0	21059203	Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion Elevated Plexin-B1 expression has been found in diverse human cancers and in non-neoplastic tissues, and it mediates diverse biological and pathological activities.	('Plexin-B1', 'Gene', '5364', (0, 9))	('Plexin-B1', 'Gene', '5364', (81, 90))	('Plexin-B1', 'Gene', (0, 9))	('Plexin-B1', 'Gene', (81, 90))	('ovarian cancer', 'Disease', (29, 43))	('inhibits', 'NegReg', (20, 28))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('invasion', 'CPA', (63, 71))	('human', 'Species', '9606', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ovarian cancer', 'Disease', 'MESH:D010051', (29, 43))	('silencing', 'Var', (10, 19))
4	21059203	Plexin-B1 expression was analyzed in normal and benign ovarian tissues and serous ovarian tumors (both borderline and malignant) by immunohistochemical staining, as well as in four human ovarian cancer cell lines (A2780, C13*, SKOV3, and OV2008) by RT-PCR and western blot analyses.	('C13*', 'Var', (221, 225))	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('benign ovarian tissues and serous ovarian tumors', 'Disease', 'MESH:D010051', (48, 96))	('human', 'Species', '9606', (181, 186))	('serous ovarian tumors', 'Phenotype', 'HP:0012887', (75, 96))	('ovarian cancer', 'Disease', (187, 201))	('C13*', 'SUBSTITUTION', 'None', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ovarian tumor', 'Phenotype', 'HP:0100615', (82, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian tumors', 'Phenotype', 'HP:0100615', (82, 96))	('SKOV3', 'CellLine', 'CVCL:0532', (227, 232))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
11	21059203	In addition, silencing of Plexin-B1 in SKOV3 cells inhibited cell migration and invasion and reorganized the cytoskeleton, whereas cell proliferation was not affected.	('invasion', 'CPA', (80, 88))	('reorganized', 'Reg', (93, 104))	('cell proliferation', 'biological_process', 'GO:0008283', ('131', '149'))	('SKOV3', 'CellLine', 'CVCL:0532', (39, 44))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('109', '121'))	('cell migration', 'biological_process', 'GO:0016477', ('61', '75'))	('cell migration', 'CPA', (61, 75))	('Plexin-B1', 'Protein', (26, 35))	('inhibited', 'NegReg', (51, 60))	('silencing', 'Var', (13, 22))
28	21059203	The results showed that silencing of Plexin-B1 inhibited migration and invasion in SKOV3 cells.	('Plexin-B1', 'Protein', (37, 46))	('SKOV3', 'CellLine', 'CVCL:0532', (83, 88))	('inhibited', 'NegReg', (47, 56))	('silencing', 'Var', (24, 33))
34	21059203	The OV2008 and C13* ovarian cancer cell lines were gifts from Dr. Rakesh Goel in the Ottawa Regional Cancer Center, Ottawa, Canada.	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (20, 34))	('C13*', 'Var', (15, 19))	('ovarian cancer', 'Disease', 'MESH:D010051', (20, 34))	('C13*', 'SUBSTITUTION', 'None', (15, 19))	('ovarian cancer', 'Disease', (20, 34))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', (101, 107))
67	21059203	To further investigate Plexin-B1 expression in ovarian cancer cells, RT-PCR and western blot analysis were used to detect Plexin-B1 mRNA and protein levels in four human ovarian cancer cell lines: SKOV3, A2780, C13* and OV2008.	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('Plexin-B1', 'Gene', (122, 131))	('ovarian cancer', 'Disease', (170, 184))	('C13*', 'Var', (211, 215))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('human', 'Species', '9606', (164, 169))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('SKOV3', 'CellLine', 'CVCL:0532', (197, 202))	('ovarian cancer', 'Disease', (47, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('C13*', 'SUBSTITUTION', 'None', (211, 215))	('ovarian cancer', 'Disease', 'MESH:D010051', (170, 184))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
77	21059203	To determine whether the Plexin-B1 siRNA-induced reduction of phospho-AKT (Ser473) would affect the proliferation of SKOV3 cells, the MTT assay was used to monitor the proliferation of untransfected SKOV3 cells and SKOV3 cells treated with Plexin-B1 siRNA2, Plexin-B1 siRNA3 or negative control siRNA.	('Plexin-B1', 'Var', (258, 267))	('AKT', 'Gene', '207', (70, 73))	('Ser', 'cellular_component', 'GO:0005790', ('75', '78'))	('reduction', 'NegReg', (49, 58))	('SKOV3', 'CellLine', 'CVCL:0532', (215, 220))	('proliferation', 'CPA', (100, 113))	('AKT', 'Gene', (70, 73))	('MTT', 'Chemical', 'MESH:C070243', (134, 137))	('SKOV3', 'CellLine', 'CVCL:0532', (199, 204))	('SKOV3', 'CellLine', 'CVCL:0532', (117, 122))	('Ser473', 'Chemical', '-', (75, 81))	('affect', 'Reg', (89, 95))	('Plexin-B1', 'Var', (240, 249))
80	21059203	To determine whether repression of Plexin-B1 expression inhibits SKOV3 cell migration and invasion, a wound-healing assay and a cell invasion assay were performed on SKOV3 cells either untransfected or transfected with Plexin-B1 siRNA2, Plexin-B1 siRNA3 or negative control siRNA for 24 h. As shown in Figure 3A-B, at 24 h and 48 h (respectively), Plexin-B1 siRNA2-treated cells showed 40% and 70% wound closure, Plexin-B1 siRNA3-treated cells showed 40% and 60% wound closure, and negative control siRNA-treated cells showed 85% and 100%, suggesting that inhibition of Plexin-B1 decreased the migration of SKOV3 cells.	('migration of SKOV3 cells', 'CPA', (594, 618))	('decreased', 'NegReg', (580, 589))	('inhibition', 'Var', (556, 566))	('Plexin-B1', 'Gene', (570, 579))	('SKOV3', 'CellLine', 'CVCL:0532', (607, 612))	('SKOV3', 'CellLine', 'CVCL:0532', (65, 70))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('wound-healing', 'biological_process', 'GO:0042060', ('102', '115'))	('SKOV3', 'CellLine', 'CVCL:0532', (166, 171))
81	21059203	As shown in Figure 3D-F, the number of SKOV3 cells that passed through the filter in the Plexin-B1 siRNA2- (100 +- 52) and siRNA3- (42 +- 36) treated groups was remarkably less than that in the untreated (825 +- 32) or treated with negative control siRNA (848 +- 41) groups, which shows that inhibition of Plexin-B1 expression suppressed SKOV3 cell invasion in vitro.	('SKOV3', 'CellLine', 'CVCL:0532', (338, 343))	('SKOV3', 'CellLine', 'CVCL:0532', (39, 44))	('inhibition', 'Var', (292, 302))	('Plexin-B1', 'Gene', (306, 315))	('SKOV3 cell invasion in vitro', 'CPA', (338, 366))	('less', 'NegReg', (172, 176))	('suppressed', 'NegReg', (327, 337))
82	21059203	To investigate how changes in Plexin-B1 expression affect the reorganization of the cytoskeleton, rhodamine-phalloidin was used to label F-actin in SKOV3 cells 24 h after a 5-h exposure to Plexin-B1 siRNA2 or siRNA3.	('affect', 'Reg', (51, 57))	('changes', 'Var', (19, 26))	('reorganization', 'MPA', (62, 76))	('F-actin', 'cellular_component', 'GO:0031941', ('137', '144'))	('rhodamine-phalloidin', 'Chemical', 'MESH:C504731', (98, 118))	('SKOV3', 'CellLine', 'CVCL:0532', (148, 153))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('84', '96'))
83	21059203	As shown in Figure 4, SKOV3 cells in the transfected groups shrank without F-actin polymerization or filopodia formation, whereas cells in the blank and control groups showed pointed filopodia or polygonal cell shapes with pointed edges, in which brightly stained longitudinal actin bundles were detected.	('transfected', 'Var', (41, 52))	('SKOV3', 'CellLine', 'CVCL:0532', (22, 27))	('F-actin', 'cellular_component', 'GO:0031941', ('75', '82'))	('polygonal cell shapes', 'CPA', (196, 217))	('filopodia formation', 'biological_process', 'GO:0046847', ('101', '120'))	('shrank', 'CPA', (60, 66))	('actin polymerization', 'biological_process', 'GO:0030041', ('77', '97'))
88	21059203	Plexin-B1 expression was found in 7/11 ovarian serous adenocarcinomas, and 6/15 ovarian adenocarcinomas expressed both Met and Plexin-B1, which was predictive of an unfavorable outcome.	('Plexin-B1', 'Var', (127, 136))	('ovarian serous adenocarcinomas', 'Disease', 'MESH:D010051', (39, 69))	('Plexin-B1', 'Gene', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('ovarian serous adenocarcinomas', 'Phenotype', 'HP:0012887', (39, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('6/15 ovarian adenocarcinomas', 'Disease', (75, 103))	('Met', 'Var', (119, 122))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (80, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('6/15 ovarian adenocarcinomas', 'Disease', 'MESH:D010051', (75, 103))	('ovarian serous adenocarcinomas', 'Disease', (39, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('found', 'Reg', (25, 30))
104	21059203	In our study, the SKOV3 cells expressed both Met and ErbB-2, and inhibition of Plexin-B1 resulted in reductions in cell motility and invasive capacity.	('Met', 'Gene', (45, 48))	('reductions', 'NegReg', (101, 111))	('ErbB-2', 'Gene', '2064', (53, 59))	('ErbB-2', 'Gene', (53, 59))	('Plexin-B1', 'Gene', (79, 88))	('cell motility', 'biological_process', 'GO:0048870', ('115', '128'))	('invasive capacity', 'CPA', (133, 150))	('cell motility', 'CPA', (115, 128))	('inhibition', 'Var', (65, 75))	('SKOV3', 'CellLine', 'CVCL:0532', (18, 23))
106	21059203	On the one hand, dimerization of Plexin-B1 is sufficient to induce ErbB2-dependent activation of Rho and to regulate the remodeling of the actin cytoskeleton and alter cell movement in response to Sema 4D.	('cell movement', 'CPA', (168, 181))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('139', '157'))	('ErbB2', 'Gene', '2064', (67, 72))	('cell movement', 'biological_process', 'GO:0048870', ('168', '181'))	('cell movement', 'biological_process', 'GO:0006928', ('168', '181'))	('dimerization', 'Var', (17, 29))	('ErbB2', 'Gene', (67, 72))	('regulate', 'Reg', (108, 116))	('alter', 'Reg', (162, 167))	('Plexin-B1', 'Gene', (33, 42))	('remodeling of the actin cytoskeleton', 'MPA', (121, 157))	('Rho', 'Protein', (97, 100))	('activation', 'PosReg', (83, 93))
134	24812576	PNM is mostly associated with primary cancers of the lung, breast, and gastrointestinal tract, and until now, it has not been reported in EOC.	('PNM', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('gastrointestinal tract', 'Disease', (71, 93))	('primary cancers of the lung', 'Disease', 'MESH:D008175', (30, 57))	('primary cancers of the lung', 'Disease', (30, 57))	('breast', 'Disease', (59, 65))	('EOC', 'Phenotype', 'HP:0025318', (138, 141))	('associated', 'Reg', (14, 24))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (71, 93))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('PNM', 'Var', (0, 3))
142	24812576	Serum levels of the muscle enzymes creatine phosphokinase (CPK), lactate dehydrogenase (LDH), myoglobin, and creatine kinase-MB (CK-MB) were markedly elevated (21311 IU/L, 3750 IU/L, 2707 ng/ml, and 198.9 ng/ml, respectively).	('Serum levels', 'MPA', (0, 12))	('lactate dehydrogenase', 'MPA', (65, 86))	('myoglobin', 'Gene', '4151', (94, 103))	('CK-MB', 'molecular_function', 'GO:0004111', ('129', '134'))	('creatine kinase-MB', 'MPA', (109, 127))	('creatine phosphokinase', 'MPA', (35, 57))	('MB (CK', 'molecular_function', 'GO:0004111', ('125', '131'))	('elevated', 'PosReg', (150, 158))	('myoglobin', 'Gene', (94, 103))	('3750 IU/L', 'Var', (172, 181))
181	16479254	Tissue microarray analysis of human FRAT1 expression and its correlation with the subcellular localisation of beta-catenin in ovarian tumours The mechanisms involved in the pathogenesis of ovarian cancer are poorly understood, but evidence suggests that aberrant activation of Wnt/beta-catenin signalling pathway plays a significant role in this malignancy.	('beta-catenin', 'Gene', '1499', (281, 293))	('ovarian cancer', 'Phenotype', 'HP:0100615', (189, 203))	('ovarian tumours', 'Disease', (126, 141))	('signalling pathway', 'biological_process', 'GO:0007165', ('294', '312'))	('malignancy', 'Disease', 'MESH:D009369', (346, 356))	('activation', 'PosReg', (263, 273))	('beta-catenin', 'Gene', (110, 122))	('aberrant', 'Var', (254, 262))	('beta-catenin', 'Gene', '1499', (110, 122))	('FRAT1', 'Gene', '10023', (36, 41))	('FRAT1', 'Gene', (36, 41))	('ovarian tumours', 'Disease', 'MESH:D010051', (126, 141))	('ovarian tumour', 'Phenotype', 'HP:0100615', (126, 140))	('malignancy', 'Disease', (346, 356))	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('ovarian cancer', 'Disease', 'MESH:D010051', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('human', 'Species', '9606', (30, 35))	('pathogenesis', 'biological_process', 'GO:0009405', ('173', '185'))	('beta-catenin', 'Gene', (281, 293))	('ovarian cancer', 'Disease', (189, 203))	('localisation', 'biological_process', 'GO:0051179', ('94', '106'))
199	16479254	Although compelling evidence has indicated a critical role for signalling by beta-catenin in the tumorigenesis of ovarian cancer, mutations in the beta-catenin gene are infrequent in ovarian carcinoma and interestingly only described in the endometrioid type of epithelial ovarian tumours (Gamallo et al, 1999; Wright et al, 1999; Ueda et al, 2001; Giles et al, 2003).	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('endometrioid type of epithelial ovarian tumours', 'Disease', 'MESH:D000077216', (241, 288))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))	('tumours', 'Phenotype', 'HP:0002664', (281, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (183, 200))	('described', 'Reg', (224, 233))	('ovarian cancer', 'Disease', (114, 128))	('endometrioid type of epithelial ovarian tumours', 'Disease', (241, 288))	('ovarian carcinoma', 'Disease', (183, 200))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', (147, 159))	('beta-catenin', 'Gene', '1499', (77, 89))	('beta-catenin', 'Gene', '1499', (147, 159))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (183, 200))	('signalling', 'biological_process', 'GO:0023052', ('63', '73'))	('mutations', 'Var', (130, 139))	('ovarian tumour', 'Phenotype', 'HP:0100615', (273, 287))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
200	16479254	Mutations of adenomatous polyposis coli (APC) or Axin occur rarely in ovarian cancer (Giles et al, 2003).	('Axin', 'Gene', '8312', (49, 53))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (13, 39))	('ovarian cancer', 'Disease', (70, 84))	('APC', 'Phenotype', 'HP:0005227', (41, 44))	('APC', 'Disease', 'MESH:D011125', (41, 44))	('adenomatous polyposis coli', 'Disease', (13, 39))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('Axin', 'Gene', (49, 53))	('APC', 'Disease', (41, 44))	('Mutations', 'Var', (0, 9))	('APC', 'cellular_component', 'GO:0005680', ('41', '44'))	('ovarian cancer', 'Disease', 'MESH:D010051', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (13, 39))
235	16479254	The excess serum was removed and slides were incubated for 60 min with anti-beta-catenin (C19220; 1 : 50; Transduction Lab, KY, USA).	('beta-catenin', 'Gene', (76, 88))	('C19220;', 'Var', (90, 97))	('Transduction', 'biological_process', 'GO:0009293', ('106', '118'))	('beta-catenin', 'Gene', '1499', (76, 88))
269	16479254	Although accumulation of cytoplasmic and nuclear beta-catenin has been observed in serous ovarian cancer (Rask et al, 2003; Kildal et al, 2005), mutations of beta-catenin in this subtype occur rarely (Gamallo et al, 1999; Wright et al, 1999; Ueda et al, 2001; Giles et al, 2003).	('serous ovarian cancer', 'Disease', (83, 104))	('beta-catenin', 'Gene', (49, 61))	('beta-catenin', 'Gene', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('beta-catenin', 'Gene', '1499', (158, 170))	('mutations', 'Var', (145, 154))	('beta-catenin', 'Gene', '1499', (49, 61))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (83, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('accumulation', 'PosReg', (9, 21))
310	25277200	In this study, we investigated the role of annexin repeats, a conserved structure of all the annexin family, responsible for platinum-resistance as well as the effect of knockdown of ANXA4.	('annexin', 'Gene', (43, 50))	('annexin', 'Gene', '105245705', (93, 100))	('knockdown', 'Var', (170, 179))	('platinum', 'Chemical', 'MESH:D010984', (125, 133))	('annexin', 'Gene', (93, 100))	('annexin', 'Gene', '105245705', (43, 50))
311	25277200	ANXA4 knockdown increased sensitivity to platinum-based drugs both in vitro and in vivo.	('sensitivity to platinum-based drugs', 'MPA', (26, 61))	('increased', 'PosReg', (16, 25))	('platinum', 'Chemical', 'MESH:D010984', (41, 49))	('ANXA4', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))
312	25277200	To identify the domain responsible for chemoresistance, ANXA4 deletion mutants were constructed by deleting annexin repeats one by one from the C terminus.	('annexin', 'Gene', (108, 115))	('deleting', 'Var', (99, 107))	('mutants', 'Var', (71, 78))	('deletion mutants', 'Var', (62, 78))	('ANXA4', 'Gene', (56, 61))	('annexin', 'Gene', '105245705', (108, 115))
313	25277200	Platinum resistance was induced both in vitro and in vivo in cells expressing either full-length ANXA4 or the deletion mutants, containing at least one intact annexin repeat.	('annexin', 'Gene', '105245705', (159, 166))	('ANXA4', 'Gene', (97, 102))	('Platinum', 'Chemical', 'MESH:D010984', (0, 8))	('annexin', 'Gene', (159, 166))	('Platinum resistance', 'CPA', (0, 19))	('deletion mutants', 'Var', (110, 126))	('induced', 'Reg', (24, 31))
314	25277200	However, cells expressing the mutant without any calcium-binding sites in the annexin repeated sequence, which is essential for ANXA4 translocation from the cytosol to plasma membrane, failed to acquire platinum resistance.	('cytosol', 'cellular_component', 'GO:0005829', ('157', '164'))	('binding', 'molecular_function', 'GO:0005488', ('57', '64'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('168', '183'))	('calcium', 'Chemical', 'MESH:D002118', (49, 56))	('failed', 'NegReg', (185, 191))	('annexin', 'Gene', '105245705', (78, 85))	('platinum resistance', 'CPA', (203, 222))	('mutant', 'Var', (30, 36))	('annexin', 'Gene', (78, 85))	('platinum', 'Chemical', 'MESH:D010984', (203, 211))
330	25277200	ANXA4 suppresses NF-kappaB transcriptional activity through interaction with the p50 subunit in a calcium-dependent manner; ANXA4 causes resistance to apoptosis induction by etoposide.	('p50', 'Gene', (81, 84))	('causes', 'Reg', (130, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('p50', 'Gene', '4790', (81, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('calcium', 'Chemical', 'MESH:D002118', (98, 105))	('interaction', 'Interaction', (60, 71))	('resistance to', 'MPA', (137, 150))	('suppresses', 'NegReg', (6, 16))	('ANXA4', 'Var', (124, 129))	('etoposide', 'Chemical', 'MESH:D005047', (174, 183))	('NF-kappaB', 'Protein', (17, 26))
331	25277200	In this study, focusing on platinum resistance, we aimed to identify the ANXA4 domain relevant to chemoresistance with regard to its structure as well as to test whether knockdown of ANXA4 expression could improve platinum resistance.	('knockdown', 'Var', (170, 179))	('ANXA4', 'Gene', (183, 188))	('platinum', 'Chemical', 'MESH:D010984', (214, 222))	('improve', 'PosReg', (206, 213))	('platinum', 'Chemical', 'MESH:D010984', (27, 35))	('platinum resistance', 'CPA', (214, 233))
337	25277200	Compared with RMG-I NC7 and untransfected control parent RMG-I cells, ANXA4 expression was markedly down-regulated at the protein level in RMG-I-Y4 and RMG-I-R5 cells (Fig.	('RMG-I-Y4', 'Var', (139, 147))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('NC7', 'CellLine', 'CVCL:1874', (20, 23))	('down-regulated', 'NegReg', (100, 114))	('expression', 'MPA', (76, 86))	('ANXA4', 'Gene', (70, 75))
341	25277200	IC50 for cisplatin and carboplatin decreased approximately 2-fold because of the knockdown of ANXA4 expression.	('ANXA4', 'Gene', (94, 99))	('carboplatin', 'Chemical', 'MESH:D016190', (23, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('decreased', 'NegReg', (35, 44))	('knockdown', 'Var', (81, 90))
342	25277200	To determine whether ANXA4 knockdown in clear cell carcinoma cells improved platinum sensitivity in vivo, NC7 and Y4 cells were subcutaneously injected in ICR nu/nu mice.	('clear cell carcinoma', 'Disease', (40, 60))	('knockdown', 'Var', (27, 36))	('mice', 'Species', '10090', (165, 169))	('NC7', 'CellLine', 'CVCL:1874', (106, 109))	('platinum', 'Chemical', 'MESH:D010984', (76, 84))	('platinum sensitivity', 'CPA', (76, 96))	('ANXA4', 'Gene', (21, 26))	('improved', 'PosReg', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (40, 60))
348	25277200	These results showed that ANXA4 knockdown in the RMG-I cell line significantly attenuated resistance to cisplatin in vivo.	('attenuated', 'NegReg', (79, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('knockdown', 'Var', (32, 41))	('ANXA4', 'Gene', (26, 31))	('resistance to cisplatin in', 'MPA', (90, 116))
349	25277200	To identify a possible resistance-related domain within the annexin repeated sequence of ANXA4, we constructed 3 deletion mutants by deleting the annexin repeats one by one from the C-terminal region.	('mutants', 'Var', (122, 129))	('annexin', 'Gene', '105245705', (146, 153))	('annexin', 'Gene', (146, 153))	('deleting', 'NegReg', (133, 141))	('annexin', 'Gene', '105245705', (60, 67))	('ANXA4', 'Gene', (89, 94))	('annexin', 'Gene', (60, 67))
350	25277200	Full-length ANXA4, 3 ANXA4 deletion mutants or the empty vector were transfected into NUGC3 cells, whose endogenous ANXA4 expression is relatively low (Supplementary Fig.	('ANXA4', 'Gene', (21, 26))	('ANXA4', 'Gene', (12, 17))	('NUGC3', 'CellLine', 'CVCL:1612', (86, 91))	('deletion mutants', 'Var', (27, 43))
351	25277200	Therefore, we established cell lines stably overexpressing full-length ANXA4 (FL-22), each ANXA4 deletion mutant (R3-6, R2-13 or R1-12) or the empty vector (NC-14).	('deletion mutant', 'Var', (97, 112))	('mutant', 'Var', (106, 112))	('ANXA4', 'Gene', (91, 96))	('FL-22', 'Chemical', '-', (78, 83))
353	25277200	Cells transfected with full-length ANXA4 and the 3 deletion ANXA4 mutants were significantly more resistant to both cisplatin and carboplatin compared with control cells, approximately with a 1.7- to 2.2-fold increase in IC50 for cisplatin (p < 0.01) and a 1.4- to 1.7-fold increase in IC50 for carboplatin (p < 0.05; Fig.	('IC50 for cisplatin', 'MPA', (221, 239))	('mutants', 'Var', (66, 73))	('carboplatin', 'Chemical', 'MESH:D016190', (295, 306))	('increase', 'PosReg', (274, 282))	('ANXA4', 'Gene', (60, 65))	('resistant', 'MPA', (98, 107))	('IC50 for carboplatin', 'MPA', (286, 306))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('deletion', 'Var', (51, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (230, 239))	('increase', 'PosReg', (209, 217))	('carboplatin', 'Chemical', 'MESH:D016190', (130, 141))
354	25277200	To test whether these deletion mutants induce platinum resistance through regulating cellular drug concentration as previously reported, we quantitated the intracellular platinum content of each deletion mutant-transfected cell clone after cisplatin treatment, which is one of the most representative platinum drugs.	('cisplatin', 'Chemical', 'MESH:D002945', (240, 249))	('regulating', 'Reg', (74, 84))	('platinum resistance', 'MPA', (46, 65))	('platinum', 'Chemical', 'MESH:D010984', (170, 178))	('platinum', 'Chemical', 'MESH:D010984', (46, 54))	('cellular drug concentration', 'MPA', (85, 112))	('deletion', 'Var', (195, 203))	('platinum', 'Chemical', 'MESH:D010984', (301, 309))	('induce', 'Reg', (39, 45))	('intracellular', 'cellular_component', 'GO:0005622', ('156', '169'))
355	25277200	Platinum accumulation was significantly reduced in cells overexpressing either full-length ANXA4 or any of the 3 deletion mutants compared with NC-14 cells regardless of the incubation time after cisplatin exposure (Fig.	('Platinum', 'Chemical', 'MESH:D010984', (0, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('deletion mutants', 'Var', (113, 129))	('ANXA4', 'Gene', (91, 96))	('reduced', 'NegReg', (40, 47))	('Platinum', 'CPA', (0, 8))
356	25277200	These results suggested that the decreased intracellular platinum contents were associated with platinum resistance of the cells transfected with ANXA4 full length and each deletion mutant.	('intracellular', 'cellular_component', 'GO:0005622', ('43', '56'))	('deletion', 'Var', (173, 181))	('platinum', 'Chemical', 'MESH:D010984', (57, 65))	('intracellular platinum contents', 'MPA', (43, 74))	('platinum resistance', 'CPA', (96, 115))	('decreased', 'NegReg', (33, 42))	('platinum', 'Chemical', 'MESH:D010984', (96, 104))	('ANXA4', 'Gene', (146, 151))
357	25277200	As specified above, platinum resistance was enhanced in cells overexpressing ANXA4 deletion mutants, which contained at least 1 intact annexin repeat.	('annexin', 'Gene', '105245705', (135, 142))	('ANXA4', 'Gene', (77, 82))	('annexin', 'Gene', (135, 142))	('platinum resistance', 'CPA', (20, 39))	('deletion mutants', 'Var', (83, 99))	('platinum', 'Chemical', 'MESH:D010984', (20, 28))	('enhanced', 'PosReg', (44, 52))
361	25277200	Similar to other deletion mutants, R1(E70A) was transfected into NUGC3 cells and designated R1(E70A)-95.	('E70A', 'Var', (95, 99))	('E70A', 'Mutation', 'p.E70A', (95, 99))	('E70A', 'Var', (38, 42))	('E70A', 'Mutation', 'p.E70A', (38, 42))	('E70A', 'SUBSTITUTION', 'None', (95, 99))	('NUGC3', 'CellLine', 'CVCL:1612', (65, 70))	('E70A', 'SUBSTITUTION', 'None', (38, 42))
364	25277200	Moreover, the intracellular platinum content of R1(E70A)-95-transfected cells did not decrease compared with that of NC-14 cells after 0 hr or 3 hr of additional incubation in cisplatin-free medium (Fig.	('E70A', 'Var', (51, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('intracellular', 'cellular_component', 'GO:0005622', ('14', '27'))	('intracellular platinum content', 'MPA', (14, 44))	('E70A', 'SUBSTITUTION', 'None', (51, 55))	('platinum', 'Chemical', 'MESH:D010984', (28, 36))
366	25277200	To determine whether the annexin deletion mutants of ANXA4 influenced the sensitivity to cisplatin in vivo, we inoculated ICR nu/nu mice with NC-14, FL-22, R1-12 or R1(E70A)-95 cells.	('annexin', 'Gene', (25, 32))	('mutants', 'Var', (42, 49))	('deletion mutants', 'Var', (33, 49))	('ANXA4', 'Gene', (53, 58))	('E70A', 'Var', (168, 172))	('mice', 'Species', '10090', (132, 136))	('FL-22', 'Chemical', '-', (149, 154))	('sensitivity to cisplatin', 'MPA', (74, 98))	('E70A', 'SUBSTITUTION', 'None', (168, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('annexin', 'Gene', '105245705', (25, 32))	('influenced', 'Reg', (59, 69))
368	25277200	Cisplatin markedly decreased tumour volume in mice injected with NC-14 and R1(E70A)-95 cells, whereas the treatment effect was relatively smaller in mice injected with FL-22 and R1-12 cells (Fig.	('tumour volume', 'Disease', 'MESH:D009369', (29, 42))	('decreased tumour', 'Disease', (19, 35))	('FL-22', 'Chemical', '-', (168, 173))	('E70A', 'SUBSTITUTION', 'None', (78, 82))	('tumour volume', 'Disease', (29, 42))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('mice', 'Species', '10090', (149, 153))	('mice', 'Species', '10090', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('decreased tumour', 'Disease', 'MESH:D009369', (19, 35))	('E70A', 'Var', (78, 82))
369	25277200	Consistent with the tumour volume, tumour growth was significantly inhibited by cisplatin in mice inoculated with NC-14 (96.5 +- 1.3%) and R1(E70A)-95 cells (87.8 +- 11.4%) compared with those injected with FL-22 (48.5 +- 11.7%) and R1-12 cells (37.7 +- 9.8%; p < 0.01; Fig.	('inhibited', 'NegReg', (67, 76))	('E70A', 'SUBSTITUTION', 'None', (142, 146))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))	('tumour', 'Disease', (20, 26))	('E70A', 'Var', (142, 146))	('tumour volume', 'Disease', 'MESH:D009369', (20, 33))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('mice', 'Species', '10090', (93, 97))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('NC-14', 'Var', (114, 119))	('FL-22', 'Chemical', '-', (207, 212))	('tumour volume', 'Disease', (20, 33))	('cisplatin', 'Var', (80, 89))	('tumour', 'Disease', (35, 41))
376	25277200	We monitored MQAE fluorescence in control cells (NC-14), in cells overexpressing full-length ANXA4 (FL-22) and in 2 deletion mutants (R1-12 and R1[E70A]-95).	('R1-12', 'Var', (134, 139))	('E70A', 'Mutation', 'p.E70A', (147, 151))	('FL-22', 'Chemical', '-', (100, 105))	('MQAE fluorescence', 'MPA', (13, 30))	('R1[E70A]-95', 'Var', (144, 155))	('ANXA4', 'Gene', (93, 98))
378	25277200	The inverse ratio of MQAE fluorescence 1/(F30/F0), which is directly proportional to the increase in [Cl-]i, was significantly elevated in the platinum-resistant cell clones FL-22 (1.12 +- 0.03) and R1-12 (1.12 +- 0.01) compared with sensitive clones, NC-14 (1.06 +- 0.01) and R1(E70A)-95 (1.06 +- 0.02; p < 0.01).	('FL-22', 'Chemical', '-', (174, 179))	('E70A', 'SUBSTITUTION', 'None', (280, 284))	('[Cl-]i', 'MPA', (101, 107))	('elevated', 'PosReg', (127, 135))	('E70A', 'Var', (280, 284))	('platinum', 'Chemical', 'MESH:D010984', (143, 151))	('MQAE fluorescence', 'MPA', (21, 38))	('platinum-resistant', 'CPA', (143, 161))
383	25277200	In this study, we showed that ANXA4 knockdown improved sensitivity to platinum drugs, and annexin repeats were involved in chemoresistance.	('sensitivity to platinum drugs', 'MPA', (55, 84))	('annexin', 'Gene', '105245705', (90, 97))	('platinum', 'Chemical', 'MESH:D010984', (70, 78))	('annexin', 'Gene', (90, 97))	('ANXA4', 'Gene', (30, 35))	('knockdown', 'Var', (36, 45))	('chemoresistance', 'CPA', (123, 138))	('improved', 'PosReg', (46, 54))	('involved', 'Reg', (111, 119))
387	25277200	recently reported that an ANXA4 knockdown improves sensitivity to carboplatin in vitro using 2 cell lines of ovarian clear cell carcinoma, OVTOKO and OVISE.	('ovarian clear cell carcinoma', 'Disease', (109, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (109, 137))	('carboplatin', 'Chemical', 'MESH:D016190', (66, 77))	('knockdown', 'Var', (32, 41))	('ANXA4', 'Gene', (26, 31))	('sensitivity to carboplatin', 'MPA', (51, 77))	('improves', 'PosReg', (42, 50))
388	25277200	To the best of our knowledge, ours is the first study to show that ANXA4 knockdown markedly improves the sensitivity to platinum-based drugs not only in vitro but also in vivo (Figs.	('improves', 'PosReg', (92, 100))	('ANXA4', 'Gene', (67, 72))	('sensitivity to platinum-based drugs', 'MPA', (105, 140))	('platinum', 'Chemical', 'MESH:D010984', (120, 128))	('knockdown', 'Var', (73, 82))
389	25277200	The result that ANXA4 knockdown improves sensitivity to platinum-based drugs suggests that ANXA4 is a good therapeutic target.	('platinum', 'Chemical', 'MESH:D010984', (56, 64))	('ANXA4', 'Gene', (16, 21))	('knockdown', 'Var', (22, 31))	('improves', 'PosReg', (32, 40))	('sensitivity to platinum-based drugs', 'MPA', (41, 76))
390	25277200	To identify the functional domain(s) of ANXA4 that could be a promising therapeutic target, we focused on annexin repeats and constructed 4 deletion mutants (R3, R2, R1 and R1[E70A]).	('R2, R1 and R1', 'Gene', '6241;6240', (162, 175))	('annexin', 'Gene', '105245705', (106, 113))	('E70A', 'Mutation', 'p.E70A', (176, 180))	('R3', 'Var', (158, 160))	('annexin', 'Gene', (106, 113))
391	25277200	Resistance to platinum drugs was enhanced in cells transfected with mutants possessing at least 1 intact annexin repeat.	('Resistance to platinum drugs', 'MPA', (0, 28))	('annexin', 'Gene', '105245705', (105, 112))	('mutants', 'Var', (68, 75))	('annexin', 'Gene', (105, 112))	('enhanced', 'PosReg', (33, 41))	('platinum', 'Chemical', 'MESH:D010984', (14, 22))
392	25277200	In contrast, the sensitivity to platinum-based drugs improved among the R1(E70A)-transfected clones because in those cells, the calcium-binding site did not function properly (Figs.	('calcium', 'Chemical', 'MESH:D002118', (128, 135))	('sensitivity to', 'MPA', (17, 31))	('platinum', 'Chemical', 'MESH:D010984', (32, 40))	('E70A', 'Mutation', 'p.E70A', (75, 79))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('improved', 'PosReg', (53, 61))	('R1(E70A)-transfected', 'Var', (72, 92))
396	25277200	By analysing the intracellular platinum accumulation, we attempted to elucidate the mechanism of the platinum resistance induced by ANXA4 and its deletion mutants.	('platinum resistance', 'CPA', (101, 120))	('deletion', 'Var', (146, 154))	('ANXA4', 'Gene', (132, 137))	('platinum', 'Chemical', 'MESH:D010984', (101, 109))	('platinum', 'Chemical', 'MESH:D010984', (31, 39))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))
397	25277200	When intracellular platinum contents were quantitated just after exposure to cisplatin or 3 hr incubation with cisplatin-free medium after exposure to cisplatin, significantly less platinum accumulated in cells transfected with the full-length ANXA4 (FL-22) and 3 deletion mutants (R3-6, R2-13 and R1-12), all of which enhanced the resistance to the platinum-based drugs.	('platinum', 'MPA', (181, 189))	('less', 'NegReg', (176, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('resistance to the platinum-based drugs', 'MPA', (332, 370))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('enhanced', 'PosReg', (319, 327))	('intracellular', 'cellular_component', 'GO:0005622', ('5', '18'))	('FL-22', 'Chemical', '-', (251, 256))	('platinum', 'Chemical', 'MESH:D010984', (19, 27))	('deletion mutants', 'Var', (264, 280))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('platinum', 'Chemical', 'MESH:D010984', (350, 358))	('ANXA4 (FL-22', 'Gene', (244, 256))	('platinum', 'Chemical', 'MESH:D010984', (181, 189))
402	25277200	In addition, ANXA4 likely enhance platinum efflux through the interaction with ATP7A.	('interaction', 'Interaction', (62, 73))	('efflux', 'biological_process', 'GO:0140115', ('43', '49'))	('platinum efflux', 'MPA', (34, 49))	('efflux', 'biological_process', 'GO:0140352', ('43', '49'))	('ANXA4', 'Var', (13, 18))	('platinum', 'Chemical', 'MESH:D010984', (34, 42))	('ATP7A', 'Gene', (79, 84))	('ATP7A', 'Gene', '538', (79, 84))	('enhance', 'PosReg', (26, 33))
405	25277200	The significant increase in [Cl-]i was observed in the cells with platinum resistance, FL-22 and R1-12, compared with cell clones without platinum resistance, NC-14 and R1(E70A)-95.	('[Cl-]i', 'MPA', (28, 34))	('platinum', 'Chemical', 'MESH:D010984', (138, 146))	('platinum', 'Chemical', 'MESH:D010984', (66, 74))	('E70A', 'Var', (172, 176))	('FL-22', 'Chemical', '-', (87, 92))	('increase', 'PosReg', (16, 24))	('E70A', 'SUBSTITUTION', 'None', (172, 176))
406	25277200	In a previous study, higher [Cl-]i was observed in cisplatin-resistant cells compared with sensitive cells, whereas the intracellular cisplatin accumulation showed the opposite pattern.	('[Cl-]i', 'MPA', (28, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('intracellular', 'cellular_component', 'GO:0005622', ('120', '133'))	('higher', 'PosReg', (21, 27))	('cisplatin-resistant', 'Var', (51, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))
409	25277200	Cisplatin becomes intracellularly activated by the aquation of 1 or 2 of the 2 chloride coordination sites, but carboplatin does not contain any chloride coordination sites.	('carboplatin', 'Chemical', 'MESH:D016190', (112, 123))	('chloride', 'Chemical', 'MESH:D002712', (145, 153))	('Cisplatin', 'Enzyme', (0, 9))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('activated', 'PosReg', (34, 43))	('aquation', 'Var', (51, 59))	('chloride', 'Chemical', 'MESH:D002712', (79, 87))
411	25277200	In this study, 3 cell clones overexpressing a deletion mutant (R3-6, R2-13, and R1-12) show stronger tolerance to cisplatin than to carboplatin in terms of their IC50; a 1.7- to 2.2-fold increase for cisplatin and only a 1.4- to 1.7-fold increase for carboplatin (Fig.	('tolerance', 'MPA', (101, 110))	('deletion', 'Var', (46, 54))	('stronger', 'PosReg', (92, 100))	('increase', 'PosReg', (187, 195))	('IC50', 'MPA', (162, 166))	('carboplatin', 'Chemical', 'MESH:D016190', (251, 262))	('cisplatin', 'Chemical', 'MESH:D002945', (200, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('carboplatin', 'Chemical', 'MESH:D016190', (132, 143))	('cisplatin', 'MPA', (200, 209))
418	25277200	The effect of ANXA4 knockdown on paclitaxel sensitivity was assessed in a previous study.	('knockdown', 'Var', (20, 29))	('ANXA4', 'Gene', (14, 19))	('paclitaxel', 'Chemical', 'MESH:D017239', (33, 43))
419	25277200	The effect of sensitivity to paclitaxel varied among different cell clones: ANXA4 knockdown in the OVTOKO cell line with acidic isoelectric point (IEPs) did not improve the sensitivity to paclitaxel, whereas OVISE cell lines with basic IEPs showed improved sensitivity to paclitaxel.	('ANXA4', 'Gene', (76, 81))	('improved', 'PosReg', (248, 256))	('sensitivity', 'MPA', (257, 268))	('knockdown', 'Var', (82, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (29, 39))	('sensitivity', 'MPA', (173, 184))	('paclitaxel', 'Chemical', 'MESH:D017239', (188, 198))	('paclitaxel', 'Chemical', 'MESH:D017239', (272, 282))
429	25277200	To generate ANXA4 deletion mutants, annexin repeat domains were deleted one by one from the C-terminal site.	('ANXA4', 'Gene', (12, 17))	('annexin', 'Gene', '105245705', (36, 43))	('annexin', 'Gene', (36, 43))	('deleted', 'NegReg', (64, 71))	('deletion mutants', 'Var', (18, 34))
431	25277200	We subsequently set out to generate an R1 mutant (the E70A mutation), whose calcium-binding site does not work because of the change of a negatively charged carboxyl group to a neutral side chain, as previously described.	('E70A', 'Mutation', 'p.E70A', (54, 58))	('change', 'Reg', (126, 132))	('calcium', 'Chemical', 'MESH:D002118', (76, 83))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('E70A', 'Var', (54, 58))
433	25277200	Full-length ANXA4, each ANXA4 deletion mutant construct and the empty vector were transfected into NUGC3 cells using Lipofectamine 2000 (Invitrogen).	('ANXA4', 'Gene', (12, 17))	('deletion mutant', 'Var', (30, 45))	('NUGC3', 'CellLine', 'CVCL:1612', (99, 104))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (117, 135))	('ANXA4', 'Gene', (24, 29))
439	25277200	Full-length ANXA4-transfected cells (FL-22), each ANXA4 deletion mutant-transfected cell clone (R3-6, R2-13, R1-12 and R1[E70A]-95), and control cells (NC-14) were cultured up to 80% confluence in 150-mm tissue culture dishes.	('deletion', 'Var', (56, 64))	('FL-22', 'Chemical', '-', (37, 42))	('E70A', 'Mutation', 'p.E70A', (122, 126))	('ANXA4', 'Gene', (50, 55))
447	25277200	The cells of the ANXA4 deletion mutant series (NC-14, FL-22, R1-12 and R1[E70A]-95) were cultured in 35-mm tissue culture dishes up to 20% confluence and incubated with a medium containing 10 mM MQAE for 4 h at 37 C. After loading, the cells were washed 5 times with Cl--free buffer and electrically stimulated under a microscope at 37 C in a humidified atmosphere with 5% CO2.	('FL-22', 'Chemical', '-', (54, 59))	('E70A', 'Mutation', 'p.E70A', (74, 78))	('deletion', 'Var', (23, 31))	('CO2', 'Chemical', '-', (373, 376))	('ANXA4', 'Gene', (17, 22))
453	26716645	Overexpression of CPT1A correlated with a poor overall survival of ovarian cancer patients.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('CPT', 'molecular_function', 'GO:0004142', ('18', '21'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('CPT1A', 'Gene', (18, 23))	('ovarian cancer', 'Disease', (67, 81))	('patients', 'Species', '9606', (82, 90))	('CPT', 'molecular_function', 'GO:0004095', ('18', '21'))	('poor', 'NegReg', (42, 46))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('overall', 'MPA', (47, 54))
454	26716645	Inactivation of CPT1A decreased cellular ATP levels and induced cell cycle arrest at G0/G1, suggesting that ovarian cancer cells depend on or are addicted to CPT1A-mediated FAO for cell cycle progression.	('CPT', 'molecular_function', 'GO:0004095', ('158', '161'))	('CPT1A', 'Gene', (16, 21))	('CPT', 'molecular_function', 'GO:0004095', ('16', '19'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('64', '81'))	('ovarian cancer', 'Disease', (108, 122))	('cell cycle arrest at G0/G1', 'CPA', (64, 90))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('CPT', 'molecular_function', 'GO:0004142', ('158', '161'))	('induced', 'Reg', (56, 63))	('Inactivation', 'Var', (0, 12))	('ATP', 'Chemical', 'MESH:D000255', (41, 44))	('FAO', 'Chemical', '-', (173, 176))	('cell cycle', 'biological_process', 'GO:0007049', ('181', '191'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CPT', 'molecular_function', 'GO:0004142', ('16', '19'))	('decreased', 'NegReg', (22, 31))	('cellular ATP levels', 'MPA', (32, 51))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))
456	26716645	The cyclin-dependent kinase inhibitor p21WAF1 (p21) was identified as most consistently and robustly induced cell cycle regulator upon inactivation of CPT1A.	('cell', 'MPA', (109, 113))	('p21WAF1', 'Gene', (38, 45))	('p21', 'Gene', (38, 41))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('109', '129'))	('CPT1A', 'Gene', (151, 156))	('p21', 'Gene', '1026', (38, 41))	('p21WAF1', 'Gene', '1026', (38, 45))	('CPT', 'molecular_function', 'GO:0004142', ('151', '154'))	('CPT', 'molecular_function', 'GO:0004095', ('151', '154'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('4', '37'))	('inactivation', 'Var', (135, 147))	('p21', 'Gene', '1026', (47, 50))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('21', '37'))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('109', '129'))	('p21', 'Gene', (47, 50))	('induced', 'Reg', (101, 108))
464	26716645	However, unlike glycolytic and lipogenic pathways where specific metabolic enzymes such as hexokinase 2 and FAS are known to be deregulated by oncogene (s) or by inactivation of tumor suppressors, there is limited evidence for cancer-associated abnormal expression or activity of the enzymes directly involved in the FAO pathway.	('FAS', 'Gene', (108, 111))	('hexokinase 2', 'Gene', (91, 103))	('tumor', 'Disease', (178, 183))	('FAS', 'Gene', '2194', (108, 111))	('activity', 'MPA', (268, 276))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('FAO', 'Chemical', '-', (317, 320))	('expression', 'MPA', (254, 264))	('hexokinase 2', 'Gene', '3099', (91, 103))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('inactivation', 'Var', (162, 174))	('cancer', 'Disease', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
475	26716645	Overexpression of CPT1A is associated with poor prognosis of ovarian cancer patients.	('ovarian cancer', 'Disease', 'MESH:D010051', (61, 75))	('patients', 'Species', '9606', (76, 84))	('CPT', 'molecular_function', 'GO:0004142', ('18', '21'))	('CPT1A', 'Gene', (18, 23))	('CPT', 'molecular_function', 'GO:0004095', ('18', '21'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ovarian cancer', 'Disease', (61, 75))	('Overexpression', 'Var', (0, 14))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))
476	26716645	Inactivation of CPT1A in ovarian cancer cell lines by pharmacological inhibition or by lentivirally-mediated knockdown led to growth arrest at G0/G1 and inhibition of tumorigenicity in SCID mice, suggesting that CPT1A-dependent FAO plays an essential role in cell cycle progression of ovarian cancer cells in vitro and in vivo.	('ovarian cancer', 'Disease', (285, 299))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ovarian cancer', 'Phenotype', 'HP:0100615', (285, 299))	('CPT1A', 'Gene', (16, 21))	('CPT', 'molecular_function', 'GO:0004095', ('16', '19'))	('cell cycle', 'biological_process', 'GO:0007049', ('259', '269'))	('SCID', 'Disease', 'MESH:D053632', (185, 189))	('ovarian cancer', 'Disease', 'MESH:D010051', (25, 39))	('CPT', 'molecular_function', 'GO:0004095', ('212', '215'))	('growth arrest', 'Phenotype', 'HP:0001510', (126, 139))	('tumor', 'Disease', (167, 172))	('Inactivation', 'Var', (0, 12))	('growth arrest at G0/G1', 'CPA', (126, 148))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('FAO', 'Chemical', '-', (228, 231))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('SCID', 'Disease', (185, 189))	('ovarian cancer', 'Disease', 'MESH:D010051', (285, 299))	('CPT', 'molecular_function', 'GO:0004142', ('16', '19'))	('ovarian cancer', 'Disease', (25, 39))	('inhibition', 'NegReg', (153, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('CPT', 'molecular_function', 'GO:0004142', ('212', '215'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mice', 'Species', '10090', (190, 194))
477	26716645	To elucidate the molecular mechanism underlying these cellular outcomes of CPT1A inhibition, we performed a PCR-based cell cycle assay and identified p21WAF1 (p21) as the most consistently and dramatically upregulated cell cycle regulator upon CPT1A inactivation.	('p21', 'Gene', '1026', (159, 162))	('p21WAF1', 'Gene', '1026', (150, 157))	('CPT', 'molecular_function', 'GO:0004095', ('244', '247'))	('CPT1A', 'Gene', (244, 249))	('p21', 'Gene', (159, 162))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('218', '238'))	('upregulated', 'PosReg', (206, 217))	('p21', 'Gene', '1026', (150, 153))	('CPT', 'molecular_function', 'GO:0004142', ('75', '78'))	('cell cycle', 'biological_process', 'GO:0007049', ('118', '128'))	('p21', 'Gene', (150, 153))	('CPT', 'molecular_function', 'GO:0004095', ('75', '78'))	('inactivation', 'Var', (250, 262))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('218', '238'))	('p21WAF1', 'Gene', (150, 157))	('CPT', 'molecular_function', 'GO:0004142', ('244', '247'))
478	26716645	We further demonstrated that CPT1A inhibition induced time-dependent phosphorylation and activation of FoxO transcription factors by AMPK, JNK and p38.	('AMPK', 'Var', (133, 137))	('FoxO transcription factors', 'Gene', (103, 129))	('JNK', 'molecular_function', 'GO:0004705', ('139', '142'))	('AMPK', 'molecular_function', 'GO:0050405', ('133', '137'))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('AMPK', 'molecular_function', 'GO:0004691', ('133', '137'))	('JNK', 'Gene', (139, 142))	('p38', 'Gene', '5594', (147, 150))	('AMPK', 'molecular_function', 'GO:0047322', ('133', '137'))	('CPT', 'molecular_function', 'GO:0004142', ('29', '32'))	('activation', 'PosReg', (89, 99))	('phosphorylation', 'MPA', (69, 84))	('JNK', 'Gene', '5599', (139, 142))	('CPT', 'molecular_function', 'GO:0004095', ('29', '32'))	('CPT1A', 'Gene', (29, 34))	('p38', 'Gene', (147, 150))	('inhibition', 'NegReg', (35, 45))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))
489	26716645	Kaplan Meier survival and the Gehan-Breslow-Wilcoxon test of the two groups using the GraphPad PRISM software indicated that CPT1A High patients had a statistically significant shorter overall survival (medium 1435 days) than that of CPT1A Low patients (medium 1767 days) (p = 0.0362) (Figure 1C), suggesting that CPT1A overexpression is associated with poorer prognosis.	('CPT', 'molecular_function', 'GO:0004095', ('234', '237'))	('CPT', 'molecular_function', 'GO:0004142', ('125', '128'))	('CPT', 'molecular_function', 'GO:0004142', ('314', '317'))	('CPT', 'molecular_function', 'GO:0004095', ('125', '128'))	('CPT', 'molecular_function', 'GO:0004095', ('314', '317'))	('CPT1A', 'Gene', (125, 130))	('patients', 'Species', '9606', (136, 144))	('shorter', 'NegReg', (177, 184))	('patients', 'Species', '9606', (244, 252))	('overall survival', 'MPA', (185, 201))	('High', 'Var', (131, 135))	('CPT', 'molecular_function', 'GO:0004142', ('234', '237'))
491	26716645	To elucidate biological functions of CPT1A in cancer cells in a more specific manner, we used lentivirus-mediated shRNA to knockdown its expression in SKOV-3, Caov-3, OVCA-432 and OVCAR-3 that expressed highest levels of endogenous CPT1A (Figure 1A).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('SKOV-3', 'CellLine', 'CVCL:0532', (151, 157))	('cancer', 'Disease', (46, 52))	('CPT', 'molecular_function', 'GO:0004142', ('37', '40'))	('CPT', 'molecular_function', 'GO:0004095', ('232', '235'))	('CPT', 'molecular_function', 'GO:0004095', ('37', '40'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('OVCA', 'Chemical', '-', (180, 184))	('knockdown', 'Var', (123, 132))	('CPT', 'molecular_function', 'GO:0004142', ('232', '235'))	('OVCA', 'Chemical', '-', (167, 171))
500	26716645	However, beta-gal-positive cells were not detectable in Caov-3 following CPT1A-shRNA knockdown or treatment with etomoxir (data not shown).	('beta-gal', 'Gene', (9, 17))	('CPT', 'molecular_function', 'GO:0004142', ('73', '76'))	('CPT', 'molecular_function', 'GO:0004095', ('73', '76'))	('CPT1A-shRNA', 'Gene', (73, 84))	('etomoxir', 'Chemical', 'MESH:C054207', (113, 121))	('knockdown', 'Var', (85, 94))	('beta-gal', 'Gene', '2720', (9, 17))
502	26716645	As shown in Figure 3A, shRNA knockdown of CPT1A or treatment with etomoxir for 24 hours induced significant increases in G0/G1 population with concomitant decreases in S and G2/M phases in all ovarian cancer cell lines examined.	('ovarian cancer', 'Disease', 'MESH:D010051', (193, 207))	('knockdown', 'Var', (29, 38))	('etomoxir', 'Chemical', 'MESH:C054207', (66, 74))	('CPT1A', 'Gene', (42, 47))	('ovarian cancer', 'Disease', (193, 207))	('increases', 'PosReg', (108, 117))	('decreases', 'NegReg', (155, 164))	('CPT', 'molecular_function', 'GO:0004142', ('42', '45'))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CPT', 'molecular_function', 'GO:0004095', ('42', '45'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))	('G0/G1 population', 'CPA', (121, 137))
504	26716645	Changes in gene expression were compared between CPT1A-sh2 knockdown cells and ctrl-sh cells or between etomoxir- and vehicle-treated cells.	('CPT1A-sh2', 'Gene', (49, 58))	('etomoxir', 'Chemical', 'MESH:C054207', (104, 112))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))	('knockdown', 'Var', (59, 68))	('CPT', 'molecular_function', 'GO:0004142', ('49', '52'))	('CPT', 'molecular_function', 'GO:0004095', ('49', '52'))
505	26716645	Interestingly, the cyclin-dependent kinase inhibitor p21 (CDKN1A in Figure 3B) was most drastically and consistently induced by inactivation of CPT1A in both cell lines.	('CPT1A', 'Gene', (144, 149))	('CPT', 'molecular_function', 'GO:0004142', ('144', '147'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('19', '52'))	('CPT', 'molecular_function', 'GO:0004095', ('144', '147'))	('CDKN1A', 'Gene', (58, 64))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('36', '52'))	('inactivation', 'Var', (128, 140))	('p21', 'Gene', '1026', (53, 56))	('CDKN1A', 'Gene', '1026', (58, 64))	('p21', 'Gene', (53, 56))	('induced', 'Reg', (117, 124))
508	26716645	For example, p16INK4A (CDKN2A) was modestly decreased by CPT1A inactivation in SKOV-3 but not in OVCA-432.	('CPT', 'molecular_function', 'GO:0004142', ('57', '60'))	('SKOV-3', 'CellLine', 'CVCL:0532', (79, 85))	('inactivation', 'Var', (63, 75))	('CDKN2A', 'Gene', (23, 29))	('p16INK4A', 'Gene', (13, 21))	('CPT', 'molecular_function', 'GO:0004095', ('57', '60'))	('OVCA', 'Chemical', '-', (97, 101))	('p16INK4A', 'Gene', '1029', (13, 21))	('CDKN2A', 'Gene', '1029', (23, 29))	('CPT1A', 'Gene', (57, 62))	('decreased', 'NegReg', (44, 53))
509	26716645	Similarly, Fos was modestly induced by inactivation of CPT1A in OVCA-432 but not in SKOV-3 (Figure 3B).	('OVCA', 'Chemical', '-', (64, 68))	('Fos', 'Gene', (11, 14))	('CPT', 'molecular_function', 'GO:0004142', ('55', '58'))	('CPT1A', 'Gene', (55, 60))	('CPT', 'molecular_function', 'GO:0004095', ('55', '58'))	('SKOV-3', 'CellLine', 'CVCL:0532', (84, 90))	('inactivation', 'Var', (39, 51))	('Fos', 'Gene', '2353', (11, 14))
510	26716645	We performed immunoblotting to confirm the predominant increase in p21 expression in association with CPT1A inactivation.	('CPT1A', 'Gene', (102, 107))	('expression', 'MPA', (71, 81))	('increase', 'PosReg', (55, 63))	('p21', 'Gene', '1026', (67, 70))	('inactivation', 'Var', (108, 120))	('CPT', 'molecular_function', 'GO:0004142', ('102', '105'))	('p21', 'Gene', (67, 70))	('CPT', 'molecular_function', 'GO:0004095', ('102', '105'))
511	26716645	As shown in Figure 3C, p21 was strongly induced by CPT1A-sh knockdown or etomoxir across ovarian cancer cell lines examined.	('etomoxir', 'Chemical', 'MESH:C054207', (73, 81))	('induced', 'Reg', (40, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (89, 103))	('p21', 'Gene', '1026', (23, 26))	('CPT', 'molecular_function', 'GO:0004142', ('51', '54'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('knockdown', 'Var', (60, 69))	('ovarian cancer', 'Disease', (89, 103))	('CPT', 'molecular_function', 'GO:0004095', ('51', '54'))	('CPT1A-sh', 'Gene', (51, 59))	('p21', 'Gene', (23, 26))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))
512	26716645	CPT1A knockdown inhibited proliferation of ovarian cancer cells not only in monolayer culture (Figure 2A) but also in soft agar (Figure 4A).	('agar', 'Chemical', 'MESH:D000362', (123, 127))	('CPT1A', 'Gene', (0, 5))	('inhibited', 'NegReg', (16, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (43, 57))	('CPT', 'molecular_function', 'GO:0004095', ('0', '3'))	('ovarian cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CPT', 'molecular_function', 'GO:0004142', ('0', '3'))	('knockdown', 'Var', (6, 15))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))	('proliferation', 'CPA', (26, 39))
514	26716645	The numbers of colonies formed in soft agar were significantly reduced in CPT1A shRNA knockdown cells.	('agar', 'Chemical', 'MESH:D000362', (39, 43))	('knockdown', 'Var', (86, 95))	('reduced', 'NegReg', (63, 70))	('CPT', 'molecular_function', 'GO:0004142', ('74', '77'))	('CPT', 'molecular_function', 'GO:0004095', ('74', '77'))	('shRNA', 'Gene', (80, 85))	('CPT1A shRNA', 'Gene', (74, 85))
516	26716645	CPT1A-sh2 knockdown also strongly inhibited initiation and enlargement of subcutaneous xenografts in SCID mice as reflected by their growth curves (Figure 4B).	('mice', 'Species', '10090', (106, 110))	('initiation', 'CPA', (44, 54))	('enlargement', 'CPA', (59, 70))	('CPT', 'molecular_function', 'GO:0004095', ('0', '3'))	('inhibited', 'NegReg', (34, 43))	('CPT', 'molecular_function', 'GO:0004142', ('0', '3'))	('CPT1A-sh2', 'Gene', (0, 9))	('SCID', 'Disease', (101, 105))	('knockdown', 'Var', (10, 19))	('SCID', 'Disease', 'MESH:D053632', (101, 105))
518	26716645	injected with CPT1A-sh2 knockdown SKOV-3 cells survived significantly longer than those injected with control cells as indicated by Kaplan Meier survival analysis (Figure 4C).	('CPT', 'molecular_function', 'GO:0004142', ('14', '17'))	('CPT', 'molecular_function', 'GO:0004095', ('14', '17'))	('survived', 'CPA', (47, 55))	('longer', 'PosReg', (70, 76))	('CPT1A-sh2', 'Gene', (14, 23))	('knockdown', 'Var', (24, 33))	('SKOV-3', 'CellLine', 'CVCL:0532', (34, 40))
520	26716645	However, many ovarian cancer cell lines including SKOV-3, Caov-3 and OVCAR-3 used in this study were known to lack p53 or carry mutant p53, suggesting a p53-independent induction of p21 to respond to inactivation of CPT1A.	('p21', 'Gene', (182, 185))	('ovarian cancer', 'Disease', (14, 28))	('lack', 'NegReg', (110, 114))	('p53', 'Gene', '7157', (115, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('p53', 'Gene', (115, 118))	('p53', 'Gene', (135, 138))	('mutant', 'Var', (128, 134))	('p53', 'Gene', '7157', (135, 138))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('OVCA', 'Chemical', '-', (69, 73))	('SKOV-3', 'CellLine', 'CVCL:0532', (50, 56))	('p21', 'Gene', '1026', (182, 185))	('ovarian cancer', 'Disease', 'MESH:D010051', (14, 28))	('CPT', 'molecular_function', 'GO:0004142', ('216', '219'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('CPT', 'molecular_function', 'GO:0004095', ('216', '219'))
524	26716645	When the FoxO-binding site was mutated to GAATTCA, activation of the p21 gene promoter by etomoxir was blocked (Figure 5A), suggesting involvement of FoxO transcription factors in upregulation of p21 in CPT1A-inactivated cells.	('p21', 'Gene', (196, 199))	('upregulation', 'PosReg', (180, 192))	('involvement', 'Reg', (135, 146))	('p21', 'Gene', (69, 72))	('etomoxir', 'Chemical', 'MESH:C054207', (90, 98))	('CPT', 'molecular_function', 'GO:0004142', ('203', '206'))	('CPT', 'molecular_function', 'GO:0004095', ('203', '206'))	('transcription', 'biological_process', 'GO:0006351', ('155', '168'))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('p21', 'Gene', '1026', (196, 199))	('mutated', 'Var', (31, 38))	('p21', 'Gene', '1026', (69, 72))
526	26716645	In further support of FoxO-dependent mechanism to induce p21, knockdown of FoxO1 or FoxO3a attenuated upregulation of p21 and inhibition of proliferation by etomoxir (Figure 5B).	('proliferation', 'CPA', (140, 153))	('p21', 'Gene', '1026', (57, 60))	('FoxO3a', 'Gene', '2309', (84, 90))	('p21', 'Gene', '1026', (118, 121))	('p21', 'Gene', (118, 121))	('FoxO1', 'Gene', (75, 80))	('FoxO1', 'Gene', '2308', (75, 80))	('FoxO3a', 'Gene', (84, 90))	('inhibition', 'NegReg', (126, 136))	('attenuated', 'NegReg', (91, 101))	('etomoxir', 'Chemical', 'MESH:C054207', (157, 165))	('p21', 'Gene', (57, 60))	('knockdown', 'Var', (62, 71))
532	26716645	As shown earlier in Figure 2C, inactivation of CPT1A decreased cellular ATP levels and activated AMPK.	('AMPK', 'MPA', (97, 101))	('inactivation', 'Var', (31, 43))	('cellular ATP levels', 'MPA', (63, 82))	('activated', 'PosReg', (87, 96))	('CPT', 'molecular_function', 'GO:0004142', ('47', '50'))	('AMPK', 'molecular_function', 'GO:0050405', ('97', '101'))	('CPT', 'molecular_function', 'GO:0004095', ('47', '50'))	('ATP', 'Chemical', 'MESH:D000255', (72, 75))	('decreased', 'NegReg', (53, 62))	('AMPK', 'molecular_function', 'GO:0004691', ('97', '101'))	('CPT1A', 'Gene', (47, 52))	('AMPK', 'molecular_function', 'GO:0047322', ('97', '101'))
533	26716645	Using an antibody for FoxO3a phosphorylated by AMPKalpha at S413, we confirmed that etomoxir treatment increased FoxO3a phosphorylation at S413 in a pattern matching well with the kinetics of AMPKalpha phosphorylation in these cells (Figure 6A).	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('increased', 'PosReg', (103, 112))	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('phosphorylation', 'MPA', (120, 135))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('FoxO3a', 'Gene', '2309', (22, 28))	('etomoxir', 'Chemical', 'MESH:C054207', (84, 92))	('at S413', 'Var', (136, 143))	('FoxO3a', 'Gene', '2309', (113, 119))	('phosphorylation', 'biological_process', 'GO:0016310', ('202', '217'))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('FoxO3a', 'Gene', (22, 28))	('phosphorylation', 'biological_process', 'GO:0016310', ('120', '135'))	('FoxO3a', 'Gene', (113, 119))
534	26716645	The AMPK inhibitor compound C prevented etomoxir-induced FoxO3a S413 phosphorylation (Figure 6A).	('etomoxir-induced', 'MPA', (40, 56))	('prevented', 'NegReg', (30, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('FoxO3a', 'Gene', '2309', (57, 63))	('AMPK', 'molecular_function', 'GO:0050405', ('4', '8'))	('etomoxir', 'Chemical', 'MESH:C054207', (40, 48))	('S413', 'Var', (64, 68))	('FoxO3a', 'Gene', (57, 63))	('AMPK', 'molecular_function', 'GO:0004691', ('4', '8'))	('AMPK', 'molecular_function', 'GO:0047322', ('4', '8'))
558	26716645	Inactivation of CPT1A induced expression of the cyclin-dependent kinase inhibitor p21 and cell cycle arrest at G0/G1.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('90', '107'))	('expression', 'MPA', (30, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('CPT', 'molecular_function', 'GO:0004095', ('16', '19'))	('p21', 'Gene', (82, 85))	('p21', 'Gene', '1026', (82, 85))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('48', '81'))	('CPT', 'molecular_function', 'GO:0004142', ('16', '19'))	('CPT1A', 'Gene', (16, 21))	('Inactivation', 'Var', (0, 12))	('cell cycle arrest at G0/G1', 'CPA', (90, 116))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('65', '81'))
