsatellite instability', 'MPA', (71, 97))	('PTEN', 'Gene', '5728', (236, 240))	('loss', 'NegReg', (147, 151))	('inactivation', 'NegReg', (133, 145))
5718	30675285	In view of current knowledge, it is clear that the intratumoral and intermetastatic heterogeneity is relatively common and can be influenced by several factors such as tumor type, presence of driver mutations, mutation load, and also by immune host reaction with clonal selection.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (56, 61))	('influenced', 'Reg', (130, 140))	('mutation load', 'Var', (210, 223))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
5725	30675285	The only exception was a SEO in patient with Lynch syndrome with germline MSH6 mutation in which the somatic mutations were different.	('Lynch syndrome', 'Disease', (45, 59))	('SEO', 'Chemical', '-', (25, 28))	('Lynch syndrome', 'Disease', 'MESH:D003123', (45, 59))	('MSH6', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))	('patient', 'Species', '9606', (32, 39))	('MSH6', 'Gene', '2956', (74, 78))
5728	30675285	The results of all these 3 molecular studies were very similar and are in concordance with the results of our study, the most important findings being: i) almost all SEOs are of clonal origin and even low stage and low-grade tumors seem to represent dissemination from one site to the other (however, without a possibility to conclusively assess the directionality); ii) all sporadic SEOs shared nonsynonymous mutations in at least one cancer driver gene of EEC and/or EOC.	('SEOs', 'Chemical', '-', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('EEC', 'Gene', '1913', (458, 461))	('SEOs', 'Chemical', '-', (384, 388))	('nonsynonymous mutations', 'Var', (396, 419))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('EOC', 'Gene', (469, 472))	('cancer', 'Disease', 'MESH:D009369', (436, 442))	('shared', 'Reg', (389, 395))	('tumors', 'Disease', (225, 231))	('cancer', 'Disease', (436, 442))	('EEC', 'Gene', (458, 461))
5735	30675285	In their case the authors detected 253 shared mutations (including ARID1A, PIK3CA, MSH6 and intronic mutation in PTEN), but more mutations were found only in EEC or EOC.	('MSH6', 'Gene', (83, 87))	('PIK3CA', 'Gene', (75, 81))	('intronic mutation', 'Var', (92, 109))	('PIK3CA', 'Gene', '5290', (75, 81))	('EEC', 'Gene', (158, 161))	('PTEN', 'Gene', (113, 117))	('MSH6', 'Gene', '2956', (83, 87))	('PTEN', 'Gene', '5728', (113, 117))	('ARID1A', 'Gene', '8289', (67, 73))	('EEC', 'Gene', '1913', (158, 161))	('ARID1A', 'Gene', (67, 73))
5736	30675285	Despite the findings of shared mutations, they proposed that these tumors were clonally unrelated and classified them as synchronous independent tumors.	('mutations', 'Var', (31, 40))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('synchronous independent tumors', 'Disease', 'MESH:D009378', (121, 151))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('synchronous independent tumors', 'Disease', (121, 151))	('tumors', 'Disease', (67, 73))
5739	30675285	Germline BARD1 mutation p.(Q564X) has been previously described in families with members affected by breast, colon and uterine cancer.	('colon', 'Disease', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BARD1', 'Gene', (9, 14))	('described', 'Reg', (54, 63))	('p.(Q564X)', 'Mutation', 'rs587780021', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('colon', 'Disease', 'MESH:D015179', (109, 114))	('uterine cancer', 'Phenotype', 'HP:0010784', (119, 133))	('cancer', 'Disease', (127, 133))	('breast', 'Disease', (101, 107))	('p.(Q564X', 'Var', (24, 32))	('BARD1', 'Gene', '580', (9, 14))
5740	30675285	Germline BRCA1 mutation p.(Q1756Pfs*73) is a known founder mutation in the Ashkenazi Jewish population and in several European countries including the Czech Republic.	('BRCA1', 'Gene', (9, 14))	('p.(Q1756Pfs*73)', 'Mutation', 'rs80357906', (24, 39))	('BRCA1', 'Gene', '672', (9, 14))	('p.(Q1756Pfs*73', 'Var', (24, 38))
5742	30675285	Pathogenic somatic HNF1B mutation NM_000458.2: c.1561_1562insC, p.(Q521Pfs*30) shared in the SEO of one patient (CS15) represents the insertion of one nucleotide (cysteine affecting codon 521 located in exon 8 polyC (C)7 sequence) resulting in frameshift and protein truncation.	('c.1561_1562insC', 'Var', (47, 62))	('protein', 'cellular_component', 'GO:0003675', ('259', '266'))	('frameshift', 'MPA', (244, 254))	('HNF1B', 'Gene', '6928', (19, 24))	('protein truncation', 'MPA', (259, 277))	('mutation', 'Var', (25, 33))	('c.1561_1562insC', 'INSERTION', 'None', (47, 62))	('cysteine', 'Chemical', 'MESH:D003545', (163, 171))	('CS', 'Chemical', 'MESH:D002586', (113, 115))	('SEO', 'Chemical', '-', (93, 96))	('HNF1B', 'Gene', (19, 24))	('patient', 'Species', '9606', (104, 111))	('p.(Q521Pfs*30)', 'Mutation', 'rs764042837', (64, 78))
5744	30675285	The tumors carried further pathogenic or likely pathogenic somatic mutations in PTEN, ARID1A, KRAS, and TP53.	('TP53', 'Gene', '7157', (104, 108))	('PTEN', 'Gene', (80, 84))	('TP53', 'Gene', (104, 108))	('KRAS', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (80, 84))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('ARID1A', 'Gene', '8289', (86, 92))	('mutations', 'Var', (67, 76))	('ARID1A', 'Gene', (86, 92))	('KRAS', 'Gene', '3845', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('pathogenic', 'Reg', (27, 37))
5745	30675285	Nevertheless, the HNF1B p.(Q521Pfs*30) mutation has been previously described in two stomach adenocarcinomas and in four renal clear cell carcinomas according to the TCGA atlas (study Kidney Renal Clear Cell Carcinoma).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('HNF1B', 'Gene', (18, 23))	('HNF1B', 'Gene', '6928', (18, 23))	('renal clear cell carcinomas', 'Disease', 'MESH:C538614', (121, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('Kidney Renal Clear Cell Carcinoma', 'Disease', (184, 217))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('p.(Q521Pfs*30', 'Var', (24, 37))	('stomach adenocarcinomas', 'Disease', (85, 108))	('Carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('p.(Q521Pfs*30)', 'Mutation', 'rs764042837', (24, 38))	('described', 'Reg', (68, 77))	('renal clear cell carcinomas', 'Disease', (121, 148))	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (184, 217))
5746	30675285	All those tumors carried also at least one of the mutations in ARID1A, TP53 (frameshift variant), PTEN and/or KRAS, which suggests a similar mutation profile in different types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutations', 'Var', (50, 59))	('KRAS', 'Gene', '3845', (110, 114))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('ARID1A', 'Gene', '8289', (63, 69))	('ARID1A', 'Gene', (63, 69))	('PTEN', 'Gene', '5728', (98, 102))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('PTEN', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('carried', 'Reg', (17, 24))	('KRAS', 'Gene', (110, 114))
5747	30675285	The incidence and significance of HNF1B mutations in EEC is unknown.	('HNF1B', 'Gene', (34, 39))	('EEC', 'Gene', (53, 56))	('mutations', 'Var', (40, 49))	('HNF1B', 'Gene', '6928', (34, 39))	('EEC', 'Gene', '1913', (53, 56))
5748	30675285	However, in our previous study we detected another pathogenic truncation mutation of this gene c.454C>T, p.(Q152X) in 1/30 EEC.	('p.(Q152X', 'Var', (105, 113))	('pathogenic', 'Reg', (51, 61))	('c.454C>T', 'Var', (95, 103))	('EEC', 'Gene', (123, 126))	('p.(Q152X)', 'Mutation', 'p.Q152X', (105, 114))	('c.454C>T', 'Mutation', 'c.454C>T', (95, 103))	('EEC', 'Gene', '1913', (123, 126))
5759	30675285	CBDCA carboplatin CCCO clear cell carcinoma of ovary CNV copy number variation CS case specification EEC endometrioid endometrial carcinoma EOC endometrioid ovarian carcinoma FFPE formalin-fixed paraffin-embedded LOH loss of heterozygosity MSI microsatellite instability MSS microsatellite stable MSI-H microsatellite instability-high NGS next generation sequencing PCR polymerase chain reaction PTX paclitaxel SEO synchronous endometrial and ovarian carcinomas SNP single nucleotide polymorphisms VAF variant allele fraction	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (118, 139))	('paraffin', 'Chemical', 'MESH:D010232', (195, 203))	('variant', 'Var', (502, 509))	('carcinoma', 'Phenotype', 'HP:0030731', (451, 460))	('SEO', 'Chemical', '-', (411, 414))	('synchronous endometrial and ovarian carcinomas', 'Disease', 'MESH:D009378', (415, 461))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (118, 139))	('paclitaxel', 'Chemical', 'MESH:D017239', (400, 410))	('VAF', 'Chemical', '-', (498, 501))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('PTX', 'Chemical', 'MESH:D017239', (396, 399))	('MSI-H', 'Disease', (297, 302))	('carcinoma of ovary', 'Disease', (34, 52))	('endometrioid ovarian carcinoma', 'Disease', (144, 174))	('EEC', 'Gene', '1913', (101, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (451, 461))	('carcinoma of ovary', 'Disease', 'MESH:D010051', (34, 52))	('formalin', 'Chemical', 'MESH:D005557', (180, 188))	('EEC', 'Gene', (101, 104))	('CBDCA', 'Chemical', 'MESH:D016190', (0, 5))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (443, 461))	('endometrioid ovarian carcinoma', 'Disease', 'MESH:D016889', (144, 174))	('carboplatin', 'Chemical', 'MESH:D016190', (6, 17))	('MSI-H', 'Disease', 'MESH:D000848', (297, 302))	('VAF', 'Gene', (498, 501))	('MSS', 'Chemical', '-', (271, 274))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (157, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (443, 460))	('endometrial carcinoma', 'Disease', (118, 139))	('CS', 'Chemical', 'MESH:D002586', (79, 81))
5774	25511212	in situ and infiltrating ductal breast carcinoma, colorectal carcinoma, bladder carcinoma, head and neck, lung and prostate cancers by rearrangement, amplification and mutation of the genes.	('prostate cancers', 'Phenotype', 'HP:0012125', (115, 131))	('ductal breast carcinoma', 'Disease', (25, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('lung and prostate cancers', 'Disease', 'MESH:D011471', (106, 131))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (72, 89))	('bladder carcinoma', 'Disease', 'MESH:D001749', (72, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('colorectal carcinoma', 'Disease', (50, 70))	('breast carcinoma', 'Phenotype', 'HP:0003002', (32, 48))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (50, 70))	('bladder carcinoma', 'Disease', (72, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('neck', 'cellular_component', 'GO:0044326', ('100', '104'))	('rearrangement', 'Var', (135, 148))	('mutation', 'Var', (168, 176))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('amplification', 'Var', (150, 163))	('ductal breast carcinoma', 'Disease', 'MESH:D018270', (25, 48))
5776	25511212	reported that about 40% of ECs overexpress Cyclin D1 and proposed that Cyclin D1 deregulation may have a role in endometrial carcinogenesis.	('Cyclin D1', 'Gene', '595', (71, 80))	('Cyclin D1', 'Gene', '595', (43, 52))	('EC', 'Phenotype', 'HP:0012114', (27, 29))	('overexpress', 'PosReg', (31, 42))	('Cyclin D1', 'Gene', (43, 52))	('Cyclin D1', 'Gene', (71, 80))	('Cyclin', 'molecular_function', 'GO:0016538', ('43', '49'))	('Cyclin', 'molecular_function', 'GO:0016538', ('71', '77'))	('ECs', 'Chemical', 'MESH:C001390', (27, 30))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (113, 139))	('endometrial carcinogenesis', 'Disease', (113, 139))	('deregulation', 'Var', (81, 93))
5812	25511212	Other mechanisms of endometrial carcinogenesis include mutations in p53 and PTEN tumor suppressor genes.	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (20, 46))	('endometrial carcinogenesis', 'Disease', (20, 46))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('mutations', 'Var', (55, 64))	('PTEN', 'Gene', (76, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('PTEN', 'Gene', '5728', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
5836	25511212	(2002) reported Ki-67 positivity in all types of mitotically active endometria: Proliferative, hyperplastic, and all forms of carcinomas.	('Ki', 'Chemical', 'MESH:C066186', (16, 18))	('Proliferative', 'Disease', (80, 93))	('hyperplastic', 'Disease', (95, 107))	('mitotically active endometria: Proliferative', 'Disease', (49, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('Ki-67', 'Gene', (16, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('positivity', 'Var', (22, 32))	('carcinomas', 'Disease', (126, 136))	('carcinomas', 'Disease', 'MESH:D002277', (126, 136))
5888	26459408	An X-chromosome clonality assay showed monoclonality of both components in a case of mixed LCNEC and mucinous carcinoma.	('X-chromosome', 'cellular_component', 'GO:0000805', ('3', '15'))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('mucinous carcinoma', 'Disease', (101, 119))	('LCNEC', 'Phenotype', 'HP:0030360', (91, 96))	('NEC', 'Phenotype', 'HP:0100634', (93, 96))	('monoclonality', 'Var', (39, 52))	('mixed LCNEC', 'Disease', (85, 96))	('LCNEC', 'Chemical', '-', (91, 96))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (101, 119))
6000	26459408	A case of LCNEC associated with serous carcinoma revealed a different pattern of microsatellite instability in both components.	('serous carcinoma', 'Disease', (32, 48))	('LCNEC', 'Chemical', '-', (10, 15))	('LCNEC', 'Disease', (10, 15))	('serous carcinoma', 'Disease', 'MESH:D018284', (32, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('microsatellite', 'Var', (81, 95))	('LCNEC', 'Phenotype', 'HP:0030360', (10, 15))	('NEC', 'Phenotype', 'HP:0100634', (12, 15))
6014	26459408	Recently, somatic and germline SMARCA4 mutations accompanied by the loss of BRG1 protein expression in immunohistochemistry have been described in SCCOHTs.	('BRG1', 'Gene', (76, 80))	('expression', 'MPA', (89, 99))	('BRG1', 'Gene', '6597', (76, 80))	('SMARCA4', 'Gene', (31, 38))	('SMARCA4', 'Gene', '6597', (31, 38))	('mutations', 'Var', (39, 48))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('loss', 'NegReg', (68, 72))	('SCCOHTs', 'Disease', (147, 154))	('protein', 'Protein', (81, 88))
6029	26459408	Currently, SCCOHT is considered to be an ovarian malignant rhabdoid tumor, as inactivation of SMARCA4 accompanied by the loss of BRG1 protein and the retention of INI- 1 in immunohistochemistry has been described in this aggressive tumor.	('ovarian malignant rhabdoid tumor', 'Disease', (41, 73))	('inactivation', 'Var', (78, 90))	('ovarian malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (41, 73))	('BRG1', 'Gene', (129, 133))	('loss', 'NegReg', (121, 125))	('SCCOHT', 'Disease', (11, 17))	('INI- 1', 'Gene', (163, 169))	('SMARCA4', 'Gene', (94, 101))	('SMARCA4', 'Gene', '6597', (94, 101))	('aggressive tumor', 'Disease', 'MESH:D001523', (221, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('retention', 'biological_process', 'GO:0051235', ('150', '159'))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('BRG1', 'Gene', '6597', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('INI- 1', 'Gene', '6598', (163, 169))	('aggressive tumor', 'Disease', (221, 237))
6043	26606135	Additionally, there is growing evidence suggesting that long non-coding RNA (lncRNA) and DNA methylation can mediate oncogenic or tumor suppressive outcomes, representing new classes of promising biomarkers.	('oncogenic', 'CPA', (117, 126))	('ncRNA', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('DNA methylation', 'biological_process', 'GO:0006306', ('89', '104'))	('ncRNA', 'Gene', '54719', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('long non-coding RNA', 'Var', (56, 75))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('tumor', 'Disease', (130, 135))	('methylation', 'Var', (93, 104))
6084	26606135	DNA methylation was the second best predictor of BRCA (test set accuracy: 0.76, N test set = 73), COAD (test set accuracy: 0.79, N test set = 67), LUSC (test set accuracy: 0.77, N test set = 42), ovarian cancer (test set accuracy: 0.7, N test set = 146), and the third best predictors in UCEC (test set accuracy: 0.8, N test set = 81).	('BRCA', 'Gene', '672', (49, 53))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('UCEC', 'Disease', (288, 292))	('BRCA', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('methylation', 'Var', (4, 15))	('COAD', 'Disease', 'MESH:D029424', (98, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (196, 210))	('ovarian cancer', 'Disease', (196, 210))	('LUSC', 'Disease', (147, 151))	('COAD', 'Disease', (98, 102))
6090	26606135	As integrative models require samples not only comprised of multi-omic profiles, but also those that fulfill the prognostic criteria, we observed a final of 20 integrated multi-omic data groups in the five cancer types, including 15 double-combination groups and 5 triple-combination groups (see Table C in S1 File).	('cancer', 'Disease', (206, 212))	('double-combination', 'Var', (233, 251))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
6114	26606135	As is well known, cancer prognosis is likely caused by a series of factors, for example, clinical variables, genetic mutations, and aberrant gene expression.	('caused', 'Reg', (45, 51))	('genetic mutations', 'Var', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('aberrant gene expression', 'Var', (132, 156))	('gene expression', 'biological_process', 'GO:0010467', ('141', '156'))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
6118	24338723	Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynecologic malignancies Up-regulated expression of telomerase reverse transcriptase (TERT) and subsequent maintenance of telomere length are essential in tumor development.	('telomere', 'cellular_component', 'GO:0005696', ('262', '270'))	('expression', 'MPA', (178, 188))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('Up-regulated', 'PosReg', (165, 177))	('transcriptase', 'molecular_function', 'GO:0003968', ('211', '224'))	('mutations', 'Var', (17, 26))	('malignancies', 'Disease', (152, 164))	('telomerase reverse transcriptase', 'Gene', (192, 224))	('telomerase reverse transcriptase', 'Gene', '7015', (34, 66))	('transcriptase', 'molecular_function', 'GO:0003899', ('53', '66'))	('transcriptase', 'molecular_function', 'GO:0034062', ('211', '224'))	('TERT', 'Gene', (226, 230))	('TERT', 'Gene', '7015', (226, 230))	('ovarian clear cell carcinoma', 'Disease', (79, 107))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (79, 107))	('tumor', 'Disease', (295, 300))	('telomerase reverse transcriptase', 'Gene', '7015', (192, 224))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('transcriptase', 'molecular_function', 'GO:0003899', ('211', '224'))	('transcriptase', 'molecular_function', 'GO:0003968', ('53', '66'))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('transcriptase', 'molecular_function', 'GO:0034062', ('53', '66'))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('telomerase reverse transcriptase', 'Gene', (34, 66))	('telomere', 'cellular_component', 'GO:0000781', ('262', '270'))