561	26716645	As further mechanism upstream of FoxO activation, inhibition of CPT1A stimulated phosphorylation of FoxO through activation of AMPK, p38 and JNK kinases.	('FoxO', 'Gene', (100, 104))	('AMPK', 'molecular_function', 'GO:0004691', ('127', '131'))	('CPT1A', 'Gene', (64, 69))	('phosphorylation', 'MPA', (81, 96))	('AMPK', 'molecular_function', 'GO:0047322', ('127', '131'))	('p38', 'Gene', '5594', (133, 136))	('inhibition', 'Var', (50, 60))	('JNK', 'Gene', '5599', (141, 144))	('activation', 'PosReg', (113, 123))	('AMPK', 'Pathway', (127, 131))	('p38', 'Gene', (133, 136))	('JNK', 'molecular_function', 'GO:0004705', ('141', '144'))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('CPT', 'molecular_function', 'GO:0004142', ('64', '67'))	('stimulated', 'PosReg', (70, 80))	('AMPK', 'molecular_function', 'GO:0050405', ('127', '131'))	('CPT', 'molecular_function', 'GO:0004095', ('64', '67'))	('JNK', 'Gene', (141, 144))
564	26716645	In the HepG2 hepatocellular carcinoma cells, etomoxir at 1 mM was found to trigger both growth inhibition and apoptotic/necrotic cell death.	('necrotic cell death', 'Disease', (120, 139))	('necrotic cell death', 'Disease', 'MESH:D003643', (120, 139))	('growth inhibition', 'CPA', (88, 105))	('HepG2', 'CellLine', 'CVCL:0027', (7, 12))	('etomoxir', 'Var', (45, 53))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (13, 37))	('necrotic cell death', 'biological_process', 'GO:0070265', ('120', '139'))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('hepatocellular carcinoma', 'Disease', (13, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (13, 37))	('etomoxir', 'Chemical', 'MESH:C054207', (45, 53))
570	26716645	In our study, etomoxir treatment and shRNA knockdown elicited strikingly similar effects on p21 and other cell cycle-related genes.	('etomoxir', 'Chemical', 'MESH:C054207', (14, 22))	('knockdown', 'Var', (43, 52))	('shRNA', 'Gene', (37, 42))	('cell cycle', 'biological_process', 'GO:0007049', ('106', '116'))	('p21', 'Gene', '1026', (92, 95))	('effects', 'Reg', (81, 88))	('cell cycle-related genes', 'Gene', (106, 130))	('p21', 'Gene', (92, 95))
582	26716645	We further asked how inhibition of CPT1A culminated in p21 induction.	('p21', 'Gene', (55, 58))	('CPT1A', 'Gene', (35, 40))	('inhibition', 'Var', (21, 31))	('CPT', 'molecular_function', 'GO:0004142', ('35', '38'))	('CPT', 'molecular_function', 'GO:0004095', ('35', '38'))	('p21', 'Gene', '1026', (55, 58))
584	26716645	Our study demonstrated that the FoxO transcription factors were required for upregulation of p21 transcription in CPT1A-depleted cells, as suggested by mutational analysis of the p21 gene promoter as well as shRNA silencing of FoxO.	('p21', 'Gene', '1026', (93, 96))	('FoxO', 'Gene', (227, 231))	('p21', 'Gene', (179, 182))	('silencing', 'NegReg', (214, 223))	('CPT', 'molecular_function', 'GO:0004142', ('114', '117'))	('mutational', 'Var', (152, 162))	('p21', 'Gene', (93, 96))	('CPT', 'molecular_function', 'GO:0004095', ('114', '117'))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('transcription', 'MPA', (97, 110))	('upregulation', 'PosReg', (77, 89))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('p21', 'Gene', '1026', (179, 182))
590	26716645	Disruption of such a control leads to phosphorylation and activation of FoxO by AMPK, JNK and p38, and the subsequent induction of p21 and cell cycle arrest at G0/G1.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (139, 156))	('AMPK', 'molecular_function', 'GO:0050405', ('80', '84'))	('p38', 'Gene', '5594', (94, 97))	('JNK', 'Gene', (86, 89))	('activation', 'PosReg', (58, 68))	('Disruption', 'Var', (0, 10))	('JNK', 'Gene', '5599', (86, 89))	('phosphorylation', 'MPA', (38, 53))	('p21', 'Gene', '1026', (131, 134))	('FoxO', 'Gene', (72, 76))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('139', '156'))	('AMPK', 'molecular_function', 'GO:0004691', ('80', '84'))	('JNK', 'molecular_function', 'GO:0004705', ('86', '89'))	('AMPK', 'molecular_function', 'GO:0047322', ('80', '84'))	('induction', 'Reg', (118, 127))	('cell cycle arrest at G0/G1', 'CPA', (139, 165))	('p38', 'Gene', (94, 97))	('p21', 'Gene', (131, 134))	('AMPK', 'Var', (80, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))
594	26716645	Antibodies used for western blotting against CPT1A, p21, p-FoxO3a (S413), p-FoxO4 (T451), p-p38 (T180/Y182), p-JNK (T183/Y185), p-Erk1/2 (T202/Y204), p-AMPK (T172), and beta-actin were obtained from Cell Signaling (Beverly, MA).	('Erk1/2', 'Gene', '5595;5594', (130, 136))	('p38', 'Gene', (92, 95))	('JNK', 'molecular_function', 'GO:0004705', ('111', '114'))	('AMPK', 'molecular_function', 'GO:0047322', ('152', '156'))	('Erk1', 'molecular_function', 'GO:0004707', ('130', '134'))	('FoxO4', 'Gene', (76, 81))	('JNK', 'Gene', (111, 114))	('FoxO3a', 'Gene', (59, 65))	('p21', 'Gene', '1026', (52, 55))	('JNK', 'Gene', '5599', (111, 114))	('T202/Y204', 'Var', (138, 147))	('beta-actin', 'Gene', (169, 179))	('FoxO3a', 'Gene', '2309', (59, 65))	('CPT', 'molecular_function', 'GO:0004095', ('45', '48'))	('Signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('p38', 'Gene', '5594', (92, 95))	('T183/Y185', 'Var', (116, 125))	('AMPK', 'molecular_function', 'GO:0050405', ('152', '156'))	('T180/Y182', 'Var', (97, 106))	('Erk1/2', 'Gene', (130, 136))	('p21', 'Gene', (52, 55))	('FoxO4', 'Gene', '4303', (76, 81))	('AMPK', 'molecular_function', 'GO:0004691', ('152', '156'))	('CPT', 'molecular_function', 'GO:0004142', ('45', '48'))	('beta-actin', 'Gene', '728378', (169, 179))
631	26716645	CPT1A-sh2 knockdown SKOV-3 cells and ctrl-sh control cells were also i.p.	('CPT', 'molecular_function', 'GO:0004095', ('0', '3'))	('CPT', 'molecular_function', 'GO:0004142', ('0', '3'))	('CPT1A-sh2', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))	('SKOV-3', 'CellLine', 'CVCL:0532', (20, 26))
637	19430562	Mutational Analysis of KRAS, BRAF, and TP53 Genes of Ovarian Serous Carcinomas in Korean Women To assess the prevalence of KRAS, BRAF, and TP53 mutations in cases of low-grade and high-grade serous carcinomas and to evaluate the clinical outcomes of these morphologically distinct carcinomas.	('Mutational', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('KRAS', 'Gene', (123, 127))	('mutations', 'Var', (144, 153))	('serous carcinomas', 'Disease', (191, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('Ovarian Serous Carcinomas', 'Disease', 'MESH:D010051', (53, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (139, 143))	('carcinomas', 'Disease', 'MESH:D002277', (198, 208))	('carcinomas', 'Disease', (281, 291))	('Ovarian Serous Carcinomas', 'Phenotype', 'HP:0012887', (53, 78))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('Carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('KRAS', 'Gene', '3845', (23, 27))	('serous carcinomas', 'Disease', 'MESH:D018284', (191, 208))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('TP53', 'Gene', '7157', (139, 143))	('KRAS', 'Gene', (23, 27))	('carcinomas', 'Disease', 'MESH:D002277', (281, 291))	('Ovarian Serous Carcinomas', 'Disease', (53, 78))	('carcinomas', 'Disease', (198, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (281, 291))	('KRAS', 'Gene', '3845', (123, 127))	('TP53', 'Gene', (39, 43))
644	19430562	Mutations in KRAS and BRAF were found in 6 (30%) and 2 (10%) patients in the low-grade carcinoma group, respectively, however, they were not found in the high-grade carcinoma group.	('carcinoma', 'Disease', (165, 174))	('carcinoma', 'Disease', (87, 96))	('BRAF', 'Gene', '673', (22, 26))	('found', 'Reg', (32, 37))	('low-grade', 'Disease', (77, 86))	('patients', 'Species', '9606', (61, 69))	('BRAF', 'Gene', (22, 26))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Disease', 'MESH:D002277', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('carcinoma', 'Disease', 'MESH:D002277', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
646	19430562	The frequency of TP53 mutations in low-grade and high-grade carcinoma groups were found in 20% (4/20) and 70.6% (12/17), respectively (p = 0.009).	('carcinoma', 'Disease', (60, 69))	('carcinoma', 'Disease', 'MESH:D002277', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))	('low-grade', 'Disease', (35, 44))
657	19430562	RAS mutation was first reported in malignant melanoma, lung, and papillary thyroid carcinoma.	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (65, 92))	('RAS', 'Gene', (0, 3))	('lung', 'Disease', (55, 59))	('malignant melanoma', 'Phenotype', 'HP:0002861', (35, 53))	('mutation', 'Var', (4, 12))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (65, 92))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (75, 92))	('papillary thyroid carcinoma', 'Disease', (65, 92))	('malignant melanoma', 'Disease', 'MESH:D008545', (35, 53))	('reported', 'Reg', (23, 31))	('malignant melanoma', 'Disease', (35, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
658	19430562	In non-invasive and invasive ovarian carcinoma, mutation of KRAS and BRAF has previously been described with KRAS mutation which was mostly detected in mucinous ovarian tumor and in serous borderline tumors, but not in invasive serous carcinoma.	('described', 'Reg', (94, 103))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (29, 46))	('KRAS', 'Gene', (60, 64))	('non-invasive', 'Disease', (3, 15))	('mucinous ovarian tumor', 'Disease', (152, 174))	('mutation', 'Var', (114, 122))	('detected', 'Reg', (140, 148))	('invasive ovarian carcinoma', 'Disease', 'MESH:D010051', (20, 46))	('serous borderline tumors', 'Disease', 'MESH:D012569', (182, 206))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))	('invasive serous carcinoma', 'Disease', 'MESH:D018284', (219, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('ovarian tumor', 'Phenotype', 'HP:0100615', (161, 174))	('invasive serous carcinoma', 'Disease', (219, 244))	('mucinous ovarian tumor', 'Disease', 'MESH:D010051', (152, 174))	('mutation', 'Var', (48, 56))	('KRAS', 'Gene', '3845', (109, 113))	('serous borderline tumors', 'Disease', (182, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('invasive ovarian carcinoma', 'Disease', (20, 46))	('KRAS', 'Gene', (109, 113))	('mucinous ovarian tumor', 'Phenotype', 'HP:0031494', (152, 174))	('KRAS', 'Gene', '3845', (60, 64))
660	19430562	Mutation of the TP53 gene is the most common mutation in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Mutation', 'Var', (0, 8))	('TP53', 'Gene', '7157', (16, 20))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('TP53', 'Gene', (16, 20))	('cancers', 'Disease', (63, 70))	('human', 'Species', '9606', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
661	19430562	It has been suggested that p53 protein alterations due to missense mutations and loss of the p53 protein by nonsense or frameshift mutations might play important roles in clonal expansion of neoplastic cells.	('p53', 'Gene', '7157', (27, 30))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('p53', 'Gene', (93, 96))	('protein', 'Protein', (31, 38))	('p53', 'Gene', '7157', (93, 96))	('missense mutations', 'Var', (58, 76))	('alterations', 'Reg', (39, 50))	('protein', 'Protein', (97, 104))	('nonsense', 'Var', (108, 116))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('loss', 'NegReg', (81, 85))	('frameshift mutations', 'Var', (120, 140))	('p53', 'Gene', (27, 30))
662	19430562	Recently, the dualistic pathway was supported by molecular genetic differences in the frequency of KRAS, BRAF, and TP53 mutations between low-grade and high-grade serous carcinomas, with KRAS and BRAF mutations being more frequent and TP53 mutations being less common in low-grade serous carcinomas.	('KRAS', 'Gene', (187, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('serous carcinomas', 'Disease', 'MESH:D018284', (163, 180))	('mutations', 'Var', (120, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (288, 298))	('TP53', 'Gene', (235, 239))	('KRAS', 'Gene', '3845', (99, 103))	('serous carcinomas', 'Disease', 'MESH:D018284', (281, 298))	('BRAF', 'Gene', '673', (196, 200))	('TP53', 'Gene', (115, 119))	('BRAF', 'Gene', (196, 200))	('KRAS', 'Gene', (99, 103))	('TP53', 'Gene', '7157', (235, 239))	('serous carcinomas', 'Disease', (163, 180))	('serous carcinomas', 'Disease', (281, 298))	('mutations', 'Var', (201, 210))	('BRAF', 'Gene', '673', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('BRAF', 'Gene', (105, 109))	('TP53', 'Gene', '7157', (115, 119))	('KRAS', 'Gene', '3845', (187, 191))
664	19430562	Therefore, the aim of this study was to analyze the molecular genetic changes, including KRAS, BRAF, and TP53 mutations, in Korean patients with ovarian serous carcinoma and to evaluate the clinical outcomes in these 2 morphologically distinct ovarian serous carcinomas.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (110, 119))	('ovarian serous carcinomas', 'Disease', (244, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('BRAF', 'Gene', '673', (95, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (244, 268))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (244, 269))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (145, 169))	('BRAF', 'Gene', (95, 99))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (244, 269))	('KRAS', 'Gene', (89, 93))	('ovarian serous carcinoma', 'Disease', (145, 169))	('KRAS', 'Gene', '3845', (89, 93))
675	19430562	DNA was purified from each section and the KRAS, BRAF, and TP53 genes were assessed for mutations using digital PCR-based techniques.	('KRAS', 'Gene', '3845', (43, 47))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (59, 63))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('mutations', 'Var', (88, 97))	('KRAS', 'Gene', (43, 47))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))
679	19430562	The mean age at diagnosis was lower in patients with low-grade carcinoma than in those with high-grade carcinoma (48.7 +- 15.0 years vs. 55.2 +- 10.7 years, p = 0.045), and there were more premenopausal women in the low-grade carcinoma group (p = 0.041).	('carcinoma', 'Disease', (226, 235))	('lower', 'NegReg', (30, 35))	('patients', 'Species', '9606', (39, 47))	('carcinoma', 'Disease', (63, 72))	('carcinoma', 'Disease', (103, 112))	('carcinoma', 'Disease', 'MESH:D002277', (226, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('low-grade', 'Var', (53, 62))	('women', 'Species', '9606', (203, 208))	('carcinoma', 'Disease', 'MESH:D002277', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
681	19430562	During the median follow-up of 67 months for the low-grade group and 45 months for the high-grade group, there were 11 (40.7%) tumor-related deaths in patients with low-grade carcinoma and 40 (54.8%) deaths in patients with high-grade carcinoma (p = 0.262).	('deaths', 'Disease', 'MESH:D003643', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('deaths', 'Disease', (141, 147))	('deaths', 'Disease', (200, 206))	('carcinoma', 'Disease', 'MESH:D002277', (235, 244))	('tumor', 'Disease', (127, 132))	('deaths', 'Disease', 'MESH:D003643', (200, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('patients', 'Species', '9606', (151, 159))	('carcinoma', 'Disease', (235, 244))	('patients', 'Species', '9606', (210, 218))	('carcinoma', 'Disease', 'MESH:D002277', (175, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('low-grade', 'Var', (165, 174))	('carcinoma', 'Disease', (175, 184))
682	19430562	There were no statistically significant differences in progression-free and overall survival rates according to FIGO stage between the two groups, but the low-grade carcinoma group in early stage (FIGO stage I and II) showed a trend for improved 5-year progression-free survival, compared with the high-grade carcinoma group (100% vs. 68.6%, p = 0.064) (Fig.	('carcinoma', 'Disease', (165, 174))	('carcinoma', 'Disease', (309, 318))	('improved', 'PosReg', (237, 245))	('low-grade', 'Var', (155, 164))	('carcinoma', 'Disease', 'MESH:D002277', (165, 174))	('progression-free survival', 'CPA', (253, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Disease', 'MESH:D002277', (309, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))
683	19430562	We found that 6 (30%) low-grade serous carcinomas contained activating KRAS mutations at codon 12 (mutations of GGT to GAT), but these mutations were not found in high-grade serous carcinomas (Table 3, Fig.	('activating', 'PosReg', (60, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('mutations', 'Var', (76, 85))	('serous carcinomas', 'Disease', 'MESH:D018284', (174, 191))	('serous carcinomas', 'Disease', (174, 191))	('KRAS', 'Gene', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('KRAS', 'Gene', '3845', (71, 75))	('GAT', 'Gene', (119, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('GAT', 'Gene', '10249', (119, 122))	('serous carcinomas', 'Disease', 'MESH:D018284', (32, 49))	('serous carcinomas', 'Disease', (32, 49))
684	19430562	BRAF mutations were not found in any of the high-grade serous carcinomas, whereas the BRAF mutation was identified only in low-grade serous carcinomas.	('serous carcinomas', 'Disease', 'MESH:D018284', (133, 150))	('serous carcinomas', 'Disease', (133, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (86, 90))	('serous carcinomas', 'Disease', 'MESH:D018284', (55, 72))	('BRAF', 'Gene', '673', (0, 4))	('serous carcinomas', 'Disease', (55, 72))	('BRAF', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('BRAF', 'Gene', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
685	19430562	Two cases (10%) of low-grade carcinoma contained a mutation in exon 15, and codon 600 was affected (V600E) (Fig.	('carcinoma', 'Disease', 'MESH:D002277', (29, 38))	('mutation in exon', 'Var', (51, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('V600E', 'Var', (100, 105))	('carcinoma', 'Disease', (29, 38))	('V600E', 'Mutation', 'rs113488022', (100, 105))
687	19430562	TP53 mutations were found in 4 of the 20 (20.0%) cases of low-grade serous carcinoma.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('serous carcinoma', 'Disease', (68, 84))	('serous carcinoma', 'Disease', 'MESH:D018284', (68, 84))	('found', 'Reg', (20, 25))
688	19430562	By contrast, mutations were found in 12 of the 17 (70.6%) cases of high-grade serous carcinoma, 6 of which were missense mutations, 2 were nonsense mutations, and 4 were deletion mutations (Fig.	('deletion mutations', 'Var', (170, 188))	('missense mutations', 'Var', (112, 130))	('serous carcinoma', 'Disease', (78, 94))	('serous carcinoma', 'Disease', 'MESH:D018284', (78, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('found', 'Reg', (28, 33))	('mutations', 'Var', (13, 22))
689	19430562	The frequency of TP53 mutations was significantly higher in high-grade than in low-grade serous carcinomas (p = 0.009).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('serous carcinomas', 'Disease', 'MESH:D018284', (89, 106))	('high-grade', 'Disease', (60, 70))	('serous carcinomas', 'Disease', (89, 106))	('higher', 'Reg', (50, 56))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
697	19430562	There were no statistically significant differences in prognosis according to FIGO stage between the two groups, but the low-grade carcinoma group showed a trend for improved progression-free survival compared with the high-grade carcinoma group of early stage.	('carcinoma', 'Disease', (230, 239))	('carcinoma', 'Disease', 'MESH:D002277', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('low-grade', 'Var', (121, 130))	('carcinoma', 'Disease', (131, 140))	('improved', 'PosReg', (166, 174))	('carcinoma', 'Disease', 'MESH:D002277', (230, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('progression-free survival', 'CPA', (175, 200))
700	19430562	In a previous mutation study, KRAS mutations were observed in approximately 50% of serous tumors with low malignant potential and low-grade serous carcinomas, however, no KRAS mutations were found in high-grade serous carcinomas.	('serous carcinomas', 'Disease', 'MESH:D018284', (140, 157))	('serous carcinomas', 'Disease', (140, 157))	('observed', 'Reg', (50, 58))	('serous carcinomas', 'Disease', 'MESH:D018284', (211, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('KRAS', 'Gene', '3845', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('serous tumors', 'Disease', 'MESH:D018284', (83, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('KRAS', 'Gene', (171, 175))	('KRAS', 'Gene', (30, 34))	('serous carcinomas', 'Disease', (211, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('serous tumors', 'Disease', (83, 96))	('KRAS', 'Gene', '3845', (30, 34))	('mutations', 'Var', (35, 44))
701	19430562	Subsequent studies confirmed these previous results and found either BRAF or KRAS mutations in 68% of low-grade serous carcinomas and in 61% of serous tumors of low malignant potential, but in none of the high-grade serous carcinomas.	('serous carcinomas', 'Disease', 'MESH:D018284', (112, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (223, 233))	('serous carcinomas', 'Disease', 'MESH:D018284', (216, 233))	('serous carcinomas', 'Disease', (112, 129))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('serous carcinomas', 'Disease', (216, 233))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('BRAF', 'Gene', (69, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('mutations', 'Var', (82, 91))	('KRAS', 'Gene', (77, 81))	('serous tumors', 'Disease', 'MESH:D018284', (144, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('KRAS', 'Gene', '3845', (77, 81))	('BRAF', 'Gene', '673', (69, 73))	('serous tumors', 'Disease', (144, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
702	19430562	Furthermore, none of the low-grade tumors contained mutations in both KRAS and BRAF, indicating that these mutations are mutually exclusive.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('KRAS', 'Gene', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('KRAS', 'Gene', '3845', (70, 74))	('tumors', 'Disease', (35, 41))	('BRAF', 'Gene', '673', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('BRAF', 'Gene', (79, 83))
703	19430562	It has also been suggested that analysis of the other components of this pathway will reveal other mutations in the 40% of cases without KRAS and BRAF mutation.	('BRAF', 'Gene', (146, 150))	('KRAS', 'Gene', '3845', (137, 141))	('mutations', 'Var', (99, 108))	('KRAS', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (146, 150))
706	19430562	In the present study, KRAS mutations were found in 30%, BRAF mutations were found in 10%, and KRAS or BRAF mutations were found in 40% of low-grade serous carcinomas, whereas no BRAF or KRAS mutations were found in high-grade serous carcinoma.	('mutations', 'Var', (27, 36))	('KRAS', 'Gene', (94, 98))	('serous carcinoma', 'Disease', 'MESH:D018284', (148, 164))	('KRAS', 'Gene', '3845', (186, 190))	('KRAS', 'Gene', (22, 26))	('found', 'Reg', (122, 127))	('BRAF', 'Gene', (178, 182))	('serous carcinoma', 'Disease', 'MESH:D018284', (226, 242))	('BRAF', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (56, 60))	('KRAS', 'Gene', (186, 190))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (102, 106))	('serous carcinomas', 'Disease', (148, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('mutations', 'Var', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('KRAS', 'Gene', '3845', (94, 98))	('serous carcinomas', 'Disease', 'MESH:D018284', (148, 165))	('serous carcinoma', 'Disease', (226, 242))	('BRAF', 'Gene', '673', (178, 182))	('KRAS', 'Gene', '3845', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
707	19430562	However, our study reported lower frequencies of KRAS or BRAF mutations than previous studies, and we suggest that the number of carcinomas due to mutation of another pathway-activating factor might be greater in Korean individuals.	('KRAS', 'Gene', '3845', (49, 53))	('BRAF', 'Gene', '673', (57, 61))	('mutation', 'Var', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('BRAF', 'Gene', (57, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('carcinomas', 'Disease', (129, 139))	('carcinomas', 'Disease', 'MESH:D002277', (129, 139))	('KRAS', 'Gene', (49, 53))
708	19430562	Mutational alteration of the TP53 gene was reported in 30-80% of cases of epithelial ovarian cancer, but few studies directly compared the expression of TP53 in low-grade and high-grade serous carcinomas.	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('serous carcinomas', 'Disease', 'MESH:D018284', (186, 203))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (74, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('epithelial ovarian cancer', 'Disease', (74, 99))	('TP53', 'Gene', '7157', (153, 157))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (74, 99))	('TP53', 'Gene', '7157', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('TP53', 'Gene', (29, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('TP53', 'Gene', (153, 157))	('Mutational alteration', 'Var', (0, 21))	('serous carcinomas', 'Disease', (186, 203))
709	19430562	A recent study found functional TP53 mutations in only one of 12 (8.3%) low-grade serous carcinomas and in 30 of 59 (50.8%) high-grade serous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('TP53', 'Gene', '7157', (32, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (32, 36))	('serous carcinomas', 'Disease', 'MESH:D018284', (135, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('serous carcinomas', 'Disease', (135, 152))	('serous carcinomas', 'Disease', 'MESH:D018284', (82, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('serous carcinomas', 'Disease', (82, 99))
710	19430562	The present study found TP53 mutations in 20.0% of low-grade serous carcinomas and 70.6% of high-grade serous carcinomas, which is significantly greater than the incidence of low-grade serous carcinoma, but similar to the incidence of high-grade serous carcinoma previously reported.	('serous carcinomas', 'Disease', (103, 120))	('serous carcinoma', 'Disease', 'MESH:D018284', (61, 77))	('serous carcinoma', 'Disease', (185, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('TP53', 'Gene', '7157', (24, 28))	('serous carcinoma', 'Disease', (246, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('serous carcinoma', 'Disease', 'MESH:D018284', (185, 201))	('serous carcinomas', 'Disease', (61, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('mutations', 'Var', (29, 38))	('serous carcinomas', 'Disease', 'MESH:D018284', (103, 120))	('serous carcinoma', 'Disease', 'MESH:D018284', (246, 262))	('serous carcinoma', 'Disease', 'MESH:D018284', (103, 119))	('TP53', 'Gene', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('serous carcinomas', 'Disease', 'MESH:D018284', (61, 78))
711	19430562	In this study, we found slightly increased incidences of TP53 mutation in both groups compared with the previous study.	('incidences', 'Reg', (43, 53))	('TP53', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))
712	19430562	However, based on the finding that there were TP53 mutations without combined KRAS or BRAF mutations in 20.0% of low-grade serous carcinomas, the possibility that they are involved in progression of low-grade to high-grade serous carcinomas cannot be excluded.	('carcinomas', 'Phenotype', 'HP:0030731', (230, 240))	('mutations', 'Var', (51, 60))	('serous carcinomas', 'Disease', 'MESH:D018284', (123, 140))	('serous carcinomas', 'Disease', (123, 140))	('TP53', 'Gene', '7157', (46, 50))	('serous carcinomas', 'Disease', 'MESH:D018284', (223, 240))	('KRAS', 'Gene', (78, 82))	('BRAF', 'Gene', '673', (86, 90))	('serous carcinomas', 'Disease', (223, 240))	('TP53', 'Gene', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('KRAS', 'Gene', '3845', (78, 82))	('BRAF', 'Gene', (86, 90))
713	19430562	described a micropapillary pattern simulating low-grade serous carcinoma which have had TP53 mutations and lacked mutations of KRAS or BRAF.	('BRAF', 'Gene', '673', (135, 139))	('serous carcinoma', 'Disease', (56, 72))	('mutations', 'Var', (93, 102))	('BRAF', 'Gene', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('serous carcinoma', 'Disease', 'MESH:D018284', (56, 72))	('KRAS', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('KRAS', 'Gene', '3845', (127, 131))
714	19430562	These tumors displaying a micropapillary architecture developed from a subset of low-grade serous carcinomas that lacked mutation of KRAS and BRAF and subsequently acquired a TP mutation, which in turn might increase the level of nuclear atypia.	('serous carcinomas', 'Disease', (91, 108))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (208, 216))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('KRAS', 'Gene', (133, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('lacked', 'NegReg', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BRAF', 'Gene', '673', (142, 146))	('KRAS', 'Gene', '3845', (133, 137))	('serous carcinomas', 'Disease', 'MESH:D018284', (91, 108))	('TP mutation', 'Var', (175, 186))	('BRAF', 'Gene', (142, 146))	('nuclear atypia', 'MPA', (230, 244))
715	19430562	We suggest that the above described suggestions might be able to explain higher frequency of TP53 mutation in Korean women.	('TP53', 'Gene', '7157', (93, 97))	('women', 'Species', '9606', (117, 122))	('TP53', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))
735	22370600	Molecular genetic studies have shown that LGSC are characterized by mutations of the KRAS, BRAF or ERBB2 genes and are relatively genetically stable.	('BRAF', 'Gene', '673', (91, 95))	('ERBB2', 'Gene', (99, 104))	('LGSC', 'Disease', (42, 46))	('ERBB2', 'Gene', '2064', (99, 104))	('BRAF', 'Gene', (91, 95))	('KRAS', 'Gene', (85, 89))	('mutations', 'Var', (68, 77))	('KRAS', 'Gene', '3845', (85, 89))
736	22370600	In contrast, HGSC are characterized by TP53 mutations and a high level of genetic instability.	('TP53', 'Gene', '7157', (39, 43))	('mutations', 'Var', (44, 53))	('HGSC', 'Disease', (13, 17))	('TP53', 'Gene', (39, 43))
742	22370600	In our study, women were identified by SNOMED topography codes starting with T87 and T86910, T86920, T86921 and T86922 and the SNOMED morphology codes M84413, M84603, M84613 and M90143.	('T86910', 'Var', (85, 91))	('T86922', 'Var', (112, 118))	('T87', 'Var', (77, 80))	('M84413', 'Var', (151, 157))	('T86920', 'Var', (93, 99))	('M84613', 'Var', (167, 173))	('women', 'Species', '9606', (14, 19))	('M90143', 'Var', (178, 184))	('M84603', 'Var', (159, 165))	('T86921', 'Var', (101, 107))
777	22370600	The survival of women with LGSC, unknown grade and HGSC in relation to stage at diagnosis is shown in Figure 1a-c. Women with LGSC had a significantly better overall survival compared with women with unknown grade and HGSC within each stage of disease (p<0.0001).	('women', 'Species', '9606', (16, 21))	('better', 'PosReg', (151, 157))	('LGSC', 'Var', (126, 130))	('Women', 'Species', '9606', (115, 120))	('women', 'Species', '9606', (189, 194))	('overall survival', 'MPA', (158, 174))
779	22370600	In addition, women with HGSC (HR=1.9; 95% CI: 1.6-2.3) had a significantly increased risk of dying compared with women with LGSC while adjusting for age and stage.	('HGSC', 'Var', (24, 28))	('women', 'Species', '9606', (13, 18))	('dying', 'Disease', (93, 98))	('women', 'Species', '9606', (113, 118))
793	22370600	In the present study, we found that histologic grade routinely made by Danish gynecologic pathologists or expert gynecologic pathologists was a significant prognostic factor in ovarian carcinoma as women with LGSC had a significantly longer survival than women with HGSC even after adjusting for age and stage.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (177, 194))	('women', 'Species', '9606', (198, 203))	('LGSC', 'Var', (209, 213))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (177, 194))	('longer', 'PosReg', (234, 240))	('ovarian carcinoma', 'Disease', (177, 194))	('women', 'Species', '9606', (255, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
815	32356124	Case report: Analysis of BRCA1 and BRCA2 gene mutations in a hereditary ovarian cancer family Breast cancer susceptibility gene 1/2 (BRCA1/2) is the most important susceptibility gene associated with hereditary ovarian cancer (HOC).	('BRCA1/2', 'Gene', '672;675', (133, 140))	('Breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('mutations', 'Var', (46, 55))	('BRCA2', 'Gene', '675', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Breast cancer', 'Disease', (94, 107))	('Breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('hereditary ovarian cancer', 'Disease', 'MESH:D010051', (61, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (211, 225))	('hereditary ovarian cancer', 'Disease', (61, 86))	('BRCA1', 'Gene', '672', (25, 30))	('BRCA1', 'Gene', (25, 30))	('BRCA1', 'Gene', '672', (133, 138))	('BRCA1/2', 'Gene', (133, 140))	('BRCA1', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('hereditary ovarian cancer', 'Disease', 'MESH:D010051', (200, 225))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('hereditary ovarian cancer', 'Disease', (200, 225))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (184, 194))	('BRCA2', 'Gene', (35, 40))
816	32356124	We aimed to screen BRAC1 and BRAC2 gene mutations in a member of a hereditary ovarian cancer family in China, and to analyze the structure and function of the mutant protein.	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hereditary ovarian cancer', 'Disease', 'MESH:D010051', (67, 92))	('BRAC2', 'Gene', (29, 34))	('mutations', 'Var', (40, 49))	('BRAC1', 'Gene', (19, 24))	('hereditary ovarian cancer', 'Disease', (67, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
818	32356124	After RNA extraction, PCR amplification was applied and the PCR products were directly sequenced and aligned, prediction and analysis of protein structure and molecular conformation that may be caused by BRCA1/2 mutation.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('caused by', 'Reg', (194, 203))	('BRCA1/2', 'Gene', (204, 211))	('mutation', 'Var', (212, 220))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('BRCA1/2', 'Gene', '672;675', (204, 211))
819	32356124	The whole gene analysis of BRCA1 and BRCA2 in ovarian cancer patients in the family showed that there were 8 mutations in BRCA1 whole gene sequencing, including 3 nonsense mutations (2314C>T, 2543T>C, 4540T>C); two mutations have been recorded, which are associated with cervical cancer (2844C>T) and endometriosis (3345A>G); three newly discovered mutations (3780A>G, 5069A>G, 3326A>T).	('endometriosis', 'Disease', 'MESH:D004715', (301, 314))	('2844C>T', 'Var', (288, 295))	('endometriosis', 'Disease', (301, 314))	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('ovarian cancer', 'Disease', (46, 60))	('associated', 'Reg', (255, 265))	('4540T>C', 'Mutation', 'g.4540T>C', (201, 208))	('2314C>T', 'Mutation', 'c.2314C>T', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('3780A>G', 'Mutation', 'rs1405241504', (360, 367))	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('3780A>G', 'Var', (360, 367))	('BRCA1', 'Gene', (122, 127))	('2314C>T', 'Var', (183, 190))	('endometriosis', 'Phenotype', 'HP:0030127', (301, 314))	('patients', 'Species', '9606', (61, 69))	('4540T>C)', 'Var', (201, 209))	('3326A>T', 'Var', (378, 385))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('2543T>C', 'Mutation', 'c.2543T>C', (192, 199))	('3345A>G', 'Mutation', 'g.3345A>G', (316, 323))	('BRCA2', 'Gene', (37, 42))	('cancer', 'Disease', (54, 60))	('mutations', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('3326A>T', 'Mutation', 'g.3326A>T', (378, 385))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('5069A>G', 'Mutation', 'rs768282987', (369, 376))	('BRCA2', 'Gene', '675', (37, 42))	('2844C>T', 'Mutation', 'c.2844C>T', (288, 295))	('3345A>G', 'Var', (316, 323))
820	32356124	Among them, 3780A>G and 5069A>G caused amino acid changes, while 3326A>T mutation caused Arg mutation to stop codon.	('3326A>T', 'Mutation', 'g.3326A>T', (65, 72))	('3780A>G', 'Var', (12, 19))	('3780A>G', 'Mutation', 'rs1405241504', (12, 19))	('3326A>T', 'Var', (65, 72))	('5069A>G', 'Mutation', 'rs768282987', (24, 31))	('5069A>G', 'Var', (24, 31))	('Arg', 'Chemical', 'MESH:D001120', (89, 92))	('Arg mutation', 'MPA', (89, 101))	('caused', 'Reg', (82, 88))	('amino acid changes', 'MPA', (39, 57))
821	32356124	A total of 7 mutations were detected in BRCA2 whole-genome sequencing, including 5 non-significant mutations (3623A>G, 4034T>C, 4790A>G, 6740G>C, 7469A>G); one no-record mutation (1716T>A), and 1 recorded mutation (1342A>C), which was associated with breast cancer and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (269, 283))	('BRCA2', 'Gene', (40, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('6740G>C', 'Var', (137, 144))	('7469A>G', 'Mutation', 'g.7469A>G', (146, 153))	('3623A>G', 'Mutation', 'rs994021816', (110, 117))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('4034T>C', 'Var', (119, 126))	('breast cancer', 'Disease', (251, 264))	('1342A>C', 'Var', (215, 222))	('6740G>C', 'Mutation', 'g.6740G>C', (137, 144))	('4790A>G', 'Mutation', 'g.4790A>G', (128, 135))	('1342A>C', 'SUBSTITUTION', 'None', (215, 222))	('ovarian cancer', 'Disease', 'MESH:D010051', (269, 283))	('BRCA2', 'Gene', '675', (40, 45))	('associated', 'Reg', (235, 245))	('3623A>G', 'Var', (110, 117))	('1716T>A', 'Mutation', 'c.1716T>A', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('4790A>G', 'Var', (128, 135))	('4034T>C', 'Mutation', 'g.4034T>C', (119, 126))	('ovarian cancer', 'Disease', (269, 283))
822	32356124	BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations were co-existing in patients (II1, II3, and II5) identified as serous adenocarcinoma grade II.	('serous adenocarcinoma', 'Disease', 'MESH:D000230', (109, 130))	('3326A>T', 'Var', (7, 14))	('BRCA1', 'Gene', (0, 5))	('1342A>C', 'Var', (27, 34))	('serous adenocarcinoma', 'Disease', (109, 130))	('1342A>C', 'SUBSTITUTION', 'None', (27, 34))	('BRCA2', 'Gene', '675', (20, 25))	('BRCA2', 'Gene', (20, 25))	('3326A>T', 'Mutation', 'g.3326A>T', (7, 14))	('patients', 'Species', '9606', (66, 74))
824	32356124	In the gene detection of III generation female, four females with BRCA2 (1342A>C) mutation were found, and one of them also carried the BRCA1 (3326A>T) mutation, who can be considered a high-risk group of HOC in this family.	('BRCA2', 'Gene', (66, 71))	('3326A>T', 'Var', (143, 150))	('BRCA1', 'Gene', (136, 141))	('1342A>C', 'Var', (73, 80))	('1342A>C', 'SUBSTITUTION', 'None', (73, 80))	('BRCA2', 'Gene', '675', (66, 71))	('3326A>T', 'Mutation', 'g.3326A>T', (143, 150))
825	32356124	Online protein structure predictions revealed that BRCA1 (3326A>T) mutations mutated AGA at this site to TGA resulting in a translated Arg (arginine) mutation as a stop codon, while BRCA2 (1342A>C) mutated AAT at this site to CAT resulting in a translated Asn mutation to His.	('1342A>C', 'Var', (189, 196))	('1342A>C', 'SUBSTITUTION', 'None', (189, 196))	('arginine', 'Chemical', 'MESH:D001120', (140, 148))	('CAT', 'Gene', (226, 229))	('TGA', 'Gene', '6899', (105, 108))	('BRCA1', 'Gene', (51, 56))	('BRCA2', 'Gene', (182, 187))	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('His', 'Chemical', 'MESH:D006639', (272, 275))	('Asn mutation', 'MPA', (256, 268))	('Arg', 'Chemical', 'MESH:D001120', (135, 138))	('CAT', 'Gene', '847', (226, 229))	('3326A>T', 'Mutation', 'g.3326A>T', (58, 65))	('AAT', 'Chemical', 'MESH:C054971', (206, 209))	('TGA', 'Gene', (105, 108))	('BRCA2', 'Gene', '675', (182, 187))	('CAT', 'molecular_function', 'GO:0004096', ('226', '229'))	('mutations', 'Var', (67, 76))	('Asn', 'Chemical', 'MESH:D001216', (256, 259))	('AAT', 'molecular_function', 'GO:0004069', ('206', '209'))
826	32356124	The BRCA1 (3326A>T) and BRCA2 (1342A>C) were detected in the HOC family, which may be the susceptibility gene of the family's HOC.	('3326A>T', 'Mutation', 'g.3326A>T', (11, 18))	('1342A>C', 'SUBSTITUTION', 'None', (31, 38))	('BRCA2', 'Gene', '675', (24, 29))	('3326A>T', 'Var', (11, 18))	('1342A>C', 'Var', (31, 38))	('BRCA1', 'Gene', (4, 9))	('BRCA2', 'Gene', (24, 29))
833	32356124	BRCA1 and BRCA2 gene mutations account for 10~18% of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (10, 15))	('ovarian cancer', 'Disease', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BRCA2', 'Gene', (10, 15))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('mutations', 'Var', (21, 30))
834	32356124	The cumulative risk of ovarian cancer in the BRCA1 and BRCA2 mutation carriers was 40% and 18%, respectively, at age 70, which was much higher than 1.4% in the general population.	('BRCA2', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ovarian cancer', 'Disease', (23, 37))	('mutation', 'Var', (61, 69))	('BRCA2', 'Gene', '675', (55, 60))	('BRCA1', 'Gene', (45, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))
835	32356124	Mutations in the BRCA1/2 gene also increase the risk of pancreatic cancer, gastric cancer, and prostate cancer.	('increase', 'PosReg', (35, 43))	('prostate cancer', 'Disease', (95, 110))	('BRCA1/2', 'Gene', '672;675', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', (56, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (95, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))	('increase the risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 73))	('BRCA1/2', 'Gene', (17, 24))
836	32356124	Detection of BRCA1/2 gene mutations contributes to screening and early diagnosis of HOCS patients.	('BRCA1/2', 'Gene', '672;675', (13, 20))	('HOCS', 'Disease', (84, 88))	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (89, 97))	('BRCA1/2', 'Gene', (13, 20))
837	32356124	Detection of BRCA gene mutations in high-risk populations to identify progenitor mutations or high-frequency mutation sites has important guiding significance for the assessment of the risk of BRCA1/2 mutation carriers.	('BRCA1/2', 'Gene', (193, 200))	('BRCA', 'Gene', '672', (193, 197))	('mutations', 'Var', (23, 32))	('BRCA1/2', 'Gene', '672;675', (193, 200))	('BRCA', 'Gene', (193, 197))	('BRCA', 'Gene', '672', (13, 17))	('BRCA', 'Gene', (13, 17))
838	32356124	In the USA and Europe, the detection of BRCA1/2 mutation has become an important screening tool for high-risk populations of ovarian cancer.	('ovarian cancer', 'Disease', (125, 139))	('BRCA1/2', 'Gene', (40, 47))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('ovarian cancer', 'Disease', 'MESH:D010051', (125, 139))	('mutation', 'Var', (48, 56))	('BRCA1/2', 'Gene', '672;675', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
840	32356124	Although hundreds of mutation sites have been found in BRCA1/2, not all mutations are associated with ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('BRCA1/2', 'Gene', (55, 62))	('associated', 'Reg', (86, 96))	('mutation', 'Var', (21, 29))	('BRCA1/2', 'Gene', '672;675', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancer', 'Disease', (102, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))
868	32356124	A total of 8 mutations were found in the whole gene sequencing of BRCA1, including 3 nonsense mutations (2314C>T, 2543T>C, 4540T>C); two mutations have been recorded, which are associated with cervical cancer (2844C>T) and endometriosis (3345A>G), respectively; three new mutations (3780A>G, 5069A>G, 3326A>T) were found that no literature has been reported.	('4540T>C', 'Mutation', 'g.4540T>C', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('3326A>T', 'Mutation', 'g.3326A>T', (301, 308))	('2314C>T', 'Var', (105, 112))	('endometriosis', 'Phenotype', 'HP:0030127', (223, 236))	('5069A>G', 'Mutation', 'rs768282987', (292, 299))	('4540T>C)', 'Var', (123, 131))	('BRCA1', 'Gene', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('3345A>G', 'Mutation', 'g.3345A>G', (238, 245))	('2543T>C', 'Mutation', 'c.2543T>C', (114, 121))	('3780A>G', 'Mutation', 'rs1405241504', (283, 290))	('3780A>G', 'Var', (283, 290))	('3345A>G', 'Var', (238, 245))	('2844C>T', 'Mutation', 'c.2844C>T', (210, 217))	('endometriosis', 'Disease', 'MESH:D004715', (223, 236))	('2844C>T', 'Var', (210, 217))	('endometriosis', 'Disease', (223, 236))	('cancer', 'Disease', (202, 208))	('associated', 'Reg', (177, 187))	('2314C>T', 'Mutation', 'c.2314C>T', (105, 112))
869	32356124	Among the three newly discovered mutations, 3780A>G and 5069A>G caused amino acid changes, while the 3326A>T mutation caused Arg mutation to a stop codon.	('Arg mutation', 'MPA', (125, 137))	('caused', 'Reg', (64, 70))	('5069A>G', 'Mutation', 'rs768282987', (56, 63))	('3780A>G', 'Mutation', 'rs1405241504', (44, 51))	('3780A>G', 'Var', (44, 51))	('3326A>T', 'Var', (101, 108))	('Arg', 'Chemical', 'MESH:D001120', (125, 128))	('3326A>T', 'Mutation', 'g.3326A>T', (101, 108))	('caused', 'Reg', (118, 124))	('5069A>G', 'Var', (56, 63))	('amino acid changes', 'MPA', (71, 89))
871	32356124	A total of 7 mutations were detected in the whole gene sequencing of BRCA2, among which 5 were non-significant mutations (3623A>G, 4034T>C, 4790A>G, 6740G>C, 7469A>G), one mutation (1716T>A) not recorded, and one recorded mutation (1342A>C) associated with breast cancer and ovarian cancer.	('6740G>C', 'Mutation', 'g.6740G>C', (149, 156))	('ovarian cancer', 'Disease', (275, 289))	('4034T>C', 'Var', (131, 138))	('3623A>G', 'Mutation', 'rs994021816', (122, 129))	('4790A>G', 'Mutation', 'g.4790A>G', (140, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (275, 289))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('1342A>C', 'Var', (232, 239))	('1342A>C', 'SUBSTITUTION', 'None', (232, 239))	('3623A>G', 'Var', (122, 129))	('1716T>A', 'Mutation', 'c.1716T>A', (182, 189))	('BRCA2', 'Gene', (69, 74))	('4790A>G', 'Var', (140, 147))	('4034T>C', 'Mutation', 'g.4034T>C', (131, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('BRCA2', 'Gene', '675', (69, 74))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('ovarian cancer', 'Disease', 'MESH:D010051', (275, 289))	('breast cancer', 'Disease', (257, 270))	('7469A>G', 'Mutation', 'g.7469A>G', (158, 165))
872	32356124	The mutation coexisting in two ovarian cancer patients, II1 and II5, was 1342A>C.	('patients', 'Species', '9606', (46, 54))	('1342A>C', 'Var', (73, 80))	('1342A>C', 'SUBSTITUTION', 'None', (73, 80))	('ovarian cancer', 'Phenotype', 'HP:0100615', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (31, 45))	('ovarian cancer', 'Disease', (31, 45))
873	32356124	Additionally, BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations were also detected in tumor tissues of II3.	('BRCA2', 'Gene', '675', (34, 39))	('1342A>C', 'Var', (41, 48))	('1342A>C', 'SUBSTITUTION', 'None', (41, 48))	('BRCA1', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BRCA2', 'Gene', (34, 39))	('tumor', 'Disease', (82, 87))	('3326A>T', 'Mutation', 'g.3326A>T', (21, 28))
874	32356124	Taken together, the 3326A>T heterozygous mutation of BRCA1 gene and the 1342A>C heterozygous mutation of BRCA2 gene were detected in the confirmed II generation ovarian cancer patients, but none of those in healthy generation II was found.	('3326A>T', 'Mutation', 'g.3326A>T', (20, 27))	('patients', 'Species', '9606', (176, 184))	('1342A>C', 'Var', (72, 79))	('3326A>T', 'Var', (20, 27))	('1342A>C', 'SUBSTITUTION', 'None', (72, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('BRCA2', 'Gene', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('II generation ovarian cancer', 'Disease', (147, 175))	('BRCA2', 'Gene', '675', (105, 110))	('BRCA1', 'Gene', (53, 58))	('II generation ovarian cancer', 'Disease', 'MESH:D016537', (147, 175))
876	32356124	No cases of ovarian cancer had been found in the III generation female in this family, but genetic tests have shown that there were 1342A>C single mutations in the BRCA2 gene in III2, III4, and III7, and there were two mutations of BRCA1 (3326A>T) and BRCA2 (1342A>C) in III8.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('BRCA2', 'Gene', '675', (164, 169))	('ovarian cancer', 'Disease', (12, 26))	('1342A>C', 'Var', (132, 139))	('1342A>C', 'Var', (259, 266))	('1342A>C', 'SUBSTITUTION', 'None', (132, 139))	('BRCA2', 'Gene', (252, 257))	('3326A>T', 'Mutation', 'g.3326A>T', (239, 246))	('1342A>C', 'SUBSTITUTION', 'None', (259, 266))	('ovarian cancer', 'Phenotype', 'HP:0100615', (12, 26))	('BRCA1 (3326A>T', 'Var', (232, 246))	('BRCA2', 'Gene', (164, 169))	('ovarian cancer', 'Disease', 'MESH:D010051', (12, 26))	('BRCA2', 'Gene', '675', (252, 257))
879	32356124	The heterozygous mutation of BRCA1 (3326A>T) mutated the codon AGA at this position to TGA, resulting in a translated Arg mutation as a stop codon, which ultimately resulted in termination of translation, protein shortening, and molecular conformational changes.	('shortening', 'NegReg', (213, 223))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('protein', 'MPA', (205, 212))	('BRCA1', 'Gene', (29, 34))	('Arg', 'Chemical', 'MESH:D001120', (118, 121))	('translation', 'biological_process', 'GO:0006412', ('192', '203'))	('3326A>T', 'Var', (36, 43))	('mutated', 'Var', (45, 52))	('3326A>T', 'Mutation', 'g.3326A>T', (36, 43))	('termination', 'MPA', (177, 188))	('TGA', 'Gene', '6899', (87, 90))	('molecular conformational', 'MPA', (229, 253))	('Arg mutation', 'MPA', (118, 130))	('TGA', 'Gene', (87, 90))
880	32356124	The heterozygous mutation of the BRCA2 (1342A>C) mutated the codon AAT at this position to CAT, resulting in the translation of the translated Asn (polar neutral amino acid) to His (positively charged basic amino acid), which ultimately caused a change in the stability of the molecular model.	('BRCA2', 'Gene', (33, 38))	('CAT', 'Gene', (91, 94))	('Asn', 'Chemical', 'MESH:D001216', (143, 146))	('CAT', 'molecular_function', 'GO:0004096', ('91', '94'))	('mutation', 'Var', (17, 25))	('translation', 'MPA', (113, 124))	('basic amino acid', 'Chemical', 'MESH:D024361', (201, 217))	('BRCA2', 'Gene', '675', (33, 38))	('His', 'Chemical', 'MESH:D006639', (177, 180))	('caused', 'Reg', (237, 243))	('translation', 'biological_process', 'GO:0006412', ('113', '124'))	('CAT', 'Gene', '847', (91, 94))	('1342A>C', 'Var', (40, 47))	('1342A>C', 'SUBSTITUTION', 'None', (40, 47))	('mutated', 'Var', (49, 56))	('AAT', 'molecular_function', 'GO:0004069', ('67', '70'))	('stability of the molecular model', 'CPA', (260, 292))	('change', 'Reg', (246, 252))	('AAT', 'Chemical', 'MESH:C054971', (67, 70))
883	32356124	We found that three women with ovarian cancer (II1, II3, and II5) in the family carried BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations, and no BRCA1 and BRCA2 mutations were detected in healthy individuals.	('BRCA2', 'Gene', (108, 113))	('BRCA1', 'Gene', (88, 93))	('BRCA2', 'Gene', '675', (152, 157))	('BRCA2', 'Gene', '675', (108, 113))	('1342A>C', 'Var', (115, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (31, 45))	('women', 'Species', '9606', (20, 25))	('1342A>C', 'SUBSTITUTION', 'None', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('3326A>T', 'Mutation', 'g.3326A>T', (95, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (31, 45))	('3326A>T', 'Var', (95, 102))	('ovarian cancer', 'Disease', (31, 45))	('BRCA2', 'Gene', (152, 157))
884	32356124	Therefore, the family can be diagnosed as a family of HOC, and the detected BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations may be oncogenes.	('3326A>T', 'Mutation', 'g.3326A>T', (83, 90))	('1342A>C', 'SUBSTITUTION', 'None', (103, 110))	('BRCA2', 'Gene', '675', (96, 101))	('1342A>C', 'Var', (103, 110))	('3326A>T', 'Var', (83, 90))	('BRCA1', 'Gene', (76, 81))	('BRCA2', 'Gene', (96, 101))
885	32356124	The daughter of the proband (III8) carries both BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations, and three females (III2, III4, and III7) carried the BRCA2 (1342A>C) mutation, which can be considered a high-risk group of HOC in this family.	('1342A>C', 'Var', (155, 162))	('BRCA2', 'Gene', (148, 153))	('BRCA2', 'Gene', '675', (68, 73))	('3326A>T', 'Mutation', 'g.3326A>T', (55, 62))	('1342A>C', 'SUBSTITUTION', 'None', (155, 162))	('BRCA1', 'Gene', (48, 53))	('BRCA2', 'Gene', '675', (148, 153))	('1342A>C', 'Var', (75, 82))	('1342A>C', 'SUBSTITUTION', 'None', (75, 82))	('BRCA2', 'Gene', (68, 73))
888	32356124	BRCA1/2 is a tumor suppressor gene and plays an important role in regulating the replication of human cells, DNA damage repair of genetic material, and normal cell growth, whose mutation can result in changes in the corresponding biological functions.	('tumor', 'Disease', (13, 18))	('cell growth', 'biological_process', 'GO:0016049', ('159', '170'))	('biological functions', 'MPA', (230, 250))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('human', 'Species', '9606', (96, 101))	('mutation', 'Var', (178, 186))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('BRCA1/2', 'Gene', (0, 7))	('changes', 'Reg', (201, 208))
890	32356124	There are hundreds of mutations in BRCA1/2 that have been found.	('BRCA1/2', 'Gene', '672;675', (35, 42))	('mutations', 'Var', (22, 31))	('BRCA1/2', 'Gene', (35, 42))
891	32356124	About 50% of hereditary breast cancers and 70~80% of hereditary ovarian cancer patients have BRCA1 mutations in their germ cells, while sporadic ovarian cancers have a BRCA1 mutation rate of less than 5%.	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('ovarian cancers', 'Phenotype', 'HP:0100615', (145, 160))	('sporadic ovarian cancers', 'Disease', (136, 160))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('hereditary ovarian cancer', 'Disease', 'MESH:D010051', (53, 78))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('hereditary ovarian cancer', 'Disease', (53, 78))	('sporadic ovarian cancers', 'Disease', 'MESH:D010051', (136, 160))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('hereditary breast cancers', 'Disease', 'MESH:D061325', (13, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('hereditary breast cancers', 'Disease', (13, 38))	('breast cancers', 'Phenotype', 'HP:0003002', (24, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('mutations', 'Var', (99, 108))	('BRCA1', 'Gene', (93, 98))	('patients', 'Species', '9606', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
892	32356124	The risk of breast cancer and ovarian cancer in BRCA2 mutation carriers is 50~85% and 10~20%, respectively.	('breast cancer', 'Disease', (12, 25))	('mutation', 'Var', (54, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('BRCA2', 'Gene', '675', (48, 53))	('ovarian cancer', 'Disease', (30, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('BRCA2', 'Gene', (48, 53))
893	32356124	It has been reported that most of the BRCA1/2 gene mutations associated with HOCS are concentrated in the 10th and 11th exon regions.	('mutations', 'Var', (51, 60))	('HOCS', 'Disease', (77, 81))	('BRCA1/2', 'Gene', '672;675', (38, 45))	('associated', 'Reg', (61, 71))	('BRCA1/2', 'Gene', (38, 45))
895	32356124	Most of the mutations at the amino or carboxy terminus of the protein result in the destruction of zinc finger structures or BRCT repeats, and these two structures play an important role in the tumor suppressor function of BRCA1.	('zinc finger structures', 'Protein', (99, 121))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('destruction', 'NegReg', (84, 95))	('BRCA1', 'Gene', (223, 228))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('play', 'Reg', (164, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('194', '210'))	('tumor', 'Disease', (194, 199))	('BRCT repeats', 'Protein', (125, 137))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('194', '210'))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
896	32356124	The most common mutations in the BRCA1 gene include S1613G on exon 16 and P871L on exon 11 in combination with E1038G, which were found in breast cancer families in India, Greece, Turkey, and Italy.	('E1038G', 'Var', (111, 117))	('E1038G', 'Mutation', 'rs16941', (111, 117))	('Turkey', 'Species', '9103', (180, 186))	('S1613G', 'Mutation', 'rs1799966', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('BRCA1', 'Gene', (33, 38))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('S1613G', 'Var', (52, 58))	('P871L', 'Var', (74, 79))	('P871L', 'Mutation', 'rs799917', (74, 79))
897	32356124	Studies in the Norwegian population have shown that 1675delA and 1135insA account for one-third of hereditary breast cancer ovarian cancer, while 816delGT and 3347delAG account for 68% of Norwegian BRCA1 mutation carriers.	('hereditary breast cancer ovarian cancer', 'Disease', (99, 138))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('816delGT', 'Mutation', 'c.816delGT', (146, 154))	('3347delAG', 'Var', (159, 168))	('3347delAG', 'Mutation', 'c.3347delAG', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('1135insA', 'Mutation', 'c.1135insA', (65, 73))	('hereditary breast cancer ovarian cancer', 'Disease', 'MESH:D061325', (99, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('1675delA', 'Mutation', 'rs886040912', (52, 60))	('816delGT', 'Var', (146, 154))	('BRCA1', 'Gene', (198, 203))	('1675delA', 'Var', (52, 60))
898	32356124	S1631G is mutated from Ser to Gly due to amino acid exchange, and this mutation site was found in the BRCA1 mutation carrier in Italy.	('BRCA1', 'Gene', (102, 107))	('carrier', 'molecular_function', 'GO:0005215', ('117', '124'))	('Gly', 'Chemical', 'MESH:D005998', (30, 33))	('S1631G', 'Mutation', 'p.S1631G', (0, 6))	('Ser', 'Chemical', 'MESH:D012694', (23, 26))	('Ser', 'cellular_component', 'GO:0005790', ('23', '26'))	('S1631G', 'Var', (0, 6))
899	32356124	Some scholars have reported that the 1100detAT and 5589del mutations of the BRCA1 gene are more common in the Chinese population.	('5589del', 'Var', (51, 58))	('BRCA1', 'Gene', (76, 81))	('5589del', 'Mutation', 'c.5589del', (51, 58))	('1100detAT', 'Var', (37, 46))
900	32356124	Shen found that BRCA1: 5589del8 has a high incidence rate in the Chinese population, which may be a high-frequency mutation point with partial ancestor effect.	('5589del8', 'Var', (23, 31))	('5589del8', 'DELETION', 'None', (23, 31))	('incidence', 'MPA', (43, 52))
901	32356124	We found 8 mutations in the BRCA1 gene of the selected HOCS family of ovarian cancer patients (6 located in exon 11).	('mutations', 'Var', (11, 20))	('ovarian cancer', 'Disease', (70, 84))	('BRCA1', 'Gene', (28, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('patients', 'Species', '9606', (85, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
902	32356124	In addition to 3 nonsense mutations, there were 2 mutations associated with cervical cancer (2844C>T) and endometriosis (3345A>G), respectively.	('endometriosis', 'Disease', 'MESH:D004715', (106, 119))	('3345A>G', 'Var', (121, 128))	('endometriosis', 'Disease', (106, 119))	('endometriosis', 'Phenotype', 'HP:0030127', (106, 119))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('3345A>G', 'Mutation', 'g.3345A>G', (121, 128))	('cancer', 'Disease', (85, 91))	('2844C>T', 'Mutation', 'c.2844C>T', (93, 100))	('2844C>T', 'Var', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('associated', 'Reg', (60, 70))
903	32356124	Moreover, we also found three new unrecorded mutations, 3780A>G, 5069A>G, and 3326A>T.	('3780A>G', 'Var', (56, 63))	('5069A>G', 'Mutation', 'rs768282987', (65, 72))	('5069A>G', 'Var', (65, 72))	('3326A>T', 'Var', (78, 85))	('3326A>T', 'Mutation', 'g.3326A>T', (78, 85))	('3780A>G', 'Mutation', 'rs1405241504', (56, 63))
904	32356124	Interestingly, the mutation that coexisted in patients with ovarian cancer (II1, II3, and II5) was 3326A>T.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (46, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('ovarian cancer', 'Disease', (60, 74))	('3326A>T', 'Var', (99, 106))	('3326A>T', 'Mutation', 'g.3326A>T', (99, 106))
905	32356124	BRCA1 (3326A>T) mutation mutated Arg to a stop codon, leading to early termination of protein chain translation and protein truncation, which also directly led to the deletion of many important structural functional regions such as BRCT domain, and the molecular model conformation has undergone tremendous changes.	('BRCA1', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('protein', 'MPA', (116, 123))	('led to', 'Reg', (156, 162))	('deletion', 'Var', (167, 175))	('Arg', 'Chemical', 'MESH:D001120', (33, 36))	('3326A>T', 'Mutation', 'g.3326A>T', (7, 14))	('translation', 'biological_process', 'GO:0006412', ('100', '111'))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('3326A>T) mutation mutated', 'Var', (7, 32))	('mutated', 'Var', (25, 32))	('protein chain translation', 'MPA', (86, 111))
907	32356124	The most common mutation in BRCA2 is protein truncation caused by frame shift, which ultimately leads to loss of protein activity.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('BRCA2', 'Gene', '675', (28, 33))	('loss', 'NegReg', (105, 109))	('protein activity', 'MPA', (113, 129))	('frame shift', 'Var', (66, 77))	('BRCA2', 'Gene', (28, 33))	('protein', 'Protein', (37, 44))
908	32356124	The S1832P, T2766I, N2781I, and K2860T mutations in BRCA2 were found to be associated with breast cancer in the Danish population.	('BRCA2', 'Gene', (52, 57))	('N2781I', 'Mutation', 'rs1434821822', (20, 26))	('breast cancer', 'Disease', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('K2860T', 'Var', (32, 38))	('BRCA2', 'Gene', '675', (52, 57))	('K2860T', 'Mutation', 'p.K2860T', (32, 38))	('T2766I', 'Var', (12, 18))	('T2766I', 'Mutation', 'p.T2766I', (12, 18))	('N2781I', 'Var', (20, 26))	('associated', 'Reg', (75, 85))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('S1832P', 'Var', (4, 10))	('S1832P', 'Mutation', 'p.S1832P', (4, 10))
909	32356124	There was also a 9023A>C mutation that causes the BRCA2 protein structure to be replaced by Pro to His.	('9023A>C', 'Mutation', 'g.9023A>C', (17, 24))	('Pro', 'Chemical', 'MESH:D011392', (92, 95))	('BRCA2', 'Gene', (50, 55))	('protein', 'Protein', (56, 63))	('9023A>C', 'Var', (17, 24))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('BRCA2', 'Gene', '675', (50, 55))	('His', 'Chemical', 'MESH:D006639', (99, 102))
910	32356124	Additionally, nonsense mutations found in Chilean breast cancer families may interfere with normal BRCA2 function.	('nonsense mutations', 'Var', (14, 32))	('interfere', 'NegReg', (77, 86))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('BRCA2', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('function', 'MPA', (105, 113))	('BRCA2', 'Gene', '675', (99, 104))
911	32356124	In the Romanian breast cancer, the 4817A>G mutation in exon 11 of the BRCA2 gene was found to change the Lys residue to Arg, which is considered to be a pathogenic mutation.	('breast cancer', 'Disease', (16, 29))	('4817A>G', 'Mutation', 'g.4817A>G', (35, 42))	('BRCA2', 'Gene', '675', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('4817A>G', 'Var', (35, 42))	('Arg', 'MPA', (120, 123))	('Lys', 'Chemical', 'MESH:D008239', (105, 108))	('change', 'Reg', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Arg', 'Chemical', 'MESH:D001120', (120, 123))	('BRCA2', 'Gene', (70, 75))	('Lys residue', 'MPA', (105, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
912	32356124	BRCA2 S2834X and 5802del4 are commonly reported in the Japanese population.	('BRCA2', 'Gene', '675', (0, 5))	('S2834X', 'Mutation', 'p.S2834X', (6, 12))	('5802del4', 'Mutation', 'c.5802del4', (17, 25))	('5802del4', 'Var', (17, 25))	('BRCA2', 'Gene', (0, 5))	('S2834X', 'Var', (6, 12))
913	32356124	A multicenter study in China showed that 3109C>T of BRCA2 is a possible ancestral mutation.	('BRCA2', 'Gene', (52, 57))	('BRCA2', 'Gene', '675', (52, 57))	('3109C>T', 'Var', (41, 48))	('3109C>T', 'Mutation', 'g.3109C>T', (41, 48))
914	32356124	We found 7 mutations in the BRCA2 gene (3 of which are located in exon 10 and 4 in exon 11), of which 1342A>G has been shown to be associated with breast cancer and ovarian cancer.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('BRCA2', 'Gene', '675', (28, 33))	('breast cancer', 'Disease', (147, 160))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('associated', 'Reg', (131, 141))	('ovarian cancer', 'Disease', 'MESH:D010051', (165, 179))	('1342A>G', 'Var', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('1342A>G', 'Mutation', 'c.1342A>G', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BRCA2', 'Gene', (28, 33))	('ovarian cancer', 'Disease', (165, 179))
916	32356124	We hypothesized that BRCA2 (1342A>C) mutations are associated with the development of ovarian cancer in this family.	('ovarian cancer', 'Disease', (86, 100))	('BRCA2', 'Gene', '675', (21, 26))	('1342A>C', 'Var', (28, 35))	('1342A>C', 'SUBSTITUTION', 'None', (28, 35))	('associated with', 'Reg', (51, 66))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('BRCA2', 'Gene', (21, 26))
917	32356124	We found that the BRCA2 (1342A>C) mutation makes Asn mutate to His at this position.	('1342A>C', 'SUBSTITUTION', 'None', (25, 32))	('BRCA2', 'Gene', '675', (18, 23))	('1342A>C', 'Var', (25, 32))	('His', 'Chemical', 'MESH:D006639', (63, 66))	('Asn', 'Chemical', 'MESH:D001216', (49, 52))	('BRCA2', 'Gene', (18, 23))	('mutate', 'Var', (53, 59))
919	32356124	reported that specific BRCA2 N372H (1342A>C) mutations increase the risk of breast cancer in women.	('increase', 'PosReg', (55, 63))	('BRCA2', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('1342A>C', 'Var', (36, 43))	('N372H', 'Var', (29, 34))	('breast cancer', 'Disease', (76, 89))	('BRCA2', 'Gene', '675', (23, 28))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('1342A>C', 'SUBSTITUTION', 'None', (36, 43))	('women', 'Species', '9606', (93, 98))	('N372H', 'SUBSTITUTION', 'None', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
920	32356124	found that the BRCA2 N372H polymorphism is associated with susceptibility to ovarian cancer, especially serous subtypes of ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (77, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('N372H', 'Var', (21, 26))	('BRCA2', 'Gene', (15, 20))	('ovarian cancer', 'Disease', (77, 91))	('N372H', 'SUBSTITUTION', 'None', (21, 26))	('serous subtypes of ovarian cancer', 'Disease', 'MESH:D018284', (104, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRCA2', 'Gene', '675', (15, 20))	('serous subtypes of ovarian cancer', 'Disease', (104, 137))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
921	32356124	We hypothesized that BRCA2 (1342A>C) mutation may be one of the potential causes of HOC in this family.	('HOC', 'Disease', (84, 87))	('1342A>C', 'Var', (28, 35))	('BRCA2', 'Gene', '675', (21, 26))	('1342A>C', 'SUBSTITUTION', 'None', (28, 35))	('BRCA2', 'Gene', (21, 26))
926	32356124	We found in this family that BRCA1 (3326A>T) caused the mutation of 1031 Arg to a stop codon, which resulted in the deletion of the C-terminal domain "BRCT" of the 1650~1724 and 1763~1842 amino acid residues.	('caused', 'Reg', (45, 51))	('BRCA1', 'Gene', (29, 34))	('Arg', 'Chemical', 'MESH:D001120', (73, 76))	('1031 Arg to', 'Var', (68, 79))	('deletion', 'Var', (116, 124))	('3326A>T', 'Mutation', 'g.3326A>T', (36, 43))	('mutation', 'Var', (56, 64))
928	32356124	Furthermore, the 1342A>C mutation of BRCA2 gene leads to abnormal structure of BRCA2 protein, which cannot bind to RAD51, RAD52, P53, etc., so that the regulatory points of cell cycle cannot be accurately located, and the damaged DNA double strand cannot be repaired, which may lead to tumor occurrence.	('abnormal', 'Reg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('P53', 'Gene', '7157', (129, 132))	('BRCA2', 'Gene', (79, 84))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('RAD52', 'Gene', '5893', (122, 127))	('DNA', 'cellular_component', 'GO:0005574', ('230', '233'))	('cell cycle', 'biological_process', 'GO:0007049', ('173', '183'))	('protein', 'Protein', (85, 92))	('1342A>C', 'Var', (17, 24))	('RAD', 'biological_process', 'GO:1990116', ('115', '118'))	('1342A>C', 'SUBSTITUTION', 'None', (17, 24))	('BRCA2', 'Gene', '675', (79, 84))	('tumor', 'Disease', (286, 291))	('BRCA2', 'Gene', (37, 42))	('RAD', 'biological_process', 'GO:1990116', ('122', '125'))	('structure', 'MPA', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('P53', 'Gene', (129, 132))	('RAD51', 'Gene', (115, 120))	('RAD51', 'Gene', '5888', (115, 120))	('BRCA2', 'Gene', '675', (37, 42))	('RAD52', 'Gene', (122, 127))	('lead to', 'Reg', (278, 285))
929	32356124	Therefore, we speculated that the mutations between BRCA1 and BRCA2 synergistically lead to the occurrence of ovarian cancer in this family.	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))	('lead to', 'Reg', (84, 91))	('ovarian cancer', 'Disease', (110, 124))	('BRCA2', 'Gene', '675', (62, 67))	('BRCA1', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('BRCA2', 'Gene', (62, 67))	('mutations', 'Var', (34, 43))
930	32356124	However, mutations in the BRCA1/2 gene are "autosomal dominant inheritance," meaning that not all mutation carriers develop cancer, but only those with this mutation have high cancer susceptibility.	('cancer', 'Disease', (124, 130))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BRCA1/2', 'Gene', (26, 33))	('BRCA1/2', 'Gene', '672;675', (26, 33))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
932	32356124	We believed that screening and follow-up of BRCA1/2 gene mutations in III generation women and their offspring may have important implications for the occurrence of ovarian cancer in this family members.	('BRCA1/2', 'Gene', (44, 51))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('ovarian cancer', 'Disease', 'MESH:D010051', (165, 179))	('mutations', 'Var', (57, 66))	('women', 'Species', '9606', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('implications', 'Reg', (130, 142))	('ovarian cancer', 'Disease', (165, 179))	('BRCA1/2', 'Gene', '672;675', (44, 51))
934	32356124	confirmed that BRCA1 mutant breast cancer is usually accompanied by a mutation in the PTEN gene.	('mutant', 'Var', (21, 27))	('PTEN', 'Gene', (86, 90))	('PTEN', 'Gene', '5728', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BRCA1', 'Gene', (15, 20))	('accompanied by', 'Reg', (53, 67))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('mutation', 'Var', (70, 78))
935	32356124	Moreover, BRCA1 gene mutations are also related to heterozygosity and microsatellite instability RAD52, RAD54, and RAD54B genes.	('RAD54B', 'Gene', '25788', (115, 121))	('RAD54', 'Gene', (104, 109))	('RAD54', 'Gene', (115, 120))	('RAD52', 'Gene', (97, 102))	('related', 'Reg', (40, 47))	('RAD', 'biological_process', 'GO:1990116', ('104', '107'))	('BRCA1', 'Gene', (10, 15))	('RAD52', 'Gene', '5893', (97, 102))	('RAD54B', 'Gene', (115, 121))	('RAD', 'biological_process', 'GO:1990116', ('97', '100'))	('RAD54', 'Gene', '8438', (115, 120))	('RAD54', 'Gene', '8438', (104, 109))	('RAD', 'biological_process', 'GO:1990116', ('115', '118'))	('mutations', 'Var', (21, 30))
940	32356124	In summary, in this study, all female members of a typical HOC family were studied, and BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations were detected, which may be the causative genes of ovarian cancer in this family.	('BRCA2', 'Gene', (108, 113))	('BRCA1', 'Gene', (88, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (185, 199))	('ovarian cancer', 'Disease', 'MESH:D010051', (185, 199))	('BRCA2', 'Gene', '675', (108, 113))	('died', 'Disease', (78, 82))	('1342A>C', 'Var', (115, 122))	('1342A>C', 'SUBSTITUTION', 'None', (115, 122))	('ovarian cancer', 'Disease', (185, 199))	('died', 'Disease', 'MESH:D003643', (78, 82))	('3326A>T', 'Mutation', 'g.3326A>T', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('3326A>T', 'Var', (95, 102))
953	31741762	Overall, our data suggest that B7-H4 is associated with a pro-inflammatory tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('B7-H4', 'Var', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('associated', 'Reg', (40, 50))	('tumor', 'Disease', (75, 80))
967	31741762	Early experiments where T cells were stimulated in the presence of B7-H4-Ig demonstrated B7-H4's role in inhibiting T cell proliferation, cytokine production, and cytotoxicity.	('T cell proliferation', 'biological_process', 'GO:0042098', ('116', '136'))	('inhibiting', 'NegReg', (105, 115))	('cytotoxicity', 'Disease', 'MESH:D064420', (163, 175))	('B7-H4', 'Var', (89, 94))	('cytokine production', 'biological_process', 'GO:0001816', ('138', '157'))	('T cell proliferation', 'CPA', (116, 136))	('cytokine production', 'MPA', (138, 157))	('B7-H4-Ig', 'Var', (67, 75))	('cytotoxicity', 'Disease', (163, 175))
989	31741762	CD3+ cells (2x105/96-well) were plated in complete media and stimulated with 1 microg/mL platebound anti-CD3 (clone OKT3) and 1 microg/mL soluble anti-CD28.	('soluble', 'cellular_component', 'GO:0005625', ('138', '145'))	('CD28', 'Gene', '940', (151, 155))	('CD28', 'Gene', (151, 155))	('anti-CD3', 'Var', (100, 108))
993	31741762	Primary antibodies used were: anti-B7-H4 (D1M8I), anti-B7-H3 (SP206), anti-CD3 (clone 2GV6 or polyclonal), anti-CD8 (clone C8/144B or 4B11), anti-FoxP3 (clone mAb22510 or 236A/E7), anti-CD20 (clone EP459Y or L26), and anti-CD68 (KP1).	('anti-CD20', 'Var', (181, 190))	('anti-B7-H4', 'Var', (30, 40))	('CD8', 'Gene', (112, 115))	('CD68', 'Gene', (223, 227))	('CD68', 'Gene', '968', (223, 227))	('FoxP3', 'Gene', '50943', (146, 151))	('B7-H3', 'Gene', '80381', (55, 60))	('CD8', 'Gene', '925', (112, 115))	('FoxP3', 'Gene', (146, 151))	('B7-H3', 'Gene', (55, 60))
1008	31741762	By distinguishing between tumor and stromal cells using the level of B7-H3 in the CD45- compartment (as described in MacGregor et al., in preparation), we found that B7-H4 was more frequently expressed by the tumor cell compartment (Figure 1(c)).	('CD45', 'Gene', '5788', (82, 86))	('B7-H3', 'Gene', '80381', (69, 74))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('B7-H4', 'Var', (166, 171))	('B7-H3', 'Gene', (69, 74))	('CD45', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
1011	31741762	While B7-H4 has previously been correlated with poor survival and other negative prognostic indicators, B7-H4 surface expression on tumor cells was not significantly associated with overall survival or time to recurrence in our cohort of patients with EOC (Supplementary Figure S2).	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('B7-H4', 'Var', (104, 109))	('tumor', 'Disease', (132, 137))	('associated', 'Reg', (166, 176))	('patients', 'Species', '9606', (238, 246))
1014	31741762	However, the frequency of APCs (CD11c+HLA-DRhigh) was higher in tumors with more B7-H4 expression (Figure 2(c)).	('CD11c', 'Gene', '3687', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('CD11c', 'Gene', (32, 37))	('B7-H4', 'Var', (81, 86))
1020	31741762	APCs from tumors expressing high levels of B7-H4 did exhibit significantly higher expression of PD-L1 (n = 15; p = 0.01 Mann-Whitney U test), and PD-L2 (n = 9; p = 0.02 Mann-Whitney U test) (Figure 3(b)) which could indicate a higher level of immune activation within the tumor.	('PD-L2', 'Gene', (146, 151))	('B7-H4', 'Var', (43, 48))	('PD-L2', 'Gene', '80380', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('expression', 'MPA', (82, 92))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (272, 277))	('higher', 'PosReg', (75, 81))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('PD-L1', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
1021	31741762	Because engagement with B7-H4 can suppress T cell activity, we analyzed the phenotype of T cells infiltrating EOC to determine whether we could observe changes in the T cell population that correlated with expression of B7-H4 on the tumor.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('T cell activity', 'CPA', (43, 58))	('B7-H4', 'Var', (24, 29))	('tumor', 'Disease', (233, 238))	('B7-H4', 'Var', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('suppress', 'NegReg', (34, 42))
1024	31741762	We did not find significant differences in CD8+, FoxP3+, or the ratio of CD8:FoxP3+ T cells infiltrating either region of B7-H4low or B7-H4high tumors (Figure 4(b)).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('CD8', 'Gene', (43, 46))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('CD8', 'Gene', '925', (43, 46))	('FoxP3', 'Gene', '50943', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('B7-H4low', 'Var', (122, 130))	('FoxP3', 'Gene', (49, 54))	('FoxP3', 'Gene', '50943', (77, 82))	('CD8', 'Gene', (73, 76))	('CD8', 'Gene', '925', (73, 76))	('FoxP3', 'Gene', (77, 82))
1031	31741762	All markers except GITR were expressed at high frequencies by CD8+ T cells, but no significant differences were observed between CD8+ T cells isolated from B7-H4low and B7-H4high tumors (Figure 5(c)).	('CD8', 'Gene', (129, 132))	('B7-H4high', 'Var', (169, 178))	('CD8', 'Gene', '925', (129, 132))	('CD8', 'Gene', (62, 65))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('CD8', 'Gene', '925', (62, 65))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('B7-H4low', 'Var', (156, 164))
1034	31741762	Of note, high frequencies of CD4+ and CD8+ T cells from tumors readily produced IFNgamma in response to stimulation suggesting that the T cells from these tumors are not fully functionally exhausted (Figure 5(e)).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', (155, 161))	('CD8', 'Gene', (38, 41))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('CD8', 'Gene', '925', (38, 41))	('CD4+', 'Var', (29, 33))	('IFNgamma', 'Protein', (80, 88))
1044	31741762	To gain insights into the biology relating to B7-H4, we examined the TCGA dataset of ovarian serous cystadenocarcinoma samples to identify genes that correlated with B7-H4 mRNA expression.	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (85, 118))	('ovarian serous cystadenocarcinoma', 'Disease', (85, 118))	('B7-H4', 'Var', (166, 171))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D010049', (85, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('mRNA expression', 'MPA', (172, 187))
1049	31741762	CXCL17, an angiogenic chemokine that has been reported to selectively attract cells of the myeloid-lineage, exhibited a high level of enrichment in B7-H4 mRNA-enriched tumors (Figure 6(a-c)).	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('CXCL17', 'Var', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
1055	31741762	To see if B7-H4 expression was positively correlated with VEGF expression in ovarian cancer we interrogated the TCGA dataset; however, there was no significant association between B7-H4 mRNA and VEGFA expression (Spearman Rho = 0.01; p = 8.4 x 10-1) (Supplementary Figure S7A).	('VEGF', 'Gene', (58, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (77, 91))	('VEGF', 'Gene', '7422', (195, 199))	('ovarian cancer', 'Disease', (77, 91))	('VEGFA', 'Gene', '7422', (195, 200))	('B7-H4', 'Var', (180, 185))	('VEGF', 'Gene', '7422', (58, 62))	('VEGF', 'Gene', (195, 199))	('expression', 'MPA', (201, 211))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('VEGFA', 'Gene', (195, 200))
1067	31741762	While B7-H4 expression was not associated with differences in frequencies of infiltrating T or B cells, B7-H4 expression correlated with higher frequencies of APC infiltration in tumors (Figure 2(c)).	('APC infiltration in tumors', 'Disease', (159, 185))	('APC', 'cellular_component', 'GO:0005680', ('159', '162'))	('APC infiltration in tumors', 'Disease', 'MESH:D011125', (159, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('higher', 'PosReg', (137, 143))	('B7-H4', 'Var', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))
1071	31741762	APCs from B7-H4high tumors expressed significantly higher levels of PD-L1 and PD-L2 than APCs from B7-H4low tumors indicating that the microenvironment associated with high B7-H4 expression on tumors correlates with high expression of other B7 family members.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('B7-H4', 'Gene', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PD-L2', 'Gene', (78, 83))	('PD-L2', 'Gene', '80380', (78, 83))	('PD-L1', 'MPA', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumors', 'Disease', (193, 199))	('B7-H4high', 'Var', (10, 19))	('higher', 'PosReg', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
1072	31741762	Because IFNgamma has been shown to induce CXCL17 and B7-H4 in a mouse model of breast cancer, we hypothesized that B7-H4 expression could be indicative of elevated levels of IFNgamma expression.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('B7-H4', 'MPA', (53, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('B7-H4', 'Var', (115, 120))	('induce', 'PosReg', (35, 41))	('CXCL17', 'MPA', (42, 48))	('mouse', 'Species', '10090', (64, 69))
1080	31741762	These data indicate differences in the biology of these two B7 family members, suggesting that therapeutics recognizing B7-H4 will target different cell types than those recognizing PD-L1 in epithelial ovarian cancer.	('B7-H4', 'Var', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (191, 216))	('epithelial ovarian cancer', 'Disease', (191, 216))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (191, 216))
1083	31741762	However, we found a strong positive correlation between B7-H4 mRNA and CXCL17 (Figure 6), a chemokine whose expression has been correlated with VEGF and increased tumor growth.	('correlated', 'Reg', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('VEGF', 'Gene', '7422', (144, 148))	('increased', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CXCL17', 'MPA', (71, 77))	('tumor', 'Disease', (163, 168))	('B7-H4 mRNA', 'Var', (56, 66))	('VEGF', 'Gene', (144, 148))
1088	31741762	In summary, our data support a correlation between B7-H4 and CXCL17 expression resulting in an accumulation of mature APCs in B7-H4-expressing tumors.	('accumulation', 'PosReg', (95, 107))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('B7-H4', 'Var', (51, 56))	('mature APCs', 'MPA', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('B7-H4-expressing', 'Var', (126, 142))
1095	28637487	Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1.	('mutations', 'Var', (25, 34))	('RAS', 'Chemical', 'MESH:D011883', (82, 85))	('MAPK', 'molecular_function', 'GO:0004707', ('86', '90'))	('NF1', 'Disease', (120, 123))	('dysregulation', 'MPA', (61, 74))	('RAS/MAPK pathway', 'Pathway', (82, 98))	('NF1', 'Gene', (42, 45))	('result in', 'Reg', (51, 60))
1099	28637487	Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context.	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('tumours', 'Disease', (176, 183))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('leukaemias', 'Disease', 'MESH:D007938', (322, 332))	('mutations', 'Var', (145, 154))	('ovary', 'Disease', (264, 269))	('cancer', 'Disease', (75, 81))	('ovary', 'Disease', 'MESH:D010051', (264, 269))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('leukaemias', 'Disease', (322, 332))	('NF1', 'Gene', (141, 144))
1100	28637487	As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('neuroblastoma', 'Phenotype', 'HP:0003006', (233, 246))	('NF1', 'Gene', (71, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('retinoic acid', 'Chemical', 'MESH:D014212', (178, 191))	('neuroblastoma', 'Disease', 'MESH:D009447', (233, 246))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('lung', 'Disease', (205, 209))	('drug resistance', 'biological_process', 'GO:0009315', ('121', '136'))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('drug resistance', 'biological_process', 'GO:0042493', ('121', '136'))	('tamoxifen', 'Chemical', 'MESH:D013629', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('breast cancers', 'Disease', 'MESH:D001943', (214, 228))	('breast cancers', 'Disease', (214, 228))	('RAS', 'Chemical', 'MESH:D011883', (53, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('breast cancers', 'Phenotype', 'HP:0003002', (214, 228))	('mutations', 'Var', (75, 84))	('neuroblastoma', 'Disease', (233, 246))
1101	28637487	Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1.	('cutaneous melanoma', 'Disease', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('neurofibromatosis type 1', 'Gene', '4763', (185, 209))	('glioblastoma', 'Disease', (134, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('NF1', 'Gene', (63, 66))	('mutation', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (112, 129))	('ovarian carcinoma', 'Disease', (112, 129))	('lung cancer', 'Disease', (99, 110))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (112, 129))	('neurofibromatosis type 1', 'Gene', (185, 209))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (185, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (134, 146))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
1102	28637487	Somatic NF1 mutations may be critical drivers in multiple cancers.	('NF1', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
1103	28637487	The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('NF1', 'Gene', (36, 39))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('mutations', 'Var', (40, 49))
1104	28637487	The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.	('mutations', 'Var', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('sporadic tumours', 'Disease', 'MESH:D009369', (65, 81))	('tumour', 'Disease', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (192, 198))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('sporadic tumours', 'Disease', (65, 81))	('NF1', 'Gene', (48, 51))
1112	28637487	NF1 is a tumour suppressor gene; in order for a particular cell to become cancerous, both alleles of a tumour suppressor gene must be mutated.	('tumour', 'Disease', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('cancerous', 'Disease', (74, 83))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('mutated', 'Var', (134, 141))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('cancerous', 'Disease', 'MESH:D009369', (74, 83))	('tumour', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
1113	28637487	This concept, known as the 'two-hit' hypothesis, was first proposed by Knudson, and the majority of NF1-associated tumours exhibit biallelic inactivation of NF1.	('biallelic', 'Var', (131, 140))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('tumours', 'Disease', (115, 122))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('NF1', 'Gene', (157, 160))	('NF1-associated', 'Gene', (100, 114))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))
1121	28637487	Hence, any loss of neurofibromin functionality, due to inactivating mutations in NF1, will result in sustained intracellular levels of active RAS-GTP, resulting in prolonged activation of the RAS/RAF/MAPK signalling pathway and ultimately a loss of growth control and increased cellular proliferation.	('increased', 'PosReg', (268, 277))	('RAS', 'Chemical', 'MESH:D011883', (192, 195))	('RAS-GTP', 'Chemical', '-', (142, 149))	('MAPK signalling', 'biological_process', 'GO:0000165', ('200', '215'))	('MAPK', 'molecular_function', 'GO:0004707', ('200', '204'))	('RAS', 'Chemical', 'MESH:D011883', (142, 145))	('RAF', 'Gene', '22882', (196, 199))	('loss', 'NegReg', (241, 245))	('loss', 'NegReg', (11, 15))	('growth control', 'CPA', (249, 263))	('intracellular levels of active RAS-GTP', 'MPA', (111, 149))	('neurofibromin', 'Protein', (19, 32))	('activation', 'PosReg', (174, 184))	('RAF', 'Gene', (196, 199))	('intracellular', 'cellular_component', 'GO:0005622', ('111', '124'))	('inactivating mutations', 'Var', (55, 77))	('signalling pathway', 'biological_process', 'GO:0007165', ('205', '223'))	('NF1', 'Gene', (81, 84))	('cellular proliferation', 'CPA', (278, 300))
1124	28637487	Indeed, the mTOR pathway is constitutively activated in neurofibromin-deficient primary cells and tumours, and is regulated by phosphorylation and inactivation of the TSC2-encoded protein tuberin by AKT, ERK and RSK.	('TSC2', 'Gene', '7249', (167, 171))	('AKT', 'Gene', (199, 202))	('RSK', 'Gene', (212, 215))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('inactivation', 'Var', (147, 159))	('RSK', 'Gene', '6196', (212, 215))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('phosphorylation', 'biological_process', 'GO:0016310', ('127', '142'))	('tuberin', 'Gene', '7249', (188, 195))	('mTOR', 'Gene', '2475', (12, 16))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('mTOR', 'Gene', (12, 16))	('AKT', 'Gene', '207', (199, 202))	('tuberin', 'Gene', (188, 195))	('TSC2', 'Gene', (167, 171))	('ERK', 'molecular_function', 'GO:0004707', ('204', '207'))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))
1126	28637487	Neurofibromin levels and therefore Ras signalling can also be affected by mechanisms other than NF1 mutation including ubiquitination.	('signalling', 'biological_process', 'GO:0023052', ('39', '49'))	('mutation', 'Var', (100, 108))	('Neurofibromin', 'Gene', '4763', (0, 13))	('affected', 'Reg', (62, 70))	('Neurofibromin', 'Gene', (0, 13))	('Ras signalling', 'MPA', (35, 49))	('NF1', 'Gene', (96, 99))	('ubiquitination', 'MPA', (119, 133))
1129	28637487	In such families, only a small proportion of the germ cells, whether sperm or ova, will carry the new NF1 mutation, but this can nevertheless result in more than one affected child being produced by clinically normal parents.	('mutation', 'Var', (106, 114))	('result in', 'Reg', (142, 151))	('NF1', 'Gene', (102, 105))	('child', 'Species', '9606', (175, 180))
1130	28637487	A major challenge for clinicians and geneticists dealing with NF1 is the successful identification and characterization of causative NF1 mutations in their patients.	('mutations', 'Var', (137, 146))	('patients', 'Species', '9606', (156, 164))	('NF1', 'Gene', (133, 136))
1131	28637487	Furthermore, some 30% of all NF1 mutations are predicted to cause aberrant splicing, and for this reason, the analysis of both RNA and DNA from patients in mutation screening protocols is clearly required.	('cause', 'Reg', (60, 65))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('NF1', 'Gene', (29, 32))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (144, 152))	('RNA', 'cellular_component', 'GO:0005562', ('127', '130'))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('aberrant splicing', 'MPA', (66, 83))
1132	28637487	Whilst the majority of NF1 splicing mutations occur within consensus acceptor and donor splice site sequences, a number of missense, nonsense, and even 'silent' mutations may also result in aberrant splicing, which are often only identifiable by screening a patient's RNA.	('result in', 'Reg', (180, 189))	('nonsense', 'Var', (133, 141))	('NF1', 'Gene', (23, 26))	('splicing', 'biological_process', 'GO:0045292', ('199', '207'))	('mutations', 'Var', (36, 45))	('patient', 'Species', '9606', (258, 265))	('splicing', 'MPA', (199, 207))	('RNA', 'cellular_component', 'GO:0005562', ('268', '271'))	('mutations', 'Var', (161, 170))	('splicing', 'biological_process', 'GO:0045292', ('27', '35'))	('missense', 'Var', (123, 131))
1133	28637487	As well as the challenges in collection and analysis of patient mRNA, a frequent issue is the difficulty in interpreting the clinical diagnostic significance of putative NF1 missense mutations, as this may require a family segregation study and/or in vitro functional analysis to determine the pathogenicity (or otherwise) of the variant in question.	('patient', 'Species', '9606', (56, 63))	('NF1', 'Gene', (170, 173))	('missense mutations', 'Var', (174, 192))
1134	28637487	Furthermore, many highly homologous NF1 pseudogene sequences are scattered throughout the human genome and can often interfere with PCR-based diagnostic tests.	('interfere', 'Reg', (117, 126))	('human', 'Species', '9606', (90, 95))	('NF1', 'Gene', (36, 39))	('pseudogene', 'Var', (40, 50))
1135	28637487	The spatial distribution of NF1 microdeletions is strongly influenced by the presence of a number of low-copy repeats (LCRs) spanning the 17q11.2 region that encompasses the NF1 gene.	('spatial', 'Gene', '219793', (4, 11))	('spatial', 'Gene', (4, 11))	('microdeletions', 'Var', (32, 46))	('NF1', 'Gene', (174, 177))	('NF1', 'Gene', (28, 31))	('influenced', 'Reg', (59, 69))
1136	28637487	Indeed, studies into NF1 microdeletions have provided a general model to understand the different mutational mechanisms underlying large genomic rearrangements associated with inherited diseases.	('NF1', 'Gene', (21, 24))	('inherited diseases', 'Disease', (176, 194))	('microdeletions', 'Var', (25, 39))	('inherited diseases', 'Disease', 'MESH:D030342', (176, 194))
1137	28637487	The NF1 mutation detection rate in classical NF1 patients can be up to 95%.	('NF1', 'Gene', (4, 7))	('patients', 'Species', '9606', (49, 57))	('mutation', 'Var', (8, 16))
1139	28637487	Mutations in multiple genes encoding the components of the RAS/MAPK pathway predispose patients to develop clinical features that overlap with those of NF1, e.g.	('predispose', 'Reg', (76, 86))	('RAS', 'Chemical', 'MESH:D011883', (59, 62))	('Mutations', 'Var', (0, 9))	('MAPK', 'molecular_function', 'GO:0004707', ('63', '67'))	('patients', 'Species', '9606', (87, 95))
1141	28637487	All cancers originate from a single cell that starts to behave abnormally due to acquired somatic mutations in its genome.	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutations in', 'Var', (98, 110))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
1142	28637487	A subset of these somatic changes, termed 'driver mutations', confer a selective growth advantage and are implicated in cancer development, whereas the remainder are considered to be 'passengers'.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('changes', 'Var', (26, 33))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('growth advantage', 'CPA', (81, 97))	('implicated', 'Reg', (106, 116))
1145	28637487	It contains data on somatic NF1 mutations in different types of tumour including melanoma (desmoplastic, skin cutaneous and uveal), breast carcinoma, neuroendocrine prostate cancer, glioblastoma, lung adenocarcinoma and squamous cell carcinoma, urothelial carcinoma, uterine carcinoma, adenoid and ovarian serous cystadenocarcinoma, paraganglioma, phaeochromocytoma, pancreatic cancer, adrenocortical carcinoma, stomach adenocarcinoma, sarcoma, oesophageal cancer, rhabdomyosarcoma and many more.	('carcinoma', 'Disease', 'MESH:D009369', (322, 331))	('carcinoma', 'Disease', 'MESH:D009369', (425, 434))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (367, 384))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (465, 481))	('sarcoma', 'Disease', 'MESH:D012509', (474, 481))	('carcinoma', 'Disease', 'MESH:D009369', (139, 148))	('sarcoma', 'Disease', (474, 481))	('cancer', 'Disease', (174, 180))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (150, 180))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (267, 284))	('carcinoma', 'Disease', (206, 215))	('neuroendocrine prostate cancer', 'Disease', (150, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (182, 194))	('carcinoma', 'Disease', (322, 331))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('breast carcinoma', 'Disease', 'MESH:D001943', (132, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('pancreatic cancer', 'Disease', (367, 384))	('NF1', 'Gene', (28, 31))	('rhabdomyosarcoma', 'Disease', (465, 481))	('carcinoma', 'Disease', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (457, 463))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('carcinoma', 'Disease', (139, 148))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (386, 410))	('paraganglioma', 'Disease', 'MESH:D010235', (333, 346))	('lung adenocarcinoma', 'Disease', (196, 215))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (412, 434))	('breast carcinoma', 'Phenotype', 'HP:0003002', (132, 148))	('carcinoma', 'Disease', 'MESH:D009369', (401, 410))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (245, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (386, 410))	('carcinoma', 'Disease', 'MESH:D009369', (275, 284))	('carcinoma', 'Disease', (256, 265))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (348, 365))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (196, 215))	('urothelial carcinoma', 'Disease', (245, 265))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (298, 331))	('carcinoma', 'Disease', (401, 410))	('carcinoma', 'Disease', (425, 434))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('carcinoma', 'Disease', (275, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('squamous cell carcinoma', 'Disease', (220, 243))	('phaeochromocytoma', 'Disease', (348, 365))	('breast carcinoma', 'Disease', (132, 148))	('cancer', 'Disease', 'MESH:D009369', (457, 463))	('stomach adenocarcinoma', 'Disease', (412, 434))	('adrenocortical carcinoma', 'Disease', (386, 410))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (196, 215))	('mutations', 'Var', (32, 41))	('ovarian serous cystadenocarcinoma', 'Disease', (298, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('glioblastoma', 'Disease', (182, 194))	('tumour', 'Disease', (64, 70))	('paraganglioma', 'Disease', (333, 346))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (465, 481))	('carcinoma', 'Disease', 'MESH:D009369', (234, 243))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('melanoma', 'Disease', (81, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (436, 443))	('paraganglioma', 'Phenotype', 'HP:0002668', (333, 346))	('pancreatic cancer', 'Disease', 'MESH:D010190', (367, 384))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (220, 243))	('carcinoma', 'Disease', 'MESH:D009369', (256, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (474, 481))	('cancer', 'Disease', (378, 384))	('cancer', 'Disease', (457, 463))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (220, 243))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('sarcoma', 'Disease', 'MESH:D012509', (436, 443))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('carcinoma', 'Disease', 'MESH:D009369', (206, 215))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (298, 331))	('sarcoma', 'Disease', (436, 443))
1146	28637487	In this review, we detail the frequency of somatic NF1 mutations in many non-NF1-associated sporadic cancers including melanoma, glioblastoma, neuroblastoma, breast cancer, ovarian serous carcinoma, paraganglioma and phaeochromocytoma, lung adenocarcinoma, lung squamous cell carcinoma, bladder, colorectal and leukaemia.	('sporadic cancers', 'Disease', 'MESH:D009369', (92, 108))	('ovarian serous carcinoma', 'Disease', (173, 197))	('paraganglioma', 'Phenotype', 'HP:0002668', (199, 212))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (257, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('lung squamous cell carcinoma', 'Disease', (257, 285))	('melanoma', 'Disease', (119, 127))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (173, 197))	('neuroblastoma', 'Disease', (143, 156))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (236, 255))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (262, 285))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (236, 255))	('glioblastoma', 'Disease', 'MESH:D005909', (129, 141))	('sporadic cancers', 'Disease', (92, 108))	('breast cancer', 'Disease', (158, 171))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('colorectal and leukaemia', 'Disease', 'MESH:D015179', (296, 320))	('glioblastoma', 'Disease', (129, 141))	('mutations', 'Var', (55, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('NF1', 'Gene', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (257, 285))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('paraganglioma and phaeochromocytoma', 'Disease', 'MESH:D010235', (199, 234))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('lung adenocarcinoma', 'Disease', (236, 255))	('bladder', 'Disease', (287, 294))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
1147	28637487	Further, it is anticipated that with the advent of powerful sequencing technologies, combined with precise microdissection of tissue, somatic NF1 mutations will be identified in additional tumour types.	('mutations', 'Var', (146, 155))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('NF1', 'Gene', (142, 145))	('identified', 'Reg', (164, 174))
1148	28637487	Elucidation of the mutational landscape of somatic NF1 mutations in a large number of sporadic tumours, their role in the initiation and progression of tumours and how they can confer resistance or sensitivity to a therapeutic intervention may provide further insight into the mechanisms underlying tumour development and ultimately aid the development and targeting of therapies.	('sporadic tumours', 'Disease', 'MESH:D009369', (86, 102))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('tumour', 'Disease', 'MESH:D009369', (299, 305))	('tumour', 'Disease', (299, 305))	('sporadic tumours', 'Disease', (86, 102))	('tumours', 'Disease', (152, 159))	('tumours', 'Disease', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('mutations', 'Var', (55, 64))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('NF1', 'Gene', (51, 54))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Disease', (152, 158))	('tumour', 'Disease', (95, 101))
1149	28637487	The frequency of somatic NF1 mutations in different sporadic tumour types derived from the literature is given in Table 1.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (29, 38))	('tumour', 'Disease', (61, 67))	('NF1', 'Gene', (25, 28))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
1155	28637487	The direct involvement of NF1 in melanoma was first reported by Andersen and colleagues in 1993 who identified a homozygous NF1 deletion in one of eight malignant melanoma cell lines which resulted in the loss of detectable NF1 mRNA and neurofibromin protein.	('NF1', 'Gene', (124, 127))	('NF1', 'Protein', (224, 227))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('loss', 'NegReg', (205, 209))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('malignant melanoma', 'Phenotype', 'HP:0002861', (153, 171))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('neurofibromin protein', 'Protein', (237, 258))	('malignant melanoma', 'Disease', 'MESH:D008545', (153, 171))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('malignant melanoma', 'Disease', (153, 171))	('deletion', 'Var', (128, 136))
1158	28637487	Many subsequent studies have identified additional somatic NF1 mutations in melanoma in 12-30% of cases.	('mutations', 'Var', (63, 72))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('NF1', 'Gene', (59, 62))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
1159	28637487	RAS/MAPK pathway dysregulation has been identified as a key culprit in non-familial melanoma, leading to the discovery of BRAF and NRAS as the most commonly mutated genes.	('RAS', 'Chemical', 'MESH:D011883', (0, 3))	('NRAS', 'Gene', (131, 135))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('dysregulation', 'Var', (17, 30))	('BRAF', 'Gene', (122, 126))	('NRAS', 'Gene', '4893', (131, 135))	('RAS', 'Chemical', 'MESH:D011883', (132, 135))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))
1160	28637487	Indeed, BRAF mutations occur in 50-70% of all cutaneous malignant melanomas, whilst NRAS alterations only occur in 19-28% of tumours.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('malignant melanomas', 'Disease', 'MESH:D008545', (56, 75))	('malignant melanomas', 'Phenotype', 'HP:0002861', (56, 75))	('tumours', 'Disease', (125, 132))	('NRAS', 'Gene', (84, 88))	('BRAF', 'Gene', (8, 12))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('malignant melanoma', 'Phenotype', 'HP:0002861', (56, 74))	('NRAS', 'Gene', '4893', (84, 88))	('malignant melanomas', 'Disease', (56, 75))	('mutations', 'Var', (13, 22))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
1161	28637487	In both cases, these gene lesions result in constitutive activation of the MAPK pathway and are believed to be early somatic events associated with melanoma initiation.	('melanoma initiation', 'Disease', 'MESH:D008545', (148, 167))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('activation', 'PosReg', (57, 67))	('melanoma initiation', 'Disease', (148, 167))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('MAPK pathway', 'Pathway', (75, 87))	('lesions', 'Var', (26, 33))
1162	28637487	The high frequency of BRAF and NRAS mutations in melanomas has recently been confirmed by high-throughput next-generation sequencing (NGS) analysis which also identified additional driver mutations, including a recurrent RAC mutation, which is the third most frequent activating mutation in sun-exposed melanomas after BRAF and NRAS mutations.	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('RAC', 'Gene', (221, 224))	('NRAS', 'Gene', '4893', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('NRAS', 'Gene', (328, 332))	('mutations', 'Var', (36, 45))	('melanomas', 'Disease', (303, 312))	('melanomas', 'Disease', (49, 58))	('melanomas', 'Phenotype', 'HP:0002861', (303, 312))	('RAC', 'Gene', '5879', (221, 224))	('NRAS', 'Gene', '4893', (328, 332))	('NRAS', 'Gene', (31, 35))	('melanomas', 'Disease', 'MESH:D008545', (303, 312))
1163	28637487	Inactivating NF1 mutations have been detected in approximately 13% of melanomas, alongside mutations in other tumour suppressor genes, including TP53, ARID2, PTEN, CDKN2A, MAP2K1 and RB1.	('RB1', 'Gene', '5925', (183, 186))	('detected', 'Reg', (37, 45))	('CDKN2A', 'Gene', '1029', (164, 170))	('PTEN', 'Gene', '5728', (158, 162))	('mutations', 'Var', (17, 26))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('NF1', 'Gene', (13, 16))	('Inactivating', 'Var', (0, 12))	('MAP2K1', 'Gene', '5604', (172, 178))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('ARID2', 'Gene', '196528', (151, 156))	('MAP2K1', 'Gene', (172, 178))	('MAP2K', 'molecular_function', 'GO:0004708', ('172', '177'))	('ARID2', 'Gene', (151, 156))	('RB1', 'Gene', (183, 186))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('CDKN2A', 'Gene', (164, 170))	('melanomas', 'Disease', (70, 79))	('PTEN', 'Gene', (158, 162))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
1164	28637487	The impact on NRAS is however non-uniform, with some NF1 mutant melanomas exhibiting full NRAS activation (i.e.	('NRAS', 'Gene', '4893', (14, 18))	('NRAS', 'Gene', (90, 94))	('melanomas', 'Disease', (64, 73))	('NF1', 'Gene', (53, 56))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('NRAS', 'Gene', '4893', (90, 94))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('mutant', 'Var', (57, 63))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('NRAS', 'Gene', (14, 18))
1165	28637487	the same activation level as oncogenic NRAS mutations), whereas others exhibit only partial activation.	('mutations', 'Var', (44, 53))	('NRAS', 'Gene', '4893', (39, 43))	('NRAS', 'Gene', (39, 43))
1166	28637487	In a mouse melanoma model, NF1 mutations cooperate with BRAF mutations in the pathogenesis of melanoma by preventing oncogene-induced senescence, an indication that NF1 plays a key role in early melanoma development.	('oncogene-induced senescence', 'MPA', (117, 144))	('mutations', 'Var', (31, 40))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('pathogenesis', 'biological_process', 'GO:0009405', ('78', '90'))	('BRAF', 'Gene', (56, 60))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('mutations', 'Var', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('NF1', 'Gene', (27, 30))	('mouse', 'Species', '10090', (5, 10))	('preventing', 'NegReg', (106, 116))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('senescence', 'biological_process', 'GO:0010149', ('134', '144'))	('melanoma', 'Disease', (11, 19))
1168	28637487	Furthermore, they observed that resistance to the BRAF inhibitor PLX4720 was attenuated by reconstitution of NF1 in these cells.	('NF1', 'Gene', (109, 112))	('resistance', 'MPA', (32, 42))	('reconstitution', 'Var', (91, 105))	('attenuated', 'NegReg', (77, 87))	('PLX4720', 'Chemical', 'MESH:C528407', (65, 72))
1169	28637487	An RNAi screen, targeting more than 16,500 genes in a BRAF inhibitor-sensitive melanoma cell line, identified NF1 as the highest ranking protein affected by BRAF inhibition, and that, NF1 knockdown abrogated the growth inhibitory effects of BRAF inhibition.	('NF1', 'Gene', (110, 113))	('NF1', 'Gene', (184, 187))	('RNAi', 'biological_process', 'GO:0016246', ('3', '7'))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('abrogated', 'NegReg', (198, 207))	('knockdown', 'Var', (188, 197))	('growth inhibitory effects', 'CPA', (212, 237))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('affected', 'Reg', (145, 153))
1170	28637487	Indeed, it was found that NF1 suppression led to a 31-fold increase in resistance to PLX4720, as well as a partial (7-fold) resistance to MEK inhibition, demonstrating that human melanoma samples with innate resistance to BRAF inhibition and sensitivity to a MEK inhibitor harboured NF1 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('resistance to PLX4720', 'MPA', (71, 92))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', (283, 286))	('mutations', 'Var', (287, 296))	('PLX4720', 'Chemical', 'MESH:C528407', (85, 92))	('human', 'Species', '9606', (173, 178))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('suppression', 'NegReg', (30, 41))	('melanoma', 'Disease', (179, 187))	('increase', 'PosReg', (59, 67))
1171	28637487	Importantly, NF1 mutations have been found in melanomas that lack both BRAF and NRAS mutations, with 25-30% of such melanomas found to harbour deleterious NF1 mutations, thus implying that NF1 inactivation has conferred aberrant MAPK pathway activation in these tumours.	('melanomas', 'Disease', (116, 125))	('activation', 'PosReg', (242, 252))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('NRAS', 'Gene', '4893', (80, 84))	('mutations', 'Var', (17, 26))	('MAPK', 'molecular_function', 'GO:0004707', ('229', '233'))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('mutations', 'Var', (159, 168))	('NF1', 'Gene', (13, 16))	('BRAF', 'Gene', (71, 75))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('inactivation', 'Var', (193, 205))	('NF1', 'Gene', (155, 158))	('NRAS', 'Gene', (80, 84))	('tumours', 'Disease', (262, 269))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('MAPK pathway', 'Pathway', (229, 241))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Disease', (46, 55))	('tumours', 'Phenotype', 'HP:0002664', (262, 269))	('tumours', 'Disease', 'MESH:D009369', (262, 269))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))
1172	28637487	BRAF/NRAS wild-type and NF1 mutant melanomas are strongly associated with UV damage, as evidenced clinically by the higher degree of solar elastosis and, at a molecular level, by a high proportion of C > T transitions at pyrimidine dimers and more frequent tandem CC>TT transitions.	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('mutant', 'Var', (28, 34))	('associated', 'Reg', (58, 68))	('NRAS', 'Gene', (5, 9))	('tandem', 'MPA', (257, 263))	('higher', 'PosReg', (116, 122))	('C > T transitions', 'Var', (200, 217))	('UV damage', 'Disease', 'MESH:C563466', (74, 83))	('NRAS', 'Gene', '4893', (5, 9))	('melanomas', 'Disease', (35, 44))	('elastosis', 'Disease', 'MESH:D005148', (139, 148))	('UV damage', 'Disease', (74, 83))	('solar', 'MPA', (133, 138))	('elastosis', 'Disease', (139, 148))	('NF1', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('pyrimidine', 'Chemical', 'MESH:C030986', (221, 231))
1175	28637487	Notably, almost half (26/56) of BRAF and NRAS wild-type melanomas had an NF1 mutation, most identified by loss of heterozygosity (LOH).	('NRAS', 'Gene', '4893', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutation', 'Var', (77, 85))	('NRAS', 'Gene', (41, 45))	('melanomas', 'Disease', (56, 65))	('NF1', 'Gene', (73, 76))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
1176	28637487	Furthermore, NF1 mutation-containing melanomas also harboured significantly more somatic mutations across all loci and occurred in significantly older patients, although they were associated with similar overall patient survival rates as compared to BRAF or RAS mutant or BRAF-RAS-NF1 wild-type melanoma.	('melanomas', 'Disease', (37, 46))	('RAS', 'Chemical', 'MESH:D011883', (277, 280))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('patient', 'Species', '9606', (212, 219))	('patient', 'Species', '9606', (151, 158))	('NF1', 'Gene', (13, 16))	('melanoma', 'Disease', (37, 45))	('mutation-containing', 'Var', (17, 36))	('patients', 'Species', '9606', (151, 159))	('melanomas', 'Disease', 'MESH:D008545', (37, 46))	('melanoma', 'Disease', (295, 303))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('RAS', 'Chemical', 'MESH:D011883', (258, 261))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('melanoma', 'Disease', 'MESH:D008545', (295, 303))	('more', 'PosReg', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('somatic', 'CPA', (81, 88))
1177	28637487	In addition, all 26 NF1 mutant BRAF-RAS wild-type melanomas carried mutations in other known RASopathy genes, including RASA2, PTPN11, SOS1, RAF1 and SPRED1.	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('PTPN11', 'Gene', (127, 133))	('mutations', 'Var', (68, 77))	('melanomas', 'Disease', (50, 59))	('RAF1', 'Gene', (141, 145))	('mutant', 'Var', (24, 30))	('PTPN11', 'Gene', '5781', (127, 133))	('RAS', 'Chemical', 'MESH:D011883', (120, 123))	('RASopathy', 'Disease', 'None', (93, 102))	('SOS1', 'Gene', '6654', (135, 139))	('RASA2', 'Gene', (120, 125))	('SPRED1', 'Gene', '161742', (150, 156))	('RASopathy', 'Disease', (93, 102))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('NF1', 'Gene', (20, 23))	('RAS', 'Chemical', 'MESH:D011883', (93, 96))	('RAS', 'Chemical', 'MESH:D011883', (36, 39))	('SPRED1', 'Gene', (150, 156))	('SOS1', 'Gene', (135, 139))	('RASA2', 'Gene', '5922', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('carried', 'Reg', (60, 67))	('RAF1', 'Gene', '5894', (141, 145))
1178	28637487	The highest frequency of somatic NF1 mutations were found in desmoplastic melanomas (14/15).	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (61, 83))	('NF1', 'Gene', (33, 36))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('mutations', 'Var', (37, 46))	('desmoplastic melanomas', 'Disease', (61, 83))
1180	28637487	The high frequency of NF1 mutations in desmoplastic melanomas appears to indicate an important role for neurofibromin in the specific biology of this type of melanoma.	('NF1', 'Gene', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('mutations', 'Var', (26, 35))	('desmoplastic melanomas', 'Disease', (39, 61))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (39, 61))
1182	28637487	mutations in CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS and PIK3C, which were found in 15/20 (75%), with NF1 mutations being found in 9/20 (45%).	('MAP3K1', 'Gene', (33, 39))	('MAP2K1', 'Gene', (25, 31))	('MAP3K1', 'Gene', '4214', (33, 39))	('ERBB2', 'Gene', '2064', (18, 23))	('mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (78, 82))	('MAP2K', 'molecular_function', 'GO:0004708', ('25', '30'))	('MET', 'Gene', '79811', (61, 64))	('PTPN11', 'Gene', (53, 59))	('SOS2', 'Gene', (72, 76))	('RAC1', 'Gene', (66, 70))	('PTPN11', 'Gene', '5781', (53, 59))	('SOS2', 'Gene', '6655', (72, 76))	('RAC1', 'Gene', '5879', (66, 70))	('CBL', 'Gene', (13, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('NRAS', 'Gene', (78, 82))	('EGFR', 'Gene', (47, 51))	('MAP3K', 'molecular_function', 'GO:0004709', ('33', '38'))	('MET', 'Gene', (61, 64))	('CBL', 'Gene', '867', (13, 16))	('BRAF', 'Gene', (41, 45))	('ERBB2', 'Gene', (18, 23))	('MAP2K1', 'Gene', '5604', (25, 31))
1184	28637487	iris, ciliary body and choroid) is rarer than cutaneous melanoma but is nevertheless the most common primary intraocular malignancy in adults, with inactivating mutations found in approximately 60% (23/38) of uveal melanomas.	('primary intraocular malignancy', 'Disease', 'MESH:D009798', (101, 131))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('uveal melanomas', 'Disease', (209, 224))	('uveal melanomas', 'Phenotype', 'HP:0007716', (209, 224))	('melanomas', 'Phenotype', 'HP:0002861', (215, 224))	('inactivating mutations', 'Var', (148, 170))	('primary intraocular malignancy', 'Disease', (101, 131))	('uveal melanomas', 'Disease', 'MESH:C536494', (209, 224))	('cutaneous melanoma', 'Disease', (46, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))
1186	28637487	In a recent study of a cohort of 75 tumours from patients with a mucosal melanoma, NF1 and RAS mutations were identified in 18.3 and 16.9% samples, respectively, whereas 8.4 and 7% of tumour samples harboured BRAF and KIT mutations.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('mucosal melanoma', 'Disease', 'MESH:D008545', (65, 81))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('mucosal melanoma', 'Disease', (65, 81))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('RAS', 'Gene', (91, 94))	('mutations', 'Var', (95, 104))	('KIT', 'Gene', (218, 221))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('KIT', 'molecular_function', 'GO:0005020', ('218', '221'))	('identified', 'Reg', (110, 120))	('patients', 'Species', '9606', (49, 57))	('NF1', 'Gene', (83, 86))	('RAS', 'Chemical', 'MESH:D011883', (91, 94))	('KIT', 'Gene', '3815', (218, 221))	('tumours', 'Disease', (36, 43))	('BRAF', 'Gene', (209, 213))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
1191	28637487	Approximately 40% of NSCLC are ADC, and several studies have reported somatic NF1 mutations in some 7-11% of ADC.	('NSCLC', 'Disease', (21, 26))	('ADC', 'Disease', (31, 34))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('NF1', 'Gene', (78, 81))	('mutations', 'Var', (82, 91))
1193	28637487	A number of potential novel therapeutic targets have been identified, including the activating mutations in KRAS, BRAF, ERBB2 and PIK3CA; the translocations in RET and ROS1; and the loss of function or deletions of TP53, NF1, CDKN2A and KEAP1.	('KRAS', 'Gene', (108, 112))	('BRAF', 'Gene', (114, 118))	('ERBB2', 'Gene', (120, 125))	('ROS1', 'Gene', (168, 172))	('CDKN2A', 'Gene', (226, 232))	('RET', 'Gene', '5979', (160, 163))	('PIK3CA', 'Gene', (130, 136))	('NF1', 'Gene', (221, 224))	('ERBB2', 'Gene', '2064', (120, 125))	('deletions', 'Var', (202, 211))	('mutations', 'Var', (95, 104))	('CDKN2A', 'Gene', '1029', (226, 232))	('RET', 'Gene', (160, 163))	('KEAP1', 'Gene', '9817', (237, 242))	('loss of function', 'NegReg', (182, 198))	('translocations', 'Var', (142, 156))	('KEAP1', 'Gene', (237, 242))	('ROS1', 'Gene', '6098', (168, 172))	('TP53', 'Gene', (215, 219))	('PIK3CA', 'Gene', '5290', (130, 136))	('KRAS', 'Gene', '3845', (108, 112))
1194	28637487	In addition to NF1 being recurrently mutated in a subset of sporadic lung ADC patients, the MAPK pathway also appears to be an important regulatory pathway involved in tumorigenesis.	('MAPK', 'molecular_function', 'GO:0004707', ('92', '96'))	('NF1', 'Gene', (15, 18))	('lung ADC', 'Disease', (69, 77))	('patients', 'Species', '9606', (78, 86))	('MAPK pathway', 'Pathway', (92, 104))	('involved', 'Reg', (156, 164))	('mutated', 'Var', (37, 44))
1195	28637487	In three quarters of the samples, the group identified mutations in NF1 and other genes that activate the RTK/RAS/RAF cell signalling pathway.	('RAF', 'Gene', '22882', (114, 117))	('mutations', 'Var', (55, 64))	('signalling pathway', 'biological_process', 'GO:0007165', ('123', '141'))	('RAF', 'Gene', (114, 117))	('NF1', 'Gene', (68, 71))	('RAS', 'Chemical', 'MESH:D011883', (110, 113))	('activate', 'PosReg', (93, 101))
1196	28637487	This study not only identified loss-of-function NF1 defects but also demonstrated that NF1 mutations (as well as KEAP1 and TP53 mutations) are far more frequent in the BRAF-RAS oncogene-negative subset of lung ADC.	('KEAP1', 'Gene', (113, 118))	('defects', 'Var', (52, 59))	('loss-of-function', 'NegReg', (31, 47))	('mutations', 'Var', (91, 100))	('RAS', 'Chemical', 'MESH:D011883', (173, 176))	('lung ADC', 'Disease', (205, 213))	('KEAP1', 'Gene', '9817', (113, 118))	('NF1', 'Gene', (48, 51))	('NF1', 'Gene', (87, 90))