6119	24338723	Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynecologic neoplasms.	('mutations', 'Var', (56, 65))	('transcriptional activation', 'MPA', (125, 151))	('gain-of-function', 'PosReg', (39, 55))	('TERT', 'Gene', '7015', (73, 77))	('neoplasms', 'Phenotype', 'HP:0002664', (250, 259))	('TERT', 'Gene', (73, 77))	('neoplasms', 'Disease', (250, 259))	('neoplasms', 'Disease', 'MESH:D009369', (250, 259))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (155, 159))
6120	24338723	We performed mutational analysis in a total of 525 gynecological cancers, and correlated TERT promoter mutations with clinicopathological features.	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
6121	24338723	With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynecologic malignancies were wild-type.	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (22, 51))	('ovarian clear cell carcinomas', 'Disease', (22, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('malignancies', 'Disease', (139, 151))	('found', 'Reg', (77, 82))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('mutations', 'Var', (62, 71))
6122	24338723	TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('oncogenesis', 'biological_process', 'GO:0007048', ('67', '78'))	('ovarian clear cell carcinoma', 'Disease', (151, 179))	('TERT', 'Gene', (0, 4))	('associated', 'Reg', (135, 145))	('mutation', 'Var', (14, 22))	('TERT', 'Gene', '7015', (0, 4))	('endometriosis', 'Phenotype', 'HP:0030127', (121, 134))	('contiguous endometriosis', 'Disease', 'MESH:D004715', (110, 134))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (151, 179))	('contiguous endometriosis', 'Disease', (110, 134))
6123	24338723	Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences (p = 0.0238).	('Ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (0, 28))	('TERT', 'Gene', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('TERT', 'Gene', '7015', (45, 49))	('Ovarian clear cell carcinoma', 'Disease', (0, 28))	('TERT', 'Gene', (86, 90))	('mutations', 'Var', (59, 68))	('higher', 'PosReg', (79, 85))	('TERT', 'Gene', '7015', (86, 90))
6124	24338723	TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression (p= 4.4x10-9) and PIK3CA mutation (p= 0.0019) in ovarian clear cell carcinomas.	('mutation', 'Var', (119, 127))	('ARID1A', 'Gene', '8289', (68, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('ARID1A', 'Gene', (68, 74))	('PIK3CA', 'Gene', '5290', (112, 118))	('ovarian clear cell carcinomas', 'Disease', (143, 172))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (143, 172))	('TERT', 'Gene', (0, 4))	('loss', 'NegReg', (60, 64))	('TERT', 'Gene', '7015', (0, 4))	('mutation', 'Var', (14, 22))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('expression', 'MPA', (83, 93))	('PIK3CA', 'Gene', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
6126	24338723	The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma.	('ovarian clear cell carcinoma', 'Disease', (256, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('pathogenesis', 'biological_process', 'GO:0009405', ('240', '252'))	('telomere', 'cellular_component', 'GO:0000781', ('189', '197'))	('play', 'Reg', (210, 214))	('ovarian clear cell carcinomas', 'Disease', (87, 116))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (256, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('ovarian cancer', 'Disease', (144, 158))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (87, 116))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('aberrations', 'Var', (174, 185))	('telomere', 'cellular_component', 'GO:0005696', ('189', '197'))	('longer', 'PosReg', (67, 73))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (87, 115))
6129	24338723	This is made possible through a variety of mechanisms, including amplification of the TERT gene, expression of transcriptional activators of TERT, and CpG methylation at the TERT promoter.	('CpG methylation', 'Var', (151, 166))	('TERT', 'Gene', (174, 178))	('TERT', 'Gene', '7015', (174, 178))	('methylation', 'Var', (155, 166))	('gene, expression', 'biological_process', 'GO:0010467', ('91', '107'))	('TERT', 'Gene', (86, 90))	('TERT', 'Gene', '7015', (86, 90))	('TERT', 'Gene', (141, 145))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))	('TERT', 'Gene', '7015', (141, 145))	('expression', 'MPA', (97, 107))	('amplification', 'Var', (65, 78))
6131	24338723	Recently, somatic mutations at the TERT promoter in human cancer have been reported in two independent studies using whole genome sequencing on sporadic melanomas and multipoint linkage analysis in melanoma-prone families.	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('melanomas', 'Disease', 'MESH:D008545', (153, 162))	('melanomas', 'Disease', (153, 162))	('melanoma', 'Disease', (153, 161))	('melanoma', 'Disease', (198, 206))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('human', 'Species', '9606', (52, 57))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('cancer', 'Disease', (58, 64))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))	('reported', 'Reg', (75, 83))	('mutations', 'Var', (18, 27))
6133	24338723	Subsequent studies reported TERT promoter mutations in other malignancies including glioma, urinary bladder carcinoma, tongue squamous cell carcinoma, and hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('urinary bladder carcinoma', 'Disease', (92, 117))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('reported', 'Reg', (19, 27))	('tongue squamous cell carcinoma', 'Disease', (119, 149))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('TERT', 'Gene', (28, 32))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 149))	('TERT', 'Gene', '7015', (28, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('urinary bladder carcinoma', 'Disease', 'MESH:D001749', (92, 117))	('hepatocellular carcinoma', 'Disease', (155, 179))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (119, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('malignancies', 'Disease', 'MESH:D009369', (61, 73))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (100, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('glioma', 'Disease', (84, 90))	('malignancies', 'Disease', (61, 73))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('mutations', 'Var', (42, 51))
6134	24338723	Mutations in these hot-spots were shown to enhance transcriptional activity of the TERT promoter in vitro, and were thought to increase the expression of TERT in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('expression', 'MPA', (140, 150))	('cancer', 'Disease', (162, 168))	('TERT', 'Gene', (154, 158))	('transcriptional activity', 'MPA', (51, 75))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (154, 158))	('TERT', 'Gene', (83, 87))	('increase', 'PosReg', (127, 135))	('TERT', 'Gene', '7015', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('enhance', 'PosReg', (43, 50))
6137	24338723	In this study, we analyzed TERT promoter mutations in a total of 525 gynecological malignancies, and evaluated the clinical significance of TERT promoter mutations in those tumors.	('mutations', 'Var', (41, 50))	('TERT', 'Gene', (140, 144))	('clinical', 'Species', '191496', (115, 123))	('TERT', 'Gene', (27, 31))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('TERT', 'Gene', '7015', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('TERT', 'Gene', '7015', (140, 144))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('malignancies', 'Disease', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
6147	24338723	All detected TERT promoter mutations were confirmed by re-sequencing.	('mutations', 'Var', (27, 36))	('TERT', 'Gene', '7015', (13, 17))	('TERT', 'Gene', (13, 17))
6157	24338723	Telomere indices were compared between ovarian clear cell carcinomas with TERT promoter mutation and those without.	('mutation', 'Var', (88, 96))	('ovarian clear cell carcinomas', 'Disease', (39, 68))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (39, 68))	('TERT', 'Gene', '7015', (74, 78))	('Telomere', 'cellular_component', 'GO:0000781', ('0', '8'))	('Telomere', 'cellular_component', 'GO:0005696', ('0', '8'))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('TERT', 'Gene', (74, 78))
6167	24338723	Two-tailed Fisher's exact test and unpaired t test were performed to determine the association between mutation status at the TERT promoter and clinico-pathological features in ovarian clear cell carcinoma.	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (177, 205))	('TERT', 'Gene', (126, 130))	('TERT', 'Gene', '7015', (126, 130))	('ovarian clear cell carcinoma', 'Disease', (177, 205))	('mutation', 'Var', (103, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))
6171	24338723	For comparison of telomere length between mutant and wild-type ovarian clear cell carcinomas, one-tailed Mann-Whitney U test was used when the telomere index was treated as a continuous variable and Fisher's exact test used when the telomere index was treated as a binary variable.	('mutant', 'Var', (42, 48))	('wild-type ovarian clear cell carcinomas', 'Disease', (53, 92))	('telomere', 'cellular_component', 'GO:0000781', ('143', '151'))	('wild-type ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (53, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('telomere', 'cellular_component', 'GO:0005696', ('233', '241'))	('telomere', 'cellular_component', 'GO:0005696', ('143', '151'))	('type ovarian clear cell carcinoma', 'Phenotype', 'HP:0031522', (58, 91))	('telomere', 'cellular_component', 'GO:0000781', ('233', '241'))	('telomere', 'cellular_component', 'GO:0000781', ('18', '26'))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('telomere', 'cellular_component', 'GO:0005696', ('18', '26'))
6172	24338723	Two-tailed Fisher's exact test was used to determine the association between TERT promoter mutation and loss of ARID1A immunoreactivity, as well as the association between TERT promoter mutation and PIK3CA mutation in ovarian clear cell carcinoma.	('ARID1A', 'Gene', (112, 118))	('loss', 'NegReg', (104, 108))	('ovarian clear cell carcinoma', 'Disease', (218, 246))	('mutation', 'Var', (91, 99))	('PIK3CA', 'Gene', (199, 205))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (77, 81))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (218, 246))	('PIK3CA', 'Gene', '5290', (199, 205))	('mutation', 'Var', (206, 214))	('TERT', 'Gene', (172, 176))	('association', 'Interaction', (152, 163))	('TERT', 'Gene', '7015', (172, 176))	('ARID1A', 'Gene', '8289', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
6174	24338723	The frequencies of TERT promoter mutations in various gynecologic cancers are summarized in Table 1.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
6175	24338723	TERT promoter mutations were detected in 40 of 525 tumor samples (7.6%; 95%CI: 5.6 - 10.2%), the majority occurring in ovarian clear cell carcinomas.	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (119, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ovarian clear cell carcinomas', 'Disease', (119, 148))	('occurring', 'Reg', (106, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('tumor', 'Disease', (51, 56))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
6177	24338723	The difference in mutation frequency was significant between clear cell carcinoma and other gynecologic neoplasms (p< 0.0001, two-tailed Fisher's exact test).	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('clear cell carcinoma', 'Disease', (61, 81))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (61, 81))	('neoplasms', 'Disease', 'MESH:D009369', (104, 113))	('neoplasms', 'Disease', (104, 113))	('mutation', 'Var', (18, 26))
6178	24338723	Among the 40 mutations, 37 were located at -124 bp from the TERT translation start site while only 3 were at -146 bp (Fig.	('TERT', 'Gene', '7015', (60, 64))	('mutations', 'Var', (13, 22))	('translation', 'biological_process', 'GO:0006412', ('65', '76'))	('TERT', 'Gene', (60, 64))
6179	24338723	Since ovarian clear cell carcinoma and endometrioid carcinoma are thought to arise from endometriotic cysts (endometriomas), we compared the TERT promoter mutation frequency between these two cancer types, and found a significantly higher frequency of TERT promoter mutation in ovarian clear cell carcinoma than in ovarian endometrioid carcinoma (p = 0.0024, two-tailed Fisher's exact test).	('endometriomas', 'Disease', (109, 122))	('cancer', 'Disease', (192, 198))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (39, 61))	('TERT', 'Gene', (141, 145))	('TERT', 'Gene', '7015', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('TERT', 'Gene', (252, 256))	('TERT', 'Gene', '7015', (252, 256))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (323, 345))	('ovarian clear cell carcinoma', 'Disease', (278, 306))	('ovarian clear cell carcinoma than in ovarian endometrioid carcinoma', 'Disease', 'MESH:D010051', (278, 345))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (39, 61))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (278, 306))	('higher', 'Reg', (232, 238))	('ovarian clear cell carcinoma', 'Disease', (6, 34))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (323, 345))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (6, 34))	('endometrioid carcinoma', 'Disease', (39, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('endometriotic cysts', 'Disease', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('endometrioid carcinoma', 'Disease', (323, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('endometriotic cysts', 'Disease', 'MESH:D003560', (88, 107))	('mutation', 'Var', (266, 274))	('endometriomas', 'Disease', 'MESH:D004715', (109, 122))
6181	24338723	To determine if TERT promoter mutation occurs early in the development of clear cell carcinoma, we analyzed 9 ovarian clear cell carcinomas with TERT promoter mutations in which there was sufficient endometriotic cyst epithelium for mutational analysis.	('TERT', 'Gene', (16, 20))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (74, 94))	('mutations', 'Var', (159, 168))	('TERT', 'Gene', '7015', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('ovarian clear cell carcinomas', 'Disease', (110, 139))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (110, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (118, 138))	('clear cell carcinoma', 'Disease', (74, 94))	('TERT', 'Gene', (145, 149))	('TERT', 'Gene', '7015', (145, 149))
6184	24338723	In a screen of 9 ovarian clear cell carcinoma cell lines, we found that three (33.3%; 95% CI: 11.7 - 64.9%) contained mutations at the TERT promoter.	('TERT', 'Gene', '7015', (135, 139))	('ovarian clear cell carcinoma', 'Disease', (17, 45))	('mutations', 'Var', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (17, 45))	('TERT', 'Gene', (135, 139))
6185	24338723	Cell lines JHOC5 and OV207 carried the hot spot mutation c.-124C>T, whereas the ES-2 cell line harbored the less common tandem mutation c.[-139C>T; -138C>T], which has been reported in a few melanomas.	('melanomas', 'Disease', (191, 200))	('-138C>T', 'Mutation', 'rs149946088', (148, 155))	('c.-124C>T', 'Var', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanomas', 'Phenotype', 'HP:0002861', (191, 200))	('melanomas', 'Disease', 'MESH:D008545', (191, 200))	('-139C>T', 'Var', (139, 146))	('c.-124C>T', 'Mutation', 'rs1242535815', (57, 66))	('JHOC5', 'CellLine', 'CVCL:4640', (11, 16))	('-139C>T', 'SUBSTITUTION', 'None', (139, 146))
6186	24338723	Cell lines harboring the c.-124C>T mutation showed a 5 to 8 fold increase of TERT mRNA expression as compared to the cell lines without TERT promoter mutation (Fig.	('increase', 'PosReg', (65, 73))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', (136, 140))	('TERT', 'Gene', '7015', (77, 81))	('TERT', 'Gene', '7015', (136, 140))	('c.-124C>T', 'Mutation', 'rs1242535815', (25, 34))	('c.-124C>T', 'Var', (25, 34))
6190	24338723	There was a trend towards longer telomere lengths in ovarian clear cell carcinomas with TERT promoter mutation relative to those without, though statistical significance was not reached (median, 1.1 vs. 0.36; p = 0.2278, one-tailed Mann-Whitney U test, Fig.	('longer', 'PosReg', (26, 32))	('ovarian clear cell carcinomas', 'Disease', (53, 82))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (53, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('TERT', 'Gene', '7015', (88, 92))	('mutation', 'Var', (102, 110))	('telomere', 'MPA', (33, 41))	('telomere', 'cellular_component', 'GO:0000781', ('33', '41'))	('telomere', 'cellular_component', 'GO:0005696', ('33', '41'))	('TERT', 'Gene', (88, 92))
6200	24338723	All clinical samples that had PIK3CA mutation, TERT promoter mutation, and ARID1A immunostaining data (n = 71) were summarized in Fig.	('PIK3CA', 'Gene', (30, 36))	('TERT', 'Gene', (47, 51))	('mutation', 'Var', (37, 45))	('TERT', 'Gene', '7015', (47, 51))	('PIK3CA', 'Gene', '5290', (30, 36))	('ARID1A', 'Gene', '8289', (75, 81))	('clinical samples', 'Species', '191496', (4, 20))	('ARID1A', 'Gene', (75, 81))
6202	24338723	We found no association between TERT promoter mutation and patients' age, FIGO stage, lymph node metastasis, nuclear atypia, and histological features.	('TERT', 'Gene', '7015', (32, 36))	('lymph node metastasis', 'CPA', (86, 107))	('patients', 'Species', '9606', (59, 67))	('FIGO stage', 'Disease', (74, 84))	('mutation', 'Var', (46, 54))	('TERT', 'Gene', (32, 36))
6208	24338723	Ovarian clear cell carcinoma and endometrioid carcinoma share several molecular genetic alterations including activating mutations in PIK3CA, and inactivating mutations and loss of expression in ARID1A and PTEN.	('ARID1A', 'Gene', '8289', (195, 201))	('PIK3CA', 'Gene', (134, 140))	('Ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (0, 28))	('ARID1A', 'Gene', (195, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('PIK3CA', 'Gene', '5290', (134, 140))	('loss of expression', 'NegReg', (173, 191))	('inactivating mutations', 'Var', (146, 168))	('Ovarian clear cell carcinoma', 'Disease', (0, 28))	('activating', 'PosReg', (110, 120))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (33, 55))	('PTEN', 'Gene', (206, 210))	('PTEN', 'Gene', '5728', (206, 210))	('endometrioid carcinoma', 'Disease', (33, 55))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (33, 55))
6211	24338723	Analysis of the mutation types reveals the likely mechanism by which TERT promoter mutations contribute to tumor development.	('mutations', 'Var', (83, 92))	('contribute', 'Reg', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('TERT', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
6212	24338723	Both hot spot mutations (c.-124C>T and c.-146C>T) at the TERT promoter create an 11-bp sequence that contains the binding motif (CCGGAA) of ETS-domain transcription factor family members, and both mutations have been shown to increase transcriptional activity of the TERT promoter.	('TERT', 'Gene', (267, 271))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('transcription factor', 'molecular_function', 'GO:0000981', ('151', '171'))	('c.-124C>T', 'Mutation', 'rs1242535815', (25, 34))	('c.-146C>T', 'Var', (39, 48))	('TERT', 'Gene', '7015', (267, 271))	('c.-146C>T', 'Mutation', 'rs572512602', (39, 48))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('transcription', 'biological_process', 'GO:0006351', ('151', '164'))	('increase', 'PosReg', (226, 234))	('transcriptional activity', 'MPA', (235, 259))	('c.-124C>T', 'Var', (25, 34))
6214	24338723	The less common tandem mutation c.[-139C>T; -138C>T] also generates an ETS binding motif.	('-139C>T', 'Var', (35, 42))	('-138C>T', 'Mutation', 'rs149946088', (44, 51))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('-139C>T', 'SUBSTITUTION', 'None', (35, 42))	('ETS binding', 'MPA', (71, 82))
6216	24338723	Abnormalities of ETS-domain family members have been implicated in a variety of human cancers through different mechanisms, including amplification, mutation, and translocation that generates fusion proteins.	('translocation', 'Disease', (163, 176))	('Abnormalities', 'Var', (0, 13))	('implicated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('mutation', 'Var', (149, 157))
6218	24338723	Since all hotspot mutations result in creation of a new ETS binding motif that is accessible to ETS factors, it is likely that these mutations turn the TERT promoter into a target of ETS-domain transcription factors.	('TERT', 'Gene', '7015', (152, 156))	('mutations', 'Var', (18, 27))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('mutations', 'Var', (133, 142))	('result in', 'Reg', (28, 37))	('TERT', 'Gene', (152, 156))	('transcription', 'biological_process', 'GO:0006351', ('194', '207'))	('ETS binding motif', 'MPA', (56, 73))
6219	24338723	Several molecular genetic abnormalities including ARID1A mutation, PIK3CA mutation, and PTEN deletion (loss of heterozygosity) have been thought to be early events in the development of ovarian clear cell carcinoma, as these alterations are frequently detected in both carcinoma and adjacent benign epithelium within the endometriotic cyst, the precursor lesion of ovarian clear cell carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (269, 278))	('carcinoma', 'Disease', (384, 393))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (186, 214))	('carcinoma', 'Disease', 'MESH:D002277', (205, 214))	('PIK3CA', 'Gene', (67, 73))	('ARID1A', 'Gene', (50, 56))	('mutation', 'Var', (74, 82))	('lesion of ovarian clear cell carcinoma', 'Disease', (355, 393))	('carcinoma', 'Disease', 'MESH:D002277', (384, 393))	('lesion of ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (355, 393))	('deletion', 'Var', (93, 101))	('ARID1A', 'Gene', '8289', (50, 56))	('mutation', 'Var', (57, 65))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (365, 393))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinoma', 'Disease', (269, 278))	('PTEN', 'Gene', (88, 92))	('carcinoma', 'Disease', (205, 214))	('PIK3CA', 'Gene', '5290', (67, 73))	('genetic abnormalities', 'Disease', 'MESH:D030342', (18, 39))	('PTEN', 'Gene', '5728', (88, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (384, 393))	('ovarian clear cell carcinoma', 'Disease', (186, 214))	('genetic abnormalities', 'Disease', (18, 39))
6220	24338723	In this study, we did not detect TERT promoter mutations in the contiguous endometriotic cyst epithelium associated with ovarian clear cell carcinomas that harbored TERT promoter mutations.	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('TERT', 'Gene', (165, 169))	('TERT', 'Gene', '7015', (165, 169))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (121, 150))	('mutations', 'Var', (179, 188))	('ovarian clear cell carcinomas', 'Disease', (121, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))
6222	24338723	This finding can be explained by the telomere crisis theory during tumor evolution, which proposes that incipient tumor clones slowly evolve while gradually acquiring somatic mutations until reaching a sufficient number of cell divisions when accumulated telomere erosion triggers senescence and/or deleterious genomic instability.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('telomere', 'cellular_component', 'GO:0005696', ('37', '45'))	('senescence', 'CPA', (281, 291))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (114, 119))	('triggers', 'Reg', (272, 280))	('senescence', 'biological_process', 'GO:0010149', ('281', '291'))	('telomere', 'cellular_component', 'GO:0005696', ('255', '263'))	('telomere', 'cellular_component', 'GO:0000781', ('255', '263'))	('genomic instability', 'CPA', (311, 330))	('telomere erosion', 'Var', (255, 271))	('telomere', 'cellular_component', 'GO:0000781', ('37', '45'))
6224	24338723	TERT promoter mutation is dispensable during the very early stage of tumor initiation because it does not provide a survival advantage until telomere attrition becomes evident.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('telomere', 'cellular_component', 'GO:0000781', ('141', '149'))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutation', 'Var', (14, 22))	('telomere', 'cellular_component', 'GO:0005696', ('141', '149'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
6227	24338723	Because ARID1A mutations correlate with loss of expression, immunohistochemistry has been used to assess ARID1A mutation status on tissue sections.	('ARID1A', 'Gene', '8289', (105, 111))	('ARID1A', 'Gene', (105, 111))	('mutations', 'Var', (15, 24))	('expression', 'MPA', (48, 58))	('loss', 'NegReg', (40, 44))	('ARID1A', 'Gene', '8289', (8, 14))	('ARID1A', 'Gene', (8, 14))
6229	24338723	This implies that intact ARID1A-containing BAF chromatin remodeling complexes may be required for TERT re-expression mediated by a mutated TERT promoter.	('TERT', 'Gene', (98, 102))	('TERT', 'Gene', '7015', (139, 143))	('chromatin', 'cellular_component', 'GO:0000785', ('47', '56'))	('ARID1A', 'Gene', '8289', (25, 31))	('mutated', 'Var', (131, 138))	('ARID1A', 'Gene', (25, 31))	('TERT', 'Gene', '7015', (98, 102))	('BAF', 'Gene', '8815', (43, 46))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('47', '67'))	('TERT', 'Gene', (139, 143))	('BAF', 'Gene', (43, 46))
6230	24338723	Alternatively, loss of ARID1A may facilitate incipient tumor cells to achieve replicative immortality.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ARID1A', 'Gene', '8289', (23, 29))	('ARID1A', 'Gene', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('loss', 'Var', (15, 19))	('facilitate', 'PosReg', (34, 44))
6232	24338723	PIK3CA, an oncogene, was found to be mutated in about one third of ovarian clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (67, 95))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutated', 'Var', (37, 44))	('ovarian clear cell carcinoma', 'Disease', (67, 95))
6233	24338723	Interestingly, in this study, we demonstrated that TERT promoter mutation and PIK3CA mutation showed strong tendency towards mutual exclusivity in 80 ovarian clear cell carcinoma samples examined.	('PIK3CA', 'Gene', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (150, 178))	('TERT', 'Gene', (51, 55))	('PIK3CA', 'Gene', '5290', (78, 84))	('mutation', 'Var', (85, 93))	('TERT', 'Gene', '7015', (51, 55))	('ovarian clear cell carcinoma', 'Disease', (150, 178))
6236	24338723	Therefore, like TERT promoter mutation, activating PIK3CA mutation confers cancer cells a growth advantage by overcoming the hurdle of replicative senescence.	('growth advantage', 'CPA', (90, 106))	('TERT', 'Gene', (16, 20))	('activating', 'PosReg', (40, 50))	('replicative senescence', 'MPA', (135, 157))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('TERT', 'Gene', '7015', (16, 20))	('cancer', 'Disease', (75, 81))	('mutation', 'Var', (58, 66))	('PIK3CA', 'Gene', (51, 57))	('overcoming', 'NegReg', (110, 120))	('replicative senescence', 'biological_process', 'GO:0090399', ('135', '157'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PIK3CA', 'Gene', '5290', (51, 57))
6237	24338723	Consequently, TERT promoter mutation is not selected in ovarian clear cell carcinomas with PIK3CA mutations.	('PIK3CA', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (91, 97))	('TERT', 'Gene', (14, 18))	('mutations', 'Var', (98, 107))	('TERT', 'Gene', '7015', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('ovarian clear cell carcinomas', 'Disease', (56, 85))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (56, 85))
6239	24338723	This finding contrasts with a previous study, in which primary gliobastoma with TERT promoter mutations had a worse prognosis than patients without TERT mutations.	('gliobastoma', 'Disease', 'None', (63, 74))	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (94, 103))	('TERT', 'Gene', (148, 152))	('TERT', 'Gene', '7015', (148, 152))	('gliobastoma', 'Disease', (63, 74))	('TERT', 'Gene', (80, 84))	('TERT', 'Gene', '7015', (80, 84))	('primary gliobastoma', 'Phenotype', 'HP:0012174', (55, 74))
6240	24338723	We note that most glioblastomas that do not have TERT promoter mutations exhibit the alternative lengthening of telomere (ALT) phenotype, which has been reported as an independent indicator of better prognosis; whereas, only a small proportion of ovarian clear cell carcinomas exhibit the ATL phenotype.	('mutations', 'Var', (63, 72))	('glioblastomas', 'Disease', (18, 31))	('telomere', 'cellular_component', 'GO:0005696', ('112', '120'))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (247, 276))	('ovarian clear cell carcinomas', 'Disease', (247, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('glioblastomas', 'Phenotype', 'HP:0012174', (18, 31))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (266, 276))	('ALT', 'molecular_function', 'GO:0004021', ('122', '125'))	('glioblastomas', 'Disease', 'MESH:D005909', (18, 31))	('telomere', 'cellular_component', 'GO:0000781', ('112', '120'))
6241	24338723	To learn more about the effect of TERT promoter mutation on patients' outcome, it would be helpful to compare the prognosis between TERT promoter mutants and wildtypes in other cancers in which ALT is uncommon, such as hepatocellular carcinomas, urothelial carcinomas, or squamous cell carcinomas of the tongue.	('carcinomas', 'Phenotype', 'HP:0030731', (257, 267))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('squamous cell carcinomas', 'Disease', (272, 296))	('hepatocellular carcinomas', 'Disease', (219, 244))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TERT', 'Gene', (132, 136))	('TERT', 'Gene', '7015', (132, 136))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (219, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('carcinomas', 'Phenotype', 'HP:0030731', (286, 296))	('patients', 'Species', '9606', (60, 68))	('mutants', 'Var', (146, 153))	('urothelial carcinomas', 'Disease', (246, 267))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('ALT', 'molecular_function', 'GO:0004021', ('194', '197'))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (246, 267))	('TERT', 'Gene', (34, 38))	('squamous cell carcinomas of the tongue', 'Phenotype', 'HP:0030413', (272, 310))	('TERT', 'Gene', '7015', (34, 38))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (272, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('carcinomas', 'Phenotype', 'HP:0030731', (234, 244))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (219, 244))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (272, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (219, 244))
6244	24338723	TERT promoter mutation showed strong tendency towards mutual exclusivity with loss of ARID1A expression and PIK3CA mutation in ovarian clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('ovarian clear cell carcinoma', 'Disease', (127, 155))	('ARID1A', 'Gene', '8289', (86, 92))	('TERT', 'Gene', (0, 4))	('ARID1A', 'Gene', (86, 92))	('loss', 'NegReg', (78, 82))	('mutation', 'Var', (14, 22))	('expression', 'MPA', (93, 103))	('PIK3CA', 'Gene', (108, 114))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (127, 155))	('TERT', 'Gene', '7015', (0, 4))	('mutation', 'Var', (115, 123))	('PIK3CA', 'Gene', '5290', (108, 114))
6249	24321270	The microRNA array showed that ectopic overexpression and knockdown of TrkB expression caused global changes in miRNA expression in EC cells.	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('TrkB', 'Gene', (71, 75))	('EC', 'Phenotype', 'HP:0012114', (132, 134))	('knockdown', 'Var', (58, 67))	('changes', 'Reg', (101, 108))
6252	24321270	Functionally, the MTT assays, clonogenic and Transwell assays showed that miR-204-5p significantly suppressed the clonogenic growth, migration and invasion of EC cells.	('suppressed', 'NegReg', (99, 109))	('invasion', 'CPA', (147, 155))	('migration', 'CPA', (133, 142))	('miR-204-5p', 'Var', (74, 84))	('rat', 'Species', '10116', (136, 139))	('clonogenic growth', 'CPA', (114, 131))	('MTT', 'Chemical', 'MESH:C070243', (18, 21))	('EC', 'Phenotype', 'HP:0012114', (159, 161))
6253	24321270	Furthermore, miR-204-5p also inhibited the growth of tumor xenografts bearing human EC cells.	('inhibited', 'NegReg', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('miR-204-5p', 'Var', (13, 23))	('EC', 'Phenotype', 'HP:0012114', (84, 86))	('tumor', 'Disease', (53, 58))	('human', 'Species', '9606', (78, 83))
6254	24321270	Importantly, we found lower miR-204-5p expression was associated with advanced FIGO stages, lymph node metastasis and probably a lower chance for survival in EC patients.	('EC', 'Phenotype', 'HP:0012114', (158, 160))	('FIGO stages', 'Disease', (79, 90))	('lymph node metastasis', 'CPA', (92, 113))	('patients', 'Species', '9606', (161, 169))	('miR-204-5p', 'Var', (28, 38))	('expression', 'MPA', (39, 49))	('lower', 'NegReg', (22, 27))	('lower', 'NegReg', (129, 134))
6255	24321270	This study uncovers a new regulatory loop involving TrkB/miR-204-5p that is critical to the tumorigenesis of EC and proposes that reestablishment of miR-204-5p expression could be explored as a potential new therapeutic target for this disease.	('miR-204-5p', 'Var', (149, 159))	('EC', 'Phenotype', 'HP:0012114', (109, 111))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('TrkB/miR-204-5p', 'Gene', (52, 67))
6268	24321270	MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) of approximately 22 bp that induce RNA interference by base-pairing with the 3' untranslated region (UTR) of a complementary messenger RNA (mRNA), which triggers either mRNA translational repression or RNA degradation.	('RNA interference', 'biological_process', 'GO:0016246', ('100', '116'))	('RNA', 'cellular_component', 'GO:0005562', ('200', '203'))	('miR', 'Gene', '220972', (11, 14))	('induce', 'Reg', (93, 99))	('miR', 'Gene', (11, 14))	('base-pairing', 'molecular_function', 'GO:0003676', ('120', '132'))	('RNA', 'cellular_component', 'GO:0005562', ('267', '270'))	('RNA interference', 'MPA', (100, 116))	('mRNA', 'MPA', (234, 238))	('RNA', 'cellular_component', 'GO:0005562', ('100', '103'))	('base-pairing', 'Var', (120, 132))	('RNA degradation', 'biological_process', 'GO:0006401', ('267', '282'))
6288	24321270	Furthermore, the miR-204-5p targeting site within the 3'UTR of TrkB (position 457-464) was highly conserved across five mammalian species (Additional file 1: Figure S1A).	('mammalian', 'Species', '9606', (120, 129))	('TrkB', 'Gene', (63, 67))	('miR-204-5p', 'Var', (17, 27))
6289	24321270	These intriguing findings suggest that miR-211-5p and miR-204-5p and TrkB are likely mutual modulators of their expression.	('miR-211-5p', 'Gene', (39, 49))	('miR-204-5p', 'Var', (54, 64))	('TrkB', 'Protein', (69, 73))	('miR-211-5p', 'Gene', '100313840', (39, 49))
6293	24321270	No reduction in luciferase activities was observed of 293 T cells transfected with the mutant TrkB 3'UTR.	('luciferase', 'Enzyme', (16, 26))	('activities', 'MPA', (27, 37))	('293 T', 'CellLine', 'CVCL:0063', (54, 59))	('TrkB', 'Gene', (94, 98))	('mutant', 'Var', (87, 93))
6294	24321270	Our finding that TrkB may be targeted by miR-204-5p led us to further delineate the actions of miR-204-5p on TrkB in endometrial cancer cells.	('endometrial cancer', 'Disease', (117, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('endometrial cancer', 'Phenotype', 'HP:0012114', (117, 135))	('miR-204-5p', 'Var', (95, 105))	('endometrial cancer', 'Disease', 'MESH:D016889', (117, 135))	('miR-204-5p', 'Var', (41, 51))
6297	24321270	Our immunoblotting assays additionally showed that HEC-1BshTrkB cells transfected with miR-204i also had noticeably increased levels of TrkB (P < 0.01) (Figure 2G and H).	('EC', 'Phenotype', 'HP:0012114', (52, 54))	('miR-204i', 'Var', (87, 95))	('levels', 'MPA', (126, 132))	('increased', 'PosReg', (116, 125))	('HEC-1B', 'CellLine', 'CVCL:0294', (51, 57))	('TrkB', 'Protein', (136, 140))
6302	24321270	Our immunoblotting assays revealed that TrkB overexpression in IshikawaTrkB cells noticeably increased the phosphorylation of JAK2 and STAT3, which, however, was aborted by TrkB knockdown in HEC-1BshTrkB cells (Figure 3C).	('HEC-1B', 'CellLine', 'CVCL:0294', (191, 197))	('EC', 'Phenotype', 'HP:0012114', (192, 194))	('increased', 'PosReg', (93, 102))	('JAK2', 'Gene', '3717', (126, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('STAT3', 'MPA', (135, 140))	('JAK2', 'Gene', (126, 130))	('TrkB', 'Protein', (40, 44))	('knockdown', 'Var', (178, 187))	('JAK', 'molecular_function', 'GO:0004713', ('126', '129'))	('phosphorylation', 'MPA', (107, 122))	('overexpression', 'PosReg', (45, 59))
6304	24321270	Moreover, inhibition of STAT3 by small interference RNA (siRNA) (Figure 3D) elevated the miR-204-5p expression in IshikawaTrkB and HEC-1B cells (P < 0.05) (Figure 3E), indicating that, indeed, TrkB activates the JAK2/STAT3 pathway in endometrial cancer cells.	('elevated', 'PosReg', (76, 84))	('JAK2', 'Gene', '3717', (212, 216))	('endometrial cancer', 'Disease', 'MESH:D016889', (234, 252))	('endometrial cancer', 'Phenotype', 'HP:0012114', (234, 252))	('JAK', 'molecular_function', 'GO:0004713', ('212', '215'))	('activates', 'PosReg', (198, 207))	('small', 'MPA', (33, 38))	('JAK2', 'Gene', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('EC', 'Phenotype', 'HP:0012114', (132, 134))	('inhibition', 'Var', (10, 20))	('endometrial cancer', 'Disease', (234, 252))	('miR-204-5p expression', 'MPA', (89, 110))	('HEC-1B', 'CellLine', 'CVCL:0294', (131, 137))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