1197	28637487	Additionally, TCGA and other groups have identified genes such as TP53, KRAS, STK11 (LKB1), EGFR and NF1 to be significantly mutated in ADC.	('NF1', 'Gene', (101, 104))	('LKB1', 'Gene', '6794', (85, 89))	('KRAS', 'Gene', (72, 76))	('ADC', 'Disease', (136, 139))	('mutated', 'Var', (125, 132))	('TP53', 'Gene', (66, 70))	('KRAS', 'Gene', '3845', (72, 76))	('STK11', 'Gene', '6794', (78, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('STK11', 'molecular_function', 'GO:0033868', ('78', '83'))	('EGFR', 'Gene', (92, 96))	('STK11', 'Gene', (78, 83))	('LKB1', 'Gene', (85, 89))
1198	28637487	By performing a genome-wide siRNA screen of both a human lung cancer cell line and a murine mutant EGFR-driven lung ADC, this revealed reduced NF1 mRNA expression in both, and furthermore, whilst the EGFR inhibitor erlotinib failed to fully inhibit RAS-ERK signalling when neurofibromin levels were reduced, treatment of neurofibromin-deficient lung cancers with MEK inhibitor restored sensitivity to erlotinib.	('signalling', 'biological_process', 'GO:0023052', ('257', '267'))	('neurofibromin-deficient lung cancers', 'Disease', 'MESH:D008175', (321, 357))	('lung cancer', 'Disease', 'MESH:D008175', (345, 356))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('human', 'Species', '9606', (51, 56))	('NF1', 'Gene', (143, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('lung cancer', 'Phenotype', 'HP:0100526', (345, 356))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('lung cancers', 'Phenotype', 'HP:0100526', (345, 357))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('murine', 'Species', '10090', (85, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('200', '204'))	('cancers', 'Phenotype', 'HP:0002664', (350, 357))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('neurofibromin-deficient lung cancers', 'Disease', (321, 357))	('deficient lung', 'Phenotype', 'HP:0002089', (335, 349))	('reduced', 'NegReg', (135, 142))	('erlotinib', 'Chemical', 'MESH:D000069347', (215, 224))	('mutant', 'Var', (92, 98))	('ERK', 'molecular_function', 'GO:0004707', ('253', '256'))	('lung cancer', 'Disease', (57, 68))	('erlotinib', 'Chemical', 'MESH:D000069347', (401, 410))	('sensitivity', 'MPA', (386, 397))	('EGFR-driven', 'Gene', (99, 110))
1199	28637487	In a recent study of 591 NSCLC, 60 had NF1 mutations (10%) whilst 141 (24%) harboured KRAS mutations.	('KRAS', 'Gene', (86, 90))	('NF1', 'Gene', (39, 42))	('NSCLC', 'Disease', (25, 30))	('KRAS', 'Gene', '3845', (86, 90))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('mutations', 'Var', (43, 52))
1200	28637487	Approximately 25% of the NF1 mutations co-occurred with mutations in known oncogenes: BRAF, ERBB2, KRAS, HRAS and NRAS.	('ERBB2', 'Gene', '2064', (92, 97))	('ERBB2', 'Gene', (92, 97))	('NRAS', 'Gene', (114, 118))	('co-occurred', 'Reg', (39, 50))	('mutations', 'Var', (29, 38))	('HRAS', 'Gene', '3265', (105, 109))	('NRAS', 'Gene', '4893', (114, 118))	('KRAS', 'Gene', (99, 103))	('NF1', 'Gene', (25, 28))	('BRAF', 'Disease', (86, 90))	('HRAS', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (99, 103))
1201	28637487	Therapeutic strategies targeting KRAS activation, including the use of inhibitors of MAP kinase signalling, may warrant investigation in NF1 mutant tumours.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('mutant', 'Var', (141, 147))	('KRAS', 'Gene', (33, 37))	('MAP', 'molecular_function', 'GO:0004239', ('85', '88'))	('NF1', 'Gene', (137, 140))	('KRAS', 'Gene', '3845', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('signalling', 'biological_process', 'GO:0023052', ('96', '106'))
1203	28637487	According to the TCGA, somatic NF1 changes are present in approximately 12% of squamous cell lung cancers (SqCC), of which four distinct subtypes have been identified: classical, primitive, basal and secretory expression.	('squamous cell lung cancers', 'Disease', (79, 105))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (79, 105))	('NF1', 'Gene', (31, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('changes', 'Var', (35, 42))	('lung cancers', 'Phenotype', 'HP:0100526', (93, 105))
1204	28637487	The basal expression subtype was found to harbour NF1 alterations, suggesting a potential direction for the treatment of such tumours.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('NF1', 'Gene', (50, 53))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('alterations', 'Var', (54, 65))	('tumours', 'Disease', (126, 133))
1207	28637487	This confirms the previously reported CD74-NRG1 fusion and also suggests that the NRG1, NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations and that this prognostic factor may be associated with poor survival.	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('NRG1', 'Gene', (43, 47))	('NF1', 'Gene', (88, 91))	('Hippo pathway', 'Gene', (96, 109))	('NRG1', 'Gene', (82, 86))	('play', 'Reg', (122, 126))	('NRG1', 'Gene', '3084', (43, 47))	('roles', 'Reg', (137, 142))	('NRG1', 'Gene', '3084', (82, 86))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('fusions', 'Var', (110, 117))
1209	28637487	Interestingly, both lung ADC and SqCC DNA displayed a significantly increased frequency of guanine (cytosine) to thymine (adenine) mutations, a type of mutation associated with exposure to tobacco smoke.	('adenine', 'Chemical', 'MESH:D000225', (122, 129))	('lung ADC', 'Disease', (20, 28))	('thymine', 'Chemical', 'MESH:D013941', (113, 120))	('guanine', 'Var', (91, 98))	('guanine', 'Chemical', 'MESH:D006147', (91, 98))	('cytosine', 'Chemical', 'MESH:D003596', (100, 108))	('tobacco', 'Species', '4097', (189, 196))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('increased', 'PosReg', (68, 77))
1211	28637487	Indeed, the mutational landscape of lung ADC is substantially different from that of SqCC of the lung or SCLC, with frequent receptor tyrosine kinase mutations found in lung ADC, that are rarely encountered in either SqCC or SCLC.	('SCLC', 'Gene', (225, 229))	('receptor tyrosine kinase', 'Gene', (125, 149))	('SCLC', 'Gene', '7864', (105, 109))	('mutations', 'Var', (150, 159))	('receptor tyrosine kinase', 'Gene', '5979', (125, 149))	('SCLC', 'Gene', (105, 109))	('SCLC', 'Gene', '7864', (225, 229))
1212	28637487	Mutations in TP53, KRAS, LKB1, NF1 and RBM10 are enriched in transversion-high tumours, whilst mutations in EGFR, RB1 and PIK3CA and in-frame insertions in the receptor tyrosine kinases EGFR and ERBB2 are enriched in transversion-low tumours.	('TP53', 'Gene', (13, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('EGFR', 'molecular_function', 'GO:0005006', ('186', '190'))	('LKB1', 'Gene', '6794', (25, 29))	('EGFR', 'Gene', (186, 190))	('KRAS', 'Gene', '3845', (19, 23))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('transversion-high tumours', 'Disease', 'MESH:D009369', (61, 86))	('NF1', 'Gene', (31, 34))	('PIK3CA', 'Gene', (122, 128))	('transversion-low tumours', 'Disease', 'MESH:D009800', (217, 241))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('KRAS', 'Gene', (19, 23))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (95, 104))	('receptor tyrosine kinase', 'Gene', '5979', (160, 184))	('transversion-high tumours', 'Disease', (61, 86))	('LKB1', 'Gene', (25, 29))	('RB1', 'Gene', (114, 117))	('ERBB2', 'Gene', (195, 200))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('receptor tyrosine kinase', 'Gene', (160, 184))	('RBM10', 'Gene', (39, 44))	('EGFR', 'Gene', (108, 112))	('PIK3CA', 'Gene', '5290', (122, 128))	('transversion-low tumours', 'Disease', (217, 241))	('ERBB2', 'Gene', '2064', (195, 200))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('RBM10', 'Gene', '8241', (39, 44))	('RB1', 'Gene', '5925', (114, 117))
1215	28637487	At least 38 genes were significantly mutated in lung ADC and 20 genes in SqCC; however, only six genes, TP53, RB1, ARIDIA, CDKN2A, PIK3CA and NF1, were significantly mutated in both tumour types, and of these, TP53, CDKN2A and PIK3CA mutations had a significantly higher frequency in lung SqCC.	('lung SqCC', 'Disease', (284, 293))	('RB1', 'Gene', (110, 113))	('TP53', 'Gene', (104, 108))	('TP53', 'Gene', (210, 214))	('PIK3CA', 'Gene', '5290', (131, 137))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('PIK3CA', 'Gene', (227, 233))	('RB1', 'Gene', '5925', (110, 113))	('CDKN2A', 'Gene', (123, 129))	('CDKN2A', 'Gene', (216, 222))	('PIK3CA', 'Gene', (131, 137))	('tumour', 'Disease', (182, 188))	('CDKN2A', 'Gene', '1029', (123, 129))	('PIK3CA', 'Gene', '5290', (227, 233))	('CDKN2A', 'Gene', '1029', (216, 222))	('mutations', 'Var', (234, 243))
1216	28637487	Recurrent alterations in lung SqCC were more similar to those of other squamous carcinomas than to alterations in lung ADCs, whilst the significantly mutated genes in lung ADC were most similar to those associated with glioblastoma and colorectal cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('alterations', 'Var', (10, 21))	('colorectal cancer', 'Disease', (236, 253))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('squamous carcinomas', 'Disease', (71, 90))	('squamous carcinomas', 'Disease', 'MESH:D002294', (71, 90))	('colorectal cancer', 'Disease', 'MESH:D015179', (236, 253))	('glioblastoma', 'Disease', (219, 231))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('lung SqCC', 'Disease', (25, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (236, 253))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))
1217	28637487	Although there is a paucity of data for small cell lung cancer (SCLC), the frequency of NF1 mutations in SCLC was found to be 2.4 and 6.9% in two independent studies.	('small cell lung cancer', 'Disease', (40, 62))	('NF1', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (92, 101))	('small cell lung cancer', 'Disease', 'MESH:D055752', (40, 62))	('SCLC', 'Gene', '7864', (105, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (40, 62))	('SCLC', 'Gene', (105, 109))	('SCLC', 'Gene', '7864', (64, 68))	('SCLC', 'Gene', (64, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))
1220	28637487	The most common non-actionable genomic alterations were found in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%), with NF1 mutations identified in only 3% of SCLC, consistent with the earlier studies.	('SCLC', 'Gene', '7864', (161, 165))	('RB1', 'Gene', '5925', (91, 94))	('TP53', 'Gene', (65, 69))	('MLL2', 'Gene', (105, 109))	('RB1', 'Gene', (91, 94))	('SCLC', 'Gene', '7864', (78, 82))	('NF1', 'Gene', (122, 125))	('SCLC', 'Gene', (78, 82))	('mutations', 'Var', (126, 135))	('MLL2', 'Gene', '8085', (105, 109))	('SCLC', 'Gene', (161, 165))
1222	28637487	Constitutional NF1 mutations are known to predispose individuals to myeloid malignancies such as chronic myelomonocytic leukaemia (CMML), JMML and acute myeloid leukaemia (AML).	('CMML', 'Disease', 'MESH:D054429', (131, 135))	('NF1', 'Gene', (15, 18))	('chronic myelomonocytic leukaemia', 'Disease', 'MESH:D015477', (97, 129))	('JMML', 'Disease', 'MESH:D054429', (138, 142))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (153, 170))	('acute myeloid leukaemia', 'Disease', (147, 170))	('mutations', 'Var', (19, 28))	('chronic myelomonocytic leukaemia', 'Disease', (97, 129))	('JMML', 'Disease', (138, 142))	('myeloid malignancies', 'Disease', 'MESH:D009369', (68, 88))	('AML', 'Disease', 'MESH:D015470', (172, 175))	('CMML', 'Disease', (131, 135))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (147, 170))	('AML', 'Disease', (172, 175))	('predispose', 'Reg', (42, 52))	('myeloid malignancies', 'Disease', (68, 88))
1223	28637487	Somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies.	('described', 'Reg', (51, 60))	('myeloid malignancies', 'Disease', 'MESH:D009369', (75, 95))	('NF1', 'Gene', (37, 40))	('deletions', 'Var', (14, 23))	('myeloid malignancies', 'Disease', (75, 95))
1224	28637487	More generally, the RAS signalling pathway has been found to be fundamental in the development of myeloid malignancies, with somatic activating mutations in NRAS and KRAS genes estimated to be present in 20 to 40% of diagnosed cases of AML, CMML and JMML.	('RAS', 'Chemical', 'MESH:D011883', (158, 161))	('RAS', 'Chemical', 'MESH:D011883', (167, 170))	('JMML', 'Disease', (250, 254))	('RAS', 'Chemical', 'MESH:D011883', (20, 23))	('signalling pathway', 'biological_process', 'GO:0007165', ('24', '42'))	('KRAS', 'Gene', (166, 170))	('CMML', 'Disease', (241, 245))	('AML', 'Disease', (236, 239))	('NRAS', 'Gene', (157, 161))	('KRAS', 'Gene', '3845', (166, 170))	('JMML', 'Disease', 'MESH:D054429', (250, 254))	('myeloid malignancies', 'Disease', 'MESH:D009369', (98, 118))	('NRAS', 'Gene', '4893', (157, 161))	('CMML', 'Disease', 'MESH:D054429', (241, 245))	('mutations', 'Var', (144, 153))	('myeloid malignancies', 'Disease', (98, 118))	('AML', 'Disease', 'MESH:D015470', (236, 239))
1226	28637487	Whilst somatic KRAS and NRAS mutations are frequently found in AML, mutations in other RAS signalling pathway genes, including NF1, occur at lower frequencies, although the reported frequency for NF1 somatic mutations ranges quite widely from 3.5 to 23.6%.	('NRAS', 'Gene', '4893', (24, 28))	('AML', 'Disease', (63, 66))	('RAS', 'Chemical', 'MESH:D011883', (25, 28))	('KRAS', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('signalling pathway', 'biological_process', 'GO:0007165', ('91', '109'))	('NF1', 'Gene', (127, 130))	('KRAS', 'Gene', '3845', (15, 19))	('RAS', 'Chemical', 'MESH:D011883', (87, 90))	('AML', 'Disease', 'MESH:D015470', (63, 66))	('NRAS', 'Gene', (24, 28))	('RAS', 'Chemical', 'MESH:D011883', (16, 19))
1227	28637487	Parkin and colleagues identified NF1 mutations in 7% of cases with AML, with a further 12% displaying copy number alterations (CNAs) involving NF1, mainly heterozygous deletions.	('AML', 'Disease', 'MESH:D015470', (67, 70))	('copy number alterations', 'Reg', (102, 125))	('NF1', 'Gene', (33, 36))	('AML', 'Disease', (67, 70))	('mutations', 'Var', (37, 46))	('NF1', 'Gene', (143, 146))
1229	28637487	In another study of AML with CBHB-MYHII rearrangements, 16% of the samples harboured NF1 deletions.	('deletions', 'Var', (89, 98))	('NF1', 'Gene', (85, 88))	('CBHB', 'Chemical', '-', (29, 33))	('AML', 'Disease', 'MESH:D015470', (20, 23))	('AML', 'Disease', (20, 23))
1230	28637487	However, high-resolution studies have failed to provide any evidence for frequent NF1 alterations in de novo AML, although they suggested that NF1 mutations may contribute to tumour progression.	('mutations', 'Var', (147, 156))	('AML', 'Disease', 'MESH:D015470', (109, 112))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('tumour', 'Disease', (175, 181))	('contribute', 'Reg', (161, 171))	('AML', 'Disease', (109, 112))	('NF1', 'Gene', (143, 146))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('alterations', 'Var', (86, 97))
1231	28637487	In this study, the authors screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches.	('deletion', 'Var', (105, 113))	('NF1', 'Gene', (101, 104))	('patients', 'Species', '9606', (84, 92))	('AML', 'Disease', (80, 83))	('AML', 'Disease', 'MESH:D015470', (80, 83))
1232	28637487	Using aCGH, a small ~0.3 Mbp minimally deleted region involving NF1 was defined; the overall frequency of NF1 deletion was 3.5% (17/485).	('NF1', 'Gene', (106, 109))	('deletion', 'Var', (110, 118))	('Mbp', 'Gene', (25, 28))	('Mbp', 'Gene', '4155', (25, 28))
1233	28637487	Furthermore, NF1 deletion was significantly associated with abnormal cytogenetics and a monosomal karyotype, whilst only one of five NF1-deleted patients acquired a coding mutation in the remaining allele.	('associated', 'Reg', (44, 54))	('deletion', 'Var', (17, 25))	('patients', 'Species', '9606', (145, 153))	('NF1', 'Gene', (13, 16))
1234	28637487	This study indicates that NF1 microlesions are infrequent in de novo AML and may be secondary events in leukemic progression.	('AML', 'Disease', (69, 72))	('NF1', 'Gene', (26, 29))	('leukemic', 'Disease', (104, 112))	('AML', 'Disease', 'MESH:D015470', (69, 72))	('microlesions', 'Var', (30, 42))
1235	28637487	The frequency of NF1 changes in myelodysplastic syndrome has been found to vary between 0 and 9%.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (32, 56))	('NF1', 'Gene', (17, 20))	('myelodysplastic syndrome', 'Disease', (32, 56))	('changes', 'Var', (21, 28))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (32, 56))
1239	28637487	The type 1 NF1 microdeletion (1.4 Mb) was reported in 2.9% (3/103) of T-ALL patients.	('patients', 'Species', '9606', (76, 84))	('microdeletion', 'Var', (15, 28))	('NF1', 'Gene', (11, 14))
1241	28637487	In 1997, Side and colleagues reported constitutional NF1 mutations in 15% of JMML patients.	('JMML', 'Disease', (77, 81))	('patients', 'Species', '9606', (82, 90))	('NF1', 'Gene', (53, 56))	('mutations', 'Var', (57, 66))	('JMML', 'Disease', 'MESH:D054429', (77, 81))
1243	28637487	JMML was once considered a unique example of RAS-driven oncogenesis because it was thought to be initiated by mutually exclusive mutations in the RAS genes (NRAS or KRAS) or in several RAS pathway regulators (PTPN11, NF1 or CBL).	('RAS', 'Chemical', 'MESH:D011883', (185, 188))	('CBL', 'Gene', (224, 227))	('oncogenesis', 'biological_process', 'GO:0007048', ('56', '67'))	('NRAS', 'Gene', '4893', (157, 161))	('RAS-', 'Chemical', 'MESH:D011883', (45, 49))	('RAS', 'Chemical', 'MESH:D011883', (158, 161))	('CBL', 'Gene', '867', (224, 227))	('RAS', 'Chemical', 'MESH:D011883', (166, 169))	('JMML', 'Disease', 'MESH:D054429', (0, 4))	('PTPN11', 'Gene', (209, 215))	('RAS', 'Chemical', 'MESH:D011883', (45, 48))	('NRAS', 'Gene', (157, 161))	('PTPN11', 'Gene', '5781', (209, 215))	('KRAS', 'Gene', '3845', (165, 169))	('mutations', 'Var', (129, 138))	('JMML', 'Disease', (0, 4))	('initiated by', 'Reg', (97, 109))	('RAS', 'Chemical', 'MESH:D011883', (146, 149))	('NF1', 'Gene', (217, 220))	('KRAS', 'Gene', (165, 169))
1245	28637487	In total, 85 somatically acquired genetic alterations were found in 83% (25/30) of patients in this sub-cohort.	('genetic alterations', 'Var', (34, 53))	('patients', 'Species', '9606', (83, 91))	('found', 'Reg', (59, 64))
1246	28637487	Genes containing somatic variants detected by whole-exome sequencing, or previously reported to be mutated in JMML, were then sequenced in the full cohort of 118 JMML cases.	('JMML', 'Disease', 'MESH:D054429', (162, 166))	('variants', 'Var', (25, 33))	('JMML', 'Disease', (110, 114))	('JMML', 'Disease', (162, 166))	('JMML', 'Disease', 'MESH:D054429', (110, 114))
1247	28637487	A total of 122 secondary clonal abnormalities, in addition to initiating RAS pathway mutations, were identified in 49% (58/118) of patients.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (85, 94))	('RAS pathway', 'Pathway', (73, 84))	('RAS', 'Chemical', 'MESH:D011883', (73, 76))
1250	28637487	Nf1/Kras double-mutant mice have been shown to develop myeloid malignancies with reduced latency and increased severity in comparison to mice with only one of the two defects because copy number variations (CNVs) in Nf1/Kras mutant mice frequently resulted in haploinsufficiency for PRC2 core subunits (SUZ12 or EZH2) or PRC2-associated factors necessary for optimal PRC2 activity (AEBP2, CDYL or JARID2).	('EZH2', 'Gene', (312, 316))	('Nf1', 'Gene', (0, 3))	('myeloid malignancies', 'Disease', (55, 75))	('CDYL', 'Gene', (389, 393))	('Kras', 'Gene', '16653', (4, 8))	('core', 'cellular_component', 'GO:0019013', ('288', '292'))	('Nf1', 'Gene', '18015', (216, 219))	('mutant', 'Var', (225, 231))	('JARID2', 'Gene', (397, 403))	('CDYL', 'Gene', '12593', (389, 393))	('Nf1', 'Gene', '18015', (0, 3))	('JARID2', 'Gene', '16468', (397, 403))	('develop', 'PosReg', (47, 54))	('mice', 'Species', '10090', (137, 141))	('AEBP2', 'Gene', '11569', (382, 387))	('Kras', 'Gene', (220, 224))	('resulted in', 'Reg', (248, 259))	('EZH2', 'Gene', '14056', (312, 316))	('mice', 'Species', '10090', (232, 236))	('AEBP2', 'Gene', (382, 387))	('copy number variations', 'Var', (183, 205))	('haploinsufficiency', 'Disease', 'MESH:D058495', (260, 278))	('Nf1', 'Gene', (216, 219))	('Kras', 'Gene', (4, 8))	('Kras', 'Gene', '16653', (220, 224))	('SUZ12', 'Gene', '52615', (303, 308))	('haploinsufficiency', 'Disease', (260, 278))	('SUZ12', 'Gene', (303, 308))	('myeloid malignancies', 'Disease', 'MESH:D009369', (55, 75))	('mice', 'Species', '10090', (23, 27))
1251	28637487	In addition, haploinsufficiency for multiple genes that regulate PRC2 function can cooperate in myeloid transformation, and other mutations in JMML target a small number of pathways specifically, including components of the RAS and PRC2 networks.	('target', 'Reg', (148, 154))	('JMML', 'Disease', (143, 147))	('PRC2', 'Gene', (65, 69))	('haploinsufficiency', 'Disease', 'MESH:D058495', (13, 31))	('myeloid transformation', 'CPA', (96, 118))	('RAS', 'Chemical', 'MESH:D011883', (224, 227))	('mutations', 'Var', (130, 139))	('cooperate', 'Reg', (83, 92))	('haploinsufficiency', 'Disease', (13, 31))	('JMML', 'Disease', 'MESH:D054429', (143, 147))
1253	28637487	Loss of function of PRC2 (due to mutations in EED or SUZ12) is also found in the vast majority of sporadic, NF1-associated, and radiotherapy-associated MPNSTs (where PRC2 loss amplifies Ras-driven transcription).	('SUZ12', 'Gene', '52615', (53, 58))	('amplifies', 'PosReg', (176, 185))	('NF1-associated', 'Disease', (108, 122))	('mutations', 'Var', (33, 42))	('PRC2', 'Gene', (166, 170))	('transcription', 'biological_process', 'GO:0006351', ('197', '210'))	('Loss of function', 'NegReg', (0, 16))	('SUZ12', 'Gene', (53, 58))	('EED', 'Gene', '8726', (46, 49))	('loss', 'NegReg', (171, 175))	('EED', 'Gene', (46, 49))	('PRC2', 'Gene', (20, 24))
1254	28637487	In a recent study focussing on characterization of serial samples from JMML patients at diagnosis and then beyond through relapse and transformation to AML, mutations were found in NF1, NRAS, KRAS, PTPN11 or CBL in 85% of patients, as well as recurrent mutations in other genes involved in signal transduction, splicing, PRC2 and transcription.	('JMML', 'Disease', (71, 75))	('NRAS', 'Gene', (186, 190))	('patients', 'Species', '9606', (222, 230))	('PTPN11', 'Gene', '5781', (198, 204))	('CBL', 'Gene', (208, 211))	('AML', 'Disease', 'MESH:D015470', (152, 155))	('KRAS', 'Gene', '3845', (192, 196))	('signal transduction', 'biological_process', 'GO:0007165', ('290', '309'))	('AML', 'Disease', (152, 155))	('mutations', 'Var', (253, 262))	('mutations', 'Var', (157, 166))	('transcription', 'biological_process', 'GO:0006351', ('330', '343'))	('KRAS', 'Gene', (192, 196))	('NF1', 'Gene', (181, 184))	('CBL', 'Gene', '867', (208, 211))	('patients', 'Species', '9606', (76, 84))	('NRAS', 'Gene', '4893', (186, 190))	('JMML', 'Disease', 'MESH:D054429', (71, 75))	('splicing', 'biological_process', 'GO:0045292', ('311', '319'))	('found', 'Reg', (172, 177))	('PTPN11', 'Gene', (198, 204))
1257	28637487	NF1 patients have an increased risk of developing breast cancer as compared to the general population.	('NF1', 'Var', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patients', 'Species', '9606', (4, 12))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
1259	28637487	A predisposition to breast cancer in NF1 patients has led researchers to postulate the potential involvement of somatic NF1 mutations in initiating and driving the malignant transformation and progression of sporadic breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('mutations', 'Var', (124, 133))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('sporadic breast cancer', 'Disease', (208, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('NF1', 'Gene', (120, 123))	('patients', 'Species', '9606', (41, 49))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (208, 230))	('predisposition', 'Reg', (2, 16))	('malignant transformation', 'CPA', (164, 188))
1262	28637487	Further analysis of the NF1 deletion-bearing tumours revealed significantly higher levels of active RAS, indicating that RAS signal transduction pathway dysregulation, through NF1 loss, may be responsible for driving malignancy in these cells.	('RAS signal', 'Pathway', (121, 131))	('NF1', 'Gene', (176, 179))	('levels', 'MPA', (83, 89))	('malignancy', 'Disease', 'MESH:D009369', (217, 227))	('malignancy', 'Disease', (217, 227))	('loss', 'NegReg', (180, 184))	('active RAS', 'MPA', (93, 103))	('RAS', 'Chemical', 'MESH:D011883', (100, 103))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('deletion-bearing', 'Var', (28, 44))	('RAS', 'Chemical', 'MESH:D011883', (121, 124))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('higher', 'PosReg', (76, 82))	('NF1', 'Gene', (24, 27))	('signal transduction', 'biological_process', 'GO:0007165', ('125', '144'))	('tumours', 'Disease', (45, 52))
1265	28637487	Hence, this study suggested that under-expression of NF1 and reduced neurofibromin activity may have a direct influence on malignant transformation and resistance to anti-cancer agents.	('activity', 'MPA', (83, 91))	('NF1', 'Gene', (53, 56))	('neurofibromin', 'Protein', (69, 82))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('under-expression', 'Var', (33, 49))	('reduced', 'NegReg', (61, 68))	('influence', 'Reg', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('resistance', 'CPA', (152, 162))	('malignant transformation', 'CPA', (123, 147))
1266	28637487	This is consistent with other studies and goes some way towards accounting for the presence of the somatic NF1 mutations found in sporadic breast tumours.	('mutations', 'Var', (111, 120))	('sporadic breast tumours', 'Disease', 'MESH:D001943', (130, 153))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('sporadic breast tumours', 'Disease', (130, 153))	('NF1', 'Gene', (107, 110))
1267	28637487	The mouse model Chaos3 is characterized by the spontaneous development of mammary tumours, due to a mutation in Mcm4 leading to chromosomal instability through disruption of the MCM2-7 complex.	('chromosomal instability', 'MPA', (128, 151))	('MCM2-7', 'Gene', '17216;17215;17217;17218;17219;17220', (178, 184))	('mouse', 'Species', '10090', (4, 9))	('Mcm4', 'Gene', (112, 116))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('MCM2-7', 'Gene', (178, 184))	('Mcm4', 'Gene', '17217', (112, 116))	('disruption', 'NegReg', (160, 170))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('mutation', 'Var', (100, 108))	('tumours', 'Disease', (82, 89))	('chromosomal instability', 'Phenotype', 'HP:0040012', (128, 151))	('leading to', 'Reg', (117, 127))
1268	28637487	Somatic NF1 deletions were found in almost all (59/60) of the mammary tumours studied in this mouse model, and upon subsequent examination of TCGA data, it was noted that NF1 is somatically mutated or deleted in 27.7% of human breast cancers.	('deletions', 'Var', (12, 21))	('NF1', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('breast cancers', 'Phenotype', 'HP:0003002', (227, 241))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancers', 'Disease', 'MESH:D001943', (227, 241))	('breast cancers', 'Disease', (227, 241))	('human', 'Species', '9606', (221, 226))	('mouse', 'Species', '10090', (94, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('found', 'Reg', (27, 32))	('tumours', 'Disease', (70, 77))
1269	28637487	Large-scale NGS to compare primary and recurrent breast cancer has found mutations in recurrent tumours which were not present in matched primary tissue.	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))	('mutations', 'Var', (73, 82))
1274	28637487	In contrast, genes generally mutated in breast cancers are subject to a low frequency of somatic mutations, including single nucleotide mutations and indels in driver genes.	('breast cancers', 'Disease', (40, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('indels', 'Var', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (40, 54))	('single nucleotide mutations', 'Var', (118, 145))	('breast cancers', 'Disease', 'MESH:D001943', (40, 54))
1277	28637487	In a recent study based on 2433 molecular profiles of breast cancer, it was noted that high levels of intra-tumour heterogeneity was generally associated with a worse clinical outcome, with one exception: highly aggressive breast tumours with 11q13-14 amplification had low levels of intra-tumour heterogeneity.	('breast cancer', 'Disease', (54, 67))	('associated', 'Reg', (143, 153))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('11q13-14 amplification', 'Var', (243, 265))	('intra-tumour', 'Disease', 'MESH:D009369', (284, 296))	('aggressive breast tumours', 'Disease', (212, 237))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('intra-tumour', 'Disease', (284, 296))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('intra-tumour', 'Disease', 'MESH:D009369', (102, 114))	('aggressive breast tumours', 'Disease', 'MESH:D001943', (212, 237))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('intra-tumour', 'Disease', (102, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))
1278	28637487	Inactivating NF1 mutations were also found to be associated with breast cancer severity score in oestrogen receptor-negative tumours.	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('tumours', 'Disease', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('NF1', 'Gene', (13, 16))	('breast cancer', 'Disease', (65, 78))	('Inactivating', 'Var', (0, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('mutations', 'Var', (17, 26))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
1279	28637487	As with melanoma and neuroblastoma, inactivation of NF1 in breast cancer is associated with resistance to drug therapy.	('neuroblastoma', 'Disease', (21, 34))	('NF1', 'Gene', (52, 55))	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('neuroblastoma', 'Phenotype', 'HP:0003006', (21, 34))	('resistance', 'MPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('associated', 'Reg', (76, 86))	('neuroblastoma', 'Disease', 'MESH:D009447', (21, 34))	('inactivation', 'Var', (36, 48))
1281	28637487	Silencing of NF1, amongst several other genes, has been shown to confer a tamoxifen-resistant phenotype, although it was noted that resistance- or sensitivity-specific gene expression patterns may give a better prediction of treatment outcome as compared to single genes.	('tamoxifen', 'Chemical', 'MESH:D013629', (74, 83))	('confer', 'Reg', (65, 71))	('NF1', 'Gene', (13, 16))	('tamoxifen-resistant phenotype', 'MPA', (74, 103))	('Silencing', 'Var', (0, 9))	('gene expression', 'biological_process', 'GO:0010467', ('168', '183'))
1286	28637487	More than a third of all ovarian serous carcinomas (OSCs) harbour somatic NF1 mutations, identifying an alternative target for treatment and an additional prognostic marker.	('NF1', 'Gene', (74, 77))	('ovarian serous carcinomas', 'Disease', (25, 50))	('mutations', 'Var', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (25, 50))
1288	28637487	Genome-wide microarray analysis of 36 primary OSC identified homozygous NF1 deletions in two tumours.	('NF1', 'Gene', (72, 75))	('tumours', 'Disease', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('deletions', 'Var', (76, 85))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('OSC', 'molecular_function', 'GO:0000250', ('46', '49'))
1289	28637487	This group subsequently screened 18 ovarian carcinoma-derived cell lines and 41 primary OSC for additional NF1 alterations, with 8/18 cell lines exhibiting marked reduction or no expression of NF1.	('reduction', 'NegReg', (163, 172))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (36, 53))	('OSC', 'molecular_function', 'GO:0000250', ('88', '91'))	('alterations', 'Var', (111, 122))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (36, 53))	('ovarian carcinoma', 'Disease', (36, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('NF1', 'Gene', (107, 110))
1290	28637487	Additionally, tumours and cell lines with NF1 lesions were found to lack KRAS and BRAF mutations, whilst exhibiting Ras pathway activation.	('activation', 'PosReg', (128, 138))	('KRAS', 'Gene', (73, 77))	('Ras pathway', 'Pathway', (116, 127))	('KRAS', 'Gene', '3845', (73, 77))	('BRAF', 'Gene', (82, 86))	('mutations', 'Var', (87, 96))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('lack', 'NegReg', (68, 72))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))	('NF1', 'Gene', (42, 45))	('lesions', 'Var', (46, 53))
1292	28637487	The Australian Ovarian Cancer Study (AOCS) specifically examined CNAs and reported regions of copy number loss at the NF1 locus in 34% (137/398) of ovarian cancer samples, comprising 157 serous adenocarcinomas from the TCGA cohort and a further 241 samples, of both endometrioid and serous subtypes.	('Cancer', 'Disease', (23, 29))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (15, 29))	('copy number loss', 'Var', (94, 110))	('ovarian cancer', 'Disease', (148, 162))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('serous adenocarcinomas', 'Disease', (187, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('serous adenocarcinomas', 'Disease', 'MESH:D000230', (187, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('ovarian cancer', 'Disease', 'MESH:D010051', (148, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('NF1', 'Gene', (118, 121))
1296	28637487	NF1 is one of a number of known paraganglioma and phaeochromocytoma susceptibility genes, constitutional mutations in which are responsible for inherited tumour syndromes.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('paraganglioma', 'Phenotype', 'HP:0002668', (32, 45))	('inherited tumour syndromes', 'Disease', (144, 170))	('inherited tumour syndromes', 'Disease', 'MESH:D009386', (144, 170))	('mutations', 'Var', (105, 114))	('NF1', 'Gene', (0, 3))	('paraganglioma and phaeochromocytoma', 'Disease', 'MESH:D010235', (32, 67))
1297	28637487	Somatic NF1 mutations occurred in 35/161 (21.7%) of sporadic phaeochromocytomas, with the majority exhibiting LOH and low NF1 mRNA expression, whilst somatic mutations in the susceptibility genes NF1, MAX, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bbeta and TMEM127 are present in 11-19% of sporadic cases.	('NF1', 'Gene', (8, 11))	('SDHA', 'Gene', (216, 220))	('SDHA', 'Gene', (240, 244))	('SDHB', 'Gene', '6390', (222, 226))	('SDHA', 'Gene', '6389', (216, 220))	('SDHC', 'Gene', (228, 232))	('SDHA', 'Gene', '6389', (240, 244))	('RET', 'Gene', '5979', (206, 209))	('TMEM127', 'Gene', (262, 269))	('VHL', 'Gene', (211, 214))	('SDHAF2', 'Gene', '54949', (240, 246))	('SDHAF2', 'Gene', (240, 246))	('sporadic phaeochromocytomas', 'Disease', (52, 79))	('LOH', 'Var', (110, 113))	('NF1', 'Gene', (196, 199))	('SDHB', 'Gene', (222, 226))	('low', 'NegReg', (118, 121))	('TMEM127', 'Gene', '55654', (262, 269))	('VHL', 'Gene', '7428', (211, 214))	('RET', 'Gene', (206, 209))	('SDHD', 'Gene', '6392', (234, 238))	('SDHC', 'Gene', '6391', (228, 232))	('mutations', 'Var', (12, 21))	('sporadic phaeochromocytomas', 'Disease', 'MESH:C538614', (52, 79))	('mRNA expression', 'MPA', (126, 141))	('occurred', 'Reg', (22, 30))	('NF1', 'Gene', (122, 125))	('SDHD', 'Gene', (234, 238))
1298	28637487	It has also been demonstrated that the majority (83%, 35/42) of sporadic phaeochromocytomas harbour a CNA in at least one of these susceptibility genes, thereby altering respective protein expression levels.	('altering', 'Reg', (161, 169))	('sporadic phaeochromocytomas', 'Disease', (64, 91))	('sporadic phaeochromocytomas', 'Disease', 'MESH:C538614', (64, 91))	('CNA', 'Var', (102, 105))	('protein expression levels', 'MPA', (181, 206))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))
1300	28637487	Furthermore, 10 of 11 tumours were also observed to harbour a somatic protein-truncating NF1 mutation in the second allele.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('tumours', 'Disease', (22, 29))	('NF1', 'Gene', (89, 92))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('mutation', 'Var', (93, 101))	('protein-truncating', 'PosReg', (70, 88))
1301	28637487	This study also identified a correlation between NF1 mutations and a biochemical phenotype: paragangliomas and phaeochromocytomas harbouring a somatic NF1 mutation were found to display higher plasma levels of normetanephrine (P = 0.005) and metanephrine (P = 0.0025), markers for catecholamine-secreting tumours.	('tumours', 'Disease', 'MESH:D009369', (305, 312))	('NF1', 'Gene', (151, 154))	('normetanephrine', 'Chemical', 'MESH:D009647', (210, 225))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))	('plasma levels of normetanephrine', 'MPA', (193, 225))	('metanephrine', 'MPA', (242, 254))	('catecholamine', 'Chemical', 'MESH:D002395', (281, 294))	('higher', 'PosReg', (186, 192))	('paraganglioma', 'Phenotype', 'HP:0002668', (92, 105))	('paragangliomas', 'Phenotype', 'HP:0002668', (92, 106))	('metanephrine', 'Chemical', 'MESH:D008676', (213, 225))	('metanephrine', 'Chemical', 'MESH:D008676', (242, 254))	('mutations', 'Var', (53, 62))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('paragangliomas and phaeochromocytomas', 'Disease', 'MESH:D010235', (92, 129))	('tumours', 'Disease', (305, 312))	('mutation', 'Var', (155, 163))	('NF1', 'Gene', (49, 52))	('tumours', 'Phenotype', 'HP:0002664', (305, 312))
1304	28637487	Almost a quarter (25/119) of the sporadic phaeochromocytomas/paragangliomas carried an inactivating NF1 mutation, of which 21/25 were associated with the loss of the wild-type allele.	('inactivating', 'Var', (87, 99))	('phaeochromocytomas/paragangliomas', 'Disease', (42, 75))	('paragangliomas', 'Phenotype', 'HP:0002668', (61, 75))	('paraganglioma', 'Phenotype', 'HP:0002668', (61, 74))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('mutation', 'Var', (104, 112))	('NF1', 'Gene', (100, 103))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (42, 75))	('sporadic phaeochromocytomas', 'Disease', (33, 60))	('sporadic phaeochromocytomas', 'Disease', 'MESH:C538614', (33, 60))
1305	28637487	Of all the somatic mutations identified in the study, 56% were located in NF1, showing that NF1 is frequently mutated in phaeochromocytomas/paragangliomas.	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (121, 154))	('NF1', 'Gene', (74, 77))	('mutated', 'Var', (110, 117))	('paragangliomas', 'Phenotype', 'HP:0002668', (140, 154))	('paraganglioma', 'Phenotype', 'HP:0002668', (140, 153))	('phaeochromocytomas/paragangliomas', 'Disease', (121, 154))	('mutations', 'Var', (19, 28))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))
1312	28637487	In this study, 4/10 neuroblastoma cell lines were observed to express either a reduced level or a complete absence of neurofibromin, with NF1 mutations being identified in two of these cell lines.	('neuroblastoma', 'Phenotype', 'HP:0003006', (20, 33))	('mutations', 'Var', (142, 151))	('neuroblastoma', 'Disease', 'MESH:D009447', (20, 33))	('neurofibromin', 'Protein', (118, 131))	('neuroblastoma', 'Disease', (20, 33))	('NF1', 'Gene', (138, 141))	('absence', 'NegReg', (107, 114))
1315	28637487	Somatic NF1 mutations in neuroblastomas have been correlated with reduced expression of neurofibromin and poor patient prognosis, whilst higher levels of expression are associated with longer progression-free survival.	('reduced', 'NegReg', (66, 73))	('NF1', 'Gene', (8, 11))	('expression', 'MPA', (74, 84))	('neuroblastomas', 'Disease', (25, 39))	('neuroblastoma', 'Phenotype', 'HP:0003006', (25, 38))	('mutations', 'Var', (12, 21))	('neurofibromin', 'Protein', (88, 101))	('patient', 'Species', '9606', (111, 118))	('neuroblastomas', 'Phenotype', 'HP:0003006', (25, 39))	('neuroblastomas', 'Disease', 'MESH:D009447', (25, 39))
1319	28637487	Loss of NF1 activates RAS-MEK signalling, which in turn represses ZNF423, a critical transcriptional coactivator of the retinoic acid receptors; neuroblastomas with low levels of both NF1 and ZNF423 have an extremely poor outcome.	('NF1', 'Gene', (8, 11))	('ZNF423', 'Gene', (66, 72))	('neuroblastomas', 'Disease', (145, 159))	('neuroblastomas', 'Disease', 'MESH:D009447', (145, 159))	('activates', 'PosReg', (12, 21))	('represses', 'NegReg', (56, 65))	('signalling', 'biological_process', 'GO:0023052', ('30', '40'))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('retinoic acid', 'Chemical', 'MESH:D014212', (120, 133))	('RAS-MEK', 'MPA', (22, 29))	('ZNF423', 'Gene', '23090', (192, 198))	('neuroblastomas', 'Phenotype', 'HP:0003006', (145, 159))	('ZNF423', 'Gene', (192, 198))	('Loss', 'Var', (0, 4))	('ZNF423', 'Gene', '23090', (66, 72))
1320	28637487	However, inhibition of MEK signalling downstream of NF1 restores responsiveness to RA, suggesting a potential therapeutic strategy to overcome RA resistance in NF1-deficient neuroblastomas.	('responsiveness to RA', 'MPA', (65, 85))	('restores', 'PosReg', (56, 64))	('RA', 'Chemical', 'MESH:D014212', (143, 145))	('neuroblastoma', 'Phenotype', 'HP:0003006', (174, 187))	('NF1-deficient neuroblastomas', 'Disease', 'MESH:C537392', (160, 188))	('RA', 'Chemical', 'MESH:D014212', (83, 85))	('neuroblastomas', 'Phenotype', 'HP:0003006', (174, 188))	('signalling', 'biological_process', 'GO:0023052', ('27', '37'))	('MEK', 'Pathway', (23, 26))	('NF1-deficient neuroblastomas', 'Disease', (160, 188))	('inhibition', 'Var', (9, 19))
1324	28637487	Glioblastoma-associated NF1 somatic mutations are well described, with recurrent driver mutations being identified in NF1 and a number of other candidate genes (IDH1, TP53, CDK4, EGFR, PI3KR1, PIK3CA, PTEN, RB1 and CDNK2A) in GBM.	('EGFR', 'Gene', (179, 183))	('PIK3CA', 'Gene', '5290', (193, 199))	('CDK4', 'Gene', (173, 177))	('mutations', 'Var', (88, 97))	('RB1', 'Gene', '5925', (207, 210))	('NF1', 'Gene', (24, 27))	('IDH1', 'Gene', '3417', (161, 165))	('NF1', 'Gene', (118, 121))	('Glioblastoma', 'Disease', (0, 12))	('PTEN', 'Gene', (201, 205))	('CDK4', 'Gene', '1019', (173, 177))	('PIK3CA', 'Gene', (193, 199))	('PTEN', 'Gene', '5728', (201, 205))	('TP53', 'Gene', (167, 171))	('EGFR', 'molecular_function', 'GO:0005006', ('179', '183'))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('mutations', 'Var', (36, 45))	('RB1', 'Gene', (207, 210))	('IDH1', 'Gene', (161, 165))	('CDK', 'molecular_function', 'GO:0004693', ('173', '176'))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('CDNK2A', 'Gene', (215, 221))
1325	28637487	A TCGA analysis assessed levels of gene expression, CNAs and DNA methylation in a cohort of 206 glioblastoma tumour samples, with recurrent mutations in NF1, AKT3, PRK3R1 and PARK2 being identified, and with 14% (13/91) of samples found to contain at least one somatic NF1 mutation.	('gene expression', 'biological_process', 'GO:0010467', ('35', '50'))	('AKT3', 'Gene', '10000', (158, 162))	('PARK2', 'Gene', (175, 180))	('PRK', 'molecular_function', 'GO:0008974', ('164', '167'))	('NF1', 'Gene', (153, 156))	('glioblastoma tumour', 'Disease', (96, 115))	('CNAs', 'MPA', (52, 56))	('DNA methylation', 'biological_process', 'GO:0006306', ('61', '76'))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('PARK2', 'Gene', '5071', (175, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('mutations', 'Var', (140, 149))	('glioblastoma tumour', 'Disease', 'MESH:D005909', (96, 115))	('PRK3R1', 'Gene', (164, 170))	('AKT3', 'Gene', (158, 162))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
1327	28637487	They found that GBM with NF1 and PTEN alterations had a distinct mesenchymal-like expression profile, with 53% of mesenchymal cases having an NF1 mutation.	('mesenchymal-like', 'CPA', (65, 81))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('NF1', 'Gene', (25, 28))	('alterations', 'Var', (38, 49))	('mutation', 'Var', (146, 154))	('NF1', 'Gene', (142, 145))
1328	28637487	In animal models, inactivation of TP53 and PTEN may cooperate with NF1 loss in the development of glioblastoma.	('NF1', 'Gene', (67, 70))	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('inactivation', 'Var', (18, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('TP53', 'Protein', (34, 38))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('loss', 'NegReg', (71, 75))
1332	28637487	Although genetic alterations in the PI3K and RAS/MAPK pathways are common in CRC and NF1 alterations have been detected in 5-6% of cases, it remains unclear as to whether NF1 mutations in CRC are related to chemotherapeutic effect.	('MAPK', 'molecular_function', 'GO:0004707', ('49', '53'))	('PI3K', 'Pathway', (36, 40))	('RAS/MAPK pathways', 'Pathway', (45, 62))	('NF1', 'Gene', (85, 88))	('RAS', 'Chemical', 'MESH:D011883', (45, 48))	('mutations', 'Var', (175, 184))	('CRC', 'Gene', (77, 80))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))
1333	28637487	The best documented molecular factors involved in urothelial transitional cell carcinoma (TCC) are the RAS proto-oncogene activation and TP53 mutations.	('mutations', 'Var', (142, 151))	('TCC', 'cellular_component', 'GO:0005579', ('90', '93'))	('urothelial transitional cell carcinoma', 'Disease', (50, 88))	('RAS', 'Chemical', 'MESH:D011883', (103, 106))	('urothelial transitional cell carcinoma', 'Disease', 'MESH:D002295', (50, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('TP53', 'Gene', (137, 141))
1334	28637487	Neurofibromin levels were also decreased in high-grade TCC, suggesting that alterations of NF1 gene expression might be involved in urinary TCC carcinogenesis.	('alterations', 'Var', (76, 87))	('NF1', 'Gene', (91, 94))	('involved', 'Reg', (120, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (144, 158))	('decreased', 'NegReg', (31, 40))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('TCC', 'cellular_component', 'GO:0005579', ('140', '143'))	('carcinogenesis', 'Disease', (144, 158))	('urinary TCC', 'Disease', (132, 143))	('Neurofibromin', 'Gene', (0, 13))	('Neurofibromin', 'Gene', '4763', (0, 13))	('high-grade', 'Var', (44, 54))	('TCC', 'cellular_component', 'GO:0005579', ('55', '58'))	('urinary TCC', 'Phenotype', 'HP:0030409', (132, 143))
1335	28637487	Whole genomic analysis performed on 35 stage IV urothelial cancers that had relapsed and progressed after primary surgery and conventional chemotherapy revealed NF1 mutations in two cases (6%).	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('urothelial cancers', 'Disease', 'MESH:D014523', (48, 66))	('NF1', 'Gene', (161, 164))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('mutations', 'Var', (165, 174))	('urothelial cancers', 'Disease', (48, 66))
1336	28637487	Integrated analysis of 131 urothelial carcinomas showed recurrent mutations in 32 genes, with 14% of tumours having NF1 mutations.	('mutations', 'Var', (66, 75))	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (27, 48))	('tumours', 'Disease', (101, 108))	('NF1', 'Gene', (116, 119))	('urothelial carcinomas', 'Disease', (27, 48))	('mutations', 'Var', (120, 129))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
1337	28637487	There are a number of other malignant tumour types that have been found to harbour NF1 alterations including neuroendocrine prostate cancer (24%), myxofibrosarcomas (10.5%) and pleomorphic liposarcomas (8%), pancreatic cancer (11%), gastric adenocarcinoma (10%) and rhabdomyosarcoma (7%).	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (266, 282))	('liposarcomas', 'Phenotype', 'HP:0012034', (189, 201))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (266, 282))	('pleomorphic liposarcomas', 'Disease', (177, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('gastric adenocarcinoma', 'Disease', (233, 255))	('malignant tumour', 'Disease', 'MESH:D009369', (28, 44))	('myxofibrosarcomas', 'Disease', (147, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (109, 139))	('pancreatic cancer', 'Disease', 'MESH:D010190', (208, 225))	('myxofibrosarcomas', 'Disease', 'None', (147, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('NF1', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('rhabdomyosarcoma', 'Disease', (266, 282))	('malignant tumour', 'Disease', (28, 44))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('alterations', 'Var', (87, 98))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('pancreatic cancer', 'Disease', (208, 225))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (233, 255))	('neuroendocrine prostate cancer', 'Disease', (109, 139))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (177, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))
1338	28637487	Somatic NF1 mutations have also been detected in 41-72% of sporadic MPNSTs, showing that NF1 inactivation plays a major role in the development of this tumour type.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('NF1', 'Gene', (8, 11))	('tumour', 'Disease', (152, 158))	('mutations', 'Var', (12, 21))	('MPNSTs', 'Disease', (68, 74))	('detected', 'Reg', (37, 45))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))
1339	28637487	Neurofibromatosis type 1, caused by constitutional inactivating mutations in the tumour suppressor gene NF1, is a neurodegenerative disorder predisposing individuals to both benign and malignant tumours.	('Neurofibromatosis type 1', 'Disease', (0, 24))	('constitutional inactivating mutations', 'Var', (36, 73))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('caused by', 'Reg', (26, 35))	('tumour', 'Disease', (195, 201))	('tumour', 'Disease', (81, 87))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('neurodegenerative disorder', 'Disease', 'MESH:D019636', (114, 140))	('malignant tumours', 'Disease', 'MESH:D009369', (185, 202))	('malignant tumours', 'Disease', (185, 202))	('neurodegenerative disorder', 'Disease', (114, 140))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (114, 140))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('NF1', 'Gene', (104, 107))
1341	28637487	Aberrations in neurofibromin result in the dysregulation of the RAS/MAPK pathway leading to unregulated cell growth and proliferation.	('RAS', 'Chemical', 'MESH:D011883', (64, 67))	('Aberrations', 'Var', (0, 11))	('dysregulation', 'MPA', (43, 56))	('cell growth', 'biological_process', 'GO:0016049', ('104', '115'))	('RAS/MAPK pathway', 'Pathway', (64, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('neurofibromin', 'Gene', (15, 28))	('unregulated', 'MPA', (92, 103))
1343	28637487	Mutations (chromosomal aberrations, nucleotide substitutions and epigenetic aberrations) in a subset of candidate genes are likely to confer a growth advantage resulting in the development of cancer.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (11, 34))	('nucleotide substitutions', 'Var', (36, 60))	('cancer', 'Disease', (192, 198))	('growth advantage', 'CPA', (143, 159))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('epigenetic aberrations', 'Var', (65, 87))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
1349	28637487	One caveat, however, is distinguishing artefactual DNA damage from the bona fide mutations that actually occurred in the tumour, given that it has been reported that mutagenic damage accounts for the majority of the erroneous identification of variants with low to moderate (1 to 5%) frequency in whole (cancer) genome sequencing studies.	('variants', 'Var', (244, 252))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cancer', 'Disease', (304, 310))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))
1350	28637487	Generally, a large number of mutations occur in cancer genomes, such as somatic mutations, CNAs, methylation aberrations and histone modifications.	('methylation aberrations', 'Var', (97, 120))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('CNAs', 'Disease', (91, 95))	('occur', 'Reg', (39, 44))	('histone', 'Protein', (125, 132))
1351	28637487	It is critical to distinguish driver mutations and driver genes (which contribute to the progression of cancer from normal to malignant states) from passenger mutations and passenger genes (which accumulate in cells but do not contribute to cancer development).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('contribute', 'Reg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
1352	28637487	A driver mutation typically confers upon a tumour only a very small growth advantage, which may be as low as a 0.4% increase in the difference between cell birth and death rates.	('mutation', 'Var', (9, 17))	('small growth', 'Phenotype', 'HP:0001510', (62, 74))	('tumour', 'Disease', (43, 49))	('growth advantage', 'CPA', (68, 84))	('death', 'Disease', 'MESH:D003643', (166, 171))	('death', 'Disease', (166, 171))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
1353	28637487	More recently, Bozic and colleagues have shown that the first, and hence most abundant, passenger mutations are influenced both by the mutation rate and by the death-birth ratio of the cancer cells.	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('influenced', 'Reg', (112, 122))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
1355	28637487	This task is made all the more daunting by the possibility that drivers and passengers are not discrete entities but rather lie along a continuum which includes latent driver mutations which 'behave as passengers but coupled with other emerging mutations, drive cancer development and drug resistance'.	('cancer', 'Disease', (262, 268))	('drug resistance', 'biological_process', 'GO:0042493', ('285', '300'))	('drive', 'PosReg', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('drug resistance', 'Phenotype', 'HP:0020174', (285, 300))	("drug resistance'", 'CPA', (285, 301))	('mutations', 'Var', (175, 184))	('drug resistance', 'biological_process', 'GO:0009315', ('285', '300'))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
1358	28637487	Of these, approximately 90% have somatic mutations in cancer; 20% have germline mutations that predispose to cancer; and 10% harbour both somatic and germline mutations.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
1367	28637487	Thus, sporadic tumours with NF1 mutations are mutually exclusive for mutations in MAPK kinase 1 (MAP2K1) or NRAS.	('mutations', 'Var', (69, 78))	('NRAS', 'Gene', (108, 112))	('sporadic tumours', 'Disease', 'MESH:D009369', (6, 22))	('MAP2K1', 'Gene', '5604', (97, 103))	('MAP2K', 'molecular_function', 'GO:0004708', ('97', '102'))	('NRAS', 'Gene', '4893', (108, 112))	('MAP2K1', 'Gene', (97, 103))	('mutations', 'Var', (32, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('sporadic tumours', 'Disease', (6, 22))	('NF1', 'Gene', (28, 31))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
1368	28637487	Strongly activating 'canonical' mutations in oncogenes (for example G12D or G12V mutations in KRAS) can drive cancer formation on their own and are known to be epistatic in relation to other canonical mutations within the same pathway.	('cancer', 'Disease', (110, 116))	('G12V', 'Mutation', 'rs121913529', (76, 80))	('KRAS', 'Gene', (94, 98))	('G12D', 'Var', (68, 72))	('G12V mutations', 'Var', (76, 90))	('G12D', 'Mutation', 'rs121913529', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('KRAS', 'Gene', '3845', (94, 98))	('drive', 'PosReg', (104, 109))	('formation', 'biological_process', 'GO:0009058', ('117', '126'))	("activating 'canonical", 'PosReg', (9, 30))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
1369	28637487	However, whether there are, for example, 'non-canonical' mutations that weakly activate oncogenes or only partially inactivate tumour suppressor activity and yet can drive cancer formation is less clear.	('formation', 'biological_process', 'GO:0009058', ('179', '188'))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('inactivate', 'NegReg', (116, 126))	('activate', 'PosReg', (79, 87))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (57, 66))	('oncogenes', 'Protein', (88, 97))	('drive', 'Reg', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('tumour', 'Disease', (127, 133))
1370	28637487	Examination of genomic data from the Cancer Cell Line Encyclopedia (CCLE) and TCGA has indicated that whilst canonical KRAS mutations do not occur with increased frequency in the context of NF1 mutations, non-canonical KRAS mutations certainly do, suggesting that such pairs of mutations might act together to confer a selective advantage in human tumours.	('tumours', 'Disease', 'MESH:D009369', (348, 355))	('KRAS', 'Gene', '3845', (219, 223))	('Cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumours', 'Disease', (348, 355))	('mutations', 'Var', (194, 203))	('tumour', 'Phenotype', 'HP:0002664', (348, 354))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('KRAS', 'Gene', (119, 123))	('Cancer', 'Disease', (37, 43))	('KRAS', 'Gene', '3845', (119, 123))	('human', 'Species', '9606', (342, 347))	('tumours', 'Phenotype', 'HP:0002664', (348, 355))	('CCLE', 'Chemical', '-', (68, 72))	('KRAS', 'Gene', (219, 223))
1371	28637487	Activation of RAS guanine nucleotide exchange factors (RAS-GEFs) was predicted to have similar effects to neurofibromin loss and that non-canonical KRAS mutations co-occur with RAS-GEF mutations in TCGA and CCLE data.	('KRAS', 'Gene', (148, 152))	('mutations', 'Var', (153, 162))	('RAS-', 'Chemical', 'MESH:D011883', (55, 59))	('TCGA', 'Gene', (198, 202))	('KRAS', 'Gene', '3845', (148, 152))	('neurofibromin', 'MPA', (106, 119))	('RAS', 'Chemical', 'MESH:D011883', (14, 17))	('RAS', 'Chemical', 'MESH:D011883', (149, 152))	('Activation', 'PosReg', (0, 10))	('RAS-', 'Chemical', 'MESH:D011883', (177, 181))	('RAS', 'Chemical', 'MESH:D011883', (55, 58))	('GEF', 'molecular_function', 'GO:0005085', ('181', '184'))	('CCLE', 'Chemical', '-', (207, 211))	('mutations', 'Var', (185, 194))	('loss', 'NegReg', (120, 124))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (18, 36))	('RAS', 'Chemical', 'MESH:D011883', (177, 180))
1372	28637487	Furthermore, increased frequencies of mutations in both NF1 and other RAS pathway activators or effectors have been found which suggests that this principle could apply more broadly to other genes in the RAS network and possibly to other oncogenic signalling pathways.	('signalling', 'biological_process', 'GO:0023052', ('248', '258'))	('RAS', 'Chemical', 'MESH:D011883', (70, 73))	('mutations', 'Var', (38, 47))	('RAS', 'Chemical', 'MESH:D011883', (204, 207))	('NF1', 'Gene', (56, 59))
1373	28637487	Furthermore, on the basis of analyses of somatic co-mutation patterns in the TCGA data sets (cBio Portal for Cancer Genomics), 9.6% of melanomas with NF1 mutations also have mutations in BRAF, NRAS or RAF1.	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('NRAS', 'Gene', (193, 197))	('Cancer', 'Disease', (109, 115))	('melanomas', 'Disease', 'MESH:D008545', (135, 144))	('NF1', 'Gene', (150, 153))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('Cancer', 'Disease', 'MESH:D009369', (109, 115))	('NRAS', 'Gene', '4893', (193, 197))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('RAF1', 'Gene', '5894', (201, 205))	('mutations', 'Var', (154, 163))	('mutations', 'Var', (174, 183))	('RAF1', 'Gene', (201, 205))	('melanomas', 'Disease', (135, 144))	('BRAF', 'Gene', (187, 191))
1374	28637487	But, whilst mutant NF1 is known to cooperate with RASopathy genes (RASA2, PTPN11, SOS1, RAF1 and SPRED1) in melanoma and although NF1 is found to be frequently mutated (25-30%) in melanomas harbouring wild-type BRAF and NRAS, it is curious that melanoma is not a tumour type associated with NF1.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('RASA2', 'Gene', (67, 72))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('NRAS', 'Gene', '4893', (220, 224))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('SOS1', 'Gene', (82, 86))	('melanoma', 'Disease', (245, 253))	('tumour', 'Phenotype', 'HP:0002664', (263, 269))	('SPRED1', 'Gene', '161742', (97, 103))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('tumour', 'Disease', 'MESH:D009369', (263, 269))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('RASA2', 'Gene', '5922', (67, 72))	('melanoma', 'Disease', (180, 188))	('tumour', 'Disease', (263, 269))	('RAF1', 'Gene', '5894', (88, 92))	('NRAS', 'Gene', (220, 224))	('RASopathy', 'Disease', 'None', (50, 59))	('SPRED1', 'Gene', (97, 103))	('PTPN11', 'Gene', (74, 80))	('RAF1', 'Gene', (88, 92))	('RASopathy', 'Disease', (50, 59))	('NF1', 'Gene', (19, 22))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('mutated', 'Var', (160, 167))	('mutant', 'Var', (12, 18))	('NF1', 'Gene', (130, 133))	('SOS1', 'Gene', '6654', (82, 86))	('melanomas', 'Disease', (180, 189))	('PTPN11', 'Gene', '5781', (74, 80))
1375	28637487	The capacity of NF1 mutations to act both cooperatively and exclusively without BRAF and NRAS mutations in melanoma may be mediated through pathways other than the MAPK pathway.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('NF1', 'Gene', (16, 19))	('melanoma', 'Disease', (107, 115))	('NRAS', 'Gene', '4893', (89, 93))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('NRAS', 'Gene', (89, 93))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))	('mutations', 'Var', (20, 29))
1376	28637487	Maertens and colleagues have identified increased activation of the PI3K/AKT/mTOR pathway in BRAF/NF1 double mutants, and a combinatorial MEK marker and mTOR inhibitor treatment has proven effective in many MEK inhibitor-resistant neoplasms.	('double mutants', 'Var', (102, 116))	('neoplasms', 'Phenotype', 'HP:0002664', (231, 240))	('AKT', 'Gene', (73, 76))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('mTOR', 'Gene', (153, 157))	('BRAF/NF1', 'Gene', (93, 101))	('mTOR', 'Gene', '2475', (153, 157))	('activation', 'PosReg', (50, 60))	('mTOR', 'Gene', '2475', (77, 81))	('neoplasms', 'Disease', 'MESH:D009369', (231, 240))	('neoplasms', 'Disease', (231, 240))	('mTOR', 'Gene', (77, 81))	('neoplasm', 'Phenotype', 'HP:0002664', (231, 239))	('AKT', 'Gene', '207', (73, 76))
1378	28637487	Moreover, whilst simultaneous inactivation of Nf1 and expression of K-RasG12D in mouse haematopoietic cells results in AML that was fatal in primary mice within 4 weeks, in ovarian serous carcinomas, cooperation between mutant TP53 and NF1 results in a poor prognosis.	('G12D', 'Mutation', 'rs121913529', (73, 77))	('Nf1', 'Gene', '18015', (46, 49))	('inactivation', 'Var', (30, 42))	('NF1', 'Gene', (236, 239))	('mutant', 'Var', (220, 226))	('ovarian serous carcinomas', 'Disease', (173, 198))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (173, 198))	('mouse', 'Species', '10090', (81, 86))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('TP53', 'Gene', (227, 231))	('mice', 'Species', '10090', (149, 153))	('AML', 'Disease', (119, 122))	('Nf1', 'Gene', (46, 49))	('K-RasG12D', 'Var', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))
1380	28637487	In melanomas harbouring BRAF V600E mutations, a BRAF inhibitor induces remission of the tumour; however, the same drug is ineffective in colorectal cancer cells harbouring identical mutations.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('V600E', 'Mutation', 'rs113488022', (29, 34))	('remission', 'MPA', (71, 80))	('tumour', 'Disease', (88, 94))	('colorectal cancer', 'Disease', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('melanomas', 'Disease', (3, 12))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('V600E', 'Var', (29, 34))	('BRAF', 'Gene', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))
1383	28637487	Why, for example, are NF1 patients not predisposed to lung tumours given that at least 10% of all sporadic lung cancers have NF1 mutations?	('lung tumours', 'Disease', (54, 66))	('NF1', 'Gene', (125, 128))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('mutations', 'Var', (129, 138))	('lung cancers', 'Disease', (107, 119))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('lung tumours', 'Disease', 'MESH:D008175', (54, 66))	('patients', 'Species', '9606', (26, 34))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancers', 'Disease', 'MESH:D008175', (107, 119))	('lung cancers', 'Phenotype', 'HP:0100526', (107, 119))
1384	28637487	The RAS/MAPK pathway, with an important role in cancer biology, is a prime target for anti-cancer agents; however, the presence of an NF1 mutation, resulting in reduced expression of neurofibromin, confers resistance to several therapeutic drugs.	('reduced', 'NegReg', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('RAS', 'Chemical', 'MESH:D011883', (4, 7))	('NF1', 'Gene', (134, 137))	('cancer', 'Disease', (48, 54))	('neurofibromin', 'Protein', (183, 196))	('presence', 'Var', (119, 127))	('mutation', 'Var', (138, 146))	('expression', 'MPA', (169, 179))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('resistance', 'MPA', (206, 216))	('MAPK', 'molecular_function', 'GO:0004707', ('8', '12'))
1385	28637487	Furthermore, NF1-associated drug resistance to RAF and EGFR inhibitors, tamoxifen and retinoic acid, has been observed in melanoma, lung cancers, breast cancers and neuroblastoma, respectively, and melanoma cells with BRAF/NF1 mutations develop resistance to BRAF inhibitors.	('RAF', 'Gene', (219, 222))	('develop', 'Reg', (237, 244))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tamoxifen', 'Chemical', 'MESH:D013629', (72, 81))	('drug resistance', 'MPA', (28, 43))	('observed', 'Reg', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('drug resistance', 'Phenotype', 'HP:0020174', (28, 43))	('melanoma', 'Disease', (198, 206))	('RAF', 'Gene', '22882', (260, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('neuroblastoma', 'Disease', (165, 178))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('breast cancers', 'Disease', (146, 160))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('RAF', 'Gene', '22882', (47, 50))	('neuroblastoma', 'Phenotype', 'HP:0003006', (165, 178))	('drug resistance', 'biological_process', 'GO:0009315', ('28', '43'))	('drug resistance', 'biological_process', 'GO:0042493', ('28', '43'))	('EGFR', 'Gene', (55, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('neuroblastoma', 'Disease', 'MESH:D009447', (165, 178))	('RAF', 'Gene', (260, 263))	('retinoic acid', 'Chemical', 'MESH:D014212', (86, 99))	('lung cancers', 'Disease', 'MESH:D008175', (132, 144))	('RAF', 'Gene', (47, 50))	('mutations', 'Var', (227, 236))	('resistance', 'MPA', (245, 255))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('RAF', 'Gene', '22882', (219, 222))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('lung cancers', 'Disease', (132, 144))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('lung cancers', 'Phenotype', 'HP:0100526', (132, 144))
1386	28637487	It is not clear whether the specific nature of the mutations could have exerted an influence on the sensitivity of the drug, as complete inactivation of NF1 has been noted to confer sensitivity to rapamycin in AML.	('AML', 'Disease', (210, 213))	('sensitivity', 'MPA', (182, 193))	('mutations', 'Var', (51, 60))	('NF1', 'Gene', (153, 156))	('rapamycin', 'Chemical', 'MESH:D020123', (197, 206))	('sensitivity', 'MPA', (100, 111))	('AML', 'Disease', 'MESH:D015470', (210, 213))	('influence', 'Reg', (83, 92))	('inactivation', 'NegReg', (137, 149))
1387	28637487	Large constitutional NF1 deletions, encompassing the NF1 gene and many adjacent genes, occur in 5-10% of NF1 cases and are often associated with a more severe phenotype including learning disabilities and increased susceptibility to MPNSTs.	('associated with', 'Reg', (129, 144))	('NF1', 'Gene', (105, 108))	('MPNSTs', 'Disease', (233, 239))	('deletions', 'Var', (25, 34))	('learning disabilities', 'Disease', 'MESH:D007859', (179, 200))	('learning disabilities', 'Disease', (179, 200))	('NF1', 'Gene', (21, 24))
1388	28637487	Intriguingly, such mutations resulting in heterozygous or homozygous loss of NF1 expression are found to occur more often as sporadic events in AML and ovarian carcinoma, based on cBioPortal data.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (152, 169))	('loss', 'NegReg', (69, 73))	('NF1', 'Gene', (77, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('mutations', 'Var', (19, 28))	('AML and ovarian carcinoma', 'Disease', 'MESH:D015470', (144, 169))	('expression', 'MPA', (81, 91))
1389	28637487	An NF1 microdeletion in combination with an abnormal karyotype is an indicator of poor prognosis in AML; 7.6% of ovarian serous cystadenocarcinomas, 2.8% of lung squamous cell carcinomas, 3.3% of glioblastomas and 1.9% of phaeochromocytomas/paragangliomas harboured deletions.	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (157, 186))	('gliomas', 'Phenotype', 'HP:0009733', (248, 255))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('glioblastomas', 'Phenotype', 'HP:0012174', (196, 209))	('ovarian serous cystadenocarcinomas', 'Disease', (113, 147))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('phaeochromocytomas/paragangliomas', 'Disease', (222, 255))	('deletions', 'Var', (266, 275))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('microdeletion', 'Var', (7, 20))	('lung squamous cell carcinomas', 'Disease', (157, 186))	('glioblastomas', 'Disease', (196, 209))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (157, 185))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (162, 186))	('NF1', 'Gene', (3, 6))	('glioblastomas', 'Disease', 'MESH:D005909', (196, 209))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (222, 255))	('AML', 'Disease', 'MESH:D015470', (100, 103))	('AML', 'Disease', (100, 103))	('ovarian serous cystadenocarcinomas', 'Disease', 'MESH:D018284', (113, 147))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (113, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('paraganglioma', 'Phenotype', 'HP:0002668', (241, 254))	('paragangliomas', 'Phenotype', 'HP:0002668', (241, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('serous cystadenocarcinomas', 'Phenotype', 'HP:0012887', (121, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
1390	28637487	NF1 amplification, and presumably increased neurofibromin expression and hence activity, has been identified in many cancers, including breast (17%), pancreatic (21.5%), uterine endometrial (1.8%) and neuroendocrine prostate cancer (21.5%).	('expression', 'MPA', (58, 68))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (201, 231))	('amplification', 'Var', (4, 17))	('NF1', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('activity', 'MPA', (79, 87))	('uterine endometrial', 'Disease', (170, 189))	('neuroendocrine prostate cancer', 'Disease', (201, 231))	('prostate cancer', 'Phenotype', 'HP:0012125', (216, 231))	('increased', 'PosReg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pancreatic', 'Disease', 'MESH:D010195', (150, 160))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('breast', 'Disease', (136, 142))	('cancers', 'Disease', (117, 124))	('increased neurofibromin', 'Phenotype', 'HP:0001067', (34, 57))	('identified', 'Reg', (98, 108))	('pancreatic', 'Disease', (150, 160))
1391	28637487	The pathological significance of sporadic NF1 point mutations, especially putative missense mutations that have been identified in many sporadic tumours, is often unclear.	('sporadic tumours', 'Disease', 'MESH:D009369', (136, 152))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('missense mutations', 'Var', (83, 101))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('sporadic tumours', 'Disease', (136, 152))	('NF1', 'Gene', (42, 45))	('point mutations', 'Var', (46, 61))
1392	28637487	Constitutional NF1 missense mutations represent about 15% of all NF1 mutations, but their frequency in sporadic tumours ranges widely from 15 to 71%.	('sporadic tumours', 'Disease', (103, 119))	('mutations', 'Var', (69, 78))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('NF1', 'Gene', (15, 18))	('sporadic tumours', 'Disease', 'MESH:D009369', (103, 119))	('NF1', 'Gene', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('missense mutations', 'Var', (19, 37))
1393	28637487	For example, through analysis of missense mutations, the arginine finger loop of the neurofibromin GRD has been found to be crucial for stabilizing the transition state of the GTPase reaction, and many missense mutations in the GRD have been found to exert a significant, pathological effect on Ras activity levels.	('missense mutations', 'Var', (202, 220))	('pathological effect', 'Reg', (272, 291))	('GTP', 'Chemical', 'MESH:D006160', (176, 179))	('GRD', 'Gene', (228, 231))	('Ras activity levels', 'MPA', (295, 314))
1394	28637487	Somatic NF1 mutations are present in tumours associated with NF1 and in a range of sporadic tumours, in different cell types and at various frequencies (Table 1).	('sporadic tumours', 'Disease', (83, 99))	('NF1', 'Gene', (8, 11))	('NF1', 'Disease', (61, 64))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('sporadic tumours', 'Disease', 'MESH:D009369', (83, 99))	('mutations', 'Var', (12, 21))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumours', 'Disease', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))
1396	28637487	Whilst it is unclear whether the biallelic loss of NF1 is common or if only heterozygous mutations of NF1 contribute to tumour progression in sporadic tumours, mouse cells heterozygous for Nf1 mutations show abnormal growth and invasion.	('growth', 'CPA', (217, 223))	('sporadic tumours', 'Disease', (142, 158))	('abnormal growth', 'Phenotype', 'HP:0001507', (208, 223))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('Nf1', 'Gene', (189, 192))	('NF1', 'Gene', (102, 105))	('sporadic tumours', 'Disease', 'MESH:D009369', (142, 158))	('tumour', 'Disease', (120, 126))	('mutations', 'Var', (193, 202))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('Nf1', 'Gene', '18015', (189, 192))	('loss', 'NegReg', (43, 47))	('tumour', 'Disease', (151, 157))	('mouse', 'Species', '10090', (160, 165))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
1397	28637487	Somatic NF1 mutations may be critical drivers in multiple cancers as well as contributing to resistance to therapy.	('NF1', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('contributing', 'Reg', (77, 89))
1398	28637487	The mutational landscape of somatic NF1 mutation should provide new insights into our understanding of the pathophysiology of cancer.	('mutation', 'Var', (40, 48))	('NF1', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
1402	28637487	The identification of somatic NF1 mutations in such a wide spectrum of tumours, including types not associated with NF1, indicates that neurofibromin is likely to play a key role in cancer, far beyond that evident in the tumour predisposition syndrome NF1.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))	('tumour', 'Disease', (221, 227))	('tumour', 'Disease', (71, 77))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('NF1', 'Gene', (30, 33))	('tumours', 'Disease', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', (182, 188))	('mutations', 'Var', (34, 43))	('tumour', 'Disease', 'MESH:D009369', (221, 227))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
1421	27347097	Conventional chemotherapy may eliminate the majority of tumor cells, but it has little impact on rare stem cell-like cells; and remaining CSCs cause tumor recurrence and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('CSCs', 'Var', (138, 142))	('cause', 'Reg', (143, 148))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
1441	27347097	In 0.1 ml DMEM, 3.0x103 or 3.0x104 NSP and SP cells were subcutaneously injected into the dorsal flank of 5-week-old female NOD/SCID mice, or intraperitoneally injected into 5-week-old female NOD/SCID mice (n=5).	('3.0x104', 'Var', (27, 34))	('mice', 'Species', '10090', (133, 137))	('SCID', 'Gene', (128, 132))	('DMEM', 'Chemical', '-', (10, 14))	('3.0x103', 'Var', (16, 23))	('NOD', 'Gene', (124, 127))	('mice', 'Species', '10090', (201, 205))	('NOD', 'Gene', '1822', (192, 195))	('SCID', 'Gene', (196, 200))	('SCID', 'Gene', '19090', (196, 200))	('SP', 'Chemical', '-', (43, 45))	('SP', 'Chemical', '-', (36, 38))	('NOD', 'Gene', '1822', (124, 127))	('SCID', 'Gene', '19090', (128, 132))	('NOD', 'Gene', (192, 195))
1471	27347097	None of the mice formed tumors 70 days following the injection of 3.0x103 NSP cells, and only 1 xenografted tumor was observed in 1 mouse at 54 days subsequent to injection of 3.0x104 NSP cells (Fig.	('3.0x103', 'Var', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SP', 'Chemical', '-', (185, 187))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Disease', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('mouse', 'Species', '10090', (132, 137))	('SP', 'Chemical', '-', (75, 77))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
1474	27347097	At 56 days post subcutaneous injection of 3.0x104 cells, the xenografted tumor size from SP cells was clearly larger than the size of the tumor from NSP cells (Fig.	('3.0x104', 'Var', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('larger', 'PosReg', (110, 116))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('SP', 'Chemical', '-', (150, 152))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('SP', 'Chemical', '-', (89, 91))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
1475	27347097	Similarly, the present study observed blood ascites and clear metastasis in the abdominal cavity of all 5 mice following the intraperitoneal injection of 3.0x103 SP cells for 50 days, but this was not observed in any of the mice following the injection of the same amount of NSP cells for 56 days (Fig.	('mice', 'Species', '10090', (106, 110))	('mice', 'Species', '10090', (224, 228))	('blood ascites', 'Disease', (38, 51))	('SP', 'Chemical', '-', (162, 164))	('blood ascites', 'Disease', 'MESH:D001201', (38, 51))	('SP', 'Chemical', '-', (276, 278))	('3.0x103 SP cells', 'Var', (154, 170))	('ascites', 'Phenotype', 'HP:0001541', (44, 51))
1486	27347097	Furthermore, the SP cell ratio to unsorted cells was significantly elevated following cisplatin treatment, from 0.38 to 10.18% (P=0.007; Fig.	('elevated', 'PosReg', (67, 75))	('SP cell ratio', 'CPA', (17, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('SP', 'Chemical', '-', (17, 19))	('cisplatin', 'Var', (86, 95))
1489	27347097	The results demonstrated that cell viability was 71.41% following cisplatin treatment, while it was reduced to 6.00% following treatment with cisplatin + verapamil (P=0.006; Fig.	('verapamil', 'Chemical', 'MESH:D014700', (154, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('cisplatin', 'Var', (66, 75))	('cell viability', 'CPA', (30, 44))
1527	33654182	High expression of CLPTM1L is associated with poor outcome in ovarian serous adenocarcinoma.	('CLPTM1L', 'Gene', (19, 26))	('High', 'Var', (0, 4))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D000230', (62, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('ovarian serous adenocarcinoma', 'Disease', (62, 91))	('expression', 'Species', '29278', (5, 15))
1543	33654182	We have previously shown that inhibition of CLPTM1L can chemosensitize pancreatic ductal adenocarcinoma to gemcitabine treatment.	('pancreatic ductal adenocarcinoma', 'Disease', (71, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (71, 103))	('inhibition', 'Var', (30, 40))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (107, 118))	('CLPTM1L', 'Gene', (44, 51))
1544	33654182	In the present study, CLPTM1L protein was found to be more abundant in platinum pre-treated ovarian tumor cells, and anti-CLPTM1L treatment was synergistic with carboplatin killing.	('CLPTM1L', 'Gene', (22, 29))	('more', 'PosReg', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ovarian tumor', 'Disease', (92, 105))	('pre', 'molecular_function', 'GO:0003904', ('80', '83'))	('carboplatin', 'Chemical', 'MESH:D016190', (161, 172))	('ovarian tumor', 'Phenotype', 'HP:0100615', (92, 105))	('anti-CLPTM1L', 'Var', (117, 129))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('ovarian tumor', 'Disease', 'MESH:D010051', (92, 105))	('platinum', 'Chemical', 'MESH:D010984', (71, 79))
1546	33654182	Likewise, anti-CLPTM1L treatment restored platinum sensitivity to novel patient-derived parental and cisplatin-conditioned ovarian tumor cell and spheroid cultures, both in vitro and in vivo.	('platinum sensitivity', 'MPA', (42, 62))	('ovarian tumor', 'Disease', 'MESH:D010051', (123, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('anti-CLPTM1L', 'Var', (10, 22))	('patient', 'Species', '9606', (72, 79))	('ovarian tumor', 'Disease', (123, 136))	('ovarian tumor', 'Phenotype', 'HP:0100615', (123, 136))	('restored', 'PosReg', (33, 41))	('platinum', 'Chemical', 'MESH:D010984', (42, 50))
1547	33654182	We present the novel finding that in addition to cell-autonomous effects of CLPTM1L on chemoresistance, CLPTM1L in cell culture supernatants and extracellular vesicle fractions can confer intercellular chemoresistance to bystander ovarian and pancreatic tumor cells.	('intercellular chemoresistance', 'CPA', (188, 217))	('pancreatic tumor', 'Disease', 'MESH:D010190', (243, 259))	('CLPTM1L', 'Var', (104, 111))	('pancreatic tumor', 'Disease', (243, 259))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (243, 259))	('extracellular vesicle', 'cellular_component', 'GO:1903561', ('145', '166'))	('ovarian', 'Disease', 'MESH:D010049', (231, 238))	('ovarian', 'Disease', (231, 238))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
1559	33654182	Kaplan-Meier analysis of the effect of CLPTM1L expression on progression free survival in ovarian cancer patients with TCGA data using KM Plotter showed an association of high CLPTM1L expression with poor outcome with a hazard ratio of 1.57 (log rank p = 6.6 x 10-6) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ovarian cancer', 'Disease', (90, 104))	('patients', 'Species', '9606', (105, 113))	('high', 'Var', (171, 175))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('expression', 'Species', '29278', (184, 194))	('ovarian cancer', 'Disease', 'MESH:D010051', (90, 104))	('expression', 'Species', '29278', (47, 57))	('expression', 'MPA', (184, 194))	('CLPTM1L', 'Gene', (176, 183))
1560	33654182	High CLPTM1L expression was also associated with poor overall survival with a hazard ratio of 1.3 (p = 0.012) (Fig.	('expression', 'Species', '29278', (13, 23))	('High', 'Var', (0, 4))	('CLPTM1L', 'Gene', (5, 12))	('expression', 'MPA', (13, 23))	('overall survival', 'MPA', (54, 70))	('poor', 'NegReg', (49, 53))
1571	33654182	We found that treatment with 102-5 anti-CLPTM1L resulted in a single major band consistent with 62 kDa CLPTM1L, which concurred with results using commercial anti-CLPTM1L and demonstrated upregulation of CLPTM1L accumulation in cisplatin-resistant ovarian tumor cells compared to parental cisplatin-sensitive cells (Fig.	('ovarian tumor', 'Disease', 'MESH:D010051', (248, 261))	('CLPTM1L', 'Gene', (204, 211))	('accumulation', 'PosReg', (212, 224))	('cisplatin', 'Chemical', 'MESH:D002945', (289, 298))	('anti-CLPTM1L', 'Var', (35, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (228, 237))	('upregulation', 'PosReg', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('ovarian tumor', 'Disease', (248, 261))	('ovarian tumor', 'Phenotype', 'HP:0100615', (248, 261))
1578	33654182	Live cell imaging measurement of cell death over a time course of 30 h demonstrated killing by human anti-CLPTM1L (102-5) alone but not by 10 microM carboplatin and potentiation of killing by carboplatin in combination with 102-5 anti-CLPTM1L (Fig.	('human', 'Species', '9606', (95, 100))	('carboplatin', 'Chemical', 'MESH:D016190', (192, 203))	('potentiation', 'PosReg', (165, 177))	('carboplatin', 'Chemical', 'MESH:D016190', (149, 160))	('cell death', 'biological_process', 'GO:0008219', ('33', '43'))	('anti-CLPTM1L', 'Var', (101, 113))
1579	33654182	The combination of 102-5 anti-CLPTM1L and carboplatin resulted in robust killing with a highly significant interaction between anti-CLPTM1L treatment and carboplatin treatment (ANOVA p < 0.02).	('anti-CLPTM1L', 'Var', (25, 37))	('carboplatin', 'Chemical', 'MESH:D016190', (154, 165))	('carboplatin', 'Chemical', 'MESH:D016190', (42, 53))	('anti-CLPTM1L', 'Var', (127, 139))
1581	33654182	Similarly, OVCAR4 human ovarian serous adenocarcinoma cells were sensitized to carboplatin by treatment with 102-5 anti-CLPTM1L (Supplementary Fig.	('CA', 'Gene', '12310', (13, 15))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D000230', (24, 53))	('102-5 anti-CLPTM1L', 'Var', (109, 127))	('sensitized', 'Reg', (65, 75))	('human', 'Species', '9606', (18, 23))	('carboplatin', 'Chemical', 'MESH:D016190', (79, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('ovarian serous adenocarcinoma', 'Disease', (24, 53))
1584	33654182	2c, phosphorylation of Akt at threonine 308 was increased in MCW-OV-SL3-CisR compared to its parental cells (Fig.	('increased', 'PosReg', (48, 57))	('MCW-OV-SL3-CisR', 'Var', (61, 76))	('Akt', 'Gene', '207', (23, 26))	('phosphorylation', 'MPA', (4, 19))	('Akt', 'Gene', (23, 26))	('threonine', 'Chemical', 'MESH:D013912', (30, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))
1587	33654182	Spheroid growth was also inhibited in a dose-dependent manner by 102-5 anti-CLPTM1L in cisplatin-resistant, stem-like cell lines HeyA8-CisR, OVCAR5-CisR (HGSOC), and PeO4 (ovarian cystadenocarcinoma) (Supplementary Fig.	('ovarian cystadenocarcinoma', 'Disease', 'MESH:D003536', (172, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('ovarian cystadenocarcinoma', 'Disease', (172, 198))	('Spheroid growth', 'CPA', (0, 15))	('anti-CLPTM1L', 'Gene', (71, 83))	('HeyA8-CisR', 'Chemical', '-', (129, 139))	('inhibited', 'NegReg', (25, 34))	('ovarian cystadenocarcinoma', 'Phenotype', 'HP:0012887', (172, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('CA', 'Gene', '12310', (143, 145))	('102-5', 'Var', (65, 70))
1588	33654182	Caspase-3 cleavage was induced by both cisplatin treatment and 102-5 anti-CLPTM1L treatment, with signal being stronger in lysates from anti-CLPTM1L-treated MCW-OV-SL3-CisR spheroids compared to cisplatin-treated spheroids (Fig.	('Caspase-3', 'Gene', (0, 9))	('anti-CLPTM1L-treated', 'Var', (136, 156))	('cleavage', 'MPA', (10, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('stronger', 'PosReg', (111, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('Caspase-3', 'Gene', '836', (0, 9))
1597	33654182	Depletion of CLPTM1L and Akt phosphorylation at T308 and cleavage of Caspase-3 upon treatment of A549, NCI-H520, and NCI-H226 lung cancer cell lines with 102-5 anti-CLPTM1L are shown in Supplementary Fig.	('cleavage', 'MPA', (57, 65))	('Caspase-3', 'Gene', (69, 78))	('NCI-H226 lung cancer', 'Disease', 'MESH:D008175', (117, 137))	('CLPTM1L', 'Gene', (13, 20))	('Caspase-3', 'Gene', '836', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('Akt', 'Gene', '207', (25, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('T308', 'Chemical', '-', (48, 52))	('Depletion', 'MPA', (0, 9))	('Akt', 'Gene', (25, 28))	('NCI-H226 lung cancer', 'Disease', (117, 137))	('phosphorylation', 'CPA', (29, 44))	('T308', 'Var', (48, 52))
1600	33654182	Depletion of CLPTM1L and Akt phosphorylation at T308 and cleavage of Caspase-3 upon treatment of Panc1, MiaPaca2, and Capan2 pancreatic cancer cell lines with 102-5 anti-CLPTM1L are shown in Supplementary Fig.	('Panc1', 'CellLine', 'CVCL:0480', (97, 102))	('cleavage', 'MPA', (57, 65))	('Caspase-3', 'Gene', (69, 78))	('Capan2', 'CellLine', 'CVCL:0026', (118, 124))	('MiaPaca2', 'CellLine', 'CVCL:0428', (104, 112))	('CLPTM1L', 'Gene', (13, 20))	('Caspase-3', 'Gene', '836', (69, 78))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('pancreatic cancer', 'Disease', (125, 142))	('Akt', 'Gene', '207', (25, 28))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('T308', 'Chemical', '-', (48, 52))	('Depletion', 'MPA', (0, 9))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))	('Akt', 'Gene', (25, 28))	('phosphorylation', 'CPA', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('T308', 'Var', (48, 52))
1602	33654182	Extracellular vesicle preparations containing exosomes from culture supernatants of OVCAR5-CisR contained CLPTM1L, but that from OVCAR5 cisplatin sensitive cells did not (Fig.	('CLPTM1L', 'Var', (106, 113))	('CA', 'Gene', '12310', (86, 88))	('CA', 'Gene', '12310', (131, 133))	('contained', 'Reg', (96, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('Extracellular vesicle', 'cellular_component', 'GO:1903561', ('0', '21'))
1610	33654182	Investigating multiple tumor types, we found that CLPTM1L was present in the extracellular vesicle fractions culture media from Panc1 pancreatic and cisplatin resistant variants of ovarian tumor cells (Figs.	('tumor', 'Disease', (189, 194))	('Panc1', 'CellLine', 'CVCL:0480', (128, 133))	('ovarian tumor', 'Disease', (181, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('pancreatic', 'Disease', 'MESH:D010195', (134, 144))	('extracellular vesicle', 'cellular_component', 'GO:1903561', ('77', '98'))	('pancreatic', 'Disease', (134, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('ovarian tumor', 'Phenotype', 'HP:0100615', (181, 194))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (23, 28))	('ovarian tumor', 'Disease', 'MESH:D010051', (181, 194))	('variants', 'Var', (169, 177))
1619	33654182	Panc1 cells treated with supernatants from cells overexpressing wild-type CLPTM1L were protected from gemcitabine killing at concentrations up to 40 nM, while those treated with no supernatant or supernatants from vector or CLPTM1L exodomain deletion mutant (CLTPM1L DeltaLoop) exhibited statistically similar dose-dependent gemcitabine killing.	('gemcitabine', 'Chemical', 'MESH:C056507', (102, 113))	('CLTPM1L', 'Gene', (259, 266))	('DeltaLoop', 'Var', (267, 276))	('gemcitabine killing', 'MPA', (102, 121))	('Panc1', 'CellLine', 'CVCL:0480', (0, 5))	('gemcitabine', 'Chemical', 'MESH:C056507', (325, 336))	('CLPTM1L', 'Var', (74, 81))
1623	33654182	Pre-treatment of serum extracellular vesicles with 102-5 anti-CLPTM1L abrogated resistance to carboplatin with significantly increased killing compared to vesicles that were not pre-treated (Fig.	('extracellular', 'cellular_component', 'GO:0005576', ('23', '36'))	('pre', 'molecular_function', 'GO:0003904', ('178', '181'))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('abrogated', 'NegReg', (70, 79))	('increased', 'PosReg', (125, 134))	('anti-CLPTM1L', 'Var', (57, 69))	('carboplatin', 'Chemical', 'MESH:D016190', (94, 105))	('102-5 anti-CLPTM1L', 'Var', (51, 69))	('killing', 'MPA', (135, 142))	('resistance to carboplatin', 'MPA', (80, 105))
1624	33654182	Having demonstrated sensitization of tumor cells to genotoxic chemotherapeutic agents and tumoricidal activity by CLPTM1L inhibition, and with a lack of in vivo evidence in ovarian cancer models, we sought to determine if anti-CLPTM1L mAb treatment could inhibit ovarian carcinoma in relevant murine models, including a cisplatin resistant tumor model.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ovarian cancer', 'Disease', (173, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (320, 329))	('ovarian cancer', 'Phenotype', 'HP:0100615', (173, 187))	('sensitization', 'biological_process', 'GO:0046960', ('20', '33'))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('murine', 'Species', '10090', (293, 299))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (263, 280))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('ovarian carcinoma', 'Disease', (263, 280))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (263, 280))	('ovarian cancer', 'Disease', 'MESH:D010051', (173, 187))	('tumor', 'Disease', (340, 345))	('anti-CLPTM1L', 'Var', (222, 234))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('tumor', 'Disease', (37, 42))	('inhibit', 'NegReg', (255, 262))
1630	33654182	with 10 mg/kg 102-5 anti-CLPTM1L resulted in inhibition of tumor growth over 8 weeks (Fig.	('inhibition', 'NegReg', (45, 55))	('tumor', 'Disease', (59, 64))	('102-5 anti-CLPTM1L', 'Var', (14, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
1633	33654182	With combination treatments of carboplatin following anti-CLPTM1L treatment, tumor load was decreased (0.23-fold) over 35 days compared to mice treated with carboplatin alone, in which tumor load increased slightly by an average of 1.23-fold (T-test p < 0.05) (Fig.	('tumor', 'Disease', (185, 190))	('increased', 'PosReg', (196, 205))	('anti-CLPTM1L', 'Var', (53, 65))	('carboplatin', 'Chemical', 'MESH:D016190', (157, 168))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('carboplatin', 'Chemical', 'MESH:D016190', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('decreased', 'NegReg', (92, 101))	('tumor', 'Disease', (77, 82))
1636	33654182	Tumor growth and volumes, monitored over 24 days post-inoculation, were significantly inhibited by both cisplatin and 102-5 anti-CLPTM1L either as individual monotherapies or as a combination (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('102-5 anti-CLPTM1L', 'Var', (118, 136))	('inhibited', 'NegReg', (86, 95))
1643	33654182	High expression of CLPTM1L and CLPTM1L expression-controlling polymorphisms in tumors are associated with poor prognosis as described here and previously in.	('CLPTM1L', 'Gene', (19, 26))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('polymorphisms', 'Var', (62, 75))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CLPTM1L', 'Gene', (31, 38))	('expression', 'Species', '29278', (39, 49))	('expression', 'Species', '29278', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
1644	33654182	Restriction of CLPTM1L surface expression to stem cell populations and tumor cells presents the potential to target quiescent residual tumor cells and to eliminate inherent or acquired resistance to multiple chemotherapeutic drugs.	('CLPTM1L', 'Gene', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (135, 140))	('expression', 'Species', '29278', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Restriction', 'Var', (0, 11))	('eliminate', 'NegReg', (154, 163))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
1645	33654182	Notably, treating platinum resistant ovarian tumor cell lines with 102-5 anti-CLPTM1L resulted in depletion of cancer stem cell markers and a corresponding sensitization to cisplatin.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ovarian tumor', 'Phenotype', 'HP:0100615', (37, 50))	('platinum resistant ovarian tumor', 'Disease', 'MESH:D010051', (18, 50))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('platinum resistant ovarian tumor', 'Disease', (18, 50))	('depletion of', 'MPA', (98, 110))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('sensitization', 'biological_process', 'GO:0046960', ('156', '169'))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('102-5', 'Var', (67, 72))	('cancer', 'Disease', (111, 117))	('sensitization to cisplatin', 'MPA', (156, 182))	('anti-CLPTM1L', 'Gene', (73, 85))
1646	33654182	Depletion of these markers of stemness and inhibition of tumor spheroid growth suggest that 102-5 anti-CLPTM1L may prevent survival of cancer stem cells or stemness-related programming.	('cancer', 'Disease', (135, 141))	('stemness-related programming', 'CPA', (156, 184))	('prevent', 'NegReg', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Depletion', 'MPA', (0, 9))	('tumor', 'Disease', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('102-5 anti-CLPTM1L', 'Var', (92, 110))
1648	33654182	Here we have demonstrated robust inhibition of tumorigenesis and sensitization of tumors to chemotherapeutic killing using anti-CLPTM1L monoclonal antibodies, which can also be achieved using shRNA depletion.	('anti-CLPTM1L', 'Var', (123, 135))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('inhibition', 'NegReg', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('sensitization', 'biological_process', 'GO:0046960', ('65', '78'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (47, 52))
1652	33654182	This was concurrent with higher Akt phosphorylation, and 102-5 anti-CLPTM1L significantly decreased Akt phosphorylation.	('Akt', 'Gene', (100, 103))	('102-5 anti-CLPTM1L', 'Var', (57, 75))	('Akt', 'Gene', '207', (32, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('Akt', 'Gene', (32, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('decreased', 'NegReg', (90, 99))	('Akt', 'Gene', '207', (100, 103))	('higher', 'PosReg', (25, 31))
1655	33654182	VEGF inhibition has exhibited a modest effect on overall survival.	('VEGF', 'Gene', '7422', (0, 4))	('VEGF', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))
1662	33654182	However, inhibition of CLPTM1L decreased Akt phosphorylation in cells treated with both wild-type CLPTM1L and DeltaLoop CLPTM1L.	('DeltaLoop', 'Var', (110, 119))	('decreased', 'NegReg', (31, 40))	('Akt', 'Gene', '207', (41, 44))	('Akt', 'Gene', (41, 44))	('inhibition', 'Var', (9, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))
1668	33654182	While increased CLPTM1L in the extracellular vesicles fraction of treated patients may be the result of generally increased vesicle shedding by tumor cells, we have demonstrated the concept that extracellular CLPTM1L can transfer chemoresistance.	('increased', 'PosReg', (6, 15))	('tumor', 'Disease', (144, 149))	('vesicle', 'cellular_component', 'GO:0031982', ('124', '131'))	('transfer', 'PosReg', (221, 229))	('vesicle shedding', 'MPA', (124, 140))	('chemoresistance', 'CPA', (230, 245))	('extracellular', 'cellular_component', 'GO:0005576', ('31', '44'))	('extracellular', 'cellular_component', 'GO:0005576', ('195', '208'))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('increased', 'PosReg', (114, 123))	('extracellular CLPTM1L', 'Var', (195, 216))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CLPTM1L', 'Var', (209, 216))	('CLPTM1L', 'Gene', (16, 23))
1688	33654182	Expression constructs for FLAG-tagged wild-type and DeltaLoop CLPTM1L were generated and transfected as described in ref.	('Expression', 'Species', '29278', (0, 10))	('DeltaLoop', 'Var', (52, 61))	('CLPTM1L', 'Gene', (62, 69))
1737	33654182	Mice were treated weekly with intraperitoneal doses of PBS control, cisplatin 2.5 mg/kg, and/or Antibody 102-5 clone 5 mg/kg in 200 microL of PBS at room temperature beginning on day 6 post-inoculation.	('PBS', 'Gene', (55, 58))	('PBS', 'Gene', (142, 145))	('PBS', 'Gene', '1131', (55, 58))	('Antibody 102-5 clone', 'Var', (96, 116))	('PBS', 'Gene', '1131', (142, 145))	('Mice', 'Species', '10090', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
1781	29577163	With further research, non-coding RNAs were demonstrated to participate in a variety of physiologic and pathologic processes and to serve an important function in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('non-coding RNAs', 'Var', (23, 38))	('participate', 'Reg', (60, 71))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
1783	29577163	Furthermore, a number of lines of evidence link the dysregulation of lncRNAs to diverse human diseases, particularly cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('dysregulation', 'Var', (52, 65))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('human', 'Species', '9606', (88, 93))	('cancer', 'Disease', (117, 123))	('lncRNAs', 'Protein', (69, 76))
1808	29577163	The most upregulated lncRNA was TCONS_l2_00000435 (fold change, 81.26) and the most downregulated lncRNA was RP11-356K23.1 (fold change, 1221.26).	('downregulated', 'NegReg', (84, 97))	('upregulated', 'PosReg', (9, 20))	('RP11', 'Gene', (109, 113))	('RP11', 'Gene', '26121', (109, 113))	('TCONS_l2_00000435', 'Var', (32, 49))
1818	29577163	The results demonstrated that FAS-AS1, AK130076, RP11-199F11.2 and AC093818.1 were upregulated and GTSE1-AS1 was downregulated in high-grade ovarian serous cancer tissues compared with healthy fallopian tube tissues (Fig.	('RP11', 'Gene', (49, 53))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (141, 162))	('GTSE1-AS1', 'Gene', (99, 108))	('AK130076', 'Var', (39, 47))	('RP11', 'Gene', '26121', (49, 53))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (141, 162))	('downregulated', 'NegReg', (113, 126))	('FAS-AS1', 'Gene', '100302740', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('FAS-AS1', 'Gene', (30, 37))	('upregulated', 'PosReg', (83, 94))	('ovarian serous cancer', 'Disease', (141, 162))	('AC093818.1', 'Var', (67, 77))	('GTSE1-AS1', 'Gene', '150384;51512;5729', (99, 108))
1830	29577163	Overexpression of UCA1 increases the proliferation, invasion, and metastasis of bladder cancer cells.	('UCA1', 'Gene', (18, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('metastasis of bladder cancer', 'Disease', 'MESH:D009362', (66, 94))	('invasion', 'CPA', (52, 60))	('proliferation', 'CPA', (37, 50))	('Overexpression', 'Var', (0, 14))	('metastasis of bladder cancer', 'Disease', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('increases', 'PosReg', (23, 32))	('UCA1', 'Gene', '652995', (18, 22))
1831	29577163	Hou et al discovered that long intergenic non protein-coding RNA, regulator of reprogramming (LINC-ROR) was upregulated in breast tumor samples, and ectopic overexpression of LINC-ROR increased breast cancer cell migration and invasion.	('LINC-ROR', 'Gene', (175, 183))	('cell migration', 'biological_process', 'GO:0016477', ('208', '222'))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('LINC-ROR', 'Gene', '100885779', (94, 102))	('invasion', 'CPA', (227, 235))	('upregulated', 'PosReg', (108, 119))	('long intergenic non protein-coding RNA, regulator of reprogramming', 'Gene', '100885779', (26, 92))	('LINC-ROR', 'Gene', (94, 102))	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('increased', 'PosReg', (184, 193))	('breast tumor', 'Disease', 'MESH:D001943', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Disease', (194, 207))	('LINC-ROR', 'Gene', '100885779', (175, 183))	('breast tumor', 'Phenotype', 'HP:0100013', (123, 135))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('ectopic overexpression', 'Var', (149, 171))	('breast tumor', 'Disease', (123, 135))
1833	29577163	In addition, dysregulation of lncRNAs, including HOTAIR, metastasis associated lung adenocarcinoma transcript 1, antisense non-coding RNA in the INK4 locus, growth arrest-specific 5, cervical carcinoma expressed PCNA regulatory lncRNA, H19, imprinted maternally expressed transcript (non-protein coding), and lncRNA-activated by TGFbeta, has been demonstrated to exacerbate several human cancers, including small-cell lung cancer, prostate cancer, gastric cancer, colorectal cancer, cervical cancer, liver cancer and pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (440, 446))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('cancer', 'Phenotype', 'HP:0002664', (456, 462))	('dysregulation', 'Var', (13, 26))	('human', 'Species', '9606', (382, 387))	('prostate cancer', 'Disease', 'MESH:D011471', (431, 446))	('gastric cancer', 'Phenotype', 'HP:0012126', (448, 462))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('INK4', 'Gene', (145, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (431, 446))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinoma', 'Disease', (89, 98))	('prostate cancer', 'Disease', (431, 446))	('pancreatic cancer', 'Disease', (517, 534))	('carcinoma', 'Disease', (192, 201))	('HOTAIR', 'Gene', '100124700', (49, 55))	('cervical cancer', 'Disease', 'MESH:D002583', (483, 498))	('colorectal cancer', 'Phenotype', 'HP:0003003', (464, 481))	('cancers', 'Phenotype', 'HP:0002664', (388, 395))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (517, 534))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('PCNA', 'molecular_function', 'GO:0003892', ('212', '216'))	('cervical cancer', 'Disease', (483, 498))	('H19', 'Gene', (236, 239))	('cancers', 'Disease', (388, 395))	('growth arrest', 'Phenotype', 'HP:0001510', (157, 170))	('liver cancer', 'Disease', 'MESH:D006528', (500, 512))	('HOTAIR', 'Gene', (49, 55))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (407, 429))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('small-cell lung cancer', 'Disease', (407, 429))	('TGFbeta', 'Gene', (329, 336))	('gastric cancer', 'Disease', (448, 462))	('PCNA', 'Gene', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (475, 481))	('RNA', 'cellular_component', 'GO:0005562', ('134', '137'))	('H19', 'Gene', '283120', (236, 239))	('TGFbeta', 'Gene', '7040', (329, 336))	('carcinoma', 'Disease', 'MESH:D002277', (89, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (517, 534))	('colorectal cancer', 'Disease', 'MESH:D015179', (464, 481))	('liver cancer', 'Phenotype', 'HP:0002896', (500, 512))	('carcinoma', 'Disease', 'MESH:D002277', (192, 201))	('liver cancer', 'Disease', (500, 512))	('lung adenocarcinoma', 'Disease', (79, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (418, 429))	('gastric cancer', 'Disease', 'MESH:D013274', (448, 462))	('colorectal cancer', 'Disease', (464, 481))	('cancers', 'Disease', 'MESH:D009369', (388, 395))	('PCNA', 'Gene', '5111', (212, 216))	('INK4', 'Gene', '1029', (145, 149))	('growth arrest-specific 5', 'Gene', '60674', (157, 181))	('exacerbate', 'PosReg', (363, 373))	('protein', 'cellular_component', 'GO:0003675', ('288', '295'))	('growth arrest-specific 5', 'Gene', (157, 181))
1846	29577163	The present study revealed that GTSE1, FAS, PTEN, TP53, and PDK1 are the associated mRNAs of GTSE1-AS1, FAS-AS1, AK130076, RP11-199F11.2 and AC093818.1, suggesting that these lncRNAs may serve a role in the development of ovarian cancer.	('PDK1', 'molecular_function', 'GO:0004740', ('60', '64'))	('PTEN', 'Gene', (44, 48))	('RP11', 'Gene', (123, 127))	('GTSE1-AS1', 'Gene', (93, 102))	('GTSE1', 'Gene', (32, 37))	('FAS-AS1', 'Gene', '100302740', (104, 111))	('PDK1', 'Gene', (60, 64))	('FAS-AS1', 'Gene', (104, 111))	('GTSE1', 'Gene', (93, 98))	('PTEN', 'Gene', '5728', (44, 48))	('TP53', 'Gene', (50, 54))	('GTSE1', 'Gene', '51512', (32, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (222, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('GTSE1', 'Gene', '51512', (93, 98))	('RP11', 'Gene', '26121', (123, 127))	('PDK1', 'Gene', '5163', (60, 64))	('AK130076', 'Var', (113, 121))	('ovarian cancer', 'Disease', (222, 236))	('TP53', 'Gene', '7157', (50, 54))	('GTSE1-AS1', 'Gene', '150384;51512;5729', (93, 102))	('AC093818.1', 'Var', (141, 151))	('ovarian cancer', 'Phenotype', 'HP:0100615', (222, 236))
1847	29577163	In particular, the expression of 4 lncRNAs (FAS-AS1, AK130076, RP11-199F11.2 and AC093818.1) was significantly increased in high-grade ovarian serous cancer tissues compared with healthy fallopian tube tissues, while the expression of GTSE1-AS1 was significantly lower.	('RP11', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('expression', 'MPA', (19, 29))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (135, 156))	('increased', 'PosReg', (111, 120))	('AK130076', 'Var', (53, 61))	('RP11', 'Gene', '26121', (63, 67))	('FAS-AS1', 'Gene', '100302740', (44, 51))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (135, 156))	('FAS-AS1', 'Gene', (44, 51))	('GTSE1-AS1', 'Gene', '150384;51512;5729', (235, 244))	('AC093818.1', 'Var', (81, 91))	('ovarian serous cancer', 'Disease', (135, 156))	('GTSE1-AS1', 'Gene', (235, 244))
1896	27213153	(iv) GP2013 in the Treatment of Patients with Previously Untreated, Advanced Stage Follicular Lymphoma.	('Patients', 'Species', '9606', (32, 40))	('Lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('Follicular Lymphoma', 'Disease', (83, 102))	('GP2013', 'Var', (5, 11))	('Follicular Lymphoma', 'Disease', 'MESH:D008224', (83, 102))
1898	27213153	(v) GP2013 in Japanese Patients with CD20 Positive Low Tumor Burden Indolent B-Cell Non-Hodgkin's Lymphoma.	('CD20', 'Gene', (37, 41))	("Non-Hodgkin's Lymphoma", 'Disease', (84, 106))	('GP2013', 'Var', (4, 10))	('Patients', 'Species', '9606', (23, 31))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	("Non-Hodgkin's Lymphoma", 'Phenotype', 'HP:0012539', (84, 106))	("Non-Hodgkin's Lymphoma", 'Disease', 'MESH:D008228', (84, 106))	('Lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('CD20', 'Gene', '54474', (37, 41))	("Hodgkin's Lymphoma", 'Phenotype', 'HP:0012189', (88, 106))
1916	27213153	(vi) Demonstrating the Equivalence of CT-P10 to MabThera with respect to the Pharmacokinetic Profile in Patients with Rheumatoid Arthritis.	('Arthritis', 'Phenotype', 'HP:0001369', (129, 138))	('CT-P10', 'Chemical', 'MESH:C000626854', (38, 44))	('Rheumatoid Arthritis', 'Phenotype', 'HP:0001370', (118, 138))	('Rheumatoid Arthritis', 'Disease', 'MESH:D001172', (118, 138))	('CT-P10', 'Var', (38, 44))	('Rheumatoid Arthritis', 'Disease', (118, 138))	('Patients', 'Species', '9606', (104, 112))
1944	27213153	(ii) GP2013 in the Treatment of Patients with Previously Untreated, Advanced Stage Follicular Lymphoma.	('Patients', 'Species', '9606', (32, 40))	('Lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('Follicular Lymphoma', 'Disease', (83, 102))	('GP2013', 'Var', (5, 11))	('Follicular Lymphoma', 'Disease', 'MESH:D008224', (83, 102))
1999	25061543	Additionally, as the patient had multiple primary cancers (thyroid cancer, breast cancer, and ovarian cancer), a further genetic analysis to detect BRCA1 or 2 mutations might be indicated.	('ovarian cancer', 'Disease', (94, 108))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('thyroid cancer', 'Disease', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (159, 168))	('patient', 'Species', '9606', (21, 28))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('thyroid cancer', 'Disease', 'MESH:D013964', (59, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('thyroid cancer', 'Phenotype', 'HP:0002890', (59, 73))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (75, 88))	('BRCA1', 'Gene', '672', (148, 153))	('BRCA1', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
2018	24348821	Deficiency or inactivation of the PI3K/Akt signaling pathway-associated regulatory genes, mutation or amplification of the PI3K gene and activation of receptors or junction molecules of its downstream signaling pathway have been identified in multiple tumor cell lines.	('PI3K gene', 'Gene', (123, 132))	('inactivation', 'NegReg', (14, 26))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('Akt signaling', 'biological_process', 'GO:0043491', ('39', '52'))	('amplification', 'Var', (102, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('tumor', 'Disease', (252, 257))	('Deficiency', 'Disease', 'MESH:D007153', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('signaling pathway', 'biological_process', 'GO:0007165', ('43', '60'))	('activation', 'PosReg', (137, 147))	('signaling pathway', 'biological_process', 'GO:0007165', ('201', '218'))	('Deficiency', 'Disease', (0, 10))	('mutation', 'Var', (90, 98))	('PI3K/Akt signaling pathway-associated', 'Pathway', (34, 71))
2050	24348821	Phosphorylation of Akt at Ser473 and Thr308 is essential for the activation of p-Akt.	('p-Akt', 'Pathway', (79, 84))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('Thr308', 'Var', (37, 43))	('Ser473', 'Var', (26, 32))	('Ser473', 'Chemical', '-', (26, 32))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Thr308', 'Chemical', '-', (37, 43))	('activation', 'PosReg', (65, 75))
2059	24348821	Philp et al found that the p85 subunit of PI3K may be a new ovarian carcinoma oncogene and that mutations in PI3KCA may play critical roles in the development of ovarian carcinoma.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (162, 179))	('ovarian carcinoma', 'Disease', (162, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (60, 77))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (60, 77))	('PI3KCA', 'Gene', (109, 115))	('ovarian carcinoma', 'Disease', (60, 77))	('roles', 'Reg', (134, 139))	('play', 'Reg', (120, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('PI3K', 'Gene', (42, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (162, 179))	('mutations', 'Var', (96, 105))
2061	24348821	In addition, western blot analyses revealed that positive Akt expression in all investigated ovarian carcinoma cell lines and gonadal hormones increased the invasion and metastasis of epithelial ovarian carcinoma cells via activation of the PI3K/Akt signaling pathway, which is consistent with the results of the current study.	('increased', 'PosReg', (143, 152))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (93, 110))	('PI3K/Akt signaling pathway', 'Pathway', (241, 267))	('ovarian carcinoma', 'Disease', (93, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('metastasis of epithelial ovarian carcinoma', 'Disease', 'MESH:D009362', (170, 212))	('Akt signaling', 'biological_process', 'GO:0043491', ('246', '259'))	('metastasis of epithelial ovarian carcinoma', 'Disease', (170, 212))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (195, 212))	('PI3K', 'molecular_function', 'GO:0016303', ('241', '245'))	('positive', 'Var', (49, 57))	('signaling pathway', 'biological_process', 'GO:0007165', ('250', '267'))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (93, 110))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (195, 212))	('Akt', 'Gene', (58, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))
2073	24348821	In the present study, the expression levels of p-Akt and cyclin D1 were analyzed in OSC samples and the prevalence of p-Akt expression was found to positively correlate with that of cyclin D1, indicating an association between the PI3K/Akt signaling pathway and OSC proliferation and apoptosis.	('cyclin D1', 'Gene', (182, 191))	('OSC', 'molecular_function', 'GO:0000250', ('84', '87'))	('apoptosis', 'CPA', (284, 293))	('p-Akt', 'Var', (118, 123))	('Akt signaling', 'biological_process', 'GO:0043491', ('236', '249'))	('cyclin', 'molecular_function', 'GO:0016538', ('57', '63'))	('cyclin D1', 'Gene', '595', (57, 66))	('OSC', 'Disease', (262, 265))	('signaling pathway', 'biological_process', 'GO:0007165', ('240', '257'))	('apoptosis', 'biological_process', 'GO:0006915', ('284', '293'))	('OSC', 'molecular_function', 'GO:0000250', ('262', '265'))	('cyclin D1', 'Gene', (57, 66))	('association', 'Interaction', (207, 218))	('cyclin', 'molecular_function', 'GO:0016538', ('182', '188'))	('cyclin D1', 'Gene', '595', (182, 191))	('apoptosis', 'biological_process', 'GO:0097194', ('284', '293'))	('PI3K', 'molecular_function', 'GO:0016303', ('231', '235'))
2078	24348821	p-Akt binds specifically to the p53 negative regulatory protein, MDM2, at Ser166 and Ser186 and relocates MDM2 to the nuclei.	('Ser186', 'Chemical', '-', (85, 91))	('Ser166', 'Chemical', '-', (74, 80))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('MDM2', 'Gene', '4193', (106, 110))	('p-Akt', 'Gene', (0, 5))	('MDM2', 'Gene', (106, 110))	('p53', 'Gene', (32, 35))	('Ser186', 'Var', (85, 91))	('p53', 'Gene', '7157', (32, 35))	('Ser166', 'Var', (74, 80))	('MDM2', 'Gene', '4193', (65, 69))	('MDM2', 'Gene', (65, 69))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('relocates', 'PosReg', (96, 105))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('binds', 'Interaction', (6, 11))
2082	24348821	In addition, p-Akt enhances beta-catenin stability, thereby improving the transcription efficiency of the LEF transcription factor, which results in the improved transcription and expression of cyclin D1.	('cyclin', 'molecular_function', 'GO:0016538', ('194', '200'))	('beta-catenin', 'Gene', (28, 40))	('cyclin D1', 'Gene', '595', (194, 203))	('beta-catenin', 'Gene', '1499', (28, 40))	('stability', 'MPA', (41, 50))	('enhances', 'PosReg', (19, 27))	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('expression', 'MPA', (180, 190))	('LEF transcription factor', 'Gene', (106, 130))	('cyclin D1', 'Gene', (194, 203))	('improving', 'PosReg', (60, 69))	('transcription', 'MPA', (162, 175))	('p-Akt', 'Var', (13, 18))	('improved', 'PosReg', (153, 161))	('transcription efficiency', 'MPA', (74, 98))	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('transcription factor', 'molecular_function', 'GO:0000981', ('110', '130'))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))
2135	19426511	The corresponding FFPE samples resulted in noticeably lower specific activities ranging from 1.6 to 7.6 pmol Cy5/mug cRNA.	('Cy5/mug', 'Var', (109, 116))	('Cy5', 'Chemical', 'MESH:C085321', (109, 112))	('specific activities', 'MPA', (60, 79))	('to 7', 'Species', '1214577', (97, 101))	('mug', 'molecular_function', 'GO:0043739', ('113', '116'))	('lower', 'NegReg', (54, 59))
2136	19426511	FFPE sample 390 had the lowest dye incorporation compared to all other samples: 1.6 and 2.4 pmol Cy5/mug cRNA for Agencourt and Ambion, respectively.	('Cy5', 'Chemical', 'MESH:C085321', (97, 100))	('mug', 'molecular_function', 'GO:0043739', ('101', '104'))	('lowest', 'NegReg', (24, 30))	('dye incorporation', 'MPA', (31, 48))	('Cy5/mug', 'Var', (97, 104))
2234	15083189	Antibodies against MCMs such as Mcm-2 or Mcm-5 have been shown to be of value in identifying malignant or premalignant lesions in a range of specimens (Williams et al, 1998; Freeman et al, 1999; Meng et al, 2001; Wharton et al, 2001; Davies et al, 2002; Going et al, 2002; Hunt et al, 2002).	('Mcm-2', 'Gene', '4171', (32, 37))	('Antibodies', 'Var', (0, 10))	('Mcm-5', 'Gene', (41, 46))	('premalignant lesions', 'Disease', (106, 126))	('Mcm-2', 'Gene', (32, 37))	('MCM', 'Gene', '4176;4171;4172;4173;4174;4175;4176', (19, 22))	('Mcm-5', 'Gene', '4174', (41, 46))	('premalignant lesions', 'Disease', 'MESH:D051437', (106, 126))	('MCM', 'Gene', (19, 22))	('malignant', 'Disease', (93, 102))
2316	15083189	There is evidence, however, to suggest that each of these tumour entities may arise de novo and these studies are based largely on the patterns of mutations in TP53 and K-RAS, each of which can show considerable heterogeneity (Teneriello et al, 1993; Herbst, 1994; Miki et al, 1994; Ortiz et al, 2001).	('tumour entities', 'Disease', (58, 73))	('mutations', 'Var', (147, 156))	('tumour entities', 'Disease', 'MESH:D009369', (58, 73))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('TP53', 'Gene', '7157', (160, 164))	('K-RAS', 'Gene', '3845', (169, 174))	('Miki', 'Gene', (265, 269))	('TP53', 'Gene', (160, 164))	('K-RAS', 'Gene', (169, 174))	('Miki', 'Gene', '253012', (265, 269))
2352	28991261	Notably, survival analysis using TCGA data from 541 OC tissues revealed that high ESRP1 expression was significantly associated with shorter 5-year survival of patients.	('shorter', 'NegReg', (133, 140))	('patients', 'Species', '9606', (160, 168))	('high', 'Var', (77, 81))	('OC', 'Phenotype', 'HP:0100615', (52, 54))	('5-year survival', 'CPA', (141, 156))	('expression', 'MPA', (88, 98))	('ESRP1', 'Gene', (82, 87))
2353	28991261	Ectopic ESRP1 expression in mesenchymal OC cells promoted cell proliferation but suppressed cell migration.	('cell migration', 'biological_process', 'GO:0016477', ('92', '106'))	('suppressed', 'NegReg', (81, 91))	('rat', 'Species', '10116', (70, 73))	('OC', 'Phenotype', 'HP:0100615', (40, 42))	('cell proliferation', 'CPA', (58, 76))	('Ectopic', 'Var', (0, 7))	('promoted', 'PosReg', (49, 57))	('cell migration', 'CPA', (92, 106))	('ESRP1', 'Gene', (8, 13))	('rat', 'Species', '10116', (100, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))
2354	28991261	Furthermore, we found that ESRP1 drives a switch from mesenchymal to epithelial phenotype characterized by reduced cell migration in association with induction of epithelial cell-specific variant of CD44 and ENAH.	('cell migration', 'biological_process', 'GO:0016477', ('115', '129'))	('reduced', 'NegReg', (107, 114))	('cell migration', 'CPA', (115, 129))	('ESRP1', 'Gene', (27, 32))	('rat', 'Species', '10116', (123, 126))	('variant', 'Var', (188, 195))	('CD44', 'Gene', (199, 203))