6310	24321270	Conversely, compared to HEC-1B cells, HEC-1BshTrkB cells, which had markedly increased miR-204-5p as measured by TaqMan PCR assays (Figure 4B, left panel), showed markedly reduced growth (P < 0.05) (Figure 4B, right panel).	('reduced', 'NegReg', (172, 179))	('miR-204-5p', 'Var', (87, 97))	('HEC-1B', 'CellLine', 'CVCL:0294', (24, 30))	('EC', 'Phenotype', 'HP:0012114', (25, 27))	('EC', 'Phenotype', 'HP:0012114', (39, 41))	('HEC-1B', 'CellLine', 'CVCL:0294', (38, 44))	('increased', 'PosReg', (77, 86))	('growth', 'MPA', (180, 186))
6312	24321270	By contrast, miR-204i noticeably increased the number of colonies compared with that of HEC-1BshTrkB cells or HEC-1BshTrkB cells transfected with the scrambled control (P < 0.01 in both) (Figure 4C, Additional file 3: Figure S3A).	('HEC-1B', 'CellLine', 'CVCL:0294', (88, 94))	('HEC-1B', 'CellLine', 'CVCL:0294', (110, 116))	('EC', 'Phenotype', 'HP:0012114', (89, 91))	('miR-204i', 'Var', (13, 21))	('increased', 'PosReg', (33, 42))	('EC', 'Phenotype', 'HP:0012114', (111, 113))
6313	24321270	These results suggest that TrkB promotes while miR-204-5p suppresses the clonogenic growth of endometrial cancer cells.	('TrkB', 'Protein', (27, 31))	('endometrial cancer', 'Disease', (94, 112))	('miR-204-5p', 'Var', (47, 57))	('endometrial cancer', 'Phenotype', 'HP:0012114', (94, 112))	('suppresses', 'NegReg', (58, 68))	('endometrial cancer', 'Disease', 'MESH:D016889', (94, 112))	('promotes', 'PosReg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
6314	24321270	We further assessed whether miR-204-5p modulated the migratory and invasive capacity of endometrial cancer cells.	('rat', 'Species', '10116', (56, 59))	('migratory', 'CPA', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('modulated', 'Reg', (39, 48))	('endometrial cancer', 'Disease', (88, 106))	('invasive capacity', 'CPA', (67, 84))	('endometrial cancer', 'Phenotype', 'HP:0012114', (88, 106))	('miR-204-5p', 'Var', (28, 38))	('endometrial cancer', 'Disease', 'MESH:D016889', (88, 106))
6315	24321270	Our Transwell assays showed that IshikawaTrkB cells displayed an enhanced capacity of migration compared to Ishikawa cells, which, however, was markedly abated by miR-204 m (vs. non-transfected or scrambled control, P < 0.05) (Figure 4D, Additional file 3: Figure S3B).	('migration', 'CPA', (86, 95))	('enhanced', 'PosReg', (65, 73))	('rat', 'Species', '10116', (89, 92))	('abated', 'NegReg', (153, 159))	('miR-204 m', 'Var', (163, 172))
6316	24321270	Conversely, HEC-1BshTrkB cells exhibited reduced migration capacity compared to HEC-1B cells, which was enhanced by miR-204i (vs. non-transfected or scrambled control, P < 0.05) (Figure 4E, Additional file 3: Figure S3B).	('reduced', 'NegReg', (41, 48))	('rat', 'Species', '10116', (52, 55))	('EC', 'Phenotype', 'HP:0012114', (81, 83))	('EC', 'Phenotype', 'HP:0012114', (13, 15))	('miR-204i', 'Var', (116, 124))	('HEC-1B', 'CellLine', 'CVCL:0294', (12, 18))	('enhanced', 'PosReg', (104, 112))	('migration capacity', 'CPA', (49, 67))	('HEC-1B', 'CellLine', 'CVCL:0294', (80, 86))
6318	24321270	These results together demonstrate that TrkB increases while miR-204-5p suppresses the clonogenic growth, migration and invasion of endometrial cancer cells in vitro.	('increases', 'PosReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('endometrial cancer', 'Disease', (132, 150))	('rat', 'Species', '10116', (30, 33))	('miR-204-5p', 'Var', (61, 71))	('invasion', 'CPA', (120, 128))	('clonogenic growth', 'CPA', (87, 104))	('rat', 'Species', '10116', (109, 112))	('endometrial cancer', 'Phenotype', 'HP:0012114', (132, 150))	('TrkB', 'Protein', (40, 44))	('migration', 'CPA', (106, 115))	('endometrial cancer', 'Disease', 'MESH:D016889', (132, 150))	('suppresses', 'NegReg', (72, 82))
6319	24321270	To address whether the phenotypic effects of miR-204-5p expression are predominately due to the suppression of TrkB, rather than one of its other cellular targets, we additionally examined whether miR-204-5p and TrkB functioned in the same pathway in modulating clonogenic growth, migration and invasion of endometrial cancer cells.	('rat', 'Species', '10116', (117, 120))	('modulating', 'Reg', (251, 261))	('rat', 'Species', '10116', (284, 287))	('invasion', 'CPA', (295, 303))	('miR-204-5p', 'Var', (197, 207))	('clonogenic growth', 'CPA', (262, 279))	('endometrial cancer', 'Disease', (307, 325))	('endometrial cancer', 'Phenotype', 'HP:0012114', (307, 325))	('migration', 'CPA', (281, 290))	('endometrial cancer', 'Disease', 'MESH:D016889', (307, 325))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('miR-204-5p', 'Var', (45, 55))
6321	24321270	As expected, cells treated with miR-204 m had no obvious change in cellular proliferation, colony formation, migration and invasion compared with wildtype Ishikawa cells (Figure 5E-H).	('rat', 'Species', '10116', (83, 86))	('cellular proliferation', 'CPA', (67, 89))	('colony formation', 'CPA', (91, 107))	('miR-204 m', 'Var', (32, 41))	('invasion', 'CPA', (123, 131))	('rat', 'Species', '10116', (112, 115))	('migration', 'CPA', (109, 118))	('formation', 'biological_process', 'GO:0009058', ('98', '107'))
6322	24321270	Together, these results suggest that TrkB is a functionally important downstream target of miR-204-5p that is involved in the clonogenic growth, migration and invasion of endometrial carcinoma cells.	('endometrial carcinoma', 'Disease', (171, 192))	('rat', 'Species', '10116', (148, 151))	('clonogenic growth', 'CPA', (126, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (171, 192))	('migration', 'CPA', (145, 154))	('miR-204-5p', 'Var', (91, 101))	('involved', 'Reg', (110, 118))	('TrkB', 'Protein', (37, 41))	('invasion', 'CPA', (159, 167))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (171, 192))
6323	24321270	We were interested in whether miR-204-5p suppressed the growth of xenografts bearing human endometrial carcinoma cells.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('suppressed', 'NegReg', (41, 51))	('miR-204-5p', 'Var', (30, 40))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('growth', 'MPA', (56, 62))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('human', 'Species', '9606', (85, 90))
6324	24321270	Compared to the scrambled control, mouse xenografts bearing IshikawaTrkB cells overexpressing miR-204-5p showed a dramatic reduction in tumor size (P < 0.05) (Figure 6B and C) and tumor weight (P < 0.05) (Figure 6D).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('miR-204-5p', 'Var', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('mouse', 'Species', '10090', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('reduction', 'NegReg', (123, 132))	('tumor', 'Disease', (136, 141))
6330	24321270	These results indicate that miR-204-5p inhibits the tumorigenicity of endometrial carcinoma cells in vivo and further suggests a tumor-suppressive effect of miR-204-5p via the TrkB/STAT3 pathway.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TrkB/STAT3 pathway', 'Pathway', (176, 194))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (52, 57))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (70, 91))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('miR-204-5p', 'Var', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('endometrial carcinoma', 'Disease', (70, 91))	('miR-204-5p', 'Var', (28, 38))	('inhibits', 'NegReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (70, 91))
6331	24321270	To further determine the correlation between the clinicopathologic characteristics of endometrial cancer patients and miR-204-5p expression, we measured the expression levels of miR-204-5p in 25 normal endometrium samples and 71 endometrial cancer tissues by TaqMan PCR assays.	('endometrial cancer', 'Disease', 'MESH:D016889', (229, 247))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (105, 113))	('endometrial cancer', 'Disease', (86, 104))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('endometrial cancer', 'Phenotype', 'HP:0012114', (86, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (86, 104))	('endometrial cancer', 'Disease', (229, 247))	('miR-204-5p', 'Var', (178, 188))	('endometrial cancer', 'Phenotype', 'HP:0012114', (229, 247))
6332	24321270	We observed a significantly lower expression of miR-204-5p in endometrial cancer tissues compared with the normal endometrium (P < 0.0001) (Figure 7A).	('endometrial cancer', 'Disease', (62, 80))	('expression', 'MPA', (34, 44))	('endometrial cancer', 'Phenotype', 'HP:0012114', (62, 80))	('lower', 'NegReg', (28, 33))	('endometrial cancer', 'Disease', 'MESH:D016889', (62, 80))	('miR-204-5p', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
6336	24321270	Furthermore, analysis of the correlation of miR-204 expression and the overall survival (OS) of uterine corpus endometrioid carcinoma (UCEC) patients (n = 279) in an independent dataset from the Cancer Genome Atlas network further showed that though UCEC patients with high mR-204 expression exhibited a higher rate of OS, no significant difference in OS was noted between UCEC patients with high and low mR-204 expression (P > 0.05) (Figure 7H).	('EC', 'Phenotype', 'HP:0012114', (137, 139))	('Cancer', 'Disease', (195, 201))	('mR-204', 'Gene', (274, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Cancer', 'Disease', 'MESH:D009369', (195, 201))	('Cancer', 'Phenotype', 'HP:0002664', (195, 201))	('rat', 'Species', '10116', (311, 314))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (111, 133))	('patients', 'Species', '9606', (255, 263))	('EC', 'Phenotype', 'HP:0012114', (375, 377))	('corpus endometrioid carcinoma', 'Disease', (104, 133))	('corpus endometrioid carcinoma', 'Disease', 'MESH:D016889', (104, 133))	('patients', 'Species', '9606', (378, 386))	('high', 'Var', (269, 273))	('patients', 'Species', '9606', (141, 149))	('EC', 'Phenotype', 'HP:0012114', (252, 254))
6337	24321270	However, high mR-204 expression was found to be associated with a higher likelihood of survival for UCEC patients (OS; 1.3164).	('survival', 'MPA', (87, 95))	('patients', 'Species', '9606', (105, 113))	('EC', 'Phenotype', 'HP:0012114', (102, 104))	('expression', 'MPA', (21, 31))	('mR-204', 'Protein', (14, 20))	('higher', 'PosReg', (66, 72))	('UCEC', 'Disease', (100, 104))	('high', 'Var', (9, 13))
6352	24321270	Epigenetic effects are a key aspect of the relationship between miRNAs and carcinogenesis.	('carcinogenesis', 'Disease', (75, 89))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('Epigenetic effects', 'Var', (0, 18))	('carcinogenesis', 'Disease', 'MESH:D063646', (75, 89))
6353	24321270	Dysregulated expression of miRNAs has recently been associated with carcinogenesis in endometrial carcinoma.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (86, 107))	('expression', 'MPA', (13, 23))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('associated', 'Reg', (52, 62))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('endometrial carcinoma', 'Disease', (86, 107))	('carcinogenesis', 'Disease', (68, 82))	('Dysregulated', 'Var', (0, 12))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (86, 107))
6356	24321270	We provide evidence that miR-204-5p, which acts as a potent tumor growth and metastasis suppressor both in vitro and in vivo, is somatically lost in human endometrial carcinoma.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (155, 176))	('endometrial carcinoma', 'Disease', (155, 176))	('metastasis', 'CPA', (77, 87))	('human', 'Species', '9606', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (155, 176))	('tumor', 'Disease', (60, 65))	('miR-204-5p', 'Var', (25, 35))
6357	24321270	The finding that miR-204-5p is downregulated in endometrial carcinoma is intriguing, as decreased miR-204-5p levels have been reported in several types of solid tumors, and suggests that loss of miR-204-5p may be a common event in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (48, 69))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('solid tumors', 'Disease', (155, 167))	('loss', 'Var', (187, 191))	('endometrial carcinoma', 'Disease', (48, 69))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (231, 236))	('downregulated', 'NegReg', (31, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (48, 69))	('decreased', 'NegReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('solid tumors', 'Disease', 'MESH:D009369', (155, 167))	('tumor', 'Disease', (161, 166))	('miR-204-5p levels', 'MPA', (98, 115))
6368	24321270	Our results are consistent with the former study in showing that miR-204-5p expression in endometrial carcinoma tissues is significantly lower than that in the normal endometrium.	('lower', 'NegReg', (137, 142))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (90, 111))	('endometrial carcinoma', 'Disease', (90, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (90, 111))	('miR-204-5p', 'Var', (65, 75))
6374	24321270	Recently, miR-204 has been suggested as a novel predictor of outcome in neuroblastoma, functioning, at least in part, by increasing the sensitivity to cisplatin through direct targeting and downregulation of anti-apoptotic BCL2 and TrkB.	('neuroblastoma', 'Disease', (72, 85))	('BCL2', 'Gene', (223, 227))	('neuroblastoma', 'Phenotype', 'HP:0003006', (72, 85))	('neuroblastoma', 'Disease', 'MESH:D009447', (72, 85))	('anti-apoptotic', 'Protein', (208, 222))	('increasing', 'PosReg', (121, 131))	('miR-204', 'Var', (10, 17))	('downregulation', 'NegReg', (190, 204))	('BCL2', 'molecular_function', 'GO:0015283', ('223', '227'))	('TrkB', 'Protein', (232, 236))	('sensitivity to cisplatin', 'MPA', (136, 160))	('BCL2', 'Gene', '596', (223, 227))
6396	24321270	Ishikawa cells were co-transfected with miR-204i and siTrkB, or miR-204i and siTrkB-NC using Lipofectamine2000.	('miR-204i', 'Var', (64, 72))	('Lipofectamine2000', 'Chemical', 'MESH:C086724', (93, 110))	('miR-204i', 'Var', (40, 48))
6417	24321270	For Western blotting assays, conducted as previously depicted, antibodies against the following proteins were used: TrkB and phospho-TrkB (both from Abcam), phospho-P44/42 MAPK (thr204/tyr204), P44/42 MAPK, phospho-JAK2 (tyr1007/1008), JAK2, phospho-STAT3 (tyr705) and STAT3 (all from Epitomics).	('MAPK', 'molecular_function', 'GO:0004707', ('172', '176'))	('P44', 'Gene', '10561', (194, 197))	('tyr1007', 'Chemical', '-', (221, 228))	('P44', 'Gene', (165, 168))	('tyr705', 'Var', (257, 263))	('thr204', 'Chemical', '-', (178, 184))	('tyr705', 'Chemical', '-', (257, 263))	('JAK2', 'Gene', (215, 219))	('tyr204', 'Chemical', '-', (185, 191))	('thr204/tyr204', 'Var', (178, 191))	('JAK2', 'Gene', '3717', (236, 240))	('MAPK', 'molecular_function', 'GO:0004707', ('201', '205'))	('P44', 'Gene', (194, 197))	('JAK', 'molecular_function', 'GO:0004713', ('215', '218'))	('tyr1007/1008', 'Var', (221, 233))	('P44', 'Gene', '10561', (165, 168))	('JAK2', 'Gene', (236, 240))	('JAK', 'molecular_function', 'GO:0004713', ('236', '239'))	('JAK2', 'Gene', '3717', (215, 219))
6419	24321270	We performed the luciferase assays using 293 T cells transiently transfected with Renilla constructs (as an internal control) or plasmids pMIRGLO-TrkB-3'UTR-WT or pMIRGLO-TrkB-3'UTR-MT with or without miR-204 m or miR-204 m NC using the Dual Luciferase Assay system following the manufacturer's instructions (Promega, Madison, WI).	('miR-204', 'Var', (214, 221))	('Renilla constructs', 'Disease', 'MESH:D000381', (82, 100))	('Renilla constructs', 'Disease', (82, 100))	('293 T', 'CellLine', 'CVCL:0063', (41, 46))	("pMIRGLO-TrkB-3'UTR-WT", 'Var', (138, 159))
6460	20804553	Although there is no consensus on sentinel node biopsy neither on the prognostic relevance of micrometastases in endometrial cancer, Yasbushita et al demonstrated the relation between the presence of micrometastases and the risk of recurrence.	('endometrial cancer', 'Phenotype', 'HP:0012114', (113, 131))	('endometrial cancer', 'Disease', 'MESH:D016889', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('metastases', 'Disease', (205, 215))	('metastases', 'Disease', 'MESH:D009362', (205, 215))	('metastases', 'Disease', (99, 109))	('presence', 'Var', (188, 196))	('endometrial cancer', 'Disease', (113, 131))	('metastases', 'Disease', 'MESH:D009362', (99, 109))
6478	20804553	The presence of single noncohesive tumour cells was recorded as submicrometastasis SNs were considered positive when they contained macrometastase, micrometastase, or submicrometastase.	('micrometastase', 'CPA', (148, 162))	('contained', 'Reg', (122, 131))	('macrometastase', 'MPA', (132, 146))	('submicrometastase', 'Var', (167, 184))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('submicrometastasis', 'Disease', (64, 82))	('tumour', 'Disease', (35, 41))
6540	20804553	Indeed, a previous study showed that micrometastasis removal in women with endometrial cancer was associated with a significant increase in disease-free survival and that the rate of recurrence reached 35.7% in patients with micrometastases over 40 months of follow-up.	('increase', 'PosReg', (128, 136))	('metastases', 'Disease', 'MESH:D009362', (230, 240))	('disease-free survival', 'CPA', (140, 161))	('patients', 'Species', '9606', (211, 219))	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('women', 'Species', '9606', (64, 69))	('endometrial cancer', 'Disease', (75, 93))	('metastases', 'Disease', (230, 240))	('micrometastasis removal', 'Var', (37, 60))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))
6628	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))
6646	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'))
6653	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))
6661	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))
6702	30828525	Cancer is a complex genetic disease associated with aberrant genomic alterations in germline or somatic genomes.	('genetic disease', 'Disease', (20, 35))	('genetic disease', 'Disease', 'MESH:D030342', (20, 35))	('aberrant genomic alterations', 'Var', (52, 80))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('associated', 'Reg', (36, 46))
6705	30828525	Clearly, these methods can be limited by the currently incomplete known pathways and interaction networks in databases.12, 13  De novo computational methods have been developed to discover driver pathways based on two observations: 1) a large number of cancer samples have mutated genes in each driver pathway or module, referred to as high coverage property, where the coverage of a gene or a module is defined as the number of samples in which the gene or genes in the module are mutated; and 2) genes in a single driver pathway are altered exclusively in a cancer sample, referred to as high exclusivity,14, 15, 16, 17 i.e., at most one driver gene in a driver pathway is mutated in most samples.	('cancer', 'Phenotype', 'HP:0002664', (560, 566))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('altered', 'Reg', (535, 542))	('mutated', 'Var', (273, 280))	('cancer', 'Disease', (560, 566))	('cancer', 'Disease', 'MESH:D009369', (560, 566))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