2368	28991261	Survival analysis using The Cancer Genome Atlas (TCGA) RNA-sequencing data revealed a significant association between high ESRP1 gene expression and longer patient survival in clear-cell renal cell carcinoma and breast cancer.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('RNA', 'cellular_component', 'GO:0005562', ('55', '58'))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('breast cancer', 'Disease', (212, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (176, 207))	('high', 'Var', (118, 122))	('expression', 'MPA', (134, 144))	('gene expression', 'biological_process', 'GO:0010467', ('129', '144'))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (28, 47))	('patient', 'Species', '9606', (156, 163))	('clear-cell renal cell carcinoma', 'Disease', (176, 207))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('ESRP1', 'Gene', (123, 128))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Cancer Genome Atlas', 'Disease', (28, 47))	('longer', 'PosReg', (149, 155))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (176, 207))
2370	28991261	ESRP1 promotes lung metastasis by regulating the alternative splicing of CD44 mRNA, and high ESRP1 gene expression correlates with significantly shorter OS in breast cancer patients.	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('high', 'Var', (88, 92))	('ESRP1', 'Gene', (0, 5))	('gene expression', 'biological_process', 'GO:0010467', ('99', '114'))	('patients', 'Species', '9606', (173, 181))	('regulating', 'Reg', (34, 44))	('lung metastasis', 'CPA', (15, 30))	('promotes', 'PosReg', (6, 14))	('ESRP1', 'Gene', (93, 98))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('expression', 'MPA', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CD44', 'Protein', (73, 77))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('alternative splicing', 'MPA', (49, 69))
2373	28991261	demonstrated that ESRP1 overexpression promotes colorectal cancer progression by stimulating growth of cancer cell.	('stimulating', 'PosReg', (81, 92))	('promotes', 'PosReg', (39, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ESRP1', 'Gene', (18, 23))	('colorectal cancer', 'Disease', (48, 65))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rat', 'Species', '10116', (7, 10))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('overexpression', 'Var', (24, 38))
2389	28991261	Copy number alteration data revealed ESRP1 gene amplification (4%, 21/557) and ESRP2 deletion (0.9%, 5/557) in 557 OC tissues (Figure 2a, top).	('ESRP2', 'Gene', '80004', (79, 84))	('rat', 'Species', '10116', (16, 19))	('ESRP2', 'Gene', (79, 84))	('amplification', 'PosReg', (48, 61))	('deletion', 'Var', (85, 93))	('ESRP1', 'Gene', (37, 42))	('OC', 'Phenotype', 'HP:0100615', (115, 117))
2390	28991261	Combined analysis of copy number alteration and gene expression data revealed that ESRP1 mRNA level is significantly higher in ESRP1-amplified OC tissues than in non ESRP1-amplified OC tissues (P<0.001), whereas ESRP2 deletion is significantly associated with lower ESRP2 gene expression (Figure 2a, bottom).	('ESRP2', 'Gene', '80004', (266, 271))	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('ESRP1-amplified', 'Gene', (127, 142))	('ESRP2', 'Gene', '80004', (212, 217))	('ESRP2', 'Gene', (266, 271))	('ESRP2', 'Gene', (212, 217))	('rat', 'Species', '10116', (37, 40))	('ESRP1', 'Gene', (83, 88))	('deletion', 'Var', (218, 226))	('OC', 'Phenotype', 'HP:0100615', (143, 145))	('OC', 'Phenotype', 'HP:0100615', (182, 184))	('gene expression', 'biological_process', 'GO:0010467', ('272', '287'))	('higher', 'PosReg', (117, 123))	('mRNA level', 'MPA', (89, 99))	('lower', 'NegReg', (260, 265))
2399	28991261	Bisulfite sequencing of a total of 15 CpG sites across 421 bp within CpG islands of the ESRP1 promoter region revealed DNA hypermethylation in ESRP1-low IOSE cells and OC cells, but a low level of DNA methylation in ESRP1-high OC cells (Figures 3b and c).	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('119', '139'))	('OC', 'Phenotype', 'HP:0100615', (168, 170))	('OC', 'Phenotype', 'HP:0100615', (227, 229))	('hypermethylation', 'Var', (123, 139))	('ESRP1', 'Gene', (88, 93))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('DNA methylation', 'biological_process', 'GO:0006306', ('197', '212'))
2403	28991261	Taken together, these findings demonstrate that DNA hypomethylation correlates with both high ESRP1 and ESRP2 expression in OC cells, but is significantly associated with high ESRP2 mRNA level, but not ESRP1 mRNA level, in OC FFPE tissues.	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('48', '67'))	('associated', 'Reg', (155, 165))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('OC', 'Phenotype', 'HP:0100615', (223, 225))	('ESRP2', 'Gene', '80004', (176, 181))	('ESRP2', 'Gene', '80004', (104, 109))	('ESRP1', 'Gene', (94, 99))	('expression', 'MPA', (110, 120))	('hypomethylation', 'Var', (52, 67))	('high', 'PosReg', (89, 93))	('ESRP2', 'Gene', (176, 181))	('ESRP2', 'Gene', (104, 109))	('OC', 'Phenotype', 'HP:0100615', (124, 126))	('rat', 'Species', '10116', (38, 41))
2410	28991261	Subgroup analysis according to pathologic stage revealed that high ESRP1 expression was significantly associated with shorter 5-year PFS (P=0.007) and OS (P=0.039) in patients with stage III OC (Figures 5c and d).	('patients', 'Species', '9606', (167, 175))	('expression', 'MPA', (73, 83))	('shorter', 'NegReg', (118, 125))	('high', 'Var', (62, 66))	('ESRP1', 'Gene', (67, 72))	('OC', 'Phenotype', 'HP:0100615', (191, 193))
2418	28991261	ESRP1 knockdown in OVCAR3 or Caov3 cells significantly inhibited cell proliferation (Figure 6e).	('ESRP1', 'Gene', (0, 5))	('rat', 'Species', '10116', (77, 80))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('cell proliferation', 'CPA', (65, 83))	('knockdown', 'Var', (6, 15))	('inhibited', 'NegReg', (55, 64))
2422	28991261	Conversely, ESRP1 knockdown in OVCAR3 cells significantly promoted cell migration (P=0.003; Figure 6g).	('knockdown', 'Var', (18, 27))	('rat', 'Species', '10116', (75, 78))	('promoted', 'PosReg', (58, 66))	('cell migration', 'CPA', (67, 81))	('cell migration', 'biological_process', 'GO:0016477', ('67', '81'))	('ESRP1', 'Gene', (12, 17))
2423	28991261	Cell migration was not affected by ESRP1 knockdown in Caov3 cells (Figure 6g).	('rat', 'Species', '10116', (8, 11))	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('Cell migration', 'CPA', (0, 14))	('ESRP1', 'Gene', (35, 40))	('knockdown', 'Var', (41, 50))
2431	28991261	Conversely, CDH1 expression was downregulated in ESRP1-knockdown OVCAR3 and Caov3 cells (Figure 7c).	('downregulated', 'NegReg', (32, 45))	('ESRP1-knockdown', 'Gene', (49, 64))	('expression', 'MPA', (17, 27))	('CDH1', 'Gene', (12, 16))	('CDH1', 'Gene', '999', (12, 16))	('ESRP1-knockdown', 'Var', (49, 64))
2433	28991261	ESRP1 knockdown in OVCAR3 or Caov3 cells caused no change in the VIM mRNA level.	('knockdown', 'Var', (6, 15))	('ESRP1', 'Gene', (0, 5))	('VIM', 'Gene', (65, 68))	('VIM', 'Gene', '7431', (65, 68))
2451	28991261	Conversely, our TCGA data analysis revealed that high ESRP1 expression is significantly associated with shorter 5-year OS and PFS of patients with OC.	('expression', 'MPA', (60, 70))	('shorter', 'NegReg', (104, 111))	('PFS', 'CPA', (126, 129))	('patients', 'Species', '9606', (133, 141))	('OC', 'Phenotype', 'HP:0100615', (147, 149))	('high', 'Var', (49, 53))	('ESRP1', 'Gene', (54, 59))
2452	28991261	Moreover, ectopic ESRP1 expression in OC cells promoted cell proliferation.	('promoted', 'PosReg', (47, 55))	('ESRP1', 'Gene', (18, 23))	('OC', 'Phenotype', 'HP:0100615', (38, 40))	('rat', 'Species', '10116', (68, 71))	('cell proliferation', 'CPA', (56, 74))	('ectopic', 'Var', (10, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))
2463	28991261	This study also demonstrated that ectopic ESRP1 expression regulates alternative splicing of CD44 and ENAH in OC cells.	('ESRP1', 'Gene', (42, 47))	('rat', 'Species', '10116', (23, 26))	('regulates', 'Reg', (59, 68))	('ENAH', 'MPA', (102, 106))	('ectopic', 'Var', (34, 41))	('OC', 'Phenotype', 'HP:0100615', (110, 112))	('CD44', 'Protein', (93, 97))	('splicing', 'biological_process', 'GO:0045292', ('81', '89'))	('alternative splicing', 'MPA', (69, 89))
2465	28991261	Importantly, levels of ENAH11a isoforms are positively correlated with a high proliferation index and E-cadherin expression in human primary breast tumor tissues, in agreement with our data showing that ectopic ESRP1 expression upregulates both CDH1 and ENAH11a expression.	('cadherin', 'molecular_function', 'GO:0008014', ('104', '112'))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('upregulates', 'PosReg', (228, 239))	('ectopic', 'Var', (203, 210))	('human', 'Species', '9606', (127, 132))	('breast tumor', 'Disease', 'MESH:D001943', (141, 153))	('ENAH11a', 'Gene', (254, 261))	('expression', 'MPA', (262, 272))	('rat', 'Species', '10116', (85, 88))	('CDH1', 'Gene', (245, 249))	('E-cadherin', 'Gene', (102, 112))	('breast tumor', 'Disease', (141, 153))	('E-cadherin', 'Gene', '999', (102, 112))	('CDH1', 'Gene', '999', (245, 249))	('high proliferation index', 'CPA', (73, 97))	('ESRP1', 'Gene', (211, 216))	('breast tumor', 'Phenotype', 'HP:0100013', (141, 153))
2474	28991261	CD44v promotes metastasis formation in rat pancreatic cancer cells, whereas CD44s suppresses lung colonization of mouse metastatic cancer cells.	('cancer', 'Disease', (131, 137))	('CD44s', 'Var', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('promotes', 'PosReg', (6, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('suppresses', 'NegReg', (82, 92))	('CD44v', 'Var', (0, 5))	('cancer', 'Disease', (54, 60))	('mouse', 'Species', '10090', (114, 119))	('rat', 'Species', '10116', (39, 42))	('formation', 'biological_process', 'GO:0009058', ('26', '35'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('metastasis formation', 'CPA', (15, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))
2475	28991261	Notably, CD44v expression including CD44v6 or soluble cleaved CD44v8-10 was associated with poor prognosis in patients with advanced epithelial OC and correlated with distant metastasis or recurrence in OC.	('CD44v6', 'Var', (36, 42))	('soluble', 'cellular_component', 'GO:0005625', ('46', '53'))	('distant metastasis', 'CPA', (167, 185))	('correlated with', 'Reg', (151, 166))	('CD44v expression', 'Var', (9, 25))	('OC', 'Phenotype', 'HP:0100615', (203, 205))	('OC', 'Phenotype', 'HP:0100615', (144, 146))	('advanced epithelial OC', 'Disease', (124, 146))	('patients', 'Species', '9606', (110, 118))	('CD44v8-10', 'Gene', (62, 71))
2478	28991261	In summary, this study demonstrates that ESRP1 and ESRP2 are overexpressed in OC tissues, and that DNA hypomethylation correlates with high expression of these genes in OC cells.	('OC', 'Phenotype', 'HP:0100615', (169, 171))	('expression', 'MPA', (140, 150))	('OC', 'Phenotype', 'HP:0100615', (78, 80))	('ESRP1', 'Gene', (41, 46))	('rat', 'Species', '10116', (30, 33))	('hypomethylation', 'Var', (103, 118))	('ESRP2', 'Gene', '80004', (51, 56))	('ESRP2', 'Gene', (51, 56))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('99', '118'))	('overexpressed', 'PosReg', (61, 74))
2479	28991261	Moreover, TCGA data analysis revealed that high ESRP1 expression is significantly associated with poor patient outcome in OC.	('expression', 'MPA', (54, 64))	('OC', 'Phenotype', 'HP:0100615', (122, 124))	('high', 'Var', (43, 47))	('ESRP1', 'Gene', (48, 53))	('patient', 'Species', '9606', (103, 110))
2483	28991261	These observations suggest that an epigenetic mechanism is involved in ESRP1 and ESRP2 overexpression, and that ESRP1 has a cancer-promoting role in OC.	('epigenetic', 'Var', (35, 45))	('cancer', 'Disease', (124, 130))	('ESRP2', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('involved', 'Reg', (59, 67))	('overexpression', 'PosReg', (87, 101))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ESRP1', 'Gene', (112, 117))	('ESRP2', 'Gene', '80004', (81, 86))	('ESRP1', 'Gene', (71, 76))	('OC', 'Phenotype', 'HP:0100615', (149, 151))
2522	24174471	Genetic disruption of PKCiota inhibits the proliferation, clonal expansion, anchorage-independent growth and enhanced tumorigenic properties of ovarian TICs.	('anchorage-independent growth', 'CPA', (76, 104))	('ovarian TICs', 'Disease', 'MESH:D020323', (144, 156))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Genetic disruption', 'Var', (0, 18))	('PKCiota', 'Gene', (22, 29))	('TIC', 'Phenotype', 'HP:0100033', (152, 155))	('tumor', 'Disease', (118, 123))	('TICs', 'Phenotype', 'HP:0100033', (152, 156))	('clonal expansion', 'CPA', (58, 74))	('enhanced', 'PosReg', (109, 117))	('ovarian TICs', 'Disease', (144, 156))	('inhibits', 'NegReg', (30, 38))
2535	24174471	In these tumor types, PKCiota gene amplification drives PKCiota expression which in turn is associated with poor prognosis.	('amplification', 'Var', (35, 48))	('PKCiota', 'Gene', (56, 63))	('expression', 'MPA', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('drives', 'PosReg', (49, 55))	('tumor', 'Disease', (9, 14))	('PKCiota gene', 'Gene', (22, 34))
2536	24174471	PKCiota confers resistance to chemotherapy-induced apoptosis of human leukemia cells, and inhibition of PKCiota expression or activity sensitizes chronic myelogenous leukemia cells to chemotherapeutic agent-induced apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('inhibition', 'Var', (90, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('215', '224'))	('sensitizes', 'Reg', (135, 145))	('apoptosis', 'biological_process', 'GO:0006915', ('215', '224'))	('leukemia', 'Disease', 'MESH:D007938', (166, 174))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('leukemia', 'Disease', (166, 174))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (154, 174))	('activity', 'MPA', (126, 134))	('human', 'Species', '9606', (64, 69))	('PKCiota', 'Gene', (104, 111))	('leukemia', 'Disease', (70, 78))	('myelogenous leukemia', 'Disease', (154, 174))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (146, 174))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (154, 174))
2537	24174471	Furthermore, over-expression of kinase-deficient PKCiota or knockdown of PKCiota expression blocked anchorage-independent growth and invasion of human non-small cell lung cancer (NSCLC) cells and human pancreatic ductal adenocarcinoma (PDAC) cells, showing that PKCiota is also required for maintenance of the transformed phenotype of cancer cells.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (151, 177))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (335, 341))	('human', 'Species', '9606', (145, 150))	('pancreatic ductal adenocarcinoma', 'Disease', (202, 234))	('anchorage-independent growth', 'CPA', (100, 128))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('blocked', 'NegReg', (92, 99))	('PDAC', 'Phenotype', 'HP:0006725', (236, 240))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (202, 234))	('knockdown', 'Var', (60, 69))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('NSCLC', 'Disease', (179, 184))	('PKCiota', 'Gene', (49, 56))	('PKCiota', 'Gene', (73, 80))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Disease', (151, 177))	('invasion', 'CPA', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('human', 'Species', '9606', (196, 201))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (202, 234))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (155, 177))	('over-expression', 'PosReg', (13, 28))
2548	24174471	In the present study, we demonstrate for the first time that PKCiota plays a pivotal role in promoting the oncogenic behavior of ovarian TICs including clonal expansion, enhanced transformed growth and tumor initiation in vivo.	('TICs', 'Phenotype', 'HP:0100033', (137, 141))	('TIC', 'Phenotype', 'HP:0100033', (137, 140))	('tumor initiation', 'Disease', (202, 218))	('promoting', 'PosReg', (93, 102))	('oncogenic behavior of ovarian TICs', 'Disease', (107, 141))	('oncogenic behavior of ovarian TICs', 'Disease', 'MESH:D013981', (107, 141))	('enhanced', 'PosReg', (170, 178))	('transformed growth', 'CPA', (179, 197))	('clonal expansion', 'Var', (152, 168))	('tumor initiation', 'Disease', 'MESH:D009369', (202, 218))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
2556	24174471	Oncospheres were enriched from SKOV3, ES2 and ID8 ovarian cancer cell lines by culturing adherent cells (50,000 cells/ml) in ultra-low attachment culture flasks (Sigma-Aldrich, St. Louis, MO) with DMEM-F12 medium containing 50 mug insulin (Sigma-Aldrich), 0.4% albumin bovine fraction V (Sigma-Aldrich), N-2 plus media supplement (Life technologies), B-27 supplement (Life technologies), 20 mug/ml EGF (PeproTech, Rocky Hill, NJ), and 20 mug/ml FGF (PeproTech) for 4 weeks.	('mug', 'molecular_function', 'GO:0043739', ('438', '441'))	('ID8 ovarian cancer', 'Disease', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('insulin', 'Gene', (231, 238))	('ID8 ovarian cancer', 'Disease', 'MESH:D010051', (46, 64))	('insulin', 'molecular_function', 'GO:0016088', ('231', '238'))	('bovine', 'Species', '9913', (269, 275))	('insulin', 'Gene', '280829', (231, 238))	('mug', 'molecular_function', 'GO:0043739', ('391', '394'))	('B-27', 'Var', (351, 355))	('mug', 'molecular_function', 'GO:0043739', ('227', '230'))	('DMEM', 'Chemical', '-', (197, 201))	('SKOV3', 'CellLine', 'CVCL:0532', (31, 36))	('EGF', 'molecular_function', 'GO:0005154', ('398', '401'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
2587	24174471	In contrast to oncosphere cells, 1,000 parental ES2 cells failed to form tumors, demonstrating the enhanced tumorigenic, tumor-initiating properties of ES2 oncosphere cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('enhanced', 'PosReg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('ES2', 'Var', (152, 155))	('tumor', 'Disease', (73, 78))	('tumors', 'Disease', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
2597	24174471	PKCiota KD significantly inhibits soft agar colony formation in both SKOV3 (left panel) and ES2 (right panel) TICs and parental cells when compared to NT KD cells.	('ES2', 'Gene', (92, 95))	('TIC', 'Disease', (110, 113))	('agar', 'Chemical', 'MESH:D000362', (39, 43))	('inhibits', 'NegReg', (25, 33))	('TICs', 'Phenotype', 'HP:0100033', (110, 114))	('formation', 'biological_process', 'GO:0009058', ('51', '60'))	('TIC', 'Phenotype', 'HP:0100033', (110, 113))	('soft agar colony formation', 'CPA', (34, 60))	('SKOV3', 'CellLine', 'CVCL:0532', (69, 74))	('TIC', 'Disease', 'None', (110, 113))	('PKCiota KD', 'Var', (0, 10))
2617	24174471	PKCiota KD also led to a commensurate decrease in both Mek and Erk phosphorylation levels (Fig.	('Erk', 'Gene', (63, 66))	('Erk', 'molecular_function', 'GO:0004707', ('63', '66'))	('Mek', 'Gene', '17242', (55, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('decrease', 'NegReg', (38, 46))	('Mek', 'Gene', (55, 58))	('Erk', 'Gene', '26413', (63, 66))	('PKCiota KD', 'Var', (0, 10))
2627	24174471	Taken together, these data demonstrate that PRKCI and ECT2 are genetically and biochemically linked in primary ovarian tumors, and suggest that in tumors harboring PRKCI and ECT2 copy number gains, the PKCiota-Par6-Ect2-Mek-Erk-MMP10 signaling axis is activated.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian tumors', 'Phenotype', 'HP:0100615', (111, 125))	('copy number gains', 'Var', (179, 196))	('activated', 'PosReg', (252, 261))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('signaling', 'biological_process', 'GO:0023052', ('234', '243'))	('PRKCI', 'Gene', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Erk', 'Gene', (224, 227))	('MMP10', 'Gene', '17384', (228, 233))	('primary ovarian tumors', 'Disease', (103, 125))	('tumors', 'Disease', (119, 125))	('primary ovarian tumors', 'Disease', 'MESH:D010051', (103, 125))	('MMP10', 'Gene', (228, 233))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('Ect2', 'Gene', '13605', (215, 219))	('Par6', 'Gene', '56513', (210, 214))	('Par6', 'Gene', (210, 214))	('Erk', 'molecular_function', 'GO:0004707', ('224', '227'))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('Mek', 'Gene', '17242', (220, 223))	('tumors', 'Disease', (147, 153))	('MMP10', 'molecular_function', 'GO:0030303', ('228', '233'))	('ECT2', 'Gene', (174, 178))	('Mek', 'Gene', (220, 223))	('Ect2', 'Gene', (215, 219))	('Erk', 'Gene', '26413', (224, 227))	('ovarian tumor', 'Phenotype', 'HP:0100615', (111, 124))
2651	24174471	Analysis of tumor tissue from diluent and ANF-treated mice revealed a decrease in mitotic index of tumor cells from ANF-treated mice when compared to diluent control mice (Fig.	('tumor', 'Disease', (99, 104))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mitotic', 'MPA', (82, 89))	('mice', 'Species', '10090', (128, 132))	('ANF-treated', 'Var', (116, 127))	('ANF', 'Chemical', 'MESH:D001310', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mice', 'Species', '10090', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (12, 17))	('decrease', 'NegReg', (70, 78))	('ANF', 'Chemical', 'MESH:D001310', (42, 45))
2664	24174471	Each of the cell lines were able to readily form oncospheres enriched in cells exhibiting characteristic features of TICs, including clonal expansion, expression of stem marker genes, enhanced anchorage-independent growth and efficient tumor-initiating activity when injected orthotopically into the ovary of recipient mice.	('anchorage-independent growth', 'CPA', (193, 221))	('clonal expansion', 'Var', (133, 149))	('mice', 'Species', '10090', (319, 323))	('oncospheres', 'Chemical', '-', (49, 60))	('TIC', 'Phenotype', 'HP:0100033', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('TICs', 'Phenotype', 'HP:0100033', (117, 121))	('expression', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('TIC', 'Disease', 'None', (117, 120))	('enhanced', 'PosReg', (184, 192))	('tumor', 'Disease', (236, 241))	('TIC', 'Disease', (117, 120))
2673	24174471	Our present results demonstrate that genetic disruption of PKCiota leads to a significant inhibition of the TIC phenotype in both human and murine ovarian TICs.	('inhibition', 'NegReg', (90, 100))	('TIC', 'Disease', 'None', (108, 111))	('genetic disruption', 'Var', (37, 55))	('TIC', 'Phenotype', 'HP:0100033', (155, 158))	('TIC', 'Phenotype', 'HP:0100033', (108, 111))	('murine', 'Species', '10090', (140, 146))	('ovarian TICs', 'Disease', 'MESH:D020323', (147, 159))	('ovarian TICs', 'Disease', (147, 159))	('TIC', 'Disease', 'None', (155, 158))	('TICs', 'Phenotype', 'HP:0100033', (155, 159))	('TIC', 'Disease', (155, 158))	('TIC', 'Disease', (108, 111))	('PKCiota', 'Gene', (59, 66))	('human', 'Species', '9606', (130, 135))
2678	24174471	Our data further demonstrate that oncogenic PKCiota signaling is active in ovarian TICs in vivo and that either genetic or pharmacologic inhibition of PKCiota leads to a significant blockade of tumor initiation in vivo.	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('blockade of tumor initiation', 'Disease', (182, 210))	('ovarian TICs', 'Disease', 'MESH:D020323', (75, 87))	('blockade of tumor initiation', 'Disease', 'MESH:D009369', (182, 210))	('ovarian TICs', 'Disease', (75, 87))	('inhibition', 'Var', (137, 147))	('TIC', 'Phenotype', 'HP:0100033', (83, 86))	('TICs', 'Phenotype', 'HP:0100033', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('PKCiota', 'Gene', (151, 158))
2683	24174471	We have validated and extended these published findings, showing that ~80% of ovarian serous tumors in the TCGA dataset exhibit gene copy number gains in PRKCI which is associated with elevated PRKCI mRNA expression.	('gains', 'PosReg', (145, 150))	('ovarian serous tumors', 'Phenotype', 'HP:0012887', (78, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ovarian serous tumors', 'Disease', 'MESH:D010051', (78, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PRKCI', 'Gene', (154, 159))	('gene copy number', 'Var', (128, 144))	('ovarian serous tumors', 'Disease', (78, 99))
2689	24174471	These data suggest a novel paradigm in which a single genetic event, chromosome 3q26 amplification, leads to coordinate amplification and overexpression of two co-operating oncogenes that together drive an ovarian TIC phenotype.	('TIC', 'Phenotype', 'HP:0100033', (214, 217))	('drive', 'PosReg', (197, 202))	('amplification', 'MPA', (120, 133))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('ovarian TIC', 'Disease', (206, 217))	('amplification', 'Var', (85, 98))	('ovarian TIC', 'Disease', 'MESH:D010051', (206, 217))	('overexpression', 'PosReg', (138, 152))
2694	26993048	Comparison of prognoses according to non-positive and positive spectrin alphaII expression detected immunohistochemically in epithelial ovarian carcinoma: a retrospective study.	('non-positive', 'Var', (37, 49))	('epithelial ovarian carcinoma', 'Disease', (125, 153))	('spectrin alphaII', 'Protein', (63, 79))	('epithelial ovarian carcinoma', 'Disease', 'MESH:D000077216', (125, 153))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (136, 153))	('spectrin', 'cellular_component', 'GO:0008091', ('63', '71'))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))
2727	26993048	Spectrin alphaII expression was scored according to the scoring criteria used in HER2 (human epidermal growth factor receptor 2) testing of breast cancer: positive 3+, equivocal 2+, and negative 0 or 1+ 16, 17.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('human', 'Species', '9606', (87, 92))	('epidermal growth factor receptor 2', 'Gene', '2064', (93, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('Spectrin', 'cellular_component', 'GO:0008091', ('0', '8'))	('HER2', 'Gene', (81, 85))	('epidermal growth factor receptor 2', 'Gene', (93, 127))	('HER2', 'Gene', '2064', (81, 85))	('positive 3+', 'Var', (155, 166))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('93', '116'))
2817	22163003	An LMP harboured a homozygous deletion on chr6 which created a GOPC-ROS1 fusion gene, previously reported as oncogenic in other cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('LMP', 'Chemical', '-', (3, 6))	('GOPC-ROS1', 'Gene', (63, 72))	('chr6', 'Gene', (42, 46))	('deletion', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('GOPC-ROS1', 'Gene', '57120;6098', (63, 72))	('cancer', 'Disease', (128, 134))
2833	22163003	Although approximately 10% of EOC, particularly tumours of the serous subtype, occur in women harbouring germline mutations of the cancer susceptibility genes BRCA1 or BRCA2 , the etiology of the remainder of ovarian serous neoplasms remains unknown.	('cancer', 'Disease', (131, 137))	('BRCA2', 'Gene', '675', (168, 173))	('tumours', 'Disease', (48, 55))	('women', 'Species', '9606', (88, 93))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (114, 123))	('ovarian serous neoplasms', 'Disease', 'MESH:D010051', (209, 233))	('EOC', 'Disease', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRCA1', 'Gene', '672', (159, 164))	('ovarian serous neoplasms', 'Disease', (209, 233))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('neoplasms', 'Phenotype', 'HP:0002664', (224, 233))	('BRCA1', 'Gene', (159, 164))	('ovarian serous neoplasms', 'Phenotype', 'HP:0012887', (209, 233))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('BRCA2', 'Gene', (168, 173))
2843	22163003	Karyotype studies have implicated chromosome 3p genes in EOC, and loss of heterozygosity (LOH) analyses have suggested that 3p genes may function as tumour suppressors.	('loss', 'Var', (66, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('EOC', 'Disease', (57, 60))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))
2844	22163003	We have previously reported LOH of 3p14-pcen in benign, LMP tumours, LGOSCs and HGOSCs.	('LMP tumours', 'Disease', 'MESH:D009369', (56, 67))	('3p14-pcen', 'Protein', (35, 44))	('HGOSCs', 'Disease', (80, 86))	('LGOSCs', 'Disease', (69, 75))	('LMP tumours', 'Disease', (56, 67))	('LOH', 'Var', (28, 31))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('benign', 'Disease', (48, 54))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
2846	22163003	This notion is supported by functional complementation studies involving the transfer of 'normal' 3p fragments, including the 3p12-pcen region, which rendered an aggressive EOC cell line harbouring LOH of the 3p arm, non-tumourigenic.	('non-tumour', 'Disease', 'MESH:D009369', (217, 227))	('LOH', 'Var', (198, 201))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('non-tumour', 'Disease', (217, 227))
2852	22163003	We relate our results to the mutational spectra derived from TP53, KRAS and BRAF genetic analyses, as these genes are mutated in ovarian tumours with varying frequencies depending on the pathology of the disease.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('mutated', 'Var', (118, 125))	('KRAS', 'Gene', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian tumours', 'Disease', 'MESH:D010051', (129, 144))	('KRAS', 'Gene', '3845', (67, 71))	('TP53', 'Gene', '7157', (61, 65))	('ovarian tumour', 'Phenotype', 'HP:0100615', (129, 143))	('TP53', 'Gene', (61, 65))	('ovarian tumours', 'Disease', (129, 144))
2858	22163003	LOH of 3p has been reported in up to 20% of benign ovarian serous tumours.	('benign ovarian serous tumours', 'Disease', (44, 73))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('LOH of', 'Var', (0, 6))	('benign ovarian serous tumours', 'Disease', 'MESH:D010051', (44, 73))	('ovarian serous tumour', 'Phenotype', 'HP:0012887', (51, 72))
2869	22163003	As summarized in  Table 2 , allelic imbalance of 3p was observed in only two LMP samples, TOV-1068T and TOV-3922GT, both of which also harboured allelic imbalances of other chromosomes.	('imbalances', 'Phenotype', 'HP:0002172', (153, 163))	('imbalance', 'Phenotype', 'HP:0002172', (153, 162))	('TOV-3922GT', 'Var', (104, 114))	('imbalance', 'Phenotype', 'HP:0002172', (36, 45))	('TOV-1068T', 'Var', (90, 99))	('harboured', 'Reg', (135, 144))	('LMP', 'Chemical', '-', (77, 80))
2870	22163003	Breaks involving the 3p arm were observed in two LMP tumours, TOV-942T and TOV-1685T.	('observed', 'Reg', (33, 41))	('LMP tumours', 'Disease', (49, 60))	('TOV-942T', 'Var', (62, 70))	('LMP tumours', 'Disease', 'MESH:D009369', (49, 60))	('TOV-1685T', 'Var', (75, 84))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
2871	22163003	Overall, chromosomal aberrations were more commonly observed in LMP cases (30 of 53 cases or 56.6%) than in benign cases (3 of 22 cases, 13.6%) ( Tables 1   and   2 ).	('observed', 'Reg', (52, 60))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (9, 32))	('LMP', 'Chemical', '-', (64, 67))	('LMP', 'Disease', (64, 67))	('chromosomal aberrations', 'Var', (9, 32))
2873	22163003	Chromosomal abnormalities were observed in all but two of the LGOSC samples (TOV-682T and TOV1284T).	('Chromosomal abnormalities', 'Disease', 'MESH:D002869', (0, 25))	('TOV1284T', 'Var', (90, 98))	('observed', 'Reg', (31, 39))	('Chromosomal abnormalities', 'Disease', (0, 25))	('TOV-682T', 'Var', (77, 85))
2877	22163003	Some of these cases exhibited identical (cases TOV-1775 and TOV-920) or similar (case TOV-4054) abnormalities, suggesting the possibility of common clonal origins in these cases, as has been proposed for malignant ovarian cancers.	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('malignant ovarian cancers', 'Disease', 'MESH:D010051', (204, 229))	('malignant ovarian cancers', 'Disease', (204, 229))	('TOV-920', 'Var', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('ovarian cancers', 'Phenotype', 'HP:0100615', (214, 229))	('ovarian cancer', 'Phenotype', 'HP:0100615', (214, 228))
2880	22163003	Furthermore, breaks occurring adjacent to cancer-associated genes may affect their regulation.	('affect', 'Reg', (70, 76))	('regulation', 'MPA', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('regulation', 'biological_process', 'GO:0065007', ('83', '93'))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('breaks', 'Var', (13, 19))
2885	22163003	Notable is the large number of ROHs (n = 14) observed in the benign bilateral tumour samples BOV-1588DT and BOV-1588GT, as compared with benign and LMP cases exhibiting no (n = 61), one (n = 8), two (n = 5) or four (n = 1) ROHs >5 Mb.	('bilateral tumour', 'Disease', 'MESH:D009369', (68, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('BOV-1588GT', 'Var', (108, 118))	('LMP', 'Chemical', '-', (148, 151))	('bilateral tumour', 'Disease', (68, 84))	('BOV-1588DT', 'Var', (93, 103))
2888	22163003	Two LMP samples (TOV-1694DT and TOV-933DT) exhibited ROHs overlapping the 3p12-p11 ROH observed in the benign sample 1781T.	('TOV-933DT', 'Var', (32, 41))	('LMP', 'Chemical', '-', (4, 7))	('p11', 'Gene', (79, 82))	('TOV-1694DT', 'Var', (17, 27))	('p11', 'Gene', '6281', (79, 82))
2890	22163003	Mutations of KRAS, BRAF and TP53 were only detected in LMP tumours and LGOSCs ( Table 2 ).	('TP53', 'Gene', '7157', (28, 32))	('BRAF', 'Gene', '673', (19, 23))	('LMP tumours', 'Disease', (55, 66))	('TP53', 'Gene', (28, 32))	('BRAF', 'Gene', (19, 23))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('Mutations', 'Var', (0, 9))	('LMP tumours', 'Disease', 'MESH:D009369', (55, 66))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
2891	22163003	As reported in independent studies, samples with mutations in KRAS or BRAF were mutually exclusive.	('KRAS', 'Gene', (62, 66))	('mutations', 'Var', (49, 58))	('KRAS', 'Gene', '3845', (62, 66))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
2892	22163003	Concordant mutation results were observed in all but one of the bilateral tumour samples (LMP case TOV-1010DT/GT).	('bilateral tumour', 'Disease', 'MESH:D009369', (64, 80))	('LMP', 'Chemical', '-', (90, 93))	('bilateral tumour', 'Disease', (64, 80))	('TOV-1010DT/GT', 'Var', (99, 112))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
2893	22163003	There were significantly more KRAS and BRAF mutations (26 of 53, 49.1%) and fewer TP53 mutations (1 of 53, 1.9%) in LMP cases as compared with KRAS and BRAF mutations (3 of 11, 18.1%) and TP53 mutations (5 of 11, 45.5%) in LGOSCs ( Tables 2   and   3 ) (p = 0.00049).	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('BRAF', 'Gene', (152, 156))	('KRAS', 'Gene', '3845', (143, 147))	('BRAF', 'Gene', '673', (39, 43))	('KRAS', 'Gene', (30, 34))	('fewer', 'NegReg', (76, 81))	('LMP', 'Chemical', '-', (116, 119))	('BRAF', 'Gene', (39, 43))	('LMP', 'Disease', (116, 119))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (143, 147))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('BRAF', 'Gene', '673', (152, 156))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', '3845', (30, 34))
2894	22163003	In general, the LMP and LGOSC cases with somatic TP53 mutations harboured disorganized genomes, particularly large numbers of intrachromosomal breaks ( Tables 2  and  3 ).	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('intrachromosomal breaks', 'CPA', (126, 149))	('intrachromosomal breaks', 'Phenotype', 'HP:0040012', (126, 149))	('LMP', 'Chemical', '-', (16, 19))	('large numbers of intrachromosomal breaks', 'Phenotype', 'HP:0040012', (109, 149))	('LMP', 'Disease', (16, 19))
2895	22163003	The LMP sample with a TP53 mutation (TOV-1685GT) has 30 of 41 chromosomal arms harbouring an aberration, similar to the average number (33.4) of chromosomal arms harbouring an aberration in the TP53 mutation positive LGOSCs.	('LMP', 'Chemical', '-', (4, 7))	('mutation', 'Var', (27, 35))	('TP53', 'Gene', '7157', (194, 198))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (194, 198))	('TP53', 'Gene', (22, 26))
2896	22163003	LMP cases with KRAS mutations contained an average of 5.3 chromosomal arms harbouring an aberration, whereas cases with BRAF mutations had an average of 1 chromosomal arm with an aberration.	('KRAS', 'Gene', (15, 19))	('BRAF', 'Gene', '673', (120, 124))	('LMP', 'Chemical', '-', (0, 3))	('BRAF', 'Gene', (120, 124))	('KRAS', 'Gene', '3845', (15, 19))	('mutations', 'Var', (20, 29))
2898	22163003	In the LMP tumours, there were significantly more KRAS mutation-positive cases that were associated with a gain of 12p (8 of 12, 66.7%) than there were in KRAS mutation-negative tumours (4 of 41, 9.8%) (p = 0.	('LMP tumours', 'Disease', (7, 18))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('KRAS', 'Gene', (155, 159))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('KRAS', 'Gene', '3845', (155, 159))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('KRAS', 'Gene', (50, 54))	('gain', 'PosReg', (107, 111))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('KRAS', 'Gene', '3845', (50, 54))	('12p', 'MPA', (115, 118))	('tumours', 'Disease', (178, 185))	('LMP tumours', 'Disease', 'MESH:D009369', (7, 18))	('mutation-positive', 'Var', (55, 72))	('tumours', 'Disease', (11, 18))
2901	22163003	A gynecologic pathologist independently reviewed the LMP and LGOSC samples that were found to harbor TP53 mutations in a blinded manner to confirm their histopathological classification.	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('LMP', 'Chemical', '-', (53, 56))
2903	22163003	Interestingly, none of the LGOSC samples harbouring TP53 mutations maintained their designation.	('TP53', 'Gene', '7157', (52, 56))	('mutations', 'Var', (57, 66))	('designation', 'MPA', (84, 95))	('TP53', 'Gene', (52, 56))
2904	22163003	TOV-553EPT and TOV-490T were reclassified as high grade carcinomas; TOV-812EPT was reclassified as a metastatic serous carcinoma, grade not determined; TOV-947DT was reclassified as a possible LMP; and TOV-81DT was reclassified as a non-invasive implant ( Tables 2   and   3 ).	('EPT', 'molecular_function', 'GO:0004307', ('7', '10'))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('carcinomas', 'Disease', (56, 66))	('TOV-947DT', 'Var', (152, 161))	('carcinomas', 'Disease', 'MESH:D002277', (56, 66))	('serous carcinoma', 'Disease', (112, 128))	('EPT', 'molecular_function', 'GO:0004307', ('75', '78'))	('LMP', 'Chemical', '-', (193, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('serous carcinoma', 'Disease', 'MESH:D018284', (112, 128))	('TOV-490T', 'Var', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('TOV-812EPT', 'Var', (68, 78))
2913	22163003	There was no evidence of promoter methylation of these genes in the analysis of either 1781T-A and 1781T-B, in contrast to evidence of methylated RASSF1A alleles in OV-90, TOV-112D, TOV-21G, and TOV-2223G, methylated CDKN2A alleles in TOV-112D, and methylated hMLH1 alleles in TOV-21G (data not shown).	('hMLH1', 'Gene', '4292', (260, 265))	('1781T-A', 'Mutation', 'c.1781T>A', (87, 94))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('methylated', 'Var', (206, 216))	('CDKN2A', 'Gene', (217, 223))	('RASSF1A', 'Gene', (146, 153))	('TOV-2223G', 'Var', (195, 204))	('CDKN2A', 'Gene', '1029', (217, 223))	('RASSF1A', 'Gene', '11186', (146, 153))	('hMLH1', 'Gene', (260, 265))
2914	22163003	The inferred 242.5 kb homozygous deletion observed at 6q22.1 in LMP tumour TOV-4054DT stood out in part because it is much larger than the size of the average homozygous deletion (28.3 kb) observed in the present study ( Table 4  ,  Figure 5A ).	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('TOV-4054DT', 'Var', (75, 85))	('LMP', 'Chemical', '-', (64, 67))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))
2915	22163003	The deletion is predicted to affect the function of ROS1, DCBLD1 and GOPC, with breakpoints occurring in all three genes ( Figure 5B ).	('GOPC', 'Gene', (69, 73))	('DCBLD1', 'Gene', (58, 64))	('affect', 'Reg', (29, 35))	('ROS1', 'Gene', (52, 56))	('deletion', 'Var', (4, 12))	('ROS1', 'Gene', '6098', (52, 56))	('DCBLD1', 'Gene', '285761', (58, 64))	('function', 'MPA', (40, 48))	('GOPC', 'Gene', '57120', (69, 73))
2917	22163003	In U118MG, the fusion gene is transcribed from the 5' end of GOPC and contains the first 7 GOPC exons and the last 9 ROS1 exons.	('U118MG', 'Var', (3, 9))	('U118MG', 'CellLine', 'CVCL:0633', (3, 9))	('GOPC', 'Gene', '57120', (61, 65))	('GOPC', 'Gene', (91, 95))	('ROS1', 'Gene', (117, 121))	('GOPC', 'Gene', '57120', (91, 95))	('ROS1', 'Gene', '6098', (117, 121))	('GOPC', 'Gene', (61, 65))
2918	22163003	As shown in  Figure 5C , TOV-4054DT harbours an aberrant transcript not present in the well-characterized ovarian cancer cell line, OV-90neor, which does not harbour a 6q22.1 anomaly (data not shown).	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('anomaly', 'Disease', 'MESH:D000014', (175, 182))	('ovarian cancer', 'Disease', (106, 120))	('TOV-4054DT', 'Var', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('anomaly', 'Disease', (175, 182))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
2919	22163003	However, a faint band corresponding in size to the aberrant 6q22.1 transcript was also visible in the RT-PCR analysis of the contralateral LMP tumour TOV-4054GT, suggesting a clonal origin of cells that contain this anomaly.	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('TOV-4054GT', 'Var', (150, 160))	('anomaly', 'Disease', 'MESH:D000014', (216, 223))	('tumour', 'Disease', (143, 149))	('anomaly', 'Disease', (216, 223))	('LMP', 'Chemical', '-', (139, 142))
2920	22163003	This is consistent with observation that both LMP tumours harbor allelic imbalance of the chr6q arm which include the ROS1, DCBLD1, and GOPC loci ( Figure 5A ).	('LMP tumours', 'Disease', 'MESH:D009369', (46, 57))	('ROS1', 'Gene', '6098', (118, 122))	('DCBLD1', 'Gene', '285761', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('imbalance', 'Phenotype', 'HP:0002172', (73, 82))	('allelic imbalance', 'Var', (65, 82))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('DCBLD1', 'Gene', (124, 130))	('LMP tumours', 'Disease', (46, 57))	('harbor', 'Reg', (58, 64))	('GOPC', 'Gene', '57120', (136, 140))	('chr6q arm', 'Gene', (90, 99))	('GOPC', 'Gene', (136, 140))	('ROS1', 'Gene', (118, 122))
2926	22163003	Although methylation of RASSF1A (3p21.31) and CDKN2A (9p21.3) has previously been reported in benign serous tumours at a low frequency, we observed no evidence of alteration of promoter CpG methylation in sample 1781T.	('methylation', 'Var', (9, 20))	('CDKN2A', 'Gene', (46, 52))	('methylation', 'biological_process', 'GO:0032259', ('190', '201'))	('benign serous tumours', 'Disease', (94, 115))	('RASSF1A', 'Gene', (24, 31))	('CDKN2A', 'Gene', '1029', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('benign serous tumours', 'Disease', 'MESH:D009369', (94, 115))	('RASSF1A', 'Gene', '11186', (24, 31))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('reported', 'Reg', (82, 90))
2928	22163003	LOH analyses of 3p loci are consistent with SNP analyses suggesting that 3p anomalies are rare occurrences in benign serous tumours, as are anomalies associated with other chromosomes.	('anomalies', 'Var', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('benign serous tumours', 'Disease', (110, 131))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('benign serous tumours', 'Disease', 'MESH:D009369', (110, 131))
2929	22163003	The absence of KRAS and BRAF mutations in our set of benign tumours is consistent with the paucity of somatic events observed in independent reports.	('benign tumours', 'Disease', (53, 67))	('KRAS', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('benign tumours', 'Disease', 'MESH:D009369', (53, 67))	('absence', 'NegReg', (4, 11))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('KRAS', 'Gene', '3845', (15, 19))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
2930	22163003	It has been proposed that the acquisition of a KRAS or BRAF mutation in a benign tumour might initiate the progression to an LMP tumour.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('mutation', 'Var', (60, 68))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('benign tumour', 'Disease', 'MESH:D009369', (74, 87))	('initiate', 'Reg', (94, 102))	('tumour', 'Disease', (81, 87))	('tumour', 'Disease', (129, 135))	('KRAS', 'Gene', (47, 51))	('benign tumour', 'Disease', (74, 87))	('BRAF', 'Gene', '673', (55, 59))	('KRAS', 'Gene', '3845', (47, 51))	('LMP', 'Chemical', '-', (125, 128))	('BRAF', 'Gene', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
2945	22163003	Interestingly, gain of chr12 was significantly associated with the presence of KRAS mutations, a finding that has been previously observed.	('chr12', 'Gene', (23, 28))	('KRAS', 'Gene', '3845', (79, 83))	('mutations', 'Var', (84, 93))	('gain', 'PosReg', (15, 19))	('KRAS', 'Gene', (79, 83))
2948	22163003	Another study indicated that NSCLC patients with both a KRAS mutation and gain of chr12 had a worse prognosis than those harbouring only one of these aberrations.	('chr12', 'Gene', (82, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('KRAS', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('KRAS', 'Gene', '3845', (56, 60))	('NSCLC', 'Disease', (29, 34))	('gain', 'PosReg', (74, 78))	('patients', 'Species', '9606', (35, 43))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))
2951	22163003	TOV-942GT harboured an amplification of the KRAS locus, and while pancreatic carcinomas have been shown to have a high KRAS mutation rate, the pathology review excluded the possibility of metastasis in this case.	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('TOV-942GT', 'Var', (0, 9))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (66, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('pancreatic carcinomas', 'Disease', (66, 87))	('KRAS', 'Gene', (119, 123))	('KRAS', 'Gene', (44, 48))	('mutation', 'Var', (124, 132))	('KRAS', 'Gene', '3845', (119, 123))	('KRAS', 'Gene', '3845', (44, 48))
2952	22163003	The low frequency of TP53 mutations in LMP samples is also consistent with independent reports.	('TP53', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('TP53', 'Gene', '7157', (21, 25))	('LMP', 'Chemical', '-', (39, 42))
2953	22163003	The TP53 mutation positive case (TOV-1685GT) was identified in a young patient (age 26), who has remained cancer-free for the follow-up period of 6.5 years.	('TP53', 'Gene', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('TOV-1685GT', 'Var', (33, 43))	('mutation positive', 'Reg', (9, 26))	('cancer', 'Disease', (106, 112))	('patient', 'Species', '9606', (71, 78))	('TP53', 'Gene', '7157', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
2954	22163003	Interestingly, both TOV-1685GT and TOV-942GT harboured extensive evidence of chromosomal instability (CIN) by SNP array analyses.	('TOV-1685GT', 'Var', (20, 30))	('CIN', 'Disease', (102, 105))	('chromosomal instability', 'CPA', (77, 100))	('CIN', 'Disease', 'MESH:D007674', (102, 105))	('TOV-942GT', 'Var', (35, 44))	('CIN', 'Phenotype', 'HP:0040012', (102, 105))	('chromosomal instability', 'Phenotype', 'HP:0040012', (77, 100))
2956	22163003	Although the relationship between somatic mutations in these genes and genomic anomalies is unknown, the high frequency of CIN in the context of TP53 mutations combined with the role of p53 in DNA damage response has been proposed in numerous studies (reviewed in Negrini et al., 2010).	('genomic anomalies', 'Disease', (71, 88))	('CIN', 'Disease', (123, 126))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('CIN', 'Disease', 'MESH:D007674', (123, 126))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('p53', 'Gene', (186, 189))	('p53', 'Gene', '7157', (186, 189))	('mutations', 'Var', (150, 159))	('genomic anomalies', 'Disease', 'MESH:D042822', (71, 88))	('CIN', 'Phenotype', 'HP:0040012', (123, 126))	('DNA damage response', 'biological_process', 'GO:0006974', ('193', '212'))
2958	22163003	All five LGOSC cases that harboured a somatic TP53 mutation exhibited extensive CIN and were later reclassified.	('CIN', 'Disease', 'MESH:D007674', (80, 83))	('TP53', 'Gene', '7157', (46, 50))	('CIN', 'Phenotype', 'HP:0040012', (80, 83))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('CIN', 'Disease', (80, 83))
2960	22163003	However, the rare instances of TP53 mutation positive LMP samples (including the LGOSC reclassified as a LMP case) would also support the notion that some LMP samples share common origins with HGOSC as they often exhibit somatic TP53 mutations and extensive CIN.	('CIN', 'Phenotype', 'HP:0040012', (258, 261))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('LMP', 'Chemical', '-', (155, 158))	('TP53', 'Gene', '7157', (229, 233))	('CIN', 'Disease', (258, 261))	('TP53', 'Gene', (229, 233))	('CIN', 'Disease', 'MESH:D007674', (258, 261))	('LMP', 'Chemical', '-', (54, 57))	('mutations', 'Var', (234, 243))	('LMP', 'Chemical', '-', (105, 108))	('exhibit', 'Reg', (213, 220))
2961	22163003	Regardless of the putative origins of EOC, our results suggest that a combination of TP53 mutation testing and SNP array analyses may facilitate the classification of malignant serous cases.	('TP53', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (85, 89))	('facilitate', 'PosReg', (134, 144))	('mutation testing', 'Var', (90, 106))	('malignant serous cases', 'Disease', (167, 189))
2963	22163003	Few unique homozygous deletions were inferred in the samples analyzed, and none overlapped regions containing known tumour suppressor genes.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('deletions', 'Var', (22, 31))	('tumour', 'Disease', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
2965	22163003	As CNVs may contain regulatory elements, it is possible that these germline homozygous deletions may affect the expression of adjacent genes, thus contributing to tumour risk or progression (reviewed by Henrichsen et al.,).	('progression', 'CPA', (178, 189))	('affect', 'Reg', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('contributing to', 'Reg', (147, 162))	('deletions', 'Var', (87, 96))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', (163, 169))	('expression', 'MPA', (112, 122))
2973	22163003	Although targeted mutation analyses of ROS1 or GOPC have not been performed in cancer samples, the Sanger Wellcome Trust COSMIC database (http://www.sanger.ac.uk/genetics/CGP/cosmic/) reported low frequencies of ROS1 sequence variations in ovarian (1/84), lung (8/131), breast (2/201), stomach (2/60), colorectal (1/133) and CNS tumours (3/477).	('tumours', 'Phenotype', 'HP:0002664', (329, 336))	('variations', 'Var', (226, 236))	('lung', 'Disease', (256, 260))	('tumour', 'Phenotype', 'HP:0002664', (329, 335))	('colorectal', 'Disease', (302, 312))	('ROS1', 'Gene', (39, 43))	('ROS1', 'Gene', (212, 216))	('CNS tumours', 'Disease', 'MESH:D016543', (325, 336))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', (79, 85))	('ovarian', 'Disease', (240, 247))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CNS tumours', 'Disease', (325, 336))	('ROS1', 'Gene', '6098', (39, 43))	('stomach', 'Disease', (286, 293))	('ROS1', 'Gene', '6098', (212, 216))	('GOPC', 'Gene', '57120', (47, 51))	('GOPC', 'Gene', (47, 51))	('breast', 'Disease', (270, 276))
2974	22163003	Of the 22 sequence variations observed in either the ovarian TCGA study or in multiple tumour types in the Sanger Wellcome Trust COSMIC database, 17 are missense mutations, with 4 occurring in the tyrosine kinase domain.	('variations', 'Var', (19, 29))	('tumour', 'Disease', (87, 93))	('missense mutations', 'Var', (153, 171))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
2975	22163003	In total, six mutations have been observed and validated in ovarian tumours, including four missense mutations and two silent mutations.	('ovarian tumours', 'Disease', (60, 75))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('ovarian tumours', 'Disease', 'MESH:D010051', (60, 75))	('ovarian tumour', 'Phenotype', 'HP:0100615', (60, 74))	('missense mutations', 'Var', (92, 110))
2976	22163003	Likewise, one mutation has been observed in GOPC; a missense mutation in an ovarian clear cell tumour.	('missense mutation', 'Var', (52, 69))	('GOPC', 'Gene', '57120', (44, 48))	('ovarian clear cell tumour', 'Disease', 'MESH:D010051', (76, 101))	('ovarian clear cell tumour', 'Disease', (76, 101))	('GOPC', 'Gene', (44, 48))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
2981	22163003	Our group is currently investigating SNP array results from HGOSCs and EOC cell lines, and no evidence of a homozygous deletion affecting this region in these aggressive EOC tumours and cell lines were observed (data not shown).	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('deletion', 'Var', (119, 127))	('aggressive EOC tumours', 'Disease', (159, 181))	('aggressive EOC tumours', 'Disease', 'MESH:D001523', (159, 181))
2985	22163003	Interestingly, chromosomal aberrations, but not genetic mutations, were observed in benign serous tumours.	('observed', 'Reg', (72, 80))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (15, 38))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('benign serous tumours', 'Disease', (84, 105))	('benign serous tumours', 'Disease', 'MESH:D009369', (84, 105))	('chromosomal aberrations', 'Var', (15, 38))
2987	22163003	A number of LMP tumours lacking KRAS or BRAF mutations harboured genomic aberrations, indicating that different initiating events may be present in these tumours.	('BRAF', 'Gene', '673', (40, 44))	('LMP tumours', 'Disease', 'MESH:D009369', (12, 23))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('mutations', 'Var', (45, 54))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('BRAF', 'Gene', (40, 44))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('KRAS', 'Gene', (32, 36))	('LMP tumours', 'Disease', (12, 23))	('KRAS', 'Gene', '3845', (32, 36))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumours', 'Disease', (154, 161))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('harboured', 'Reg', (55, 64))
2999	22163003	LOH analysis was performed using polymorphic microsatellite repeat markers representing various 3p loci: D3S1304 and D3S1515 at 3p26.2; D3S1581 and D3S3640 at 3p21.31; D3S1274 and D3S1542 at 3p12.3; D3S1538 and D3S2388 at 3p12.2; and D3S2386 and D3S2318 at 3p11.2.	('D3S1274', 'Var', (168, 175))	('D3S2388', 'Var', (211, 218))	('D3S1515', 'Var', (117, 124))	('D3S1538', 'Var', (199, 206))	('D3S1542', 'Var', (180, 187))	('D3S1304', 'Var', (105, 112))	('D3S3640', 'Var', (148, 155))	('p11', 'Gene', (258, 261))	('D3S2318', 'Var', (246, 253))	('D3S2386', 'Var', (234, 241))	('D3S1581', 'Var', (136, 143))	('p11', 'Gene', '6281', (258, 261))
3000	22163003	Genetic analysis of the 3p12 locus in the tumour sample 1781T was determined using seven polymorphic microsatellite markers: D3S3507, D3S1274, D3S3049, D3S3508, D3S3633, D3S3679, and D3S2318.	('D3S1274', 'Var', (134, 141))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('D3S3633', 'Var', (161, 168))	('D3S2318', 'Var', (183, 190))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('D3S3679', 'Var', (170, 177))	('tumour', 'Disease', (42, 48))	('D3S3508', 'Var', (152, 159))	('D3S3507', 'Var', (125, 132))	('D3S3049', 'Var', (143, 150))
3003	22163003	Mutation analysis of tumour DNA samples was designed to detect variants in the protein coding exons 2 to 11 of TP53, as well as the common mutations in exon 2 of KRAS and exons 11 and 15 of BRAF.	('KRAS', 'Gene', (162, 166))	('BRAF', 'Gene', (190, 194))	('variants', 'Var', (63, 71))	('TP53', 'Gene', '7157', (111, 115))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('KRAS', 'Gene', '3845', (162, 166))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('TP53', 'Gene', (111, 115))	('tumour', 'Disease', (21, 27))	('BRAF', 'Gene', '673', (190, 194))
3004	22163003	Peripheral blood lymphocyte DNA from case sample TOV-1685GT was also examined for TP53 mutations in exon 10.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('mutations in', 'Var', (87, 99))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))
3005	22163003	Mutation analyses of case sample 1781T were also performed to identify variants in protein coding regions of the chr3 genes ROBO1, GBE1 and VGLL3.	('variants', 'Var', (71, 79))	('chr3', 'Gene', (113, 117))	('GBE1', 'Gene', (131, 135))	('VGLL3', 'Gene', '389136', (140, 145))	('GBE1', 'Gene', '2632', (131, 135))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('VGLL3', 'Gene', (140, 145))	('ROBO1', 'Gene', '6091', (124, 129))	('ROBO1', 'Gene', (124, 129))
3007	22163003	Sequence chromatograms, reviewed by at least two observers, were compared with NCBI reference sequence (RefSeq) reported in GenBank: NM_133631.3 (ROBO1), NM_000158.3 (GBE1), NM_016206.2 (VGLL3), NM_000546.4 (TP53), NM_004985.3 (KRAS) and NM_004333.4 (BRAF).	('NM_004333.4', 'Var', (238, 249))	('VGLL3', 'Gene', '389136', (187, 192))	('GBE1', 'Gene', (167, 171))	('NM_016206.2', 'Var', (174, 185))	('KRAS', 'Gene', (228, 232))	('VGLL3', 'Gene', (187, 192))	('NM_000158.3', 'Var', (154, 165))	('NM_000546.4', 'Var', (195, 206))	('BRAF', 'Gene', (251, 255))	('NM_004985.3', 'Var', (215, 226))	('BRAF', 'Gene', '673', (251, 255))	('TP53', 'Gene', (208, 212))	('ROBO1', 'Gene', (146, 151))	('TP53', 'Gene', '7157', (208, 212))	('KRAS', 'Gene', '3845', (228, 232))	('ROBO1', 'Gene', '6091', (146, 151))	('GBE1', 'Gene', '2632', (167, 171))
3008	22163003	In addition, TP53 variants were evaluated based on information in the International Agency for Research on Cancer (IARC) TP53 Database (www-p53.iarc.fr).	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('variants', 'Var', (18, 26))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TP53', 'Gene', '7157', (13, 17))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))
3015	22163003	The distribution of mutations in KRAS, BRAF and TP53 between the LMP and LGOSC cases was compared using the Fisher Exact test (Statistical Product and Service Solution Package, SPSS, Chicago, IL).	('TP53', 'Gene', '7157', (48, 52))	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', (39, 43))	('TP53', 'Gene', (48, 52))	('KRAS', 'Gene', (33, 37))	('LMP', 'Chemical', '-', (65, 68))	('KRAS', 'Gene', '3845', (33, 37))	('mutations', 'Var', (20, 29))
3016	22163003	This software uses a hidden Markov model containing 9 different tumour states, encompassing loss of 1 or 2 copies, copy number neutral LOH, and 5 different gain states allowing for different patterns of allele retention.	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('retention', 'biological_process', 'GO:0051235', ('210', '219'))	('tumour', 'Disease', (64, 70))	('loss', 'NegReg', (92, 96))	('copy number neutral', 'Var', (115, 134))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
3019	30482155	A data science approach for the classification of low-grade and high-grade ovarian serous carcinomas Copy Number Alternations (CNAs) is defined as somatic gain or loss of DNA regions.	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (75, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Copy Number', 'Var', (101, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (75, 100))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('ovarian serous carcinomas', 'Disease', (75, 100))
3027	30482155	The patterns captured by Bag-of-Segments features correlate with current clinical knowledge: low grade ovarian tumors being related to aneuploidy events associated to mitotic errors while high grade ovarian tumors are induced by DNA repair gene malfunction.	('ovarian tumors', 'Disease', 'MESH:D010051', (103, 117))	('mitotic', 'Var', (167, 174))	('aneuploidy', 'Disease', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian tumors', 'Disease', 'MESH:D010051', (199, 213))	('DNA repair', 'biological_process', 'GO:0006281', ('229', '239'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('aneuploidy', 'Disease', 'MESH:D000782', (135, 145))	('ovarian tumors', 'Disease', (199, 213))	('ovarian tumor', 'Phenotype', 'HP:0100615', (199, 212))	('ovarian tumors', 'Phenotype', 'HP:0100615', (103, 117))	('DNA', 'cellular_component', 'GO:0005574', ('229', '232'))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('ovarian tumors', 'Phenotype', 'HP:0100615', (199, 213))	('ovarian tumors', 'Disease', (103, 117))	('ovarian tumor', 'Phenotype', 'HP:0100615', (103, 116))