6706	30828525	The phenomenon has led to the hypothesis that mutation in a single driver gene is usually sufficient to disturb the pathway and drive the cancer.	('cancer', 'Disease', (138, 144))	('pathway', 'Pathway', (116, 123))	('mutation', 'Var', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('drive', 'Reg', (128, 133))	('disturb', 'Reg', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
6739	30828525	Enrichment analysis against the KEGG pathway database44 using DAVID42, 43 revealed that these genes were significantly enriched for chronic myeloid leukemia (hsa05220, p = 1.11E-06), LAML (hsa05221, p = 1.37E-05), central carbon metabolism in cancer (hsa05230, p = 2.34E-05), microRNAs in cancer (hsa05206, p = 8.04E-05), Ras signaling pathway (hsa04014, p = 2.86E-04), cell cycle (hsa04110, p = 3.11E-04) and pathways in cancer (hsa05200, p = 4.69E-04).	('central carbon metabolism', 'MPA', (214, 239))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('cancer', 'Disease', (422, 428))	('metabolism', 'biological_process', 'GO:0008152', ('229', '239'))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('Ras signaling pathway', 'Pathway', (322, 343))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (132, 156))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (132, 156))	('pathways', 'Pathway', (410, 418))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('cancer', 'Disease', 'MESH:D009369', (422, 428))	('hsa04110', 'Var', (382, 390))	('cell', 'Pathway', (370, 374))	('signaling pathway', 'biological_process', 'GO:0007165', ('326', '343'))	('cancer', 'Disease', (243, 249))	('cell cycle', 'biological_process', 'GO:0007049', ('370', '380'))	('hsa04014', 'Var', (345, 353))	('chronic myeloid leukemia', 'Disease', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (289, 295))
6747	30828525	The genes were also enriched for KEGG pathways such as pancreatic cancer (hsa05212, p = 2.33E-06), bladder cancer (hsa05219, p = 1.04E-05), pathways in cancer (hsa05200, p = 3.35E-05), and non-small cell lung cancer (hsa05223, p = 3.64E-05).	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (189, 215))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('KEGG pathways', 'Pathway', (33, 46))	('cancer', 'Disease', (152, 158))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (193, 215))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('pancreatic cancer', 'Disease', (55, 72))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (189, 215))	('hsa05200', 'Var', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('pathways', 'Pathway', (140, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('non-small cell lung cancer', 'Disease', (189, 215))	('cancer', 'Disease', (107, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('cancer', 'Disease', (209, 215))	('bladder cancer', 'Disease', (99, 113))	('cancer', 'Disease', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
6749	30828525	Of the 12 genes (CFH, CHD8, CR1, EP400, F13A1, HCFC1, ITGAM, ITGAX, LILRB2, NAV1, and NAV2) that are not NCG cancer genes, several genes have been reported to be related to lung cancer.	('HCFC1', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('CR1', 'Gene', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('CFH', 'Disease', 'MESH:C562875', (17, 20))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('F13A1', 'Gene', (40, 45))	('CFH', 'Disease', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('EP400', 'Var', (33, 38))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('related', 'Reg', (162, 169))
6848	29098518	Among the three tracers, 99mTc had a higher detection rate than IDC (77.9 vs 17.0%, p < 0.01).	('detection', 'MPA', (44, 53))	('higher', 'PosReg', (37, 43))	('IDC', 'Chemical', 'MESH:D007203', (64, 67))	('99mTc', 'Var', (25, 30))	('Tc', 'Chemical', 'MESH:D013667', (28, 30))
6852	29098518	Laparoscopy (aOR 0.09, 95% CI 0.01-0.75), <50% myometrial invasion (aOR 0.17, 95% CI 0.03-0.89) and low-grade tumors (aOR 0.18, 95% CI 0.03-0.98) were independently associated with the FN rate.	('<50', 'Var', (42, 45))	('aOR', 'molecular_function', 'GO:0033726', ('13', '16'))	('Laparoscopy', 'Disease', (0, 11))	('aOR', 'molecular_function', 'GO:0033726', ('68', '71'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('low-grade', 'Var', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('aOR', 'molecular_function', 'GO:0033726', ('118', '121'))
6877	29098518	In conclusion, patients with < 50% myometrial invasion and low-grade tumors not only had higher detection rates, but also had lower FN rates.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patients', 'Species', '9606', (15, 23))	('detection rates', 'MPA', (96, 111))	('lower', 'NegReg', (126, 131))	('low-grade', 'Var', (59, 68))	('myometrial invasion', 'CPA', (35, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('higher', 'PosReg', (89, 95))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
6883	27926484	In addition, in a meta-analysis of non-female cancer patients from TCGA datasets and 12 independent studies, hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/metastasis-free survival (MFS)/progression-free survival (PFS) were pooled to assess the prognostic value of high H19 expression.	('MFS', 'Disease', (275, 278))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('MFS', 'Disease', 'MESH:D008382', (275, 278))	('H19', 'Gene', '283120', (363, 366))	('high', 'Var', (358, 362))	('H19', 'Gene', (363, 366))
6885	27926484	Multivariate Cox regression analysis showed that high H19 expression could independently predict a poorer prognosis in cervical cancer patients (HR=4.099, p<0.05).	('patients', 'Species', '9606', (135, 143))	('expression', 'MPA', (58, 68))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('cervical cancer', 'Disease', (119, 134))	('H19', 'Gene', '283120', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (49, 53))	('H19', 'Gene', (54, 57))
6886	27926484	In the meta-analysis, patients with high H19 expression showed a poorer outcome in non-female cancer (p<0.05).	('H19', 'Gene', '283120', (41, 44))	('H19', 'Gene', (41, 44))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('high', 'Var', (36, 40))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
6887	27926484	These results suggest that high lncRNA H19 expression is predictive of an unfavorable prognosis in two female cancers (uterine corpus endometrioid cancer and cervical cancer) as well as in non-female cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (127, 153))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (167, 173))	('cervical cancer', 'Disease', (158, 173))	('cervical cancer', 'Disease', 'MESH:D002583', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (134, 153))	('corpus endometrioid cancer', 'Disease', (127, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('H19', 'Gene', (39, 42))	('cancer', 'Disease', (110, 116))	('cancers', 'Disease', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('H19', 'Gene', '283120', (39, 42))	('cancer', 'Disease', (200, 206))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', (147, 153))	('expression', 'MPA', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
6895	27926484	We evaluated the prognostic power of high lncRNA H19 expression for female cancers and pooled the prognostic ability of high H19 expression in non-female cancers according to TCGA datasets and the available literature.	('H19', 'Gene', '283120', (49, 52))	('H19', 'Gene', (49, 52))	('high', 'Var', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Disease', (75, 82))	('H19', 'Gene', (125, 128))	('H19', 'Gene', '283120', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
6900	27926484	There were no significant differences in clinicopathological variables between patients with high H19 expression and those with low H19 expression in patients with uterine corpus endometrioid cancer, cervical cancer, uterine carcinosarcoma, breast cancer, and ovarian cancer (p > 0.05; Supplementary Table S1-S6).	('ovarian cancer', 'Disease', (260, 274))	('patients', 'Species', '9606', (150, 158))	('H19', 'Gene', '283120', (98, 101))	('ovarian cancer', 'Phenotype', 'HP:0100615', (260, 274))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (172, 198))	('high', 'Var', (93, 97))	('carcinosarcoma', 'Disease', (225, 239))	('H19', 'Gene', (132, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('corpus endometrioid cancer', 'Disease', (172, 198))	('carcinosarcoma', 'Disease', 'MESH:D002296', (225, 239))	('cervical cancer', 'Disease', (200, 215))	('cervical cancer', 'Disease', 'MESH:D002583', (200, 215))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (179, 198))	('ovarian cancer', 'Disease', 'MESH:D010051', (260, 274))	('expression', 'MPA', (102, 112))	('H19', 'Gene', '283120', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (217, 239))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('breast cancer', 'Disease', (241, 254))	('patients', 'Species', '9606', (79, 87))	('H19', 'Gene', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
6909	27926484	However, high H19 expression was associated with a shorter relapse-free survival (RFS; HR = 2.261, 95% CI = 1.077 - 4.747, p = 0.0310) in cervical cancer patients when compared with patients with low H19 expression (Figure 1C-1D).	('H19', 'Gene', '283120', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('H19', 'Gene', (14, 17))	('shorter', 'NegReg', (51, 58))	('patients', 'Species', '9606', (154, 162))	('H19', 'Gene', '283120', (200, 203))	('H19', 'Gene', (200, 203))	('patients', 'Species', '9606', (182, 190))	('relapse-free survival', 'CPA', (59, 80))	('cervical cancer', 'Disease', (138, 153))	('cervical cancer', 'Disease', 'MESH:D002583', (138, 153))	('high', 'Var', (9, 13))
6916	27926484	Because the above results suggested that high H19 expression could predict an unfavorable prognosis in some female cancer patients, we next assessed whether it had prognostic ability in patients with non-female cancer (Pan-cancer excluding the female cancers, including 25 cancers).	('non-female', 'Disease', (200, 210))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('cancers', 'Disease', (273, 280))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('expression', 'MPA', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('Pan-cancer', 'Disease', 'MESH:C537931', (219, 229))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('H19', 'Gene', (46, 49))	('patients', 'Species', '9606', (186, 194))	('H19', 'Gene', '283120', (46, 49))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('patients', 'Species', '9606', (122, 130))	('cancers', 'Disease', (251, 258))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('high', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('Pan-cancer', 'Disease', (219, 229))
6926	27926484	Under a random-effect model, non-female cancer patients with high H19 expression had shorter OS than those with low H19 expression (Figure 3; pooling HR = 1.33, 95 % CI = 1.11 - 1.59, p = 0.002).	('shorter', 'NegReg', (85, 92))	('H19', 'Gene', '283120', (66, 69))	('H19', 'Gene', (66, 69))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('H19', 'Gene', '283120', (116, 119))	('expression', 'Var', (70, 80))	('H19', 'Gene', (116, 119))
6928	27926484	With a random-effect model, shorter OS was observed in non-female cancer patients with high H19 expression than those with low H19 expression (Figure 4; pooling HR = 1.31, 95 % CI = 1.09 - 1.59, p = 0.004).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (73, 81))	('H19', 'Gene', '283120', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('H19', 'Gene', '283120', (127, 130))	('H19', 'Gene', (92, 95))	('expression', 'Var', (96, 106))	('cancer', 'Disease', (66, 72))	('H19', 'Gene', (127, 130))
6929	27926484	These results suggested that high H19 expression could predict inferior clinical outcomes on OS time in non-female cancer patients.	('high', 'Var', (29, 33))	('H19', 'Gene', (34, 37))	('cancer', 'Disease', (115, 121))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('inferior', 'NegReg', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('patients', 'Species', '9606', (122, 130))	('OS time', 'Disease', (93, 100))	('H19', 'Gene', '283120', (34, 37))
6931	27926484	As shown in Figure 5, there was no heterogeneity (p' = 0.54, I2 = 0 %; p' = 0.80, I2 = 0 %) in DFS or DFS/RFS/MFS/PFS.	('MFS', 'Disease', 'MESH:D008382', (110, 113))	('MFS', 'Disease', (110, 113))	('DFS', 'Var', (95, 98))
6935	27926484	These results suggested that high H19 expression could predict an adverse prognosis on DFS or DFS/RFS/MFS/PFS in non-female cancer patients, and predict adverse OS and DFS/RFS/MFS/PFS in non-female cancer patients by pooling meta-analysis.	('high', 'Var', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('predict', 'Reg', (145, 152))	('cancer', 'Disease', (124, 130))	('DFS', 'Var', (87, 90))	('H19', 'Gene', (34, 37))	('MFS', 'Disease', (176, 179))	('cancer', 'Disease', (198, 204))	('expression', 'MPA', (38, 48))	('patients', 'Species', '9606', (205, 213))	('MFS', 'Disease', 'MESH:D008382', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('MFS', 'Disease', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (131, 139))	('H19', 'Gene', '283120', (34, 37))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('MFS', 'Disease', 'MESH:D008382', (176, 179))
6946	27926484	In order to assess the potential prognostic value of H19 expression in female cancers, we analyzed six datasets for female cancers from TCGA, and discovered that high expression of H19 had an unfavorable prognostic influence on OS and RFS in uterine corpus endometrioid cancer and cervical cancer, but not in breast cancer and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', 'MESH:D001943', (309, 322))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('breast cancer', 'Disease', (309, 322))	('high expression', 'Var', (162, 177))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('ovarian cancer', 'Disease', 'MESH:D010051', (327, 341))	('RFS', 'Disease', (235, 238))	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (250, 276))	('H19', 'Gene', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('H19', 'Gene', (53, 56))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (257, 276))	('H19', 'Gene', '283120', (181, 184))	('corpus endometrioid cancer', 'Disease', (250, 276))	('ovarian cancer', 'Disease', (327, 341))	('breast cancer', 'Phenotype', 'HP:0003002', (309, 322))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cervical cancer', 'Disease', (281, 296))	('cervical cancer', 'Disease', 'MESH:D002583', (281, 296))	('cancers', 'Disease', (123, 130))	('ovarian cancer', 'Phenotype', 'HP:0100615', (327, 341))	('H19', 'Gene', '283120', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
6949	27926484	Consistent with some reports that H19 expression could serve as a poor prognostic factor, our results further indicated that high expression of H19 predicted an unfavorable prognosis in non-female cancer patients.	('patients', 'Species', '9606', (204, 212))	('H19', 'Gene', (34, 37))	('H19', 'Gene', '283120', (34, 37))	('H19', 'Gene', '283120', (144, 147))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('H19', 'Gene', (144, 147))	('predicted', 'Reg', (148, 157))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('high', 'Var', (125, 129))
6954	27926484	In conclusion, we found that high lncRNA H19 expression predicted an inferior prognosis in two female cancers (uterine corpus endometrioid cancer and cervical cancer), as well as in non-female cancer patients.	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (119, 145))	('cancer', 'Disease', (193, 199))	('cervical cancer', 'Disease', (150, 165))	('cervical cancer', 'Disease', 'MESH:D002583', (150, 165))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (159, 165))	('H19', 'Gene', '283120', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('corpus endometrioid cancer', 'Disease', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('high', 'Var', (29, 33))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (126, 145))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (102, 108))	('inferior', 'NegReg', (69, 77))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (45, 55))	('H19', 'Gene', (41, 44))
6974	23232571	Pathogenesis and the role of ARID1A mutation in endometriosis-related ovarian neoplasms Endometriosis-related ovarian neoplasms (ERONs) are a unique group of tumors as they are associated with endometriosis, especially endometriosis presenting as an ovarian endometriotic cyst (endometrioma).	('neoplasms', 'Phenotype', 'HP:0002664', (118, 127))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('endometriosis', 'Phenotype', 'HP:0030127', (193, 206))	('ovarian neoplasm', 'Phenotype', 'HP:0100615', (110, 126))	('endometriosis', 'Phenotype', 'HP:0030127', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('ovarian neoplasms', 'Disease', 'MESH:D010051', (70, 87))	('tumors', 'Disease', (158, 164))	('endometrioma', 'Disease', (278, 290))	('ovarian neoplasms', 'Disease', 'MESH:D010051', (110, 127))	('Endometriosis-related ovarian neoplasms', 'Disease', 'MESH:D004715', (88, 127))	('endometriosis', 'Disease', 'MESH:D004715', (219, 232))	('ovarian neoplasm', 'Phenotype', 'HP:0100615', (70, 86))	('endometriosis', 'Disease', (219, 232))	('ovarian neoplasms', 'Disease', (70, 87))	('ovarian endometriotic cyst', 'Disease', (250, 276))	('Endometriosis-related ovarian neoplasms', 'Disease', (88, 127))	('endometrioma', 'Disease', 'MESH:D004715', (278, 290))	('neoplasm', 'Phenotype', 'HP:0002664', (78, 86))	('Endometriosis', 'Phenotype', 'HP:0030127', (88, 101))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('endometriosis', 'Phenotype', 'HP:0030127', (219, 232))	('ovarian neoplasms', 'Phenotype', 'HP:0100615', (70, 87))	('ARID1A', 'Gene', (29, 35))	('endometriosis', 'Disease', 'MESH:D004715', (193, 206))	('ovarian neoplasms', 'Phenotype', 'HP:0100615', (110, 127))	('Pathogenesis', 'biological_process', 'GO:0009405', ('0', '12'))	('endometriosis', 'Disease', (193, 206))	('ovarian endometriotic cyst', 'Disease', 'MESH:D010048', (250, 276))	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('endometriosis', 'Disease', 'MESH:D004715', (48, 61))	('ARID1A', 'Gene', '8289', (29, 35))	('endometriosis', 'Disease', (48, 61))	('associated', 'Reg', (177, 187))	('mutation', 'Var', (36, 44))
6977	23232571	The endometriotic cyst contains abundant iron-induced reactive oxygen species which are thought to be mutagenic, and chronic exposure of cystic epithelium to this microenvironment facilitates the accumulation of somatic mutations that ultimately result in tumor development.	('iron', 'Chemical', 'MESH:D007501', (41, 45))	('somatic mutations', 'Var', (212, 229))	('result in', 'Reg', (246, 255))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (54, 77))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('facilitates', 'PosReg', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('iron', 'Chemical', 'MESH:D007501', (171, 175))	('tumor', 'Disease', (256, 261))
6978	23232571	Molecular analyses of ERONs, including genome-wide screens, have identified several molecular genetic alterations that lead to aberrant activation or inactivation of pathways involving ARID1A, PI3K, Wnt, and PP2A.	('inactivation', 'NegReg', (150, 162))	('PP2A', 'Gene', (208, 212))	('ARID1A', 'Gene', '8289', (185, 191))	('ARID1A', 'Gene', (185, 191))	('PI3K', 'Var', (193, 197))	('activation', 'PosReg', (136, 146))	('pathways', 'Pathway', (166, 174))	('PP2A', 'Gene', '5524', (208, 212))	('PI3K', 'molecular_function', 'GO:0016303', ('193', '197'))	('alterations', 'Var', (102, 113))
6979	23232571	Among all molecular genetic changes identified to date, inactivating mutations of the ARID1A tumor suppressor gene are the most common in ERON.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('common', 'Reg', (128, 134))	('inactivating mutations', 'Var', (56, 78))	('tumor', 'Disease', (93, 98))	('ARID1A', 'Gene', '8289', (86, 92))	('ARID1A', 'Gene', (86, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('ERON', 'Disease', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
6989	23232571	Common molecular genetic alterations in ERON such as PTEN deletion and microsatellite instability can also be detected in the normal-appearing epithelial cells of endometriotic cysts.	('detected', 'Reg', (110, 118))	('ERON', 'Gene', (40, 44))	('endometriotic cysts', 'Disease', 'MESH:D003560', (163, 182))	('PTEN', 'Gene', (53, 57))	('deletion', 'Var', (58, 66))	('microsatellite', 'MPA', (71, 85))	('endometriotic cysts', 'Disease', (163, 182))
6996	23232571	These studies come to the conclusion that somatic ARID1A mutations are uniquely associated with ERONs.	('ERONs', 'Disease', (96, 101))	('mutations', 'Var', (57, 66))	('associated', 'Reg', (80, 90))	('ARID1A', 'Gene', '8289', (50, 56))	('ARID1A', 'Gene', (50, 56))
7045	23232571	It has been thought that DNA damage is the underlying driving force propelling tumor development through creating molecular genetic alterations in several cancer-related genes and the pathways they control.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('alterations', 'Var', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
7046	23232571	We summarize the most common molecular genetic alterations in ERONs with special emphasis on ARID1A mutations in the next section (Fig.	('ARID1A', 'Gene', '8289', (93, 99))	('mutations', 'Var', (100, 109))	('ARID1A', 'Gene', (93, 99))
7048	23232571	report that mutations of PIK3CA occur not only in CCCs but also in the concurrent endometriotic epithelium.	('CCCs', 'Disease', (50, 54))	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', (25, 31))	('PIK3CA', 'Gene', '5290', (25, 31))	('occur', 'Reg', (32, 37))
7049	23232571	Since the mutation is detected even in the associated endometriosis, which lacks cytological atypia, it has been suggested that these mutations occur during the early stage of tumorigenesis in ovarian CCC, i.e., during malignant transformation of endometriosis.	('endometriosis', 'Phenotype', 'HP:0030127', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ovarian CCC', 'Disease', (193, 204))	('tumor', 'Disease', (176, 181))	('endometriosis', 'Disease', 'MESH:D004715', (247, 260))	('CCC', 'cellular_component', 'GO:0030896', ('201', '204'))	('endometriosis', 'Disease', (247, 260))	('ovarian CCC', 'Disease', 'MESH:C535313', (193, 204))	('endometriosis', 'Phenotype', 'HP:0030127', (247, 260))	('mutations', 'Var', (134, 143))	('endometriosis', 'Disease', (54, 67))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('endometriosis', 'Disease', 'MESH:D004715', (54, 67))
7050	23232571	The relatively high frequency of PIK3CA mutations in ovarian CCC contrasts with rare PIK3CA mutations in ovarian high-grade serous carcinoma, the most common and aggressive type of ovarian cancer.	('serous carcinoma', 'Disease', 'MESH:D018284', (124, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (181, 195))	('PIK3CA', 'Gene', '5290', (33, 39))	('ovarian CCC', 'Disease', (53, 64))	('ovarian high', 'Phenotype', 'HP:0008209', (105, 117))	('PIK3CA', 'Gene', '5290', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mutations', 'Var', (40, 49))	('CCC', 'cellular_component', 'GO:0030896', ('61', '64'))	('serous carcinoma', 'Disease', (124, 140))	('ovarian CCC', 'Disease', 'MESH:C535313', (53, 64))	('aggressive type of ovarian cancer', 'Disease', 'MESH:D010051', (162, 195))	('PIK3CA', 'Gene', (33, 39))	('aggressive type of ovarian cancer', 'Disease', (162, 195))	('PIK3CA', 'Gene', (85, 91))
7052	23232571	Loss of heterozygosity at the PTEN locus is reported in both the carcinoma and associated endometriotic cyst epithelium in some cases, suggesting that inactivation of the PTEN tumor suppressor, like mutation of PIK3CA, is a relatively early molecular event in the development of ovarian CCC.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('PIK3CA', 'Gene', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PIK3CA', 'Gene', '5290', (211, 217))	('tumor suppressor', 'biological_process', 'GO:0051726', ('176', '192'))	('carcinoma', 'Disease', (65, 74))	('inactivation', 'Var', (151, 163))	('ovarian CCC', 'Disease', 'MESH:C535313', (279, 290))	('tumor', 'Disease', (176, 181))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('176', '192'))	('CCC', 'cellular_component', 'GO:0030896', ('287', '290'))	('PTEN', 'Gene', (171, 175))	('carcinoma', 'Disease', 'MESH:D002277', (65, 74))	('ovarian CCC', 'Disease', (279, 290))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
7053	23232571	Mutations that are commonly detected in other types of ovarian cancer such as KRAS, BRAF, and TP53 have been found in only a few CCCs.	('ovarian cancer', 'Disease', (55, 69))	('BRAF', 'Gene', '673', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('BRAF', 'Gene', (84, 88))	('TP53', 'Gene', '7157', (94, 98))	('KRAS', 'Gene', (78, 82))	('TP53', 'Gene', (94, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('Mutations', 'Var', (0, 9))	('ovarian cancer', 'Disease', 'MESH:D010051', (55, 69))	('KRAS', 'Gene', '3845', (78, 82))
7060	23232571	In ovarian EC, several molecular genetic alterations have been reported including CTNNB1 and PTEN mutations along with microsatellite instability, of which alterations are also detected in uterine endometrioid carcinoma (Fig.	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (197, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('PTEN', 'Gene', (93, 97))	('endometrioid carcinoma', 'Disease', (197, 219))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (197, 219))	('ovarian EC', 'Disease', (3, 13))	('CTNNB1', 'Gene', (82, 88))	('EC', 'Phenotype', 'HP:0012114', (11, 13))	('detected', 'Reg', (177, 185))	('mutations', 'Var', (98, 107))	('CTNNB1', 'Gene', '1499', (82, 88))	('microsatellite instability', 'MPA', (119, 145))	('ovarian EC', 'Disease', 'MESH:D010051', (3, 13))
7062	23232571	Dysregulation of Wnt/beta-catenin signaling occurs in 16-38% of ovarian ECs, most often as a result of activating mutations of CTNNB1.	('ovarian EC', 'Disease', (64, 74))	('beta-catenin', 'Gene', '1499', (21, 33))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('mutations', 'Var', (114, 123))	('activating', 'PosReg', (103, 113))	('CTNNB1', 'Gene', (127, 133))	('EC', 'Phenotype', 'HP:0012114', (72, 74))	('Dysregulation', 'MPA', (0, 13))	('ovarian EC', 'Disease', 'MESH:D010051', (64, 74))	('beta-catenin', 'Gene', (21, 33))	('CTNNB1', 'Gene', '1499', (127, 133))
7063	23232571	Interestingly, CTNNB1 mutation is highly characteristic of ECs, as CTNNB1 mutation is not found in other types of ovarian carcinoma.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (114, 131))	('mutation', 'Var', (22, 30))	('CTNNB1', 'Gene', (15, 21))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (114, 131))	('ovarian carcinoma', 'Disease', (114, 131))	('CTNNB1', 'Gene', '1499', (67, 73))	('CTNNB1', 'Gene', '1499', (15, 21))	('EC', 'Phenotype', 'HP:0012114', (59, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('ECs', 'Disease', (59, 62))	('CTNNB1', 'Gene', (67, 73))
7064	23232571	On the other hand, PTEN is mutated in 14-20% of ovarian ECs and in 46% of those with loss of heterozygosity (LOH) of 10q23.	('mutated', 'Var', (27, 34))	('ovarian EC', 'Disease', (48, 58))	('PTEN', 'Gene', (19, 23))	('EC', 'Phenotype', 'HP:0012114', (56, 58))	('ovarian EC', 'Disease', 'MESH:D010051', (48, 58))
7065	23232571	Similar to CTNNB1, PTEN mutation is uncommon in other types of ovarian carcinomas.	('CTNNB1', 'Gene', '1499', (11, 17))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (63, 81))	('ovarian carcinomas', 'Disease', (63, 81))	('PTEN', 'Gene', (19, 23))	('CTNNB1', 'Gene', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (63, 81))	('mutation', 'Var', (24, 32))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (63, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))
7066	23232571	It has been reported that 10q23 LOH and PTEN mutations occurred in both endometrioid cysts and adjacent EC, a result supporting a possible precursor role of endometriosis in the carcinogenesis of ovarian ECs.	('LOH', 'NegReg', (32, 35))	('mutations', 'Var', (45, 54))	('endometrioid cysts', 'Disease', (72, 90))	('PTEN', 'Gene', (40, 44))	('endometriosis', 'Phenotype', 'HP:0030127', (157, 170))	('endometriosis in the carcinogenesis of ovarian ECs', 'Disease', 'MESH:D004715', (157, 207))	('EC', 'Phenotype', 'HP:0012114', (204, 206))	('endometriosis in the carcinogenesis of ovarian ECs', 'Disease', (157, 207))	('EC', 'Phenotype', 'HP:0012114', (104, 106))	('10q23', 'Gene', (26, 31))	('occurred', 'Reg', (55, 63))
7067	23232571	Experimentally, Wnt and PI3K/PTEN pathway alterations are sufficient to induce ovarian EC development as evidenced by an engineered mouse model.	('alterations', 'Var', (42, 53))	('ovarian EC', 'Disease', (79, 89))	('induce', 'PosReg', (72, 78))	('EC', 'Phenotype', 'HP:0012114', (87, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('24', '28'))	('PI3K/PTEN pathway', 'Pathway', (24, 41))	('ovarian EC', 'Disease', 'MESH:D010051', (79, 89))	('mouse', 'Species', '10090', (132, 137))
7070	23232571	Among them, somatic ARID1A mutation was independently shown by both studies to be the major molecular genetic change in ERONs.	('mutation', 'Var', (27, 35))	('ARID1A', 'Gene', '8289', (20, 26))	('ARID1A', 'Gene', (20, 26))	('ERONs', 'Disease', (120, 125))
7074	23232571	ARID1A mutation occurs in approximately 50% of ovarian CCC and 40% of ovarian EC, as well as in 30% of uterine endometrioid carcinomas.	('ovarian EC', 'Disease', 'MESH:D010051', (70, 80))	('EC', 'Phenotype', 'HP:0012114', (78, 80))	('CCC', 'cellular_component', 'GO:0030896', ('55', '58'))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (111, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('ARID1A', 'Gene', '8289', (0, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (111, 134))	('ovarian EC', 'Disease', (70, 80))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (111, 133))	('ARID1A', 'Gene', (0, 6))	('ovarian CCC', 'Disease', (47, 58))	('endometrioid carcinomas', 'Disease', (111, 134))	('mutation', 'Var', (7, 15))	('ovarian CCC', 'Disease', 'MESH:C535313', (47, 58))	('occurs', 'Reg', (16, 22))
7075	23232571	Although SMARCA4 mutations are not detected in CCC, it has been recently shown that lung adenocarcinomas harboring ARID1A mutations usually do not have SMARCA4 mutations and vice versa, indicating the ARID1A/Brg1 complex is important for tumor suppression.	('mutations', 'Var', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('ARID1A', 'Gene', '8289', (115, 121))	('SMARCA4', 'Gene', (152, 159))	('SMARCA4', 'Gene', (9, 16))	('ARID1A', 'Gene', (201, 207))	('Brg1', 'Gene', (208, 212))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (84, 104))	('ARID1A', 'Gene', '8289', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('Brg1', 'Gene', '6597', (208, 212))	('tumor', 'Disease', (238, 243))	('SMARCA4', 'Gene', '6597', (152, 159))	('SMARCA4', 'Gene', '6597', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('CCC', 'cellular_component', 'GO:0030896', ('47', '50'))	('lung adenocarcinomas', 'Disease', (84, 104))	('mutations', 'Var', (122, 131))	('ARID1A', 'Gene', (115, 121))
7076	23232571	ARID1A mutations occur randomly in the coding regions, the great majority being frameshift and nonsense, leading to lost expression of ARID1A, suggesting that ARID1A is a tumor suppressor gene (Fig.	('nonsense', 'Var', (95, 103))	('lost', 'NegReg', (116, 120))	('frameshift', 'Var', (80, 90))	('ARID1A', 'Gene', '8289', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('expression', 'MPA', (121, 131))	('ARID1A', 'Gene', '8289', (159, 165))	('ARID1A', 'Gene', (0, 6))	('ARID1A', 'Gene', (159, 165))	('ARID1A', 'Gene', '8289', (135, 141))	('ARID1A', 'Gene', (135, 141))	('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'))	('mutations', 'Var', (7, 16))
7078	23232571	As expected, inactivating mutations of ARID1A and TP53 are functionally synonymous, as mutations in either TP53 or ARID1A abolish the transcription of their target tumor suppressors such as CDKN1A, allowing uncontrolled cellular proliferation in ERONs.	('CDKN1A', 'Gene', (190, 196))	('abolish', 'NegReg', (122, 129))	('tumor', 'Disease', (164, 169))	('transcription', 'MPA', (134, 147))	('CDKN1A', 'Gene', '1026', (190, 196))	('allowing', 'Reg', (198, 206))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('TP53', 'Gene', '7157', (50, 54))	('ARID1A', 'Gene', '8289', (115, 121))	('ARID1A', 'Gene', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('TP53', 'Gene', (50, 54))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('ARID1A', 'Gene', '8289', (39, 45))	('mutations', 'Var', (87, 96))	('ARID1A', 'Gene', (39, 45))
7079	23232571	Of note, co-occurrence of ARID1A and TP53 mutations can be found in other cancer types  and thus the mutual exclusive nature of ARID1A and TP53 mutations may be tumor type dependent.	('ARID1A', 'Gene', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TP53', 'Gene', '7157', (139, 143))	('TP53', 'Gene', '7157', (37, 41))	('cancer', 'Disease', (74, 80))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('ARID1A', 'Gene', '8289', (128, 134))	('TP53', 'Gene', (139, 143))	('ARID1A', 'Gene', (128, 134))	('TP53', 'Gene', (37, 41))	('tumor', 'Disease', (161, 166))	('ARID1A', 'Gene', '8289', (26, 32))
7080	23232571	The fact that frameshift and non-sense mutations result in loss of ARID1A expression is clear, as those mutants produce truncated mRNAs that are readily degraded.	('expression', 'MPA', (74, 84))	('frameshift', 'Var', (14, 24))	('mutants', 'Var', (104, 111))	('loss', 'NegReg', (59, 63))	('ARID1A', 'Gene', '8289', (67, 73))	('truncated mRNAs', 'MPA', (120, 135))	('ARID1A', 'Gene', (67, 73))
7082	23232571	A very recent study using biochemical assays demonstrates that, like frameshift mutations, the in-frame mutations that have been analyzed also lose their ability to inhibit cellular proliferation or to activate transcription of p21, a downstream effector of ARID1A.	('mutations', 'Var', (104, 113))	('ARID1A', 'Gene', '8289', (258, 264))	('activate', 'PosReg', (202, 210))	('ARID1A', 'Gene', (258, 264))	('cellular proliferation', 'CPA', (173, 195))	('p21', 'Gene', '1026', (228, 231))	('transcription', 'biological_process', 'GO:0006351', ('211', '224'))	('p21', 'Gene', (228, 231))	('lose', 'NegReg', (143, 147))	('transcription', 'MPA', (211, 224))	('inhibit', 'NegReg', (165, 172))
7083	23232571	Given that ARID1A mutation is associated with loss of its expression, undetectable ARID1A immunoreactivity has been proposed as a surrogate marker for the presence of inactivating ARID1A mutations in tissues.	('loss', 'NegReg', (46, 50))	('expression', 'MPA', (58, 68))	('ARID1A', 'Gene', '8289', (11, 17))	('ARID1A', 'Gene', (11, 17))	('ARID1A', 'Gene', '8289', (83, 89))	('ARID1A', 'Gene', (83, 89))	('ARID1A', 'Gene', '8289', (180, 186))	('mutation', 'Var', (18, 26))	('ARID1A', 'Gene', (180, 186))
7085	23232571	However, we have correlated ARID1A mutational status and immunoreactivity in a series of cases and show that all tumors harboring ARID1A mutations in one or both alleles lose ARID1A immunoreactivity either completely or clonally (Fig.	('ARID1A', 'Gene', '8289', (130, 136))	('ARID1A', 'Gene', '8289', (175, 181))	('ARID1A', 'Gene', (130, 136))	('ARID1A', 'Gene', (175, 181))	('lose', 'NegReg', (170, 174))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('ARID1A', 'Gene', '8289', (28, 34))	('ARID1A', 'Gene', (28, 34))	('mutations', 'Var', (137, 146))	('immunoreactivity', 'MPA', (182, 198))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
7088	23232571	The role of ARID1A inactivation in early molecular pathogenesis of CCC is illustrated in two recent reports.	('pathogenesis', 'biological_process', 'GO:0009405', ('51', '63'))	('CCC', 'Disease', (67, 70))	('ARID1A', 'Gene', '8289', (12, 18))	('inactivation', 'Var', (19, 31))	('ARID1A', 'Gene', (12, 18))	('CCC', 'cellular_component', 'GO:0030896', ('67', '70'))
7094	23232571	However, some reports document a loss of ARID1A expression in 15%-20% of such cases., 75 Taken together, similarly to mutations in PTEN and PIK3CA, the evidence indicates that loss of ARID1A expression, presumably due to mutations, is an early molecular event in the development of the majority of ERONs.	('PIK3CA', 'Gene', (140, 146))	('loss', 'Var', (176, 180))	('ARID1A', 'Gene', '8289', (41, 47))	('ARID1A', 'Gene', '8289', (184, 190))	('ARID1A', 'Gene', (41, 47))	('PIK3CA', 'Gene', '5290', (140, 146))	('ARID1A', 'Gene', (184, 190))
7099	23232571	Moreover, somatic ARID1A mutations were detected in 2 representative SMBTs, which showed complete loss of ARID1A.	('mutations', 'Var', (25, 34))	('SMBTs', 'Chemical', '-', (69, 74))	('ARID1A', 'Gene', '8289', (106, 112))	('ARID1A', 'Gene', (106, 112))	('ARID1A', 'Gene', '8289', (18, 24))	('loss', 'NegReg', (98, 102))	('ARID1A', 'Gene', (18, 24))