3031	30482155	Defined as somatic gain or loss of DNA regions, Copy Number Alterations (CNAs) are reflective of genomic instability, frequently affecting functionally important genes, such as tumor suppressors and oncogenes.	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Copy Number Alterations', 'Var', (48, 71))	('tumor', 'Disease', (177, 182))	('affecting', 'Reg', (129, 138))
3034	30482155	Small deletion events may target local regions of the genome harboring tumor suppressor genes locations, while amplifications preferentially target oncogenes locations.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('Small deletion', 'Var', (0, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('target', 'Reg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
3039	30482155	The majority (96%) of high grade serous carcinomas have TP53 mutations and show high levels of chromosomal copy number changes through the entire genome, whereas low grade serous carcinomas do not have TP53 mutations, show KRAS and BRAF mutations and in most cases are near diploid.	('BRAF', 'Gene', '673', (232, 236))	('serous carcinomas', 'Disease', 'MESH:D018284', (172, 189))	('BRAF', 'Gene', (232, 236))	('TP53', 'Gene', (202, 206))	('TP53', 'Gene', '7157', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('serous carcinomas', 'Disease', 'MESH:D018284', (33, 50))	('mutations', 'Var', (237, 246))	('KRAS', 'Gene', '3845', (223, 227))	('mutations', 'Var', (61, 70))	('serous carcinomas', 'Disease', (172, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('TP53', 'Gene', '7157', (202, 206))	('KRAS', 'Gene', (223, 227))	('TP53', 'Gene', (56, 60))	('serous carcinomas', 'Disease', (33, 50))	('chromosomal copy number changes', 'MPA', (95, 126))
3055	30482155	To obtain a step-wise signal of a proper level of complexity, the CART algorithm is tuned by modifying the cost-complexity parameter (Cp).	('CART', 'Gene', (66, 70))	('CART', 'Gene', '9607', (66, 70))	('modifying', 'Var', (93, 102))
3070	30482155	The patterns captured by these two groups correlate with current clinical knowledge: low grade ovarian tumors being related to aneuploidy events associated to mitotic errors while high grade ovarian tumors are induced by DNA repair gene malfunction.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('ovarian tumors', 'Disease', (191, 205))	('ovarian tumor', 'Phenotype', 'HP:0100615', (191, 204))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('DNA repair', 'biological_process', 'GO:0006281', ('221', '231'))	('ovarian tumor', 'Phenotype', 'HP:0100615', (95, 108))	('aneuploidy', 'Disease', 'MESH:D000782', (127, 137))	('ovarian tumors', 'Phenotype', 'HP:0100615', (191, 205))	('ovarian tumors', 'Disease', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('ovarian tumors', 'Phenotype', 'HP:0100615', (95, 109))	('DNA', 'cellular_component', 'GO:0005574', ('221', '224'))	('mitotic', 'Var', (159, 166))	('ovarian tumors', 'Disease', 'MESH:D010051', (191, 205))	('ovarian tumors', 'Disease', 'MESH:D010051', (95, 109))	('aneuploidy', 'Disease', (127, 137))
3081	22405464	Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation.	('normal differentiation', 'CPA', (190, 212))	('deregulate', 'Reg', (179, 189))	('give rise to', 'Reg', (55, 67))	('Clonal', 'Var', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('serous carcinomas', 'Disease', 'MESH:D018284', (68, 85))	('serous carcinomas', 'Disease', (68, 85))
3090	22405464	Recently, studies of both asymptomatic women with germline BRCA1 or BRCA2 mutations as well as those from the general population with pelvic serous carcinoma, have detected precancerous or early cancerous lesions - serous tubal intraepithelial carcinoma (STIC) - in the fallopian tubal fimbria.	('BRCA1', 'Gene', '672', (59, 64))	('BRCA1', 'Gene', (59, 64))	('cancerous lesions - serous tubal intraepithelial carcinoma', 'Disease', 'MESH:D002278', (195, 253))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('fimbria', 'cellular_component', 'GO:0009289', ('286', '293'))	('BRCA2', 'Gene', '675', (68, 73))	('women', 'Species', '9606', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('pelvic serous carcinoma', 'Disease', (134, 157))	('cancer', 'Disease', (195, 201))	('fallopian tubal fimbria', 'Disease', (270, 293))	('fallopian tubal fimbria', 'Disease', 'MESH:D011274', (270, 293))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('mutations', 'Var', (74, 83))	('pelvic serous carcinoma', 'Disease', 'MESH:D010386', (134, 157))	('BRCA2', 'Gene', (68, 73))	('cancer', 'Disease', (176, 182))
3095	22405464	Type I tumors are not clinically aggressive, generally present at early stage, rarely harbor TP53 mutations, but instead display mutations involving specific cell signaling pathways, including KRAS, BRAF, ERBB2, PTEN, CTNNB1, PIK3CA, ARID1A, and PPP2R1A.	('cell signaling pathways', 'Pathway', (158, 181))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('TP53', 'Gene', (93, 97))	('KRAS', 'Gene', '3845', (193, 197))	('ARID1A', 'Gene', (234, 240))	('BRAF', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (199, 203))	('PPP2R1A', 'Gene', '5518', (246, 253))	('PTEN', 'Gene', '5728', (212, 216))	('CTNNB1', 'Gene', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('PIK3CA', 'Gene', (226, 232))	('KRAS', 'Gene', (193, 197))	('ARID1A', 'Gene', '8289', (234, 240))	('PPP2R1A', 'Gene', (246, 253))	('involving', 'Reg', (139, 148))	('ERBB2', 'Gene', (205, 210))	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('TP53', 'Gene', '7157', (93, 97))	('Type I tumors', 'Disease', (0, 13))	('ERBB2', 'Gene', '2064', (205, 210))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('mutations', 'Var', (129, 138))	('CTNNB1', 'Gene', '1499', (218, 224))	('mutations', 'Var', (98, 107))	('PTEN', 'Gene', (212, 216))	('PIK3CA', 'Gene', '5290', (226, 232))
3096	22405464	Type II tumors, which include high-grade serous carcinomas (HG-SC), high-grade endometrioid carcinomas, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas, frequently display TP53 mutations and are genetically unstable.	('display', 'Reg', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (79, 102))	('carcinosarcomas', 'Disease', (139, 154))	('tumors', 'Disease', (8, 14))	('TP53', 'Gene', '7157', (209, 213))	('undifferentiated carcinomas', 'Disease', (161, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('serous carcinomas', 'Disease', 'MESH:D018284', (41, 58))	('mutations', 'Var', (214, 223))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (161, 188))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (79, 102))	('Type II tumors', 'Disease', (0, 14))	('TP53', 'Gene', (209, 213))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('tumors', 'Disease', (131, 137))	('carcinosarcomas', 'Disease', 'MESH:D002296', (139, 154))	('serous carcinomas', 'Disease', (41, 58))	('endometrioid carcinomas', 'Disease', (79, 102))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('Type II tumors', 'Disease', 'MESH:D009369', (0, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
3099	22405464	HG-SC is characterized by high levels of genetic instability, a very high frequency of TP53 gene mutations, and low frequency of the molecular aberrations that typify Type I carcinomas including KRAS and BRAF mutations.	('mutations', 'Var', (97, 106))	('TP53', 'Gene', '7157', (87, 91))	('BRAF', 'Gene', (204, 208))	('typify Type I carcinomas', 'Disease', 'MESH:D017827', (160, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('TP53', 'Gene', (87, 91))	('HG-SC', 'Disease', (0, 5))	('KRAS', 'Gene', '3845', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('KRAS', 'Gene', (195, 199))	('typify Type I carcinomas', 'Disease', (160, 184))	('BRAF', 'Gene', '673', (204, 208))
3121	22405464	Since most of ovarian carcinomas that are identified in BRCA mutation carriers are HG-SCs, examination of prophylactic salpingo-oophorectomy specimens should theoretically reveal a precursor lesion in the ovary in at least a subset of these patients.	('ovarian carcinomas', 'Disease', (14, 32))	('mutation', 'Var', (61, 69))	('lesion in the ovary', 'Phenotype', 'HP:0100615', (191, 210))	('BRCA', 'Gene', '672', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (14, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('BRCA', 'Gene', (56, 60))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (14, 31))	('SCs', 'molecular_function', 'GO:0004776', ('86', '89'))	('patients', 'Species', '9606', (241, 249))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (14, 32))
3125	22405464	There have now been numerous subsequent studies, in which fallopian tubes were more carefully examined, that confirmed the existence and incidence of STICs and early invasive tubal carcinomas in BRCA mutation carriers that underwent risk reducing salpingo-oophorectomy procedures.	('BRCA', 'Gene', '672', (195, 199))	('BRCA', 'Gene', (195, 199))	('fallopian tubes', 'Disease', (58, 73))	('STICs', 'Disease', (150, 155))	('invasive tubal carcinomas', 'Disease', (166, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('mutation', 'Var', (200, 208))	('invasive tubal carcinomas', 'Disease', 'MESH:D011274', (166, 191))	('fallopian tubes', 'Disease', 'MESH:D005184', (58, 73))
3134	22405464	The above observations and similar other studies, gave support to the proposal that STICs, which almost always were detected in the fimbria, may be the source of HG-SCs in both BRCA mutation carriers as well as women who do not have a known genetic predisposition for ovarian cancer.	('ovarian cancer', 'Disease', (268, 282))	('women', 'Species', '9606', (211, 216))	('fimbria', 'cellular_component', 'GO:0009289', ('132', '139'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (268, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('mutation', 'Var', (182, 190))	('BRCA', 'Gene', '672', (177, 181))	('ovarian cancer', 'Disease', 'MESH:D010051', (268, 282))	('BRCA', 'Gene', (177, 181))	('SCs', 'molecular_function', 'GO:0004776', ('165', '168'))
3139	22405464	Initial benign appearing secretory cell proliferations can be frequently identified in the fallopian tubes with BRCA mutations or serous carcinomas, either associated with p53 alterations (so-called p53 signatures), or found with other genetic alterations in the absence of alterations in p53 (secretory cell outgrowths or SCOUTs).	('BRCA', 'Gene', (112, 116))	('mutations', 'Var', (117, 126))	('p53', 'Gene', (199, 202))	('serous carcinomas', 'Disease', 'MESH:D018284', (130, 147))	('p53', 'Gene', (289, 292))	('fallopian tubes', 'Disease', (91, 106))	('serous carcinomas', 'Disease', (130, 147))	('p53', 'Gene', '7157', (199, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('p53', 'Gene', '7157', (289, 292))	('p53', 'Gene', '7157', (172, 175))	('alterations', 'Var', (176, 187))	('fallopian tubes', 'Disease', 'MESH:D005184', (91, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('associated', 'Reg', (156, 166))	('BRCA', 'Gene', '672', (112, 116))	('p53', 'Gene', (172, 175))
3142	22405464	In a study by Lee et al, p53 signatures were observed in 37% and 33% of women with and without BRCA mutations respectively.	('p53', 'Gene', (25, 28))	('mutations', 'Var', (100, 109))	('p53', 'Gene', '7157', (25, 28))	('BRCA', 'Gene', (95, 99))	('observed', 'Reg', (45, 53))	('BRCA', 'Gene', '672', (95, 99))	('women', 'Species', '9606', (72, 77))
3144	22405464	p53 signature shares several attributes with STIC, including: 1) fimbrial location in > 80%; 2) intense p53 immunoreactivity; 3) involvement of the secretory cell; 4) evidence of DNA damage as manifested by punctuate immunopositivity for gamma-H2AX; 5) TP53 mutations in approximately 60%; 6) identical TP53 mutations with concurrent STIC lesions; 7) occasionally, direct continuity with STIC.	('mutations', 'Var', (258, 267))	('p53', 'Gene', (0, 3))	('p53', 'Gene', (104, 107))	('p53', 'Gene', '7157', (0, 3))	('TP53', 'Gene', '7157', (303, 307))	('TP53', 'Gene', (303, 307))	('p53', 'Gene', '7157', (104, 107))	('mutations', 'Var', (308, 317))	('STIC', 'Disease', (45, 49))	('STIC lesions', 'Disease', (334, 346))	('TP53', 'Gene', '7157', (253, 257))	('TP53', 'Gene', (253, 257))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))
3146	22405464	To determine whether the same lesions also occur in the ovarian epithelium or cortical inclusions, Folkins et al examined the ovaries of 75 BRCA mutation carriers, only one OSE showed p53 signature and none in cortical inclusions, confirming that p53 signatures preferentially arise in fallopian tube epithelium rather than OSE.	('BRCA', 'Gene', '672', (140, 144))	('ovarian epithelium', 'Disease', (56, 74))	('BRCA', 'Gene', (140, 144))	('p53', 'Gene', (184, 187))	('p53', 'Gene', '7157', (184, 187))	('ovarian epithelium', 'Disease', 'MESH:D010049', (56, 74))	('p53', 'Gene', '7157', (247, 250))	('OSE', 'Chemical', '-', (173, 176))	('OSE', 'Chemical', '-', (324, 327))	('p53', 'Gene', (247, 250))	('mutation', 'Var', (145, 153))
3147	22405464	Based on these findings, a sequence of pathogenetic events has been proposed that under some genotoxic events, secretory cells are prone to DNA damage, followed by TP53 mutation and progressive loss of cell cycle control, which eventuate in the development of carcinoma.	('TP53', 'Gene', '7157', (164, 168))	('carcinoma', 'Disease', (260, 269))	('mutation', 'Var', (169, 177))	('TP53', 'Gene', (164, 168))	('cell cycle control', 'biological_process', 'GO:1901987', ('202', '220'))	('cell cycle control', 'CPA', (202, 220))	('loss', 'NegReg', (194, 198))	('carcinoma', 'Disease', 'MESH:D002277', (260, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))
3148	22405464	The frequency of p53 signatures in women with and without BRCA mutations is nearly the same, suggesting that p53 signature is not directly linked to this genetic risk factor.	('mutations', 'Var', (63, 72))	('women', 'Species', '9606', (35, 40))	('BRCA', 'Gene', '672', (58, 62))	('BRCA', 'Gene', (58, 62))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
3150	22405464	In contrast, it is hypothesized that for the women who have BRCA mutations, they are particularly susceptible to subsequent events, such as loss of BRCA1 or BRCA2 function since they have had a preexisting germline mutation.	('BRCA', 'Gene', (157, 161))	('BRCA', 'Gene', '672', (148, 152))	('BRCA1', 'Gene', '672', (148, 153))	('BRCA', 'Gene', (148, 152))	('BRCA2', 'Gene', (157, 162))	('BRCA1', 'Gene', (148, 153))	('function', 'MPA', (163, 171))	('BRCA', 'Gene', '672', (60, 64))	('women', 'Species', '9606', (45, 50))	('loss', 'NegReg', (140, 144))	('BRCA', 'Gene', '672', (157, 161))	('BRCA2', 'Gene', '675', (157, 162))	('BRCA', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
3154	22405464	Some studies investigated the frequency of SCOUTs using the patterns of BCL2/p73 immunostaining in tubes from women with serous carcinoma, inherited mutations in BRCA1 or BRCA2 and benign controls.	('mutations', 'Var', (149, 158))	('serous carcinoma', 'Disease', (121, 137))	('BRCA1', 'Gene', '672', (162, 167))	('serous carcinoma', 'Disease', 'MESH:D018284', (121, 137))	('BCL2', 'molecular_function', 'GO:0015283', ('72', '76'))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('BCL2', 'Gene', '596', (72, 76))	('p73', 'Gene', '7161', (77, 80))	('BRCA2', 'Gene', (171, 176))	('BRCA1', 'Gene', (162, 167))	('p73', 'Gene', (77, 80))	('BCL2', 'Gene', (72, 76))	('BRCA2', 'Gene', '675', (171, 176))	('women', 'Species', '9606', (110, 115))
3157	22405464	All three entities can, on occasion, be demonstrated in continuity, and may share identical TP53 mutations and loss of PAX2 staining.	('mutations', 'Var', (97, 106))	('PAX2', 'Gene', '5076', (119, 123))	('TP53', 'Gene', '7157', (92, 96))	('PAX2', 'Gene', (119, 123))	('TP53', 'Gene', (92, 96))
3158	22405464	These findings indicate that PAX2 dysfunction is involved in HG-SC development.	('dysfunction', 'Var', (34, 45))	('HG-SC', 'Disease', (61, 66))	('PAX2', 'Gene', (29, 33))	('involved', 'Reg', (49, 57))	('PAX2', 'Gene', '5076', (29, 33))
3159	22405464	However, only a few SCOUTs with both abnormal p53 and PAX2 expression (p53 signatures) are linked firmly enough to pelvic serous cancers to be confirmatory of a causal relationship.	('pelvic serous cancers', 'Disease', (115, 136))	('PAX2', 'Gene', '5076', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p53', 'Gene', (46, 49))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('pelvic serous cancers', 'Disease', 'MESH:D010386', (115, 136))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (46, 49))	('p53', 'Gene', '7157', (71, 74))	('PAX2', 'Gene', (54, 58))	('abnormal', 'Var', (37, 45))
3162	22405464	Intense p53 immunoreactivity and TP53 gene mutations have been observed in STICs, and half of p53 signatures display TP53 mutations.	('p53', 'Gene', (94, 97))	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (94, 97))	('STICs', 'Disease', (75, 80))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('p53', 'Gene', '7157', (8, 11))	('TP53', 'Gene', '7157', (33, 37))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', (33, 37))
3163	22405464	In some cases p53 signatures and STICs share identical TP53 mutations with the concomitant HG-SC, suggesting a clonal relationship between them.	('HG-SC', 'Disease', (91, 96))	('TP53', 'Gene', '7157', (55, 59))	('p53', 'Gene', (14, 17))	('TP53', 'Gene', (55, 59))	('p53', 'Gene', '7157', (14, 17))	('mutations', 'Var', (60, 69))
3197	22405464	Mutations in TP53 were seen in at least 96% of cases, and BRCA1/2 alterations were seen in 22% of tumors due to a combination of germline and somatic mutations.	('TP53', 'Gene', (13, 17))	('tumors', 'Disease', (98, 104))	('seen', 'Reg', (83, 87))	('BRCA1/2', 'Gene', '672;675', (58, 65))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('BRCA1/2', 'Gene', (58, 65))
3199	22405464	In general, most of the mutations in TP53 are frameshift or nonsense mutations that increase the stability of the altered and truncated protein, leading to accumulation detectable by immunohistochemistry.	('TP53', 'Gene', (37, 41))	('frameshift', 'Var', (46, 56))	('stability', 'MPA', (97, 106))	('increase', 'PosReg', (84, 92))	('mutations', 'Var', (24, 33))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('TP53', 'Gene', '7157', (37, 41))	('accumulation', 'PosReg', (156, 168))
3200	22405464	However, the mutations are sometimes insertions, deletions, or stop codons leading to lack of p53 production.	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('lack', 'NegReg', (86, 90))	('deletions', 'Var', (49, 58))	('insertions', 'Var', (37, 47))
3201	22405464	Intense p53 staining and TP53 mutations have been observed in p53 signatures and STIC of fallopian tubes.	('TP53', 'Gene', (25, 29))	('p53', 'Gene', (8, 11))	('fallopian tubes', 'Disease', (89, 104))	('p53', 'Gene', '7157', (8, 11))	('TP53', 'Gene', '7157', (25, 29))	('mutations', 'Var', (30, 39))	('fallopian tubes', 'Disease', 'MESH:D005184', (89, 104))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
3204	22405464	In contrast, there is little, if any, difference in the frequency of p53 signatures in BRCA mutation carriers versus non-carriers, which suggest that although TP53 mutations are necessary in the genesis of HG-SC, they are not sufficient to trigger a sequence of neoplasia.	('mutation', 'Var', (92, 100))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('BRCA', 'Gene', '672', (87, 91))	('neoplasia', 'Phenotype', 'HP:0002664', (262, 271))	('neoplasia', 'Disease', 'MESH:D009369', (262, 271))	('BRCA', 'Gene', (87, 91))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (159, 163))	('HG-SC', 'Disease', (206, 211))	('neoplasia', 'Disease', (262, 271))	('mutations', 'Var', (164, 173))
3206	22405464	BRCA1 or BRCA2 gene mutations represent a high-risk factor for HG-SC, and women harboring such mutations have a 30% to 70% chance of developing ovarian cancer by the age of 70.	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', (9, 14))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('women', 'Species', '9606', (74, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('BRCA2', 'Gene', '675', (9, 14))	('HG-SC', 'Disease', (63, 68))	('ovarian cancer', 'Disease', (144, 158))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('BRCA1', 'Gene', '672', (0, 5))	('mutations', 'Var', (20, 29))
3208	22405464	As previously noted, up to 22% of HG-SC have germline or somatic mutations in BRCA1/2.	('BRCA1/2', 'Gene', '672;675', (78, 85))	('germline', 'Var', (45, 53))	('BRCA1/2', 'Gene', (78, 85))	('HG-SC', 'Disease', (34, 39))
3209	22405464	Approximately 11% of HG-SCs have lost BRCA1 expression through DNA hypermethylation, and that epigenetic silencing of BRCA1 is mutually exclusive of either BRCA1 or BRCA2 mutations.	('BRCA2', 'Gene', '675', (165, 170))	('expression', 'MPA', (44, 54))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('63', '83'))	('SCs', 'molecular_function', 'GO:0004776', ('24', '27'))	('epigenetic silencing', 'Var', (94, 114))	('BRCA1', 'Gene', (38, 43))	('BRCA1', 'Gene', '672', (118, 123))	('BRCA1', 'Gene', '672', (156, 161))	('BRCA2', 'Gene', (165, 170))	('BRCA1', 'Gene', (118, 123))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('lost', 'NegReg', (33, 37))	('BRCA1', 'Gene', '672', (38, 43))	('BRCA1', 'Gene', (156, 161))
3210	22405464	Only one-wild allele of BRCA1 or BRCA2 is sufficient for DNA repair mechanism, and additional somatic loss of the wild-type allele is needed in the development of carcinoma in women with germline BRCA mutations.	('BRCA', 'Gene', (196, 200))	('mutations', 'Var', (201, 210))	('BRCA1', 'Gene', '672', (24, 29))	('BRCA', 'Gene', '672', (24, 28))	('carcinoma', 'Disease', 'MESH:D002277', (163, 172))	('BRCA2', 'Gene', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('BRCA', 'Gene', (24, 28))	('DNA repair', 'biological_process', 'GO:0006281', ('57', '67'))	('BRCA1', 'Gene', (24, 29))	('carcinoma', 'Disease', (163, 172))	('BRCA', 'Gene', '672', (33, 37))	('BRCA2', 'Gene', '675', (33, 38))	('BRCA', 'Gene', (33, 37))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('BRCA', 'Gene', '672', (196, 200))	('women', 'Species', '9606', (176, 181))
3211	22405464	Many studies have found such LOH of BRCA in early ovarian serous carcinoma, STIC, and even in some OEIs/OSE in ovaries from prophylactic oophorectomy specimens, indicating that loss of BRCA function is an early event in HG-SCs.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('BRCA', 'Gene', '672', (185, 189))	('BRCA', 'Gene', (185, 189))	('ovarian serous carcinoma', 'Disease', (50, 74))	('BRCA', 'Gene', '672', (36, 40))	('loss', 'Var', (177, 181))	('SCs', 'molecular_function', 'GO:0004776', ('223', '226'))	('BRCA', 'Gene', (36, 40))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (50, 74))	('STIC', 'Disease', (76, 80))	('OSE', 'Chemical', '-', (104, 107))
3212	22405464	TP53 mutations and BRCA1/BRCA2 inactivations are both early events in HG-SCs, and the specific carcinogenetic sequence of these gene alterations is becoming clearer.	('BRCA2', 'Gene', (25, 30))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('inactivations', 'Var', (31, 44))	('SCs', 'molecular_function', 'GO:0004776', ('73', '76'))	('BRCA2', 'Gene', '675', (25, 30))	('mutations', 'Var', (5, 14))	('BRCA1', 'Gene', '672', (19, 24))	('BRCA1', 'Gene', (19, 24))	('HG-SCs', 'Disease', (70, 76))
3213	22405464	p53 signature is common in women with and without inherited mutations in BRCA1 or BRCA2 .	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('BRCA2', 'Gene', (82, 87))	('BRCA1', 'Gene', '672', (73, 78))	('BRCA2', 'Gene', '675', (82, 87))	('BRCA1', 'Gene', (73, 78))	('mutations', 'Var', (60, 69))	('women', 'Species', '9606', (27, 32))	('common', 'Reg', (17, 23))
3214	22405464	On the other hand, in a small series of STIC and p53 signatures analyzed in women with germline BRCA1 mutations, loss of the wide-type BRCA1 allele was observed in STIC but not in the p53 signature foci.	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('BRCA1', 'Gene', '672', (96, 101))	('BRCA1', 'Gene', '672', (135, 140))	('p53', 'Gene', (184, 187))	('p53', 'Gene', '7157', (184, 187))	('loss', 'NegReg', (113, 117))	('mutations', 'Var', (102, 111))	('BRCA1', 'Gene', (135, 140))	('BRCA1', 'Gene', (96, 101))	('women', 'Species', '9606', (76, 81))
3215	22405464	These findings indicate that loss of BRCA1 and/or BRCA2 function is not necessary for p53 signature's formation and is presumed a later event than TP53 mutation.	('p53', 'Gene', (86, 89))	('TP53', 'Gene', (147, 151))	('p53', 'Gene', '7157', (86, 89))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('BRCA2', 'Gene', (50, 55))	('loss', 'Var', (29, 33))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA2', 'Gene', '675', (50, 55))	('TP53', 'Gene', '7157', (147, 151))	('BRCA1', 'Gene', (37, 42))
3216	22405464	For example, despite the abundance of TP53 mutations in LFS, inactivation of a second critical gene- such as BRCA- is not more likely to occur in this syndrome, leading to a similar frequency of ovarian cancer therein with that of the general population.	('inactivation', 'Var', (61, 73))	('LFS', 'Disease', 'MESH:D016864', (56, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (195, 209))	('ovarian cancer', 'Disease', 'MESH:D010051', (195, 209))	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('BRCA', 'Gene', '672', (109, 113))	('LFS', 'Disease', (56, 59))	('ovarian cancer', 'Disease', (195, 209))	('leading to', 'Reg', (161, 171))	('BRCA', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('TP53', 'Gene', '7157', (38, 42))
3218	22405464	Genome-wide analysis of DNA copy number alterations has demonstrated significant numbers of amplifications and deletions, among which the alterations in cyclin E1, AKT2, Notch3, PIK3CA, c-Myc, RB1, CDKN2A/B, CDK12, CSMD1, CSMD3, DOCK4, NF1, FAT3, GABRA6 are most common.	('AKT2', 'Gene', '208', (164, 168))	('NF1', 'Gene', '4763', (236, 239))	('c-Myc', 'Gene', '4609', (186, 191))	('DOCK4', 'Gene', '9732', (229, 234))	('GABRA6', 'Gene', '2559', (247, 253))	('FAT3', 'Gene', (241, 245))	('CSMD3', 'Gene', (222, 227))	('AKT2', 'Gene', (164, 168))	('CDK', 'molecular_function', 'GO:0004693', ('208', '211'))	('CDK12', 'Gene', '51755', (208, 213))	('GABRA6', 'Gene', (247, 253))	('cyclin E1', 'Gene', (153, 162))	('PIK3CA', 'Gene', (178, 184))	('NF1', 'Gene', (236, 239))	('alterations', 'Var', (138, 149))	('DOCK4', 'Gene', (229, 234))	('cyclin', 'molecular_function', 'GO:0016538', ('153', '159'))	('CDKN2A/B', 'Gene', (198, 206))	('FAT3', 'Gene', '120114', (241, 245))	('RB1', 'Gene', (193, 196))	('CSMD1', 'Gene', '64478', (215, 220))	('alterations', 'Var', (40, 51))	('CSMD1', 'Gene', (215, 220))	('Notch3', 'Gene', '4854', (170, 176))	('Notch3', 'Gene', (170, 176))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('CDK12', 'Gene', (208, 213))	('CDKN2A/B', 'Gene', '1029;1030', (198, 206))	('c-Myc', 'Gene', (186, 191))	('PIK3CA', 'Gene', '5290', (178, 184))	('RB1', 'Gene', '5925', (193, 196))	('CSMD3', 'Gene', '114788', (222, 227))	('cyclin E1', 'Gene', '898', (153, 162))
3219	22405464	Genetically, LG-SCs are relatively stable and typically display a variety of mutations related to specific signaling pathways, including KRAS or BRAF but very rarely TP53.	('display', 'Reg', (56, 63))	('BRAF', 'Gene', (145, 149))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('TP53', 'Gene', '7157', (166, 170))	('SCs', 'molecular_function', 'GO:0004776', ('16', '19'))	('mutations', 'Var', (77, 86))	('TP53', 'Gene', (166, 170))	('KRAS', 'Gene', (137, 141))	('KRAS', 'Gene', '3845', (137, 141))	('BRAF', 'Gene', '673', (145, 149))
3220	22405464	One study found KRAS mutations at codons 12 and 13 in 35% of LG-SCs and in 33% of borderline tumors.	('LG-SCs', 'Disease', (61, 67))	('borderline tumors', 'Disease', (82, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('KRAS', 'Gene', (16, 20))	('borderline tumors', 'Disease', 'MESH:D012569', (82, 99))	('SCs', 'molecular_function', 'GO:0004776', ('64', '67'))	('KRAS', 'Gene', '3845', (16, 20))	('mutations', 'Var', (21, 30))
3221	22405464	Similarly, BRAF mutations at codon 599 were seen in 30% of LG-SC and 28% of serous borderline tumors.	('serous borderline tumors', 'Disease', (76, 100))	('LG-SC', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('serous borderline tumors', 'Disease', 'MESH:D012569', (76, 100))	('BRAF', 'Gene', '673', (11, 15))	('seen', 'Reg', (44, 48))	('BRAF', 'Gene', (11, 15))
3223	22405464	Thus, more than 60% of LG-SCs and borderline tumors have mutations of KRAS, BRAF or ERBB2.	('ERBB2', 'Gene', (84, 89))	('BRAF', 'Gene', (76, 80))	('LG-SCs', 'Disease', (23, 29))	('BRAF', 'Gene', '673', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('borderline tumors', 'Disease', (34, 51))	('KRAS', 'Gene', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('KRAS', 'Gene', '3845', (70, 74))	('SCs', 'molecular_function', 'GO:0004776', ('26', '29'))	('mutations', 'Var', (57, 66))	('ERBB2', 'Gene', '2064', (84, 89))	('borderline tumors', 'Disease', 'MESH:D012569', (34, 51))
3224	22405464	Furthermore, KRAS or BRAF mutations can be detected even in benign cystadenomas, indicating they are early events in the carcinogenesis of LG-SC.	('benign cystadenomas', 'Disease', (60, 79))	('benign cystadenomas', 'Disease', 'MESH:D003537', (60, 79))	('BRAF', 'Gene', '673', (21, 25))	('mutations', 'Var', (26, 35))	('BRAF', 'Gene', (21, 25))	('LG-SC', 'Disease', (139, 144))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
3228	22405464	TP53 mutation is an early event, which may result in clonal alterations that is the latent precursor, p53 signature.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('p53', 'Gene', '7157', (102, 105))	('result in', 'Reg', (43, 52))	('clonal', 'MPA', (53, 59))	('p53', 'Gene', (102, 105))	('mutation', 'Var', (5, 13))
3231	22405464	Two possibilities exist for how this detachment and implantation occurs: 1) Given the close spatial relationship between the ovarian surface and the tubal fimbriated end, ovulation or non-ovulation induced disruption of the ovarian surface, may offer an opportunity for the adjacent tubal epithelium to detach and implant in the ovarian stroma and 2) Adhesion of tubal epithelium on the ovarian surface, from inflammation or other factors, and ongoing stromal growth around it may eventuate in fallopian tube derived-OEI formation.	('ovulation', 'biological_process', 'GO:0030728', ('188', '197'))	('ovarian stroma', 'Disease', 'MESH:D010051', (329, 343))	('ovulation', 'biological_process', 'GO:0030728', ('171', '180'))	('inflammation', 'biological_process', 'GO:0006954', ('409', '421'))	('ovarian stroma', 'Disease', (329, 343))	('formation', 'biological_process', 'GO:0009058', ('521', '530'))	('disruption', 'Var', (206, 216))	('eventuate', 'Reg', (481, 490))	('inflammation', 'Disease', 'MESH:D007249', (409, 421))	('inflammation', 'Disease', (409, 421))	('fallopian tube derived-OEI formation', 'CPA', (494, 530))
3232	22405464	The acquisition of KRAS or BRAF and possibly other mutations in tubal derived OEIs and serous cystadenomas result in their transformation to serous borderline tumors and ultimately, LG-SC.	('transformation', 'Reg', (123, 137))	('serous cystadenomas', 'Phenotype', 'HP:0012887', (87, 106))	('serous cystadenoma', 'Phenotype', 'HP:0012887', (87, 105))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('LG-SC', 'Disease', (182, 187))	('KRAS', 'Gene', (19, 23))	('BRAF', 'Gene', '673', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('KRAS', 'Gene', '3845', (19, 23))	('serous borderline tumors', 'Disease', 'MESH:D012569', (141, 165))	('serous cystadenomas', 'Disease', (87, 106))	('acquisition', 'Var', (4, 15))	('BRAF', 'Gene', (27, 31))	('serous cystadenomas', 'Disease', 'MESH:D018293', (87, 106))	('serous borderline tumors', 'Disease', (141, 165))
3237	22405464	In one large multi-institutional prospective study of 35000 women screened with CA-125 and transvaginal ultrasounds, 70% of the women presented with advanced stage disease, which was no different from unscreened populations.	('women', 'Species', '9606', (128, 133))	('advanced', 'Disease', (149, 157))	('women', 'Species', '9606', (60, 65))	('presented with', 'Reg', (134, 148))	('CA-125', 'Var', (80, 86))
3244	22405464	Clonal expansions of the tubal secretory cell probably give rise to both low- and high-grade serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('give rise', 'Reg', (55, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('normal differentiation', 'CPA', (215, 237))	('Clonal', 'Var', (0, 6))	('serous carcinomas', 'Disease', 'MESH:D018284', (93, 110))	('low-', 'Disease', (73, 77))	('serous carcinomas', 'Disease', (93, 110))	('deregulate', 'Reg', (204, 214))
3257	31399054	CN is upregulated in ovarian cancer tissues with later-stage and that the expression of CN, CA72-4, and CEA was remarkably associated with poor prognosis in unique subtype of ovarian cancer.	('associated', 'Reg', (123, 133))	('subtype of ovarian cancer', 'Disease', 'MESH:D010051', (164, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('CEA', 'Gene', '5670', (104, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (175, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (21, 35))	('expression', 'Var', (74, 84))	('CEA', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('upregulated', 'PosReg', (6, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('ovarian cancer', 'Disease', (21, 35))	('CA72-4', 'Var', (92, 98))	('subtype of ovarian cancer', 'Disease', (164, 189))
3290	31399054	Kaplan-Meier curve with log-rank test presenting the disease-free survival and overall survival of ovarian cancer exhibiting high or low CN expression.	('ovarian cancer', 'Phenotype', 'HP:0100615', (99, 113))	('ovarian cancer', 'Disease', 'MESH:D010051', (99, 113))	('low', 'NegReg', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ovarian cancer', 'Disease', (99, 113))	('high', 'Var', (125, 129))
3311	31399054	As observed by Peuker et al., calcineurin and downstream signalling pathways are activated in colorectal cancer tumors and cell lines, and inhibition of calcineurin decreases cancer stem cell survival and proliferation.	('inhibition', 'Var', (139, 149))	('calcineurin', 'molecular_function', 'GO:0004722', ('30', '41'))	('calcineurin', 'molecular_function', 'GO:0004723', ('30', '41'))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('calcineurin', 'Enzyme', (30, 41))	('calcineurin', 'molecular_function', 'GO:0004723', ('153', '164'))	('activated', 'PosReg', (81, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('calcineurin', 'molecular_function', 'GO:0004722', ('153', '164'))	('colorectal cancer tumors', 'Disease', (94, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('decreases cancer', 'Disease', 'MESH:D009369', (165, 181))	('colorectal cancer tumors', 'Disease', 'MESH:D015179', (94, 118))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('signalling', 'biological_process', 'GO:0023052', ('57', '67'))	('decreases cancer', 'Disease', (165, 181))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('downstream signalling pathways', 'Pathway', (46, 76))
3336	31399054	CA72-4 is less sensitive than CA125 for EOC, but it is not influenced by pregnancy or the menstrual cycle, and it is only slightly influenced by inflammatory conditions.	('CA125', 'Gene', '94025', (30, 35))	('CA72-4', 'Var', (0, 6))	('menstrual cycle', 'biological_process', 'GO:0044850', ('90', '105'))	('CA125', 'Gene', (30, 35))	('OC', 'Phenotype', 'HP:0100615', (41, 43))
3342	31399054	In the present study, we have, for the first time, found that CN is significantly upregulated in ovarian cancer tissues with later-stage and that the expression of CN, CEA, and CA72-4 was remarkably associated with poor prognosis in unique subtype of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('associated', 'Reg', (199, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (251, 265))	('ovarian cancer', 'Disease', (97, 111))	('upregulated', 'PosReg', (82, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (251, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CA72-4', 'Var', (177, 183))	('CEA', 'Gene', (168, 171))	('subtype of ovarian cancer', 'Disease', (240, 265))	('subtype of ovarian cancer', 'Disease', 'MESH:D010051', (240, 265))	('CEA', 'Gene', '5670', (168, 171))
3351	20001801	As there are a vast number of genes for which molecular genetic changes and aberrant gene expression have been reported in ovarian cancer, this review will only focus on summarizing those exemplified genes that have been demonstrated to have biological functions in promoting ovarian cancer development and potential clinical significance.	('ovarian cancer', 'Disease', 'MESH:D010051', (276, 290))	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (123, 137))	('aberrant', 'Var', (76, 84))	('ovarian cancer', 'Disease', (276, 290))	('promoting', 'PosReg', (266, 275))	('ovarian cancer', 'Disease', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('ovarian cancer', 'Phenotype', 'HP:0100615', (276, 290))
3359	20001801	As a result, a number of genes with molecular genetic changes and aberrant gene expression have been discovered in ovarian cancer, and several of those gene products may have clinical implications.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('changes', 'Var', (54, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('aberrant', 'Var', (66, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('gene expression', 'biological_process', 'GO:0010467', ('75', '90'))	('ovarian cancer', 'Disease', (115, 129))
3372	20001801	For example, high-grade serous carcinoma, the most common and malignant type of ovarian cancer, is characterized by very frequent TP53 mutations and CCNE1 (encoding cyclin E1) amplification, while low-grade serous carcinoma harbors either KRAS, BRAF or ERRB2 mutations in approximately two-thirds of cases.	('malignant type of ovarian cancer', 'Disease', (62, 94))	('serous carcinoma harbors', 'Disease', (207, 231))	('cyclin', 'molecular_function', 'GO:0016538', ('165', '171'))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CCNE1', 'Gene', (149, 154))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('cyclin E1', 'Gene', '898', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('mutations', 'Var', (135, 144))	('KRAS', 'Gene', '3845', (239, 243))	('serous carcinoma', 'Disease', (24, 40))	('TP53', 'Gene', (130, 134))	('CCNE1', 'Gene', '898', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('ERRB2', 'Gene', (253, 258))	('serous carcinoma', 'Disease', 'MESH:D018284', (207, 223))	('amplification', 'PosReg', (176, 189))	('malignant type of ovarian cancer', 'Disease', 'MESH:D010051', (62, 94))	('KRAS', 'Gene', (239, 243))	('cyclin E1', 'Gene', (165, 174))	('serous carcinoma', 'Disease', 'MESH:D018284', (24, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('serous carcinoma harbors', 'Disease', 'MESH:C537062', (207, 231))	('TP53', 'Gene', '7157', (130, 134))
3373	20001801	Clear-cell carcinoma is unique for its high percentage of PIK3CA activating mutations when purified tumor samples and cell lines are analyzed.	('Clear-cell carcinoma', 'Disease', 'MESH:C538614', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (100, 105))	('activating', 'PosReg', (65, 75))	('PIK3CA', 'Gene', (58, 64))	('Clear-cell carcinoma', 'Disease', (0, 20))	('PIK3CA', 'Gene', '5290', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
3374	20001801	Endometrioid carcinoma has unique aberration in a signaling pathway invovling somatic mutations of CTNNB1 (encoding beta-catenin), PTEN and PIK3CA.	('signaling pathway', 'biological_process', 'GO:0007165', ('50', '67'))	('mutations', 'Var', (86, 95))	('PIK3CA', 'Gene', (140, 146))	('CTNNB1', 'Gene', (99, 105))	('PTEN', 'Gene', (131, 135))	('Endometrioid carcinoma', 'Disease', 'MESH:D016889', (0, 22))	('PTEN', 'Gene', '5728', (131, 135))	('PIK3CA', 'Gene', '5290', (140, 146))	('CTNNB1', 'Gene', '1499', (99, 105))	('signaling pathway', 'Pathway', (50, 67))	('Endometrioid carcinoma', 'Phenotype', 'HP:0012114', (0, 22))	('Endometrioid carcinoma', 'Disease', (0, 22))	('beta-catenin', 'Gene', (116, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('beta-catenin', 'Gene', '1499', (116, 128))
3382	20001801	This results in protease cleavages and the release of the Notch intracellular domain (NICD), which is then translocated into the nucleus where it cooperates with the DNA-binding protein CSL to activate transcription of Notch downstream effectors (Figure 3).	('intracellular', 'cellular_component', 'GO:0005622', ('64', '77'))	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('Notch', 'Gene', '4851;4854', (219, 224))	('Notch', 'Gene', '4851;4854', (58, 63))	('protease', 'MPA', (16, 24))	('transcription', 'MPA', (202, 215))	('Notch', 'Gene', (219, 224))	('Notch', 'Gene', (58, 63))	('transcription', 'biological_process', 'GO:0006351', ('202', '215'))	('CSL', 'Gene', (186, 189))	('release', 'MPA', (43, 50))	('results in', 'Reg', (5, 15))	('activate', 'PosReg', (193, 201))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('nucleus', 'cellular_component', 'GO:0005634', ('129', '136'))	('CSL', 'Gene', '3516', (186, 189))	('DNA-binding', 'molecular_function', 'GO:0003677', ('166', '177'))	('cleavages', 'Var', (25, 34))
3384	20001801	have identified Notch3 gene (19p13.12) amplification in 19.5% of ovarian high-grade serous carcinomas.	('amplification', 'Var', (39, 52))	('ovarian high', 'Phenotype', 'HP:0008209', (65, 77))	('19p13.12', 'Gene', (29, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('Notch3', 'Gene', '4854', (16, 22))	('serous carcinomas', 'Disease', 'MESH:D018284', (84, 101))	('Notch3', 'Gene', (16, 22))	('serous carcinomas', 'Disease', (84, 101))
3387	20001801	These studies suggest that constitutive Notch3 expression due to gene amplification or epigenetic activation participates in the development of ovarian serous carcinomas.	('ovarian serous carcinomas', 'Disease', (144, 169))	('Notch3', 'Gene', '4854', (40, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('Notch3', 'Gene', (40, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (144, 169))	('gene amplification', 'Var', (65, 83))	('participates', 'Reg', (109, 121))	('epigenetic activation', 'Var', (87, 108))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (144, 169))
3391	20001801	Amplification of the chromosome 11q13.5 locus is frequently detected in several types of human cancer, including ovarian serous carcinoma, of which 11q13.5 amplification was associated with significantly shorter overall survival in ovarian cancer patients.	('amplification', 'Var', (156, 169))	('11q13.5', 'Gene', (148, 155))	('detected', 'Reg', (60, 68))	('shorter', 'NegReg', (204, 211))	('cancer', 'Disease', (240, 246))	('ovarian cancer', 'Disease', 'MESH:D010051', (232, 246))	('human', 'Species', '9606', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cancer', 'Disease', (95, 101))	('overall survival', 'MPA', (212, 228))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ovarian cancer', 'Disease', (232, 246))	('ovarian serous carcinoma', 'Disease', (113, 137))	('patients', 'Species', '9606', (247, 255))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('ovarian cancer', 'Phenotype', 'HP:0100615', (232, 246))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (113, 137))	('Amplification', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))
3392	20001801	In order to explore the molecular mechanisms by which amplification of this locus contributes to disease aggressiveness, investigators have screened the candidate genes within this amplicon for their contribution to drug resistance.	('contributes', 'Reg', (82, 93))	('aggressiveness', 'Disease', (105, 119))	('drug resistance', 'biological_process', 'GO:0009315', ('216', '231'))	('amplification', 'Var', (54, 67))	('drug resistance', 'Phenotype', 'HP:0020174', (216, 231))	('aggressiveness', 'Phenotype', 'HP:0000718', (105, 119))	('drug resistance', 'biological_process', 'GO:0042493', ('216', '231'))	('aggressiveness', 'Disease', 'MESH:D001523', (105, 119))
3393	20001801	Hepatitis B virus x-associated protein (HBXAP [Rsf-1]) was found to be the only gene in which knockdown sensitized tumor cells to paclitaxel.	('knockdown', 'Var', (94, 103))	('Rsf-1', 'Gene', '51773', (47, 52))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('HBXAP', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('HBXAP', 'Gene', '51773', (40, 45))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('sensitized', 'Reg', (104, 114))	('paclitaxel', 'Chemical', 'MESH:D017239', (130, 140))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('Rsf-1', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
3396	20001801	Downregulation of hSNF2H or disruption of hSNF2H and HBXAP (Rsf-1) interaction enhanced paclitaxel sensitivity in tumor cells with HBXAP (Rsf-1) upregulation.	('HBXAP', 'Gene', (53, 58))	('Rsf-1', 'Gene', '51773', (60, 65))	('Downregulation', 'NegReg', (0, 14))	('HBXAP', 'Gene', (131, 136))	('hSNF2H', 'Gene', '8467', (18, 24))	('Rsf-1', 'Gene', (138, 143))	('disruption', 'Var', (28, 38))	('enhanced', 'PosReg', (79, 87))	('tumor', 'Disease', (114, 119))	('paclitaxel', 'Chemical', 'MESH:D017239', (88, 98))	('hSNF2H', 'Gene', (42, 48))	('interaction', 'Interaction', (67, 78))	('Rsf-1', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('HBXAP', 'Gene', '51773', (53, 58))	('hSNF2H', 'Gene', (18, 24))	('HBXAP', 'Gene', '51773', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('paclitaxel sensitivity', 'MPA', (88, 110))	('Rsf-1', 'Gene', '51773', (138, 143))	('hSNF2H', 'Gene', '8467', (42, 48))
3406	20001801	In ovarian cancer, 11q13.5 amplification in ovarian serous carcinomas contributes to shorter overall survival as compared with those without 11q13.5 amplification (Figure 2).	('shorter', 'NegReg', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('overall survival', 'MPA', (93, 109))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (44, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('11q13.5 amplification', 'Var', (19, 40))	('ovarian serous carcinomas', 'Disease', (44, 69))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (44, 69))
3410	20001801	Third, hSNF2H has been shown to be required for cell proliferation and survival in HBXAP (Rsf-1) expressing OVCAR3 cells, but not in SKOV3 cells with or without Rsf-1 induction.	('SKOV3', 'CellLine', 'CVCL:0532', (133, 138))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))	('Rsf-1', 'Gene', '51773', (161, 166))	('Rsf-1', 'Gene', (90, 95))	('HBXAP', 'Gene', (83, 88))	('hSNF2H', 'Gene', (7, 13))	('Rsf-1', 'Gene', '51773', (90, 95))	('HBXAP', 'Gene', '51773', (83, 88))	('expressing', 'Var', (97, 107))	('Rsf-1', 'Gene', (161, 166))	('hSNF2H', 'Gene', '8467', (7, 13))
3419	20001801	Induced expression of the NAC1 deletion mutant (N130), exclusively containing the BTB/POZ domain, disrupts NAC1 nuclear bodies, prevents tumor formation and promotes tumor cell apoptosis in a mouse tumor xenograft model.	('mouse', 'Species', '10090', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('promotes', 'PosReg', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('NAC1', 'Gene', (26, 30))	('NAC1', 'Protein', (107, 111))	('N130', 'Var', (48, 52))	('NAC', 'cellular_component', 'GO:0005854', ('107', '110'))	('formation', 'biological_process', 'GO:0009058', ('143', '152'))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (166, 171))	('BTB', 'Chemical', '-', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('prevents', 'NegReg', (128, 136))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('NAC', 'cellular_component', 'GO:0005854', ('26', '29'))	('disrupts', 'NegReg', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
3434	20001801	Similar to the protein level, the FASN transcript level in SKOV3 cells was significantly reduced by N130 induction or by NAC1 knockdown.	('NAC1', 'Gene', (121, 125))	('FASN', 'Gene', (34, 38))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('FASN', 'Gene', '2194', (34, 38))	('SKOV3', 'CellLine', 'CVCL:0532', (59, 64))	('N130', 'Gene', (100, 104))	('reduced', 'NegReg', (89, 96))	('knockdown', 'Var', (126, 135))	('NAC', 'cellular_component', 'GO:0005854', ('121', '124'))
3436	20001801	Moreover, C93, a new FASN inhibitor, induced massive apoptosis in carboplatin-/paclitaxel-resistant ovarian cancer cells.	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('ovarian cancer', 'Disease', (100, 114))	('apoptosis', 'CPA', (53, 62))	('FASN', 'Gene', (21, 25))	('FASN', 'Gene', '2194', (21, 25))	('carboplatin', 'Chemical', 'MESH:D016190', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (100, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('C93', 'Var', (10, 13))
3441	20001801	Besides, a recent study demonstrated that the antitumor effects of FASN inhibitors in ovarian cancer cells may also be in part mediated by modulating other signaling pathways, including AMP-activated kinase, AKT and ErbB2, suggesting an alternative role of the metabolism-independent pathway involved in FASN-mediated tumor development (Figure 2).	('ovarian cancer', 'Disease', (86, 100))	('FASN', 'Gene', '2194', (67, 71))	('FASN', 'Gene', '2194', (304, 308))	('metabolism', 'biological_process', 'GO:0008152', ('261', '271'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('inhibitors', 'Var', (72, 82))	('AKT', 'Gene', '207', (208, 211))	('ErbB2', 'Gene', (216, 221))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', (50, 55))	('FASN', 'Gene', (67, 71))	('FASN', 'Gene', (304, 308))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('AMP-activated kinase', 'Pathway', (186, 206))	('signaling pathways', 'Pathway', (156, 174))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('AKT', 'Gene', (208, 211))	('modulating', 'Reg', (139, 149))	('ErbB2', 'Gene', '2064', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))
3446	20001801	Recent studies have demonstrated that Muc4 is involved in tyrosine kinase receptor-related signal transduction, and Muc4 expression can inhibit apoptosis induced by multiple insults including chemotherapeutic agents and the loss of cellular adhesion via ErbB2-dependent and ErbB2-independent mechanisms.	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('ErbB2', 'Gene', (274, 279))	('Muc4 expression', 'Var', (116, 131))	('inhibit', 'NegReg', (136, 143))	('ErbB2', 'Gene', (254, 259))	('ErbB2', 'Gene', '2064', (274, 279))	('apoptosis', 'CPA', (144, 153))	('signal transduction', 'biological_process', 'GO:0007165', ('91', '110'))	('expression', 'Var', (121, 131))	('cellular adhesion', 'CPA', (232, 249))	('ErbB2', 'Gene', '2064', (254, 259))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('loss', 'NegReg', (224, 228))
3449	20001801	Molecularly, inhibition of Muc4 expression suppresses pancreatic tumor cell growth and metastasis.	('pancreatic tumor', 'Disease', (54, 70))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (54, 70))	('suppresses', 'NegReg', (43, 53))	('cell growth', 'biological_process', 'GO:0016049', ('71', '82'))	('inhibition', 'Var', (13, 23))	('pancreatic tumor', 'Disease', 'MESH:D010190', (54, 70))	('Muc4', 'Protein', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
3450	20001801	Like in pancreatic cancer cells, Muc4 directly interacts with and stabilizes HER2 in ovarian cancer cells, and it has been demonstrated that Muc4 activates ERRB2 (Her2) signaling and enhances the motility of human ovarian cancer cells in vitro, probably through phosphorylation of focal adhesion kinase (FAK), Akt and ERK, downstream effectors of Her2.	('motility of human ovarian cancer', 'Disease', 'MESH:D010051', (196, 228))	('Akt', 'Gene', (310, 313))	('HER2', 'Gene', (77, 81))	('ovarian cancer', 'Disease', (85, 99))	('pancreatic cancer', 'Disease', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('FAK', 'molecular_function', 'GO:0004717', ('304', '307'))	('phosphorylation', 'biological_process', 'GO:0016310', ('262', '277'))	('enhances', 'PosReg', (183, 191))	('Akt', 'Gene', '207', (310, 313))	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('Her2', 'Gene', '2064', (347, 351))	('focal adhesion kinase', 'Gene', (281, 302))	('FAK', 'Gene', (304, 307))	('ERK', 'Gene', '5594', (318, 321))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Her2', 'Gene', (347, 351))	('ovarian cancer', 'Disease', 'MESH:D010051', (214, 228))	('activates', 'PosReg', (146, 155))	('FAK', 'Gene', '5747', (304, 307))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (8, 25))	('motility of human ovarian cancer', 'Disease', (196, 228))	('Her2', 'Gene', '2064', (163, 167))	('HER2', 'Gene', '2064', (77, 81))	('ERK', 'Gene', (318, 321))	('Her2', 'Gene', (163, 167))	('focal adhesion', 'cellular_component', 'GO:0005925', ('281', '295'))	('ovarian cancer', 'Disease', 'MESH:D010051', (85, 99))	('ERRB2', 'Protein', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('Muc4', 'Var', (141, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (214, 228))	('pancreatic cancer', 'Disease', 'MESH:D010190', (8, 25))	('ERK', 'molecular_function', 'GO:0004707', ('318', '321'))	('focal adhesion kinase', 'Gene', '5747', (281, 302))
3466	20001801	Future clinical trials may determine if M912 has a potential for cancer treatment in patients with pancreatic and ovarian cancer.	('pancreatic and ovarian cancer', 'Disease', 'MESH:D010190', (99, 128))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (85, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('M912', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
3476	20001801	Therefore, inhibition of apoE expression inactivates the apoE-related pathway(s), resulting in cell-cycle arrest and apoptosis.	('arrest', 'Disease', (106, 112))	('apoE', 'Gene', (25, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('95', '112'))	('apoE-related pathway', 'Pathway', (57, 77))	('inhibition', 'Var', (11, 21))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('apoptosis', 'CPA', (117, 126))	('arrest', 'Disease', 'MESH:D006323', (106, 112))	('inactivates', 'NegReg', (41, 52))
3477	20001801	In addition to lipid transport and signal transduction as described above, apoE may modify the tumor microenvironment to maintain tumor proliferation and survival, as a previous study has demonstrated that apoE induces expression of subendothelial heparan sulfate proteoglycan, which may be critical for apoE in preventing programmed cell death.	('apoE', 'Var', (206, 210))	('programmed cell death', 'biological_process', 'GO:0012501', ('323', '344'))	('signal transduction', 'biological_process', 'GO:0007165', ('35', '54'))	('proteoglycan', 'molecular_function', 'GO:0005203', ('264', '276'))	('expression', 'MPA', (219, 229))	('subendothelial heparan sulfate proteoglycan', 'Protein', (233, 276))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('lipid transport', 'biological_process', 'GO:0006869', ('15', '30'))	('tumor', 'Disease', (130, 135))	('lipid', 'Chemical', 'MESH:D008055', (15, 20))	('tumor', 'Disease', (95, 100))
3542	20001801	In the 'canonical' NF-kappaB pathway, activated by TNF-alpha, IL-1 and other stimuli, IkappaBalpha is phosphorylated at ser32 and ser36 predominantly by IKKbeta, and is subjected thereafter to ubiquitination and degradation in the 26S proteosome.	('ser36', 'Chemical', '-', (130, 135))	('TNF-alpha', 'Gene', '7124', (51, 60))	('NF-kappaB', 'Gene', (19, 28))	('IL-1', 'Gene', (62, 66))	('ser32', 'Var', (120, 125))	('IKKbeta', 'Gene', (153, 160))	('IkappaBalpha', 'Gene', (86, 98))	('ser', 'cellular_component', 'GO:0005790', ('120', '123'))	('ser32', 'Chemical', '-', (120, 125))	('degradation', 'biological_process', 'GO:0009056', ('212', '223'))	('IL-1', 'molecular_function', 'GO:0005149', ('62', '66'))	('TNF-alpha', 'Gene', (51, 60))	('IKKbeta', 'Gene', '3551', (153, 160))	('ser', 'cellular_component', 'GO:0005790', ('130', '133'))	('NF-kappaB', 'Gene', '4790', (19, 28))	('ser36', 'Var', (130, 135))	('IkappaBalpha', 'Gene', '4792', (86, 98))
3545	20001801	Post-translational modifications regulate the activity of the IKK complex, IkappaB proteins and the NF-kappaB subunits themselves, among them phosphorylation of NF-kappaB p65 at Ser536, which results in enhanced transactivation potential and nuclear translocation of NF-kappaB p65.	('NF-kappaB', 'Gene', '4790', (161, 170))	('IKK complex', 'cellular_component', 'GO:0008385', ('62', '73'))	('NF-kappaB p65', 'Gene', (161, 174))	('transactivation', 'biological_process', 'GO:2000144', ('212', '227'))	('NF-kappaB p65', 'Gene', '5970', (161, 174))	('activity', 'MPA', (46, 54))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('Ser536', 'Var', (178, 184))	('nuclear translocation', 'MPA', (242, 263))	('NF-kappaB', 'Gene', (267, 276))	('Ser536', 'Chemical', '-', (178, 184))	('NF-kappaB', 'Gene', (100, 109))	('NF-kappaB', 'Gene', '4790', (267, 276))	('regulate', 'Reg', (33, 41))	('enhanced', 'PosReg', (203, 211))	('NF-kappaB', 'Gene', (161, 170))	('NF-kappaB', 'Gene', '4790', (100, 109))	('NF-kappaB p65', 'Gene', (267, 280))	('transactivation potential', 'MPA', (212, 237))	('NF-kappaB p65', 'Gene', '5970', (267, 280))	('Ser', 'cellular_component', 'GO:0005790', ('178', '181'))	('IKK', 'molecular_function', 'GO:0008384', ('62', '65'))
3550	20001801	Data available from in vitro and in vivo ovarian carcinoma models suggest that inhibition of NF-kappaB enhances the efficacy of cisplatin and paclitaxel in the treatment of this tumor.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('tumor', 'Disease', (178, 183))	('efficacy', 'MPA', (116, 124))	('paclitaxel', 'Chemical', 'MESH:D017239', (142, 152))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (41, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('NF-kappaB', 'Gene', '4790', (93, 102))	('inhibition', 'Var', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (41, 58))	('ovarian carcinoma', 'Disease', (41, 58))	('NF-kappaB', 'Gene', (93, 102))	('enhances', 'PosReg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
3570	20001801	Recently, it has been shown that osteopontin is a substrate of caspase-8, and proteolytic cleavage by casepase-8 and its cleavage product subsequently induces cell death via the p53 pathway.	('cell death', 'biological_process', 'GO:0008219', ('159', '169'))	('proteolytic cleavage', 'Var', (78, 98))	('caspase-8', 'Gene', (63, 72))	('osteopontin', 'Gene', '6696', (33, 44))	('induces', 'Reg', (151, 158))	('casepase-8', 'Gene', (102, 112))	('cell death', 'CPA', (159, 169))	('osteopontin', 'Gene', (33, 44))	('caspase-8', 'Gene', '841', (63, 72))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))
3656	32967504	The intra-group comparison results were as follows: CUEDC2 score 1.35 +- 0.60, 1.54 +- 0.57, 1.78 +- 0.71, and 2.13 +- 0.27 in FIGO stage I, II, III, and IV, respectively.	('CUEDC2', 'Gene', (52, 58))	('1.54', 'Var', (79, 83))	('CUEDC2', 'Gene', '79004', (52, 58))
3696	32967504	High expression was observed in tissues from patients with advanced stages of serous ovarian cancer, and expression of CUEDC2 was positively correlated with DFS but not OS.	('correlated', 'Reg', (141, 151))	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('expression', 'MPA', (5, 15))	('DFS', 'Disease', (157, 160))	('expression', 'Var', (105, 115))	('CUEDC2', 'Gene', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (45, 53))	('serous ovarian cancer', 'Disease', (78, 99))	('CUEDC2', 'Gene', '79004', (119, 125))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (78, 99))