7100	23232571	The loss of expression of ARID1A and the presence of inactivating mutations of ARID1A further link this tumor to CCC and EC, and provide molecular evidence that SMBT is a member of ERON.	('loss of', 'NegReg', (4, 11))	('ARID1A', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('SMBT', 'Chemical', '-', (161, 165))	('EC', 'Phenotype', 'HP:0012114', (121, 123))	('tumor', 'Disease', (104, 109))	('expression', 'MPA', (12, 22))	('CCC', 'cellular_component', 'GO:0030896', ('113', '116'))	('inactivating mutations', 'Var', (53, 75))	('ARID1A', 'Gene', '8289', (79, 85))	('ARID1A', 'Gene', (79, 85))	('ARID1A', 'Gene', '8289', (26, 32))	('CCC', 'Disease', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
7103	23232571	ERONs are characterized by common molecular genetic changes that involve ARID1A, PI3K, and PP2A pathways, but they also have unique molecular changes such as microsatellite instability and CTNNB1 mutations, which occur in ovarian EC, and overexpression of HNF-1beta, which is found in CCC.	('PP2A', 'Gene', '5524', (91, 95))	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('CTNNB1', 'Gene', '1499', (189, 195))	('overexpression', 'PosReg', (238, 252))	('PP2A', 'Gene', (91, 95))	('ovarian EC', 'Disease', 'MESH:D010051', (222, 232))	('EC', 'Phenotype', 'HP:0012114', (230, 232))	('HNF-1beta', 'Gene', '6928', (256, 265))	('HNF-1beta', 'Gene', (256, 265))	('CTNNB1', 'Gene', (189, 195))	('PI3K', 'Pathway', (81, 85))	('ARID1A', 'Gene', '8289', (73, 79))	('ovarian EC', 'Disease', (222, 232))	('ARID1A', 'Gene', (73, 79))	('CCC', 'cellular_component', 'GO:0030896', ('285', '288'))	('mutations', 'Var', (196, 205))	('microsatellite instability', 'MPA', (158, 184))
7104	23232571	It would be of considerable interest to determine the molecular switch that dictates the development of different types of ERON, and to determine how those early molecular alterations including ARID1A, PTEN, and PIK3CA mutations collaborate in driving neoplastic transformation from an endometriotic cyst to an ERON.	('driving', 'Reg', (244, 251))	('PIK3CA', 'Gene', (212, 218))	('dictates', 'Reg', (76, 84))	('endometriotic cyst', 'Disease', (286, 304))	('ARID1A', 'Gene', '8289', (194, 200))	('neoplastic transformation', 'CPA', (252, 277))	('ARID1A', 'Gene', (194, 200))	('PTEN', 'Gene', (202, 206))	('PIK3CA', 'Gene', '5290', (212, 218))	('mutations', 'Var', (219, 228))
7109	30155248	The immunohistochemical markers used were estrogen receptor (ER), Ki-67 and p53.	('estrogen receptor', 'Gene', (42, 59))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('estrogen receptor', 'Gene', '2099', (42, 59))	('Ki-67', 'Var', (66, 71))	('ER', 'Gene', '2099', (61, 63))
7110	30155248	Accordingly, the patients were divided into groups as follows: 54 cases type I vs. 25 cases type II; 48 cases with myometrial invasion <1/2 vs. 31 cases without myometrial invasion >=1/2; 63 cases with lymphovascular invasion vs. 16 cases without lymphovascular invasion; 57 cases with ER (+) vs. 22 cases with ER (-); 24 cases with Ki-67 (+) vs. 55 cases with Ki-67 (-); and 29 cases with p53 (+) vs. 50 cases with p53 (-).	('p53', 'Gene', '7157', (416, 419))	('ER', 'Gene', '2099', (286, 288))	('Ki-67', 'Var', (361, 366))	('p53', 'Gene', (390, 393))	('patients', 'Species', '9606', (17, 25))	('p53', 'Gene', '7157', (390, 393))	('Ki-67 (+', 'Var', (333, 341))	('ER', 'Gene', '2099', (311, 313))	('p53', 'Gene', (416, 419))
7136	30155248	The sections were incubated with the following primary antibodies: ER (rabbit monoclonal, clone SP1, 1:1, Ventana, Tucson, AZ, USA); Ki-67 (mouse monoclonal, clone MIB-1, 1:50, Dako, Glostrup, Denmark), and p53 (mouse monoclonal, clone DO-7, 1:50, Dako).	('mouse', 'Species', '10090', (140, 145))	('MIB-1, 1', 'Gene', '57534', (164, 172))	('rabbit', 'Species', '9986', (71, 77))	('SP1, 1:1', 'Gene', '6667', (96, 104))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('ER', 'Gene', '2099', (67, 69))	('Ki-67', 'Var', (133, 138))	('mouse', 'Species', '10090', (212, 217))
7139	30155248	The immunoexpression of ER, Ki-67 and p53 was semi-quantitatively evaluated as low (-) or high (+) as follows: ER (-) <30% vs. (+) >=30%; Ki-67 (-) <30% vs. (+) >=30%; and p53 (-) <80% vs. (+) >=80%.	('p53', 'Gene', (38, 41))	('ER', 'Gene', '2099', (24, 26))	('Ki-67', 'Var', (138, 143))	('p53', 'Gene', '7157', (38, 41))	('ER', 'Gene', '2099', (111, 113))	('p53', 'Gene', '7157', (172, 175))	('p53', 'Gene', (172, 175))
7142	30155248	1 and Table I), 57 cases had ER (+) vs. 22 cases with ER (-); 24 cases had Ki-67 (+) vs. 55 cases with Ki-67 (-); 29 cases had p53 (+) vs. 50 cases with p53 (-).	('p53', 'Gene', '7157', (127, 130))	('ER', 'Gene', '2099', (29, 31))	('p53', 'Gene', '7157', (153, 156))	('p53', 'Gene', (153, 156))	('ER', 'Gene', '2099', (54, 56))	('Ki-67', 'Var', (75, 80))	('p53', 'Gene', (127, 130))
7143	30155248	The percentage of cases with ER (+), Ki-67 (+) and p53 (+) for type I EMC was 85.2, 25.9 and 25.9 %, respectively, and for type II, 44, 40 and 60%, respectively.	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', (51, 54))	('EMC', 'cellular_component', 'GO:0072546', ('70', '73'))	('Ki-67 (+', 'Var', (37, 45))	('EMC', 'Phenotype', 'HP:0012114', (70, 73))	('ER', 'Gene', '2099', (29, 31))
7161	30155248	p53 mutations are found in 5-10% of all endometrioid carcinomas, but occur in 50% of endometrioid carcinomas G3, and even more frequently (90%) in serous carcinoma.	('found', 'Reg', (18, 23))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (40, 62))	('serous carcinoma', 'Disease', 'MESH:D018284', (147, 163))	('p53', 'Gene', '7157', (0, 3))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (85, 108))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (40, 63))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (85, 107))	('p53', 'Gene', (0, 3))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('endometrioid carcinomas', 'Disease', (40, 63))	('mutations', 'Var', (4, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('serous carcinoma', 'Disease', (147, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('endometrioid carcinomas', 'Disease', (85, 108))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (40, 63))
7238	28984210	Figure 4c shows the percentage of samples with mutations of the 32 TargetCancer genes, their function classification, and number of targeting drugs.	('Cancer', 'Disease', (73, 79))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (47, 56))
7239	28984210	Indeed, for the 32 Target Cancer genes, there was a significant correlation between the percentages of samples with mutations and numbers of targeted drugs (Pearson's correlation: r = 0.40, P = 0.0230).	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (116, 125))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Disease', (26, 32))
7241	28984210	Its mutations significantly occur in the brain cancer GBM (27.1%), lung cancer (13.5%), COAD/READ (5.8%), HNSC (6.2%).	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('occur', 'Reg', (28, 33))	('brain cancer', 'Disease', 'MESH:D001932', (41, 53))	('COAD', 'Disease', 'MESH:D029424', (88, 92))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('brain cancer', 'Phenotype', 'HP:0030692', (41, 53))	('READ', 'Disease', 'None', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (4, 13))	('brain cancer', 'Disease', (41, 53))	('COAD', 'Disease', (88, 92))	('lung cancer', 'Disease', (67, 78))	('HNSC', 'Disease', (106, 110))	('READ', 'Disease', (93, 97))
7365	27139150	Finally, the term "mixed epithelial carcinoma" has in some cases been used to describe tumors with ambiguous features of both endometrioid and serous carcinomas; there are indications that many of these are instead microsatellite instability - high endometrioid carcinomas or those with POLE mutations.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('serous carcinomas', 'Disease', (143, 160))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (249, 272))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('carcinomas', 'Phenotype', 'HP:0030731', (262, 272))	('epithelial carcinoma', 'Disease', (25, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tumors', 'Disease', (87, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('endometrioid carcinomas', 'Disease', (249, 272))	('serous carcinomas', 'Disease', 'MESH:D018284', (143, 160))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (25, 45))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (25, 45))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (249, 271))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('microsatellite instability - high', 'Var', (215, 248))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (249, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))
7377	27139150	However, notable nuclear atypia in grade 1 or 2 tumors raises the grade by 1.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('nuclear atypia', 'Var', (17, 31))	('raises', 'PosReg', (55, 61))	('grade', 'MPA', (66, 71))
7386	27139150	Among the histology subtypes, G3EC had a higher proportion of patients with lymphovascular invasion and recurrent disease.	('recurrent disease', 'CPA', (104, 121))	('lymphovascular invasion', 'CPA', (76, 99))	('G3EC', 'Var', (30, 34))	('patients', 'Species', '9606', (62, 70))	('EC', 'Phenotype', 'HP:0012114', (32, 34))
7387	27139150	The proportion of patients who died was higher given a consensus diagnosis of GE3C, compared to tumors with a reclassified diagnosis.	('GE3C', 'Var', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('patients', 'Species', '9606', (18, 26))
7404	22976498	Molecular genetic alterations such as PTEN deletion and microsatellite instability, which occur in clear cell and endometrioid carcinomas, can be detected in the epithelial cells of endometriotic cysts  and a clonal relationship between endometriosis and endometriosis-related ovarian carcinomas has been demonstrated in several studies .	('endometriosis', 'Disease', 'MESH:D004715', (237, 250))	('endometriosis', 'Disease', (237, 250))	('endometriosis-related ovarian carcinomas', 'Disease', 'MESH:D004715', (255, 295))	('endometriosis', 'Phenotype', 'HP:0030127', (255, 268))	('PTEN', 'Gene', '5728', (38, 42))	('microsatellite', 'MPA', (56, 70))	('endometrioid carcinomas', 'Disease', (114, 137))	('endometriosis', 'Phenotype', 'HP:0030127', (237, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('carcinomas', 'Phenotype', 'HP:0030731', (285, 295))	('endometriosis-related ovarian carcinomas', 'Disease', (255, 295))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (114, 137))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (277, 295))	('deletion', 'Var', (43, 51))	('endometriosis', 'Disease', 'MESH:D004715', (255, 268))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (114, 136))	('endometriosis', 'Disease', (255, 268))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (114, 137))	('PTEN', 'Gene', (38, 42))
7410	22976498	The great majority of ARID1A mutations are non-sense, frameshift, and in-frame mutations, leading to loss of expression of BAF250a.	('BAF250a', 'Gene', '8289', (123, 130))	('expression', 'MPA', (109, 119))	('loss', 'NegReg', (101, 105))	('mutations', 'Var', (29, 38))	('frameshift', 'Var', (54, 64))	('ARID1A', 'Gene', (22, 28))	('BAF250a', 'Gene', (123, 130))	('ARID1A', 'Gene', '8289', (22, 28))	('non-sense', 'Var', (43, 52))
7411	22976498	Accordingly, loss of expression of ARID1A (BAF250a) immunoreactivity can be used as a surrogate marker for ARID1A inactivating mutations in formalin fixed, paraffin embedded tissue .	('BAF250a', 'Gene', '8289', (43, 50))	('ARID1A', 'Gene', '8289', (107, 113))	('ARID1A', 'Gene', (107, 113))	('expression', 'MPA', (21, 31))	('inactivating mutations', 'Var', (114, 136))	('paraffin', 'Chemical', 'MESH:D010232', (156, 164))	('formalin', 'Chemical', 'MESH:D005557', (140, 148))	('ARID1A', 'Gene', '8289', (35, 41))	('ARID1A', 'Gene', (35, 41))	('BAF250a', 'Gene', (43, 50))	('loss of', 'NegReg', (13, 20))
7429	22976498	Since previous studies demonstrated that loss of nuclear expression generally correlated with mutation of the ARID1A gene , absence of nuclear staining was interpreted as a presumable ARID1A mutation.	('mutation', 'Var', (94, 102))	('ARID1A', 'Gene', '8289', (184, 190))	('ARID1A', 'Gene', (184, 190))	('ARID1A', 'Gene', '8289', (110, 116))	('ARID1A', 'Gene', (110, 116))	('correlated', 'Reg', (78, 88))	('nuclear expression', 'MPA', (49, 67))	('loss', 'NegReg', (41, 45))
7450	22976498	Inactivating ARIDIA mutations are the most common molecular genetic alteration reported thus far in ovarian clear cell and endometrioid carcinomas.	('ARIDIA', 'Gene', (13, 19))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (123, 146))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (123, 145))	('ovarian clear cell and endometrioid carcinomas', 'Disease', 'MESH:D016889', (100, 146))	('Inactivating', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('mutations', 'Var', (20, 29))
7451	22976498	These mutations result in loss of expression of the protein encoded by ARID1A (BAF250a) which normally suppresses cellular proliferation through a p53-dependent transcription regulation of several tumor suppressors including CDKN1A (encoding p21) and SMAD3 .	('expression', 'MPA', (34, 44))	('BAF250a', 'Gene', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('p21', 'Gene', '1026', (242, 245))	('SMAD3', 'Gene', (251, 256))	('regulation', 'biological_process', 'GO:0065007', ('175', '185'))	('CDKN1A', 'Gene', (225, 231))	('CDKN1A', 'Gene', '1026', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('suppresses', 'NegReg', (103, 113))	('ARID1A', 'Gene', (71, 77))	('mutations', 'Var', (6, 15))	('BAF250a', 'Gene', '8289', (79, 86))	('p21', 'Gene', (242, 245))	('loss', 'NegReg', (26, 30))	('ARID1A', 'Gene', '8289', (71, 77))	('p53', 'Gene', '7157', (147, 150))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('cellular proliferation', 'CPA', (114, 136))	('transcription', 'biological_process', 'GO:0006351', ('161', '174'))	('SMAD3', 'Gene', '4088', (251, 256))	('tumor', 'Disease', (197, 202))	('p53', 'Gene', (147, 150))
7453	22976498	Delineating the "timing" of ARID1A mutations is not only of biologic interest but also has important clinical implications.	('ARID1A', 'Gene', '8289', (28, 34))	('ARID1A', 'Gene', (28, 34))	('mutations', 'Var', (35, 44))
7458	22976498	Like ARID1A mutation, inactivation of the PTEN tumor suppressor gene and activation of PIK3CA due to somatic mutations have also been reported as early events in the development of endometriosis-related carcinomas since loss of PTEN is observed in endometriotic cysts associated with and without carcinoma  and activating PIK3CA mutation is detected in endometriotic cysts associated with carcinoma .	('PIK3CA', 'Gene', (322, 328))	('ARID1A', 'Gene', (5, 11))	('carcinoma', 'Disease', (296, 305))	('endometriosis', 'Disease', 'MESH:D004715', (181, 194))	('PTEN', 'Gene', (228, 232))	('endometriosis', 'Disease', (181, 194))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('carcinoma', 'Disease', 'MESH:D002277', (203, 212))	('ARID1A', 'Gene', '8289', (5, 11))	('carcinomas', 'Disease', (203, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (389, 398))	('endometriosis', 'Phenotype', 'HP:0030127', (181, 194))	('PTEN', 'Gene', '5728', (228, 232))	('carcinoma', 'Disease', (389, 398))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('carcinoma', 'Disease', 'MESH:D002277', (296, 305))	('PTEN', 'Gene', (42, 46))	('PIK3CA', 'Gene', '5290', (87, 93))	('PIK3CA', 'Gene', '5290', (322, 328))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('endometriotic cysts', 'Disease', (248, 267))	('tumor', 'Disease', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))	('carcinomas', 'Disease', 'MESH:D002277', (203, 213))	('PTEN', 'Gene', '5728', (42, 46))	('carcinoma', 'Disease', (203, 212))	('carcinoma', 'Disease', 'MESH:D002277', (389, 398))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))	('PIK3CA', 'Gene', (87, 93))	('mutation', 'Var', (12, 20))	('activating', 'PosReg', (311, 321))	('loss', 'NegReg', (220, 224))
7459	22976498	Although the factors that might be responsible for the development of mutations of ARID1A, PIK3CA and PTEN in endometriotic cyst epithelium remain unclear, it is conceivable that "incessant menstruation" associated with endometriosis leads to repeated episodes of hemorrhage and inflammation which may facilitate the accumulation of oxygen free radical species and other genotoxic molecules within the cysts that contribute to malignant transformation .	('PIK3CA', 'Gene', (91, 97))	('inflammation', 'Disease', (279, 291))	('hemorrhage', 'Disease', (264, 274))	('mutations', 'Var', (70, 79))	('facilitate', 'PosReg', (302, 312))	('hemorrhage', 'Disease', 'MESH:D006470', (264, 274))	('endometriosis', 'Disease', 'MESH:D004715', (220, 233))	('PIK3CA', 'Gene', '5290', (91, 97))	('inflammation', 'Disease', 'MESH:D007249', (279, 291))	('endometriosis', 'Disease', (220, 233))	('ARID1A', 'Gene', '8289', (83, 89))	('endometriosis', 'Phenotype', 'HP:0030127', (220, 233))	('ARID1A', 'Gene', (83, 89))	('accumulation', 'PosReg', (317, 329))	('oxygen free radical species', 'MPA', (333, 360))	('PTEN', 'Gene', (102, 106))	('oxygen free radical', 'Chemical', '-', (333, 352))	('PTEN', 'Gene', '5728', (102, 106))
7460	22976498	High concentration of free iron in the fluid of endometriotic cysts has been proposed to be responsible for iron-induced persistent oxidative stress and for induction of mutations in endometriotic cyst epithelium .	('iron', 'Chemical', 'MESH:D007501', (27, 31))	('mutations', 'Var', (170, 179))	('iron', 'Chemical', 'MESH:D007501', (108, 112))	('endometriotic cyst epithelium', 'Gene', (183, 212))	('persistent oxidative stress', 'MPA', (121, 148))	('oxidative stress', 'Phenotype', 'HP:0025464', (132, 148))
7462	22976498	That epidemiological study reported frequent association of loss of ARID1A expression with self-reported endometriosis but clearly did include histologic confirmation.	('ARID1A', 'Gene', '8289', (68, 74))	('association', 'Interaction', (45, 56))	('ARID1A', 'Gene', (68, 74))	('endometriosis', 'Phenotype', 'HP:0030127', (105, 118))	('loss', 'Var', (60, 64))	('endometriosis', 'Disease', 'MESH:D004715', (105, 118))	('expression', 'MPA', (75, 85))	('endometriosis', 'Disease', (105, 118))
7474	22976498	Future studies of women with endometriosis, particularly endometriotic cysts, should evaluate if molecular testing including ARID1A expression and mutation as well as molecular changes in PTEN and PIK3CA (by analyzing endometrioma content, for example) is useful in identifying women at a higher risk of developing clear cell or endometrioid carcinoma .	('PIK3CA', 'Gene', (197, 203))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (329, 351))	('mutation', 'Var', (147, 155))	('clear cell', 'Disease', (315, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('endometrioma', 'Disease', 'MESH:D004715', (218, 230))	('PTEN', 'Gene', '5728', (188, 192))	('endometriosis', 'Disease', 'MESH:D004715', (29, 42))	('women', 'Species', '9606', (278, 283))	('endometriosis', 'Disease', (29, 42))	('endometrioid carcinoma', 'Disease', (329, 351))	('endometriosis', 'Phenotype', 'HP:0030127', (29, 42))	('PIK3CA', 'Gene', '5290', (197, 203))	('ARID1A', 'Gene', (125, 131))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (329, 351))	('endometrioma', 'Disease', (218, 230))	('ARID1A', 'Gene', '8289', (125, 131))	('PTEN', 'Gene', (188, 192))	('women', 'Species', '9606', (18, 23))
7521	33242930	When surgical staging was taken into consideration, the LN dissected group had a better prognosis than the non-dissected group in all surgical stages, except for stage Ia.	('LN dissected', 'Var', (56, 68))	('age', 'Gene', (164, 167))	('age', 'Gene', (145, 148))	('age', 'Gene', '5973', (164, 167))	('age', 'Gene', '5973', (145, 148))
7522	33242930	Considering the surgical stage and histological type, the LN dissected group had a better prognosis than the non-dissected group at all surgical stages, except for stage Ia G1 and stage Ia G2.	('age', 'Gene', (147, 150))	('age', 'Gene', '5973', (166, 169))	('age', 'Gene', (182, 185))	('age', 'Gene', (27, 30))	('age', 'Gene', '5973', (182, 185))	('age', 'Gene', '5973', (147, 150))	('age', 'Gene', (166, 169))	('age', 'Gene', '5973', (27, 30))	('LN dissected', 'Var', (58, 70))
7532	33242930	However, in the intermediate- and high-risk groups, the 5-year RFS rate was 64.8% and 80.7%, and the 5-year OS rate was 72.6% and 83.2%, in the groups that underwent PLN alone and PLN+PAN, respectively.	('PAN', 'cellular_component', 'GO:0022623', ('184', '187'))	('RFS', 'Disease', (63, 66))	('RFS', 'Disease', 'MESH:D005198', (63, 66))	('PLN', 'Chemical', '-', (166, 169))	('PLN+PAN', 'Var', (180, 187))	('PLN', 'Chemical', '-', (180, 183))
7533	33242930	The RFS and OS rates were, therefore, significantly better in the PLN+PAN group than in the PLN alone group.	('PLN', 'Chemical', '-', (92, 95))	('PAN', 'cellular_component', 'GO:0022623', ('70', '73'))	('PLN+PAN', 'Var', (66, 73))	('PLN', 'Chemical', '-', (66, 69))	('RFS', 'Disease', (4, 7))	('better', 'PosReg', (52, 58))	('RFS', 'Disease', 'MESH:D005198', (4, 7))
7550	29189288	Next-generation sequencing using 12 samples (11 primary tumors and 1 metastatic tumor) revealed 42 single nucleotide variations in 16 genes, mostly in KRAS (10/12) and ARID1A (9/12).	('single nucleotide variations', 'Var', (99, 127))	('KRAS', 'Gene', '3845', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('ARID1A', 'Gene', '8289', (168, 174))	('ARID1A', 'Gene', (168, 174))	('tumor', 'Disease', (80, 85))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('KRAS', 'Gene', (151, 155))
7559	29189288	A recent study that used next-generation sequencing (NGS) for targeted genomic profiling reported that the majority of MNAC examined harbored KRAS mutation, suggesting that KRAS mutation is involved in MNAC development.	('KRAS', 'Gene', (142, 146))	('MNAC', 'Disease', (119, 123))	('harbored', 'Reg', (133, 141))	('mutation', 'Var', (147, 155))	('KRAS', 'Gene', '3845', (142, 146))	('KRAS', 'Gene', (173, 177))	('KRAS', 'Gene', '3845', (173, 177))
7584	29189288	The p53 immunostaining pattern was interpreted as a missense-mutation, nonsense-mutation, or wild-type pattern when p53 expression was diffuse and strong (>60% of tumor cell nuclei), absent (<5%), or focal and weakly positive, respectively.	('p53', 'Gene', '7157', (4, 7))	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('absent', 'NegReg', (183, 189))	('p53', 'Gene', '7157', (116, 119))	('tumor', 'Disease', (163, 168))	('missense-mutation', 'Var', (52, 69))	('nonsense-mutation', 'Var', (71, 88))	('p53', 'Gene', (4, 7))	('p53', 'Gene', (116, 119))
7587	29189288	Single nucleotide variants (SNVs) and insertions and deletions (indels) were identified using MuTect (http://archive.broadinstitute.org/cancer/cga/mutect) and Pindel (http://gmt.genome.wustl.edu/packages/pindel/), respectively.	('cga', 'Gene', (143, 146))	('deletions', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('gmt', 'molecular_function', 'GO:0033804', ('174', '177'))	('cancer', 'Disease', (136, 142))	('cga', 'Gene', '1113', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
7663	29189288	The most commonly detected SNV in UB-MNAC was activating KRAS mutation (10/12), including G12V (6/12), G12C (2/12), and G12D (2/12).	('G12V', 'Mutation', 'rs121913529', (90, 94))	('G12C', 'Var', (103, 107))	('G12C', 'Mutation', 'rs121913530', (103, 107))	('G12D', 'Var', (120, 124))	('KRAS', 'Gene', (57, 61))	('G12D', 'Mutation', 'rs121913529', (120, 124))	('KRAS', 'Gene', '3845', (57, 61))	('activating', 'PosReg', (46, 56))	('G12V', 'Var', (90, 94))	('UB-MNAC', 'Chemical', '-', (34, 41))
7664	29189288	The second most common SNV was ARID1A mutation (9/12), including T294P (6/12), Q288P (2/12), and Q287Pfs (1/12).	('Q288P', 'Var', (79, 84))	('T294P', 'Var', (65, 70))	('ARID1A', 'Gene', '8289', (31, 37))	('T294P', 'Mutation', 'p.T294P', (65, 70))	('ARID1A', 'Gene', (31, 37))	('Q287Pfs', 'Var', (97, 104))	('Q288P', 'Mutation', 'p.Q288P', (79, 84))
7666	29189288	Of note, primary (case 13A) and metastatic (case 13B) tumors exhibited identical mutations in KRAS and ARID1A and shared the same CNV pattern.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('KRAS', 'Gene', (94, 98))	('ARID1A', 'Gene', '8289', (103, 109))	('metastatic', 'CPA', (32, 42))	('ARID1A', 'Gene', (103, 109))	('KRAS', 'Gene', '3845', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
7667	29189288	Additional PTEN mutation (D268E) was detected in metastatic tumor only, indicating that PTEN mutation is a relatively late event in the sequence of genetic alterations in UB-MNAC.	('PTEN', 'Gene', (11, 15))	('UB-MNAC', 'Gene', (171, 178))	('PTEN', 'Gene', '5728', (11, 15))	('D268E', 'Var', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PTEN', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PTEN', 'Gene', '5728', (88, 92))	('D268E', 'Mutation', 'rs398123328', (26, 31))	('UB-MNAC', 'Chemical', '-', (171, 178))	('tumor', 'Disease', (60, 65))
7706	29189288	In this study, analyses of NGS data revealed that 10/12 cases of UB-MNAC harbored activating KRAS mutation.	('KRAS', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('activating', 'PosReg', (82, 92))	('KRAS', 'Gene', '3845', (93, 97))	('UB-MNAC', 'Chemical', '-', (65, 72))
7707	29189288	This finding is consistent with previous observations by Mirkovic et al, who reported activating KRAS and NRAS mutations in 12/17 and 1/17 cases of MNAC, respectively.	('mutations', 'Var', (111, 120))	('KRAS', 'Gene', (97, 101))	('KRAS', 'Gene', '3845', (97, 101))	('NRAS', 'Gene', (106, 110))	('activating', 'PosReg', (86, 96))	('MNAC', 'Disease', (148, 152))	('NRAS', 'Gene', '4893', (106, 110))
7708	29189288	Considering that the majority (12/17) of tumor samples in their report were of cervical origin, KRAS mutation appears to be a driver mutation in MNAC of either UC or corpus.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('UC', 'Phenotype', 'HP:0030160', (160, 162))	('KRAS', 'Gene', '3845', (96, 100))	('mutation', 'Var', (101, 109))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('KRAS', 'Gene', (96, 100))
7709	29189288	In addition, we found that 9/12 cases harbored ARID1A mutation.	('mutation', 'Var', (54, 62))	('ARID1A', 'Gene', '8289', (47, 53))	('ARID1A', 'Gene', (47, 53))	('harbored', 'Reg', (38, 46))
7710	29189288	In line with this finding, Mirkovic et al reported ARID1A mutation in 6/17 cases.	('mutation', 'Var', (58, 66))	('ARID1A', 'Gene', '8289', (51, 57))	('reported', 'Reg', (42, 50))	('ARID1A', 'Gene', (51, 57))
7711	29189288	The most common ARID1A mutation in UB-MNAC was T294P, which has been also reported in endometrial endometrioid carcinoma, serous carcinoma, and carcinosarcoma.	('UB-MNAC', 'Chemical', '-', (35, 42))	('T294P', 'Mutation', 'p.T294P', (47, 52))	('carcinosarcoma', 'Disease', 'MESH:D002296', (144, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('UB-MNAC', 'Gene', (35, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinosarcoma', 'Disease', (144, 158))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (86, 120))	('endometrial endometrioid carcinoma', 'Disease', (86, 120))	('serous carcinoma', 'Disease', (122, 138))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (98, 120))	('serous carcinoma', 'Disease', 'MESH:D018284', (122, 138))	('ARID1A', 'Gene', '8289', (16, 22))	('T294P', 'Var', (47, 52))	('ARID1A', 'Gene', (16, 22))
7712	29189288	Two ARID1A mutations (Q288P and Q287Pfs) identified in this study were novel missense mutations.	('Q288P', 'Mutation', 'p.Q288P', (22, 27))	('ARID1A', 'Gene', '8289', (4, 10))	('ARID1A', 'Gene', (4, 10))	('Q287Pfs', 'Var', (32, 39))	('Q288P', 'Var', (22, 27))
7714	29189288	In fact, 1q gain is the most common chromosomal alteration across all types of endometrial carcinoma.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (79, 100))	('1q gain', 'Var', (9, 16))	('endometrial carcinoma', 'Disease', (79, 100))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (79, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))
7724	29189288	NGS data revealed distinct molecular features of UB-MNAC, including frequent somatic mutations of KRAS and ARID1A and gain of 1q.	('UB-MNAC', 'Chemical', '-', (49, 56))	('ARID1A', 'Gene', '8289', (107, 113))	('ARID1A', 'Gene', (107, 113))	('mutations', 'Var', (85, 94))	('gain', 'PosReg', (118, 122))	('KRAS', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (98, 102))
7767	29554794	The cytologic grade was closely related to histologic grade, and a high cytologic score was correlated with p53 mutation and myometrial invasion.	('p53', 'Gene', '7157', (108, 111))	('myometrial', 'Disease', (125, 135))	('p53', 'Gene', (108, 111))	('mutation', 'Var', (112, 120))
7839	29400013	In our study, there were no differences of clinico-pathological factors of the cases with or without seromucinous component, and coexistence of seromucinous component in endometrioid carcinoma was a better prognostic factor.	('seromucinous', 'Var', (144, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (170, 192))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (170, 192))	('coexistence', 'Var', (129, 140))	('endometrioid carcinoma', 'Disease', (170, 192))
7851	29400013	The patients with seromucinous component in endometrioid carcinomas had better progression-free survival.	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (44, 67))	('progression-free survival', 'CPA', (79, 104))	('seromucinous component', 'Var', (18, 40))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('better', 'PosReg', (72, 78))	('patients', 'Species', '9606', (4, 12))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (44, 66))	('endometrioid carcinomas', 'Disease', (44, 67))
7879	29113165	Several paraffin blocks, containing lesions of the deepest invasion, LVI and control areas for each case, were chosen for immunohistochemical examination using antibodies against D2-40 (M3619, Dako, Glostrup, Denmark) and desmin (D33; Dako).	('desmin', 'cellular_component', 'GO:0045098', ('222', '228'))	('desmin', 'Gene', '1674', (222, 228))	('paraffin', 'Chemical', 'MESH:D010232', (8, 16))	('desmin', 'cellular_component', 'GO:0045100', ('222', '228'))	('desmin', 'Gene', (222, 228))	('M3619', 'Var', (186, 191))
7933	26551621	A tissue microarray was constructed from 27 representative tumors with CEF and 14 without CEF, and sections were stained for WT-1, p16, and p53.	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('p16', 'Gene', '1029', (131, 134))	('WT-1', 'Gene', (125, 129))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('CEF', 'Var', (71, 74))	('WT-1', 'Gene', '7490', (125, 129))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('p16', 'Gene', (131, 134))
7954	26551621	Recent molecular and protein studies have shown that a proportion of tumors previously classified as "high-grade endometrioid carcinomas" display similar genetic and immunophenotypic profiles to high-grade OSC  and a subset of these tumors demonstrate solid, pseudo-endometrioid and/or transitional-cell-like growth patterns ("SET pattern") that are increasingly thought to be part of the spectrum of OSC, particularly in the presence of a BRCA1 mutation.	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (113, 136))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BRCA1', 'Gene', '672', (440, 445))	('mutation', 'Var', (446, 454))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA1', 'Gene', (440, 445))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('transitional-cell-like growth patterns', 'CPA', (286, 324))	('endometrioid carcinomas', 'Disease', (113, 136))	('solid', 'CPA', (252, 257))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Disease', (69, 75))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (113, 136))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (113, 135))
7981	26551621	Aberrant p53 expression was defined as nuclear positivity in >50% of tumor cells or complete absence of staining in the presence of a positive internal control.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('tumor', 'Disease', (69, 74))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
8029	26551621	Madore and colleagues  identified two high-grade, high-stage, WT-1-negative OEC with concurrent beta-catenin and TP53 aberrations.	('beta-catenin', 'Gene', '1499', (96, 108))	('aberrations', 'Var', (118, 129))	('WT-1', 'Gene', (62, 66))	('TP53', 'Gene', '7157', (113, 117))	('WT-1', 'Gene', '7490', (62, 66))	('OEC', 'Disease', (76, 79))	('TP53', 'Gene', (113, 117))	('beta-catenin', 'Gene', (96, 108))
8031	26551621	For example, incorrectly classifying a high-grade OSC as OEC might deprive the patient of the opportunity to be tested for germline BRCA1/BRCA2 mutations, which may have several downstream repercussions, including (i) affecting the choice of adjuvant chemotherapeutic agents such as PARP inhibitors; (ii) prognostic assessment; and (iii) appropriate screening and surveillance of other family members.	('BRCA2', 'Gene', '675', (138, 143))	('deprive', 'NegReg', (67, 74))	('tested', 'Reg', (112, 118))	('OSC', 'molecular_function', 'GO:0000250', ('50', '53'))	('PARP', 'Gene', (283, 287))	('PARP', 'Gene', '142', (283, 287))	('BRCA1', 'Gene', '672', (132, 137))	('patient', 'Species', '9606', (79, 86))	('BRCA2', 'Gene', (138, 143))	('BRCA1', 'Gene', (132, 137))	('mutations', 'Var', (144, 153))	('affecting', 'Reg', (218, 227))
8038	26551621	The most recent literature on the topic reports that OSC-SETs constitute a variant of OSC with association with BRCA1 mutation or promoter methylation, presentation at younger age, better prognosis and infrequent association with serous tubal intraepithelial carcinoma.	('association', 'Interaction', (95, 106))	('OSC', 'Disease', (86, 89))	('promoter', 'MPA', (130, 138))	('serous tubal intraepithelial carcinoma', 'Disease', 'MESH:D002278', (230, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (248, 268))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('OSC', 'molecular_function', 'GO:0000250', ('86', '89'))	('mutation', 'Var', (118, 126))	('BRCA1', 'Gene', '672', (112, 117))	('OSC', 'molecular_function', 'GO:0000250', ('53', '56'))	('serous tubal intraepithelial carcinoma', 'Disease', (230, 268))	('BRCA1', 'Gene', (112, 117))
8061	28611530	reported that systematic lymphadenectomy, including para-aortic lymphadenectomy, has therapeutic significance for patients at intermediate/high risk of recurrence, such as those with deeply invasive lesions, high-grade histology, and tumors of serous carcinoma, clear cell carcinoma, or carcinosarcoma features of endometrial cancer.	('carcinosarcoma', 'Disease', (287, 301))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('high-grade', 'Var', (208, 218))	('endometrial cancer', 'Disease', (314, 332))	('tumors of serous carcinoma', 'Disease', (234, 260))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (262, 282))	('clear cell carcinoma', 'Disease', (262, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('tumors of serous carcinoma', 'Disease', 'MESH:D009369', (234, 260))	('endometrial cancer', 'Phenotype', 'HP:0012114', (314, 332))	('endometrial cancer', 'Disease', 'MESH:D016889', (314, 332))	('carcinosarcoma', 'Disease', 'MESH:D002296', (287, 301))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
8092	28611530	In the current study, laparoscopic surgery with para-aortic lymph node dissection for patients at intermediate/high risk of recurrence, such as those with deeply invasive lesions, high-grade histology, and tumors of serous carcinoma, clear cell carcinoma, or carcinosarcoma features of endometrial cancer had roughly the same operation time, less intraoperative blood loss, and a shorter hospital stay than laparotomic surgery.	('intraoperative blood loss', 'Disease', 'MESH:D016063', (347, 372))	('carcinosarcoma', 'Disease', (259, 273))	('high-grade', 'Var', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('endometrial cancer', 'Disease', (286, 304))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('clear cell carcinoma', 'Disease', (234, 254))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (234, 254))	('carcinosarcoma', 'Disease', 'MESH:D002296', (259, 273))	('endometrial cancer', 'Disease', 'MESH:D016889', (286, 304))	('endometrial cancer', 'Phenotype', 'HP:0012114', (286, 304))	('intraoperative blood loss', 'Disease', (347, 372))	('tumors of serous carcinoma', 'Disease', (206, 232))	('tumors of serous carcinoma', 'Disease', 'MESH:D009369', (206, 232))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('patients', 'Species', '9606', (86, 94))
8100	28611530	In the SEPAL [survival effect of para-aortic lymphadenectomy] study, Todo showed that para-aortic lymphadenectomy improved the prognosis of patients with intermediate- to high-risk endometrial cancer.	('intermediate- to high-risk', 'Disease', (154, 180))	('para-aortic', 'Var', (86, 97))	('endometrial cancer', 'Disease', 'MESH:D016889', (181, 199))	('improved', 'PosReg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('patients', 'Species', '9606', (140, 148))	('endometrial cancer', 'Disease', (181, 199))	('endometrial cancer', 'Phenotype', 'HP:0012114', (181, 199))