3762	31879572	In addition, biological adhesion (GO:0022610; P-value = 2.04E-17) and MAPK cascade (GO:0000165; P-value = 2.00E-17) play important roles in cell development processes related to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('MAPK cascade', 'biological_process', 'GO:0000165', ('70', '82'))	('biological adhesion', 'CPA', (13, 32))	('GO:0000165;', 'Var', (84, 95))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('cell development processes', 'CPA', (140, 166))	('cancer', 'Disease', (178, 184))	('play', 'Reg', (116, 120))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('biological adhesion', 'biological_process', 'GO:0022610', ('13', '32'))	('GO:0022610', 'Var', (34, 44))	('cell development', 'biological_process', 'GO:0048468', ('140', '156'))
3764	31879572	This showed that the genes are enriched in most of the vital processes in cancer and tumor progression including: apoptotic process (GO:0006915; P-value =3.47E-06), the regulation of the cell cycle (GO:0051726; P-value =4.48E), cell proliferation (GO:0042127; P-value = 1.26E-11), cell death (GO:0010941; P-value =4.95E-07), and cell differentiation (GO:0045595; P-value = 1.06E-07).	('tumor', 'Disease', (85, 90))	('cell death', 'CPA', (281, 291))	('regulation', 'biological_process', 'GO:0065007', ('169', '179'))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('apoptotic process', 'CPA', (114, 131))	('cancer', 'Disease', (74, 80))	('cell death', 'biological_process', 'GO:0008219', ('281', '291'))	('cell cycle', 'CPA', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cell differentiation', 'biological_process', 'GO:0030154', ('329', '349'))	('cell proliferation', 'biological_process', 'GO:0008283', ('228', '246'))	('cell differentiation', 'CPA', (329, 349))	('GO:0010941;', 'Var', (293, 304))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cell cycle', 'biological_process', 'GO:0007049', ('187', '197'))	('apoptotic process', 'biological_process', 'GO:0006915', ('114', '131'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cell proliferation', 'CPA', (228, 246))
3765	31879572	Our study also found that five genes are also involved in the enrichment of estrogen (GO:0043627; P-value = 1.22E-04) and four in the enrichment of progesterone (GO:0032570; P-value = 3.53E-06).	('GO:0043627;', 'Var', (86, 97))	('progesterone', 'Chemical', 'MESH:D011374', (148, 160))	('involved', 'Reg', (46, 54))	('estrogen', 'Disease', (76, 84))
3788	31879572	The frequency of alteration in cBio Cancer Genomics Portal is defined by mutation, copy number amplification, and homozygous deletion in tumor samples.	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('Cancer', 'Disease', (36, 42))	('copy number amplification', 'Var', (83, 108))	('tumor', 'Disease', (137, 142))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('alteration', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
3790	31879572	For example, of the 585 cases of TCGA ovarian epithelial tumor, the frequency of genetic alterations was 60.17% of which the highest alteration was observed in amplification (37.44%, 219 cases) followed by deep deletion (10.6%, 62 cases) (Fig.	('deep deletion', 'Var', (206, 219))	('epithelial tumor', 'Phenotype', 'HP:0031492', (46, 62))	('amplification', 'Var', (160, 173))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('TCGA ovarian epithelial tumor', 'Disease', (33, 62))	('ovarian epithelial tumor', 'Phenotype', 'HP:0025318', (38, 62))	('TCGA ovarian epithelial tumor', 'Disease', 'MESH:D010051', (33, 62))
3791	31879572	In 1,169 cases of ovarian cancer, we observed 54.06% alteration and 41.75% of these were due to amplification.	('amplification', 'Var', (96, 109))	('alteration', 'MPA', (53, 63))	('ovarian cancer', 'Disease', (18, 32))	('due', 'Reg', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (18, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (18, 32))
3795	31879572	These results showed the importance of endometriosis-related genes in the development of cancers in women as a consequence of their function in promoting a large number of copy number gains.	('endometriosis', 'Disease', (39, 52))	('women', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('endometriosis', 'Phenotype', 'HP:0030127', (39, 52))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('copy number gains', 'Var', (172, 189))	('cancers', 'Disease', (89, 96))	('endometriosis', 'Disease', 'MESH:D004715', (39, 52))	('promoting', 'PosReg', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
3796	31879572	In addition to the sample analysis, we explored the genomic alterations in multiple genes across several tumor samples (Figs.	('genomic alterations', 'Var', (52, 71))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
3804	31879572	MME, SOX17, AGTR1, PGR, and ESR1 had the highest amplifications frequency ranging from 4% to 11% in ovarian serous cystadenocarcinoma.	('AGTR1', 'Gene', '185', (12, 17))	('MME', 'Gene', '4321', (0, 3))	('SOX17', 'Gene', '64321', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('ESR1', 'Gene', (28, 32))	('MME', 'Gene', (0, 3))	('amplifications', 'Var', (49, 63))	('ovarian serous cystadenocarcinoma', 'Disease', (100, 133))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (100, 133))	('PGR', 'Gene', '5241', (19, 22))	('PGR', 'Gene', (19, 22))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (100, 133))	('SOX17', 'Gene', (5, 10))	('AGTR1', 'Gene', (12, 17))	('ESR1', 'Gene', '2099', (28, 32))
3808	31879572	Therefore, all these endometriosis-related genes are associated with gene amplification events across the four cancers of women TCGA samples.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('gene amplification events', 'Var', (69, 94))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('endometriosis', 'Disease', 'MESH:D004715', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('women', 'Species', '9606', (122, 127))	('endometriosis', 'Disease', (21, 34))	('associated', 'Reg', (53, 63))	('endometriosis', 'Phenotype', 'HP:0030127', (21, 34))
3814	31879572	The TCGA ovarian serous cystadenocarcinoma patients had >40% genetic alteration/expression (median) (Fig.	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (9, 42))	('patients', 'Species', '9606', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (9, 42))	('genetic alteration/expression', 'Var', (61, 90))	('ovarian serous cystadenocarcinoma', 'Disease', (9, 42))
3815	31879572	Overall, most of cancer cohort patients showed >20% genetic alterations.	('genetic alterations', 'Var', (52, 71))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('patients', 'Species', '9606', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
3822	31879572	TCGA data sets collected from the eleven studies provided 7,462 samples in which the maximum rate of genetic alteration occurred in endometrial carcinoma (36.86% of 529 cases), followed by ovarian epithelial tumor (27.69% of 585 cases), invasive breast carcinoma (26.7% of 1,086 cases), and ovarian cancer (26.26% of 1,169 cases) (Fig.	('ovarian cancer', 'Disease', 'MESH:D010051', (291, 305))	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (237, 262))	('epithelial tumor', 'Phenotype', 'HP:0031492', (197, 213))	('breast carcinoma', 'Phenotype', 'HP:0003002', (246, 262))	('ovarian cancer', 'Disease', (291, 305))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (132, 153))	('endometrial carcinoma', 'Disease', (132, 153))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('invasive breast carcinoma', 'Disease', (237, 262))	('ovarian epithelial tumor', 'Disease', 'MESH:D010051', (189, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (132, 153))	('ovarian epithelial tumor', 'Disease', (189, 213))	('ovarian cancer', 'Phenotype', 'HP:0100615', (291, 305))	('genetic alteration', 'Var', (101, 119))	('ovarian epithelial tumor', 'Phenotype', 'HP:0025318', (189, 213))
3823	31879572	Functional enrichment analysis revealed that the nine genes were associated with a number of key cancer pathways and reproductive system biological processes including: the progesterone receptor signalling pathway (GO:0050847; P-value =2.90E-03); the hormone-mediated signalling pathway (GO:0009755; P-value = 1.46E-04); and the intracellular receptor signalling pathway (GO:0030522; P-value = 3.20E-04) (Table S3).	('hormone-mediated signalling pathway', 'Pathway', (251, 286))	('cancer', 'Disease', (97, 103))	('intracellular receptor signalling pathway', 'Pathway', (329, 370))	('signalling pathway', 'biological_process', 'GO:0007165', ('268', '286'))	('GO:0009755;', 'Var', (288, 299))	('progesterone receptor signalling pathway', 'biological_process', 'GO:0050847', ('173', '213'))	('signalling pathway', 'biological_process', 'GO:0007165', ('352', '370'))	('hormone-mediated signalling', 'biological_process', 'GO:0009755', ('251', '278'))	('associated', 'Reg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('intracellular', 'cellular_component', 'GO:0005622', ('329', '342'))	('progesterone receptor', 'Gene', (173, 194))	('progesterone receptor', 'Gene', '5241', (173, 194))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
3839	31879572	Estrogen also increases the risk of ovarian cancer, particularly after menopause.	('ovarian cancer', 'Disease', 'MESH:D010051', (36, 50))	('menopause', 'biological_process', 'GO:0042697', ('71', '80'))	('ovarian cancer', 'Disease', (36, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('Estrogen', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
3846	31879572	The dysregulation of protein kinase stimulated by several oncogenic driver mutations was found to accelerate uncontrolled cellular proliferation in kinase-dependent tumour growth.	('tumour growth', 'Disease', (165, 178))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('tumour growth', 'Disease', 'MESH:D006130', (165, 178))	('dysregulation', 'Var', (4, 17))	('accelerate', 'PosReg', (98, 108))	('mutations', 'Var', (75, 84))	('uncontrolled', 'MPA', (109, 121))	('protein kinase', 'Enzyme', (21, 35))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
3854	31879572	In addition, a truncated form of PTN was shown to act as a dominant-negative effector on the proliferation and angiogenesis of breast cancer cells, in vitro and in vivo.	('angiogenesis', 'CPA', (111, 123))	('proliferation', 'CPA', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('PTN', 'Gene', (33, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('angiogenesis', 'biological_process', 'GO:0001525', ('111', '123'))	('truncated', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('PTN', 'Gene', '5764', (33, 36))
3863	31879572	High rate (5%) of mutation frequency was observed in macrophage metalloelastase (MME), which is a zinc-dependent endoprotease and also involved in ECM re-modulation and conversion of plasminogen to angiostatin.	('macrophage metalloelastase', 'Gene', (53, 79))	('mutation', 'Var', (18, 26))	('MME', 'Gene', '4321', (81, 84))	('macrophage metalloelastase', 'Gene', '4321', (53, 79))	('MME', 'Gene', (81, 84))
3977	28693127	Emerging evidence has demonstrated that the dysregulated expression of eIF6 is important in several types of human cancer, including head and neck carcinoma, colorectal cancer, non-small cell lung cancer and ovarian serous adenocarcinoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('cancer', 'Disease', (169, 175))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (177, 203))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('dysregulated', 'Var', (44, 56))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (208, 237))	('neck carcinoma', 'Disease', (142, 156))	('neck carcinoma', 'Disease', 'MESH:D006258', (142, 156))	('expression', 'MPA', (57, 67))	('important', 'Reg', (79, 88))	('eIF6', 'Gene', (71, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('non-small cell lung cancer', 'Disease', (177, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (133, 156))	('colorectal cancer', 'Disease', (158, 175))	('cancer', 'Disease', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (177, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('neck', 'cellular_component', 'GO:0044326', ('142', '146'))	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('ovarian serous adenocarcinoma', 'Disease', (208, 237))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
3995	28693127	For nuclear export in mammalian cells, eIF6 is phosphorylated in vitro at Ser-175 and Ser-174 by the nuclear isoforms of casein kinase (CK) CK1alpha or CK1delta, thereby promoting the formation of pre-60S ribosomal particles in the cytoplasm.	('CK', 'Gene', '149420', (152, 154))	('cytoplasm', 'cellular_component', 'GO:0005737', ('232', '241'))	('CK1', 'Species', '2498238', (152, 155))	('formation', 'MPA', (184, 193))	('pre', 'molecular_function', 'GO:0003904', ('197', '200'))	('promoting', 'PosReg', (170, 179))	('mammalian', 'Species', '9606', (22, 31))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('CK', 'Gene', '149420', (140, 142))	('Ser', 'Chemical', 'MESH:D012694', (74, 77))	('Ser-174', 'Var', (86, 93))	('pre-60S', 'Protein', (197, 204))	('casein kinase', 'Gene', (121, 134))	('CK1', 'Species', '2498238', (140, 143))	('Ser', 'Chemical', 'MESH:D012694', (86, 89))	('casein kinase', 'Gene', '149420', (121, 134))	('Ser', 'cellular_component', 'GO:0005790', ('86', '89'))	('nuclear export', 'biological_process', 'GO:0051168', ('4', '18'))	('CK', 'Gene', '149420', (136, 138))	('formation', 'biological_process', 'GO:0009058', ('184', '193'))
3998	28693127	It should be noted that cytoplasmic eIF6 in mammalian cells is also phosphorylated by receptors for activated C kinase 1 (RACK1)/protein kinase C (PKC) signaling at positions Ser-174, Ser-175 and Ser-235 (Fig.	('Ser', 'Chemical', 'MESH:D012694', (175, 178))	('Ser', 'cellular_component', 'GO:0005790', ('184', '187'))	('receptors for activated C kinase 1', 'Gene', '10399', (86, 120))	('Ser', 'Chemical', 'MESH:D012694', (196, 199))	('receptors for activated C kinase 1', 'Gene', (86, 120))	('Ser', 'cellular_component', 'GO:0005790', ('196', '199'))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('Ser', 'cellular_component', 'GO:0005790', ('175', '178'))	('Ser-174', 'Var', (175, 182))	('Ser', 'Chemical', 'MESH:D012694', (184, 187))	('mammalian', 'Species', '9606', (44, 53))	('Ser-175', 'Var', (184, 191))	('PKC', 'molecular_function', 'GO:0004697', ('147', '150'))	('Ser-235', 'Var', (196, 203))
4000	28693127	SBDS, the protein mutated in Shwachman-Bodian-Diamond syndrome, and EFL1 release the anti-association factor eIF6 from the surface of the 60S subunit.	('EFL1', 'Gene', '79631', (68, 72))	('SBDS', 'Gene', (0, 4))	('mutated', 'Var', (18, 25))	('Shwachman-Bodian-Diamond syndrome', 'Disease', (29, 62))	('SBDS', 'Gene', '51119', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('EFL1', 'Gene', (68, 72))	('anti-association factor', 'MPA', (85, 108))
4004	28693127	The C-terminal of eIF6 is subject to RACK1-PKCbetaII complex phosphorylation at Ser-235, which modulates the protumorigenic activity of eIF6, whereas mutation of the phosphorylation site at Ser235 of eIF6 in mouse models reduces translation and lymphomagenesis.	('translation', 'biological_process', 'GO:0006412', ('229', '240'))	('Ser', 'cellular_component', 'GO:0005790', ('80', '83'))	('lymphomagenesis', 'CPA', (245, 260))	('translation', 'MPA', (229, 240))	('mutation', 'Var', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('reduces', 'NegReg', (221, 228))	('Ser', 'Chemical', 'MESH:D012694', (80, 83))	('Ser', 'cellular_component', 'GO:0005790', ('190', '193'))	('Ser', 'Chemical', 'MESH:D012694', (190, 193))	('mouse', 'Species', '10090', (208, 213))	('tumor', 'Disease', (112, 117))	('Ser235', 'Chemical', '-', (190, 196))	('eIF6', 'Gene', (200, 204))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))	('modulates', 'Reg', (95, 104))
4015	28693127	mRNA translation controls distinct cellular processes, including tumorigenesis, cell migration, adhesion and growth, and cell-cycle control.	('controls', 'Reg', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('cell migration', 'CPA', (80, 94))	('cell-cycle control', 'biological_process', 'GO:1901987', ('121', '139'))	('cell-cycle control', 'CPA', (121, 139))	('growth', 'CPA', (109, 115))	('translation', 'biological_process', 'GO:0006412', ('5', '16'))	('cell migration', 'biological_process', 'GO:0016477', ('80', '94'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mRNA', 'Var', (0, 4))	('adhesion', 'CPA', (96, 104))
4019	28693127	In addition, differentially-expressed eIF6 may serve a critical function in colon carcinogenesis and provide a novel marker in surgical pathology.	('colon carcinogenesis', 'Disease', (76, 96))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (76, 96))	('differentially-expressed', 'Var', (13, 37))	('eIF6', 'Gene', (38, 42))
4053	28693127	However, the aberrant activation of Wnt/beta-catenin signaling leads to the dysregulation of cellular growth and development, and contributes to human tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('leads to', 'Reg', (63, 71))	('activation', 'PosReg', (22, 32))	('tumor', 'Disease', (151, 156))	('human', 'Species', '9606', (145, 150))	('cellular growth', 'biological_process', 'GO:0016049', ('93', '108'))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (40, 52))	('contributes to', 'Reg', (130, 144))	('aberrant', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('dysregulation', 'MPA', (76, 89))
4055	28693127	Although the molecular mechanism remains to be clarified, previous research has demonstrated that dysregulation of Wnt/beta-catenin signaling results in large accumulation of beta-catenin in the nucleus.	('beta-catenin', 'Gene', '1499', (119, 131))	('nucleus', 'cellular_component', 'GO:0005634', ('195', '202'))	('dysregulation', 'Var', (98, 111))	('beta-catenin', 'Gene', '1499', (175, 187))	('accumulation', 'PosReg', (159, 171))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('beta-catenin', 'Gene', (119, 131))	('beta-catenin', 'Gene', (175, 187))
4057	28693127	Previous research has demonstrated that eIF6 serves as a factor participating in Wnt/beta-catenin signaling and the distribution of eIF6 and beta4 is altered in colonic adenoma and carcinoma.	('colonic adenoma and carcinoma', 'Disease', 'MESH:D000236', (161, 190))	('beta-catenin', 'Gene', '1499', (85, 97))	('altered', 'Reg', (150, 157))	('beta4', 'Gene', (141, 146))	('beta4', 'Gene', '10717', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('beta-catenin', 'Gene', (85, 97))	('eIF6', 'Var', (132, 136))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('distribution', 'MPA', (116, 128))
4058	28693127	Furthermore, in SW480 cells transfected with full-length eIF6, the level of activated beta-catenin was reduced compared with controls.	('eIF6', 'Gene', (57, 61))	('full-length', 'Var', (45, 56))	('beta-catenin', 'Gene', (86, 98))	('reduced', 'NegReg', (103, 110))	('beta-catenin', 'Gene', '1499', (86, 98))	('SW480', 'CellLine', 'CVCL:0546', (16, 21))
4059	28693127	The question may therefore be raised as to whether eIF6 has the same effect as Dickkopf antagonists on the Wnt/beta-catenin signaling pathway.	('Dickkopf', 'Gene', (79, 87))	('beta-catenin', 'Gene', (111, 123))	('Dickkopf', 'Gene', '22943', (79, 87))	('eIF6', 'Var', (51, 55))	('beta-catenin', 'Gene', '1499', (111, 123))	('signaling pathway', 'biological_process', 'GO:0007165', ('124', '141'))
4066	28693127	Aberrant expression of Cdc42 is pivotal in tumorigenesis, including that of breast carcinoma.	('Aberrant expression', 'Var', (0, 19))	('breast carcinoma', 'Phenotype', 'HP:0003002', (76, 92))	('Cdc42', 'Gene', '998', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Cdc42', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('breast carcinoma', 'Disease', (76, 92))	('tumor', 'Disease', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('breast carcinoma', 'Disease', 'MESH:D001943', (76, 92))
4070	28693127	This is supported by the fact that Cdc42 mRNA expression levels exhibit little or no difference following eIF6 overexpression, which also demonstrates that eIF6 may target the translation of specific mRNAs.	('translation', 'MPA', (176, 187))	('Cdc42', 'Gene', (35, 40))	('translation', 'biological_process', 'GO:0006412', ('176', '187'))	('target', 'Reg', (165, 171))	('Cdc42', 'Gene', '998', (35, 40))	('eIF6', 'Var', (156, 160))
4071	28693127	In A2780 cells overexpressing eIF6, ML-141, a selective and potent inhibitor of Cdc42 GTPase, has been demonstrated to significantly decrease migratory activity.	('migratory activity', 'CPA', (142, 160))	('A2780', 'CellLine', 'CVCL:0134', (3, 8))	('decrease', 'NegReg', (133, 141))	('ML-141', 'Var', (36, 42))	('eIF6', 'Var', (30, 34))	('Cdc42', 'Gene', (80, 85))	('Cdc42', 'Gene', '998', (80, 85))
4083	28693127	As a consequence, understanding the signaling network in which eIF6 lies may contribute novel insights into the pathogenesis of cancer, and offer a promising target for the development of novel antineoplastic agents.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('pathogenesis', 'biological_process', 'GO:0009405', ('112', '124'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('eIF6', 'Var', (63, 67))	('cancer', 'Disease', (128, 134))
4100	19159301	Molecular studies of OSCs show very distinct genetic alterations between low and high grade neoplasms, with the low grade/well differentiated ones having frequent K-Ras and/or B-Raf mutations in approximately 65% of the tumors and rarely showing p53 mutations, while high grade OSCs show p53 mutations in 50-80% of the cases.	('OSCs', 'Phenotype', 'HP:0012887', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('B-Raf', 'Gene', '673', (176, 181))	('neoplasms', 'Phenotype', 'HP:0002664', (92, 101))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('OSCs', 'Phenotype', 'HP:0012887', (278, 282))	('p53', 'Gene', (246, 249))	('p53', 'Gene', (288, 291))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('p53', 'Gene', '7157', (246, 249))	('neoplasms', 'Disease', (92, 101))	('p53', 'Gene', '7157', (288, 291))	('neoplasms', 'Disease', 'MESH:D009369', (92, 101))	('B-Raf', 'Gene', (176, 181))	('K-Ras', 'Gene', '3845', (163, 168))	('mutations', 'Var', (182, 191))	('K-Ras', 'Gene', (163, 168))
4152	19159301	Two independent sets of replicate tumor samples (UM-OS-7T/UM-OS-7Tb and UM-OS-014T (met 1 and met 2)) were found to cluster tightly together with the corresponding replicate OSC sample.	('UM-OS-014T', 'Var', (72, 82))	('UM-OS-7T/UM-OS-7Tb', 'CellLine', 'CVCL:Z610', (49, 67))	('UM-OS-7T/UM-OS-7Tb', 'Var', (49, 67))	('tumor', 'Disease', (34, 39))	('OSC', 'molecular_function', 'GO:0000250', ('174', '177'))	('met 1', 'Gene', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('met 1', 'Gene', '3004', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
4178	19159301	Acetylation of the lysine residues at the N-terminus of histone proteins removes positive charges, thus reducing the affinity between histones and DNA, and allowing for RNA polymerase and transcription factors to access the promoter region.	('DNA', 'Protein', (147, 150))	('affinity', 'Interaction', (117, 125))	('allowing', 'Reg', (156, 164))	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('Acetylation', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('reducing', 'NegReg', (104, 112))	('access', 'Interaction', (213, 219))	('removes', 'NegReg', (73, 80))	('histones', 'Protein', (134, 142))	('lysine', 'Chemical', 'MESH:D008239', (19, 25))	('transcription', 'biological_process', 'GO:0006351', ('188', '201'))	('positive charges', 'MPA', (81, 97))	('RNA polymerase', 'Enzyme', (169, 183))
4218	22403726	However, mutational profiling studies have yielded more consistent results, showing that both serous and endometrioid tumors have aggressive, high-grade subtypes with mutations in the TP53 gene despite their obvious histological differences.	('serous', 'Disease', (94, 100))	('endometrioid tumors', 'Disease', 'MESH:D016889', (105, 124))	('serous', 'Chemical', '-', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (167, 176))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('endometrioid tumors', 'Disease', (105, 124))
4219	22403726	Low-grade subtypes are most common in endometrioid tumors with mutations predominantly occurring in WNT and PIK3CA pathways.	('mutations', 'Var', (63, 72))	('common', 'Reg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('endometrioid tumors', 'Disease', (38, 57))	('endometrioid tumors', 'Disease', 'MESH:D016889', (38, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('PIK3CA', 'Gene', (108, 114))	('occurring', 'Reg', (87, 96))	('PIK3CA', 'Gene', '5290', (108, 114))
4221	22403726	In ovarian tumors, DNA methylation silences expression of critical genes, and creates genetic haploinsufficiency, while hypomethylation at other sites enables expression of normally silenced genes.	('ovarian tumors', 'Disease', 'MESH:D010051', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('methylation', 'Var', (23, 34))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('silences', 'NegReg', (35, 43))	('genetic haploinsufficiency', 'Disease', (86, 112))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('expression of critical genes', 'MPA', (44, 72))	('ovarian tumors', 'Disease', (3, 17))	('ovarian tumor', 'Phenotype', 'HP:0100615', (3, 16))	('genetic haploinsufficiency', 'Disease', 'MESH:D030342', (86, 112))	('ovarian tumors', 'Phenotype', 'HP:0100615', (3, 17))
4234	22403726	Five serous tumor samples showed a distinct profile, with many loci being unmethylated (i.e., methylation level <0.2), indicating either a failure to maintain X-inactivation or copy number alterations with relative excess of the active X.	('serous tumor', 'Disease', (5, 17))	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('copy number alterations', 'Var', (177, 200))	('serous tumor', 'Disease', 'MESH:D018284', (5, 17))
4265	22403726	For instance, BRCA1 was hypermethylated in 2 of 16 (12.5%) of ovarian serous samples.	('BRCA1', 'Gene', '672', (14, 19))	('BRCA1', 'Gene', (14, 19))	('ovarian serous', 'Disease', 'MESH:D010051', (62, 76))	('ovarian serous', 'Disease', (62, 76))	('hypermethylated', 'Var', (24, 39))
4266	22403726	The tumor suppressor RASSF1A showed evidence of complete methylation in 11 tumors, and single-copy methylation in 4 more (31% of serous, and 60% of endometrioid).	('tumor', 'Disease', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('RASSF1A', 'Gene', (21, 28))	('serous', 'Disease', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (75, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('methylation', 'MPA', (57, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('single-copy methylation', 'Var', (87, 110))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('RASSF1A', 'Gene', '11186', (21, 28))	('serous', 'Chemical', '-', (129, 135))
4268	22403726	Notably, differentially methylated genes had a large presence in these networks, interacting with important genes in ovarian tumor development including AKT, PI3K, VEGF, and estrogen receptor.	('ovarian tumor', 'Disease', 'MESH:D010051', (117, 130))	('estrogen receptor', 'Gene', (174, 191))	('estrogen receptor', 'Gene', '2099', (174, 191))	('AKT', 'Gene', '207', (153, 156))	('VEGF', 'Gene', '7422', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('differentially methylated genes', 'Var', (9, 40))	('interacting', 'Interaction', (81, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('158', '162'))	('AKT', 'Gene', (153, 156))	('ovarian tumor', 'Disease', (117, 130))	('VEGF', 'Gene', (164, 168))	('ovarian tumor', 'Phenotype', 'HP:0100615', (117, 130))
4288	22403726	RB1 was recently reported by TCGA to be involved in serous tumor etiology, through mutation or deletion in 67% of tumors.	('deletion', 'Var', (95, 103))	('serous tumor', 'Disease', (52, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutation', 'Var', (83, 91))	('serous tumor', 'Disease', 'MESH:D018284', (52, 64))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('RB1', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('involved', 'Reg', (40, 48))
4289	22403726	The involvement of the RB1 pathway is consistent with concurrent Rb1 and Tp53 mutation in mice, which simulates characteristics of aggressive serous ovarian cancers, including formation of ascites and metastasis.	('Rb1', 'Gene', '19645', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('formation', 'biological_process', 'GO:0009058', ('176', '185'))	('mutation', 'Var', (78, 86))	('aggressive serous ovarian cancers', 'Disease', 'MESH:D010051', (131, 164))	('aggressive serous ovarian cancers', 'Disease', (131, 164))	('Tp53', 'Gene', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('ascites', 'Disease', (189, 196))	('Tp53', 'Gene', '22059', (73, 77))	('mice', 'Species', '10090', (90, 94))	('ascites', 'Phenotype', 'HP:0001541', (189, 196))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('ovarian cancers', 'Phenotype', 'HP:0100615', (149, 164))	('ascites', 'Disease', 'MESH:D001201', (189, 196))	('RB1 pathway', 'Pathway', (23, 34))	('involvement', 'Reg', (4, 15))	('Rb1', 'Gene', (65, 68))
4295	22403726	Studies in hepatocellular carcinoma have identified mutations in the beta-catenin gene in association with a methylator phenotype.	('mutations', 'Var', (52, 61))	('hepatocellular carcinoma', 'Disease', (11, 35))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (11, 35))	('beta-catenin', 'Gene', (69, 81))	('beta-catenin', 'Gene', '1499', (69, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (11, 35))
4296	22403726	Mutations in beta-catenin are also common in endometrial tumors, and suggest follow-up experiments to assess a direct relationship to DNA methylation in endometrioid tumors.	('common', 'Reg', (35, 41))	('beta-catenin', 'Gene', '1499', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('DNA methylation', 'biological_process', 'GO:0006306', ('134', '149'))	('endometrial tumors', 'Disease', 'MESH:D016889', (45, 63))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('endometrioid tumors', 'Disease', (153, 172))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('beta-catenin', 'Gene', (13, 25))	('endometrioid tumors', 'Disease', 'MESH:D016889', (153, 172))	('endometrial tumors', 'Disease', (45, 63))
4307	22403726	Tumors: TCGA-09-0367-01A-01D-0359-05, TCGA-09-0365-01A-02D-0359-05, TCGA-09-0366-01A-01D-0359-05, TCGA-09-0369-01A-01D-0359-05.	('TCGA-09-0369-01A-01', 'CellLine', 'CVCL:6244', (98, 117))	('TCGA-09-0367-01A-01D-0359', 'CellLine', 'CVCL:6244', (8, 33))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TCGA-09-0366-01A-01D-0359-05', 'Var', (68, 96))	('TCGA-09-0365-01A-02D-0359-05', 'Var', (38, 66))	('TCGA-09-0366-01A-01D-0359', 'CellLine', 'CVCL:6244', (68, 93))
4366	19383911	High-grade (HG) serous carcinomas contain frequent TP53 mutations while low-grade (LG) carcinomas arise from serous borderline tumors (SBT) and harbor mutations in KRAS/BRAF/ERBB2 pathway.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('KRAS', 'Gene', '3845', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('carcinomas', 'Disease', (87, 97))	('KRAS', 'Gene', (164, 168))	('carcinomas', 'Disease', (23, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('serous carcinomas', 'Disease', (16, 33))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('ERBB2', 'Gene', (174, 179))	('serous borderline tumors', 'Disease', 'MESH:D012569', (109, 133))	('ERBB2', 'Gene', '2064', (174, 179))	('carcinomas', 'Disease', 'MESH:D002277', (87, 97))	('High-grade', 'Disease', (0, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('serous carcinomas', 'Disease', 'MESH:D018284', (16, 33))	('carcinomas', 'Disease', 'MESH:D002277', (23, 33))	('mutations', 'Reg', (151, 160))	('serous borderline tumors', 'Disease', (109, 133))
4368	19383911	As well, the extent of deletion of tumor suppressors in ovarian serous carcinomas has not been well-studied.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('deletion', 'Var', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('tumor', 'Disease', (35, 40))	('ovarian serous carcinomas', 'Disease', (56, 81))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (56, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (56, 81))
4371	19383911	Hemizygous ch1p36 deletion was common in LG serous carcinomas but was rarely seen in SBT.	('ch1p', 'Gene', (11, 15))	('common', 'Reg', (31, 37))	('LG serous carcinomas', 'Disease', (41, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('LG serous carcinomas', 'Disease', 'MESH:D018284', (41, 61))	('ch1p', 'Gene', '51430', (11, 15))	('deletion', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
4373	19383911	In contrast, in HG serous carcinomas, significant numbers of amplifications and deletions including homozygous deletions were identified.	('HG serous carcinomas', 'Disease', (16, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (16, 36))	('deletions', 'Var', (80, 89))
4374	19383911	Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4% and 4.3%, respectively, in independent 47 affinity-purified HG serous carcinomas.	('DOCK4', 'Gene', '9732', (70, 75))	('CDKN2A/B', 'Gene', (49, 57))	('DOCK4', 'Gene', (70, 75))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (189, 209))	('deletions', 'Var', (17, 26))	('Rb1', 'Gene', (44, 47))	('CSMD1', 'Gene', (59, 64))	('CSMD1', 'Gene', '64478', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('CDKN2A/B', 'Gene', '1029;1030', (49, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('HG serous carcinomas', 'Disease', (189, 209))
4383	19383911	Molecular genetic analysis has demonstrated that SBT/LG serous carcinomas typically display sequence mutations in KRAS/BRAF/ERBB2, but with infrequent mutations in TP53.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('mutations', 'Var', (101, 110))	('LG serous carcinomas', 'Disease', 'MESH:D018284', (53, 73))	('BRAF', 'Gene', '673', (119, 123))	('KRAS', 'Gene', (114, 118))	('BRAF', 'Gene', (119, 123))	('KRAS', 'Gene', '3845', (114, 118))	('LG serous carcinomas', 'Disease', (53, 73))	('ERBB2', 'Gene', '2064', (124, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('ERBB2', 'Gene', (124, 129))
4384	19383911	In contrast, HG serous carcinomas often present in advanced stages (stages III-IV) and rarely harbor mutations in KRAS/BRAF/ERBB2.	('HG serous carcinomas', 'Disease', 'MESH:D018284', (13, 33))	('mutations', 'Var', (101, 110))	('BRAF', 'Gene', '673', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('KRAS', 'Gene', (114, 118))	('HG serous carcinomas', 'Disease', (13, 33))	('BRAF', 'Gene', (119, 123))	('KRAS', 'Gene', '3845', (114, 118))	('ERBB2', 'Gene', '2064', (124, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('ERBB2', 'Gene', (124, 129))
4385	19383911	HG serous carcinomas grow rapidly and are highly aggressive and over than 75% of these tumors harbor TP53 mutations.	('HG serous carcinomas', 'Disease', 'MESH:D018284', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('tumors', 'Disease', (87, 93))	('HG serous carcinomas', 'Disease', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
4386	19383911	DNA copy number alterations including chromosomal amplification, deletion and aneuploidy are the hallmarks of neoplasia.	('neoplasia', 'Disease', (110, 119))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('aneuploidy', 'Disease', 'MESH:D000782', (78, 88))	('neoplasia', 'Disease', 'MESH:D009369', (110, 119))	('neoplasia', 'Phenotype', 'HP:0002664', (110, 119))	('aneuploidy', 'Disease', (78, 88))	('chromosomal', 'CPA', (38, 49))	('deletion', 'Var', (65, 73))
4387	19383911	Amplification is one of the mechanisms that leads to an increase in activity of oncogenes and development of drug resistance, while allelic deletion results in inactivation of tumor suppressors.	('Amplification', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('increase', 'PosReg', (56, 64))	('oncogenes', 'Protein', (80, 89))	('drug resistance', 'biological_process', 'GO:0042493', ('109', '124'))	('drug resistance', 'MPA', (109, 124))	('tumor', 'Disease', (176, 181))	('drug resistance', 'biological_process', 'GO:0009315', ('109', '124'))	('allelic deletion', 'Var', (132, 148))	('inactivation', 'NegReg', (160, 172))	('activity', 'MPA', (68, 76))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('development', 'Reg', (94, 105))
4410	19383911	Western blot analysis was performed on representative HG tumors to test if tumors with apparent homozygous deletions expressed the gene products.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('deletions', 'Var', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
4424	19383911	As compared to SBTs and LG tumors, HG tumors demonstrated the highest level of DNA copy number alterations as their overall CIN index was significantly higher than the CIN index of either LG serous carcinomas or SBTs (Fig 1B).	('higher', 'PosReg', (152, 158))	('LG tumors', 'Disease', 'MESH:D009369', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('CIN', 'Disease', (124, 127))	('CIN', 'Disease', 'MESH:D007674', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('LG serous carcinomas', 'Disease', (188, 208))	('LG tumors', 'Disease', (24, 33))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('CIN', 'Disease', (168, 171))	('CIN', 'Phenotype', 'HP:0040012', (124, 127))	('LG serous carcinomas', 'Disease', 'MESH:D018284', (188, 208))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('alterations', 'Var', (95, 106))	('CIN', 'Disease', 'MESH:D007674', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (27, 33))	('CIN', 'Phenotype', 'HP:0040012', (168, 171))
4425	19383911	LG serous carcinomas also exhibited a significantly higher CIN index than SBTs, indicating that there were more chromosomal rearrangements in LG serous carcinomas than in SBT tumors (Fig 1B).	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('SBT tumors', 'Disease', 'MESH:D009369', (171, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('CIN', 'Phenotype', 'HP:0040012', (59, 62))	('LG serous carcinomas', 'Disease', (142, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('LG serous carcinomas', 'Disease', 'MESH:D018284', (142, 162))	('CIN', 'Disease', (59, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('LG serous carcinomas', 'Disease', 'MESH:D018284', (0, 20))	('chromosomal rearrangements', 'Var', (112, 138))	('CIN', 'Disease', 'MESH:D007674', (59, 62))	('SBT tumors', 'Disease', (171, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('LG serous carcinomas', 'Disease', (0, 20))
4427	19383911	Our results demonstrated that the most significant DNA copy number changes in LG carcinomas were deletions at ch1p36 and ch9p21.3 which occurred in 7/12 and 6/12 of LG tumors, respectively (Fig 2).	('LG carcinoma', 'Phenotype', 'HP:0002665', (78, 90))	('LG carcinoma', 'Disease', 'MESH:D002277', (78, 90))	('LG tumors', 'Disease', 'MESH:D009369', (165, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('ch9p21.3', 'Gene', (121, 129))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('LG tumors', 'Disease', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('ch1p', 'Gene', '51430', (110, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('carcinomas', 'Disease', 'MESH:D002277', (81, 91))	('deletions', 'Var', (97, 106))	('occurred', 'Reg', (136, 144))	('carcinomas', 'Disease', (81, 91))	('ch1p', 'Gene', (110, 114))	('LG carcinoma', 'Disease', (78, 90))
4430	19383911	Minimal mapping of the ch1p36 deletion in these 7 LG serous carcinomas revealed that there were two immediately adjacent deleted regions; one spanning the interval from 5,579,980 to 16,540,200 bp, and the other spanning the interval from 17,035,400 to 31,700,900 bp (Fig 3).	('ch1p', 'Gene', '51430', (23, 27))	('LG serous carcinomas', 'Disease', (50, 70))	('ch1p', 'Gene', (23, 27))	('deletion', 'Var', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('LG serous carcinomas', 'Disease', 'MESH:D018284', (50, 70))
4434	19383911	Minimal mapping of the two LG serous carcinomas with homozygous deletion in ch9p21.3 region demonstrated that the core deletion, spanning 21,945,000 to 22,009,700 bp and which harbors the CDKN2A/B locus, encodes p16, p15, and Arf (p14) (Fig 4A).	('CDKN2A/B', 'Gene', (188, 196))	('LG serous carcinomas', 'Disease', (27, 47))	('p16', 'Gene', (212, 215))	('deletion', 'Var', (64, 72))	('CDKN2A/B', 'Gene', '1029;1030', (188, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('p15', 'Gene', (217, 220))	('LG serous carcinomas', 'Disease', 'MESH:D018284', (27, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('p15', 'Gene', '1030', (217, 220))	('p14', 'Gene', (231, 234))	('Arf', 'Gene', (226, 229))	('core', 'cellular_component', 'GO:0019013', ('114', '118'))	('p16', 'Gene', '1029', (212, 215))	('p14', 'Gene', '1029', (231, 234))
4436	19383911	Additional genomic alterations present in LG serous carcinoma but not in SBTs included a 3-fold gain at ch1q and a hemizygous deletion of the entire X chromosome.	('serous carcinoma', 'Disease', 'MESH:D018284', (45, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('ch1q', 'Gene', (104, 108))	('gain', 'PosReg', (96, 100))	('X chromosome', 'cellular_component', 'GO:0000805', ('149', '161'))	('deletion', 'Var', (126, 134))	('serous carcinoma', 'Disease', (45, 61))
4438	19383911	The current 250K SNP array analysis revealed that the most frequently amplified regions in HG serous carcinomas were the loci at ch3q, ch12p, and ch19p, all of which have been reported in our previous study using a 10K SNP array platform.	('ch3q', 'Var', (129, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('HG serous carcinomas', 'Disease', (91, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (91, 111))	('ch12p', 'Var', (135, 140))	('ch19p', 'Var', (146, 151))
4439	19383911	Supplementary Table 2 summarizes the most common amplicons identified among HG serous carcinomas in this study.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('HG serous carcinomas', 'Disease', (76, 96))	('amplicons', 'Var', (49, 58))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (76, 96))
4441	19383911	In this regard, we took advantage of affinity purification of tumor cells which would enhance the sensitivity in detecting homozygous deletions.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('deletions', 'Var', (134, 143))	('enhance', 'PosReg', (86, 93))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
4442	19383911	Among the loci that were deleted were Rb1 (ch13q14.2), CDKN2A/B (ch9p21.3), CSMD1 (ch8q23.1-23.3), and DOCK4 (ch7q31.1), all of which have been previously reported to be homozygously deleted in human cancers (Fig 4B).	('CSMD1', 'Gene', (76, 81))	('DOCK4', 'Gene', '9732', (103, 108))	('CSMD1', 'Gene', '64478', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('CDKN2A/B', 'Gene', (55, 63))	('DOCK4', 'Gene', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('ch13q14.2', 'Var', (43, 52))	('human', 'Species', '9606', (194, 199))	('Rb1', 'Gene', (38, 41))	('CDKN2A/B', 'Gene', '1029;1030', (55, 63))
4443	19383911	None of the deletions were present in the matched normal tissues, indicating that these homozygous deletions in HG serous carcinomas were somatic changes acquired during tumor progression.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('deletions', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('HG serous carcinomas', 'Disease', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (112, 132))
4444	19383911	To further assess the frequency of deletions of Rb1, CDKN2A, CSMD1 and DOCK4, we used genomic quantitative real-time PCR on an independent panel of 47 affinity-purified HG serous carcinomas.	('HG serous carcinomas', 'Disease', (169, 189))	('CDKN2A', 'Gene', (53, 59))	('CDKN2A', 'Gene', '1029', (53, 59))	('CSMD1', 'Gene', (61, 66))	('CSMD1', 'Gene', '64478', (61, 66))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (169, 189))	('DOCK4', 'Gene', '9732', (71, 76))	('deletions', 'Var', (35, 44))	('DOCK4', 'Gene', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('Rb1', 'Gene', (48, 51))
4445	19383911	The frequency of homozygous deletion of Rb1, CDKN2A, CSMD1 and DOCK4 was 10.6%, 6.4%, 6.4% and 4.3%, respectively.	('CDKN2A', 'Gene', '1029', (45, 51))	('CSMD1', 'Gene', (53, 58))	('CSMD1', 'Gene', '64478', (53, 58))	('Rb1', 'Gene', (40, 43))	('CDKN2A', 'Gene', (45, 51))	('deletion', 'Var', (28, 36))	('DOCK4', 'Gene', '9732', (63, 68))	('DOCK4', 'Gene', (63, 68))
4446	19383911	Specific antibodies against two of the known tumor suppressors, pRb and p16 (encoded by CDKN2A), were available which permitted us to determine if the deletion affected protein expression.	('CDKN2A', 'Gene', (88, 94))	('affected', 'Reg', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('p16', 'Gene', '1029', (72, 75))	('CDKN2A', 'Gene', '1029', (88, 94))	('tumor', 'Disease', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('protein expression', 'MPA', (169, 187))	('deletion', 'Var', (151, 159))	('pRb', 'Gene', '5925', (64, 67))	('p16', 'Gene', (72, 75))	('pRb', 'Gene', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
4448	19383911	As shown in Figure 5, two HG serous carcinomas with homozygous deletions in the Rb1 locus completely lost pRb protein expression.	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('HG serous carcinomas', 'Disease', (26, 46))	('Rb1', 'Gene', (80, 83))	('deletions', 'Var', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (26, 46))	('pRb', 'Gene', (106, 109))	('lost', 'NegReg', (101, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('expression', 'MPA', (118, 128))	('pRb', 'Gene', '5925', (106, 109))
4451	19383911	Three HG serous carcinomas harboring homozygous deletions of the CDKN2A locus did not express detectable p16 protein.	('CDKN2A', 'Gene', '1029', (65, 71))	('p16', 'Gene', (105, 108))	('express', 'MPA', (86, 93))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (6, 26))	('CDKN2A', 'Gene', (65, 71))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('p16', 'Gene', '1029', (105, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('deletions', 'Var', (48, 57))	('not', 'NegReg', (82, 85))	('HG serous carcinomas', 'Disease', (6, 26))
4455	19383911	MPSC-1, a LG carcinoma cell line that harbored hemizygous deletion at the miR-34a locus and expressed a low level of endogenous miR-34a as compared to normal ovarian surface epithelial cells was selected for functional study (Fig 6 A & B).	('miR-34a', 'Gene', '407040', (128, 135))	('miR-34a', 'Gene', (128, 135))	('LG carcinoma', 'Phenotype', 'HP:0002665', (10, 22))	('LG carcinoma', 'Disease', 'MESH:D002277', (10, 22))	('LG carcinoma', 'Disease', (10, 22))	('miR-34a', 'Gene', '407040', (74, 81))	('deletion', 'Var', (58, 66))	('miR-34a', 'Gene', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('MPSC-1', 'CellLine', 'CVCL:9822', (0, 6))
4458	19383911	Furthermore, miR-34a mimic treatment was associated with a higher percentage of apoptotic cells in MPSC-1 cells than the mimic control (t test, p<0.05, data not shown), a result consistent with previous reports.	('apoptotic cells', 'CPA', (80, 95))	('MPSC-1', 'CellLine', 'CVCL:9822', (99, 105))	('mimic', 'Var', (21, 26))	('miR-34a', 'Gene', '407040', (13, 20))	('miR-34a', 'Gene', (13, 20))
4467	19383911	First, we applied high resolution SNP arrays on affinity-purified tumor cells, an approach that provides high sensitivity and specificity in detecting subtle DNA copy number alterations, especially hemizygous and homozygous deletions.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('deletions', 'Var', (224, 233))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('DNA', 'Gene', (158, 161))
4472	19383911	We chose miR-34a to investigate its function and found that transfected miR-34a can suppress cellular proliferation and induce apoptosis in LG carcinoma cells.	('LG carcinoma', 'Phenotype', 'HP:0002665', (140, 152))	('miR-34a', 'Gene', (72, 79))	('induce', 'PosReg', (120, 126))	('LG carcinoma', 'Disease', (140, 152))	('miR-34a', 'Gene', '407040', (9, 16))	('LG carcinoma', 'Disease', 'MESH:D002277', (140, 152))	('suppress', 'NegReg', (84, 92))	('apoptosis', 'CPA', (127, 136))	('miR-34a', 'Gene', (9, 16))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('miR-34a', 'Gene', '407040', (72, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('transfected', 'Var', (60, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))	('cellular proliferation', 'CPA', (93, 115))
4476	19383911	It should be noted that the 1p36 deletion encompasses a large chromosomal region containing more than 80 genes; therefore, further studies are required to delineate the culprit tumor suppressor gene(s) located at this region.	('chromosomal region', 'cellular_component', 'GO:0098687', ('62', '80'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('177', '193'))	('deletion', 'Var', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('1p36', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor suppressor', 'biological_process', 'GO:0051726', ('177', '193'))	('tumor', 'Disease', (177, 182))
4477	19383911	Second, frequent deletion at the ch9p21 region corresponding to the CDKN2A/B locus encodes three well-known tumor suppressor proteins, p14 (Arf), p16 and p15, was observed in LG serous carcinoma.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('observed', 'Reg', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p15', 'Gene', '1030', (154, 157))	('p16', 'Gene', '1029', (146, 149))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('CDKN2A/B', 'Gene', '1029;1030', (68, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('tumor', 'Disease', (108, 113))	('p14', 'Gene', (135, 138))	('deletion', 'Var', (17, 25))	('serous carcinoma', 'Disease', (178, 194))	('serous carcinoma', 'Disease', 'MESH:D018284', (178, 194))	('CDKN2A/B', 'Gene', (68, 76))	('p16', 'Gene', (146, 149))	('p14', 'Gene', '1029', (135, 138))	('p15', 'Gene', (154, 157))
4481	19383911	This observation is of considerable interest because SBTs and LG carcinomas frequently contain activating KRAS and BRAF mutations, but rarely contain TP53 mutations.	('KRAS', 'Gene', '3845', (106, 110))	('BRAF', 'Gene', '673', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('BRAF', 'Gene', (115, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('carcinomas', 'Disease', (65, 75))	('carcinomas', 'Disease', 'MESH:D002277', (65, 75))	('SBTs', 'Disease', (53, 57))	('LG carcinoma', 'Phenotype', 'HP:0002665', (62, 74))	('LG carcinoma', 'Disease', (62, 74))	('KRAS', 'Gene', (106, 110))	('mutations', 'Var', (120, 129))	('LG carcinoma', 'Disease', 'MESH:D002277', (62, 74))	('activating', 'PosReg', (95, 105))
4482	19383911	Thus, retained CDKN2A/B in SBTs may prevent progression to LG carcinoma despite the presence of activating KRAS and BRAF mutations frequently observed in SBTs.	('prevent', 'NegReg', (36, 43))	('KRAS', 'Gene', (107, 111))	('mutations', 'Var', (121, 130))	('CDKN2A/B', 'Gene', '1029;1030', (15, 23))	('LG carcinoma', 'Phenotype', 'HP:0002665', (59, 71))	('BRAF', 'Gene', '673', (116, 120))	('activating', 'PosReg', (96, 106))	('LG carcinoma', 'Disease', (59, 71))	('BRAF', 'Gene', (116, 120))	('KRAS', 'Gene', '3845', (107, 111))	('LG carcinoma', 'Disease', 'MESH:D002277', (59, 71))	('CDKN2A/B', 'Gene', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
4483	19383911	When CDKN2A/B locus is deleted, the check point becomes defective and tumor cells may escape from cell cycle arrest and exploit the oncogenic functions of mutated KRAS/BRAF, leading to LG tumor progression.	('tumor', 'Disease', (188, 193))	('mutated', 'Var', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('98', '115'))	('CDKN2A/B', 'Gene', '1029;1030', (5, 13))	('KRAS', 'Gene', (163, 167))	('tumor', 'Disease', (70, 75))	('KRAS', 'Gene', '3845', (163, 167))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('BRAF', 'Gene', '673', (168, 172))	('CDKN2A/B', 'Gene', (5, 13))	('leading to', 'Reg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('deleted', 'Var', (23, 30))	('BRAF', 'Gene', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
4485	19383911	These include relatively frequent homozygous deletions of Rb1 and CDKN2A/B.	('CDKN2A/B', 'Gene', '1029;1030', (66, 74))	('deletions', 'Var', (45, 54))	('Rb1', 'Gene', (58, 61))	('CDKN2A/B', 'Gene', (66, 74))
4486	19383911	Homozygous deletions in either of these regions accounted for 17% (8/47) HG serous carcinomas.	('HG serous carcinomas', 'Disease', (73, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (73, 93))	('Homozygous', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('accounted for', 'Reg', (48, 61))
4487	19383911	Since both genes are probably silenced by additional molecular mechanisms such as promoter hypermethylation, the inactivation in either gene in HG serous carcinomas is expected to be very frequent.	('HG serous carcinomas', 'Disease', 'MESH:D018284', (144, 164))	('promoter hypermethylation', 'Var', (82, 107))	('HG serous carcinomas', 'Disease', (144, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
4490	19383911	It is well-known that HG serous carcinomas harbor frequent TP53 mutation; however the molecular genetic changes in Rb1 and CDKN2A were previously not recognized because somatic mutations in these genes are rare in HG serous carcinomas.	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('HG serous carcinomas', 'Disease', (214, 234))	('HG serous carcinomas', 'Disease', (22, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('CDKN2A', 'Gene', (123, 129))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (214, 234))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (22, 42))	('CDKN2A', 'Gene', '1029', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
4491	19383911	In addition, our results demonstrating that deletions and down-regulation of the Rb/p16 pathway often coexist with TP53 mutations, suggest that Rb1 and TP53 act independently and perhaps are equally important in the development of HG serous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('deletions', 'Var', (44, 53))	('HG serous carcinomas', 'Disease', (231, 251))	('p16', 'Gene', '1029', (84, 87))	('TP53', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('HG serous carcinomas', 'Disease', 'MESH:D018284', (231, 251))	('down-regulation', 'NegReg', (58, 73))	('p16', 'Gene', (84, 87))
4492	19383911	The genetic analysis reported here provides an explanation why mouse ovarian cancer model generated by inducible deletion of Rb1 and TP53 in ovarian epithelium results in tumors with morphology closely resembled its human counterpart.	('ovarian cancer', 'Disease', (69, 83))	('mouse', 'Species', '10090', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('human', 'Species', '9606', (216, 221))	('Rb1', 'Gene', (125, 128))	('deletion', 'Var', (113, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('TP53', 'Gene', (133, 137))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
4495	19383911	Deletions in ch8p23 have been detected in several other types of human cancer including squamous cell carcinoma.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('human', 'Species', '9606', (65, 70))	('cancer', 'Disease', (71, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('detected', 'Reg', (30, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('ch8p23', 'Gene', (13, 19))	('squamous cell carcinoma', 'Disease', (88, 111))	('Deletions', 'Var', (0, 9))
4496	19383911	As well, comprehensive sequencing analysis has revealed somatic mutations of CSMD1 in colon and breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancers', 'Phenotype', 'HP:0003002', (96, 110))	('revealed', 'Reg', (47, 55))	('CSMD1', 'Gene', '64478', (77, 82))	('CSMD1', 'Gene', (77, 82))	('mutations', 'Var', (64, 73))	('colon and breast cancers', 'Disease', 'MESH:D001943', (86, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
4501	19383911	In addition, LG serous carcinomas harbor higher numbers of sub-chromosomal alterations than do SBTs.	('LG serous carcinomas', 'Disease', 'MESH:D018284', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('sub-chromosomal alterations', 'Var', (59, 86))	('LG serous carcinomas', 'Disease', (13, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))
4504	19383911	For HG tumors, deletions in the Rb-p16 pathway may contribute to its development, and CSMD1 and DOCK4 may represent new tumor suppressor genes.	('DOCK4', 'Gene', '9732', (96, 101))	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('development', 'MPA', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('p16', 'Gene', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('DOCK4', 'Gene', (96, 101))	('p16', 'Gene', '1029', (35, 38))	('tumors', 'Disease', (7, 13))	('contribute', 'Reg', (51, 61))	('tumor', 'Disease', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('deletions', 'Var', (15, 24))	('CSMD1', 'Gene', '64478', (86, 91))	('CSMD1', 'Gene', (86, 91))	('tumor', 'Disease', (7, 12))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
4613	30588241	Knockout of MTF1 Inhibits the Epithelial to Mesenchymal Transition in Ovarian Cancer Cells Due to peritoneal metastasis and frequent recurrence, ovarian cancer has the highest mortality among gynecological cancers.	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Inhibits', 'NegReg', (17, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (145, 159))	('Epithelial to Mesenchymal Transition', 'CPA', (30, 66))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (70, 84))	('Epithelial to Mesenchymal Transition', 'biological_process', 'GO:0001837', ('30', '66'))	('MTF1', 'Gene', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('MTF1', 'Gene', '4520', (12, 16))	('ovarian cancer', 'Disease', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('Knockout', 'Var', (0, 8))	('Ovarian Cancer', 'Disease', (70, 84))	('Ovarian Cancer', 'Disease', 'MESH:D010051', (70, 84))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('peritoneal metastasis', 'CPA', (98, 119))	('cancers', 'Disease', 'MESH:D009369', (206, 213))
4616	30588241	Knockout of MTF1 using lentiviral CRISPR/Cas9 nickase vector-mediated gene editing inhibited EMT by upregulating epithelial cell markers E-cadherin and cytokeratin 7, and downregulating mesenchymal markers Snai2 and beta-catenin in ovarian cancer SKOV3 and OVCAR3 cells.	('beta-catenin', 'Gene', (216, 228))	('beta-catenin', 'Gene', '1499', (216, 228))	('inhibited', 'NegReg', (83, 92))	('epithelial cell', 'CPA', (113, 128))	('downregulating', 'NegReg', (171, 185))	('ovarian cancer', 'Disease', 'MESH:D010051', (232, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('MTF1', 'Gene', (12, 16))	('EMT', 'CPA', (93, 96))	('Snai2', 'Gene', (206, 211))	('SKOV3', 'CellLine', 'CVCL:0532', (247, 252))	('cytokeratin 7', 'Gene', '3855', (152, 165))	('MTF1', 'Gene', '4520', (12, 16))	('editing', 'Var', (75, 82))	('cytokeratin 7', 'Gene', (152, 165))	('Cas', 'cellular_component', 'GO:0005650', ('41', '44'))	('ovarian cancer', 'Disease', (232, 246))	('cadherin', 'molecular_function', 'GO:0008014', ('139', '147'))	('mesenchymal markers', 'CPA', (186, 205))	('Knockout', 'Var', (0, 8))	('E-cadherin', 'Gene', (137, 147))	('E-cadherin', 'Gene', '999', (137, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (232, 246))	('EMT', 'biological_process', 'GO:0001837', ('93', '96'))	('upregulating', 'PosReg', (100, 112))	('Snai2', 'Gene', '6591', (206, 211))
4617	30588241	Loss of MTF1 reduced cell proliferation, migration, and invasion in both SKOV3 and OVCAR3 cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('21', '39'))	('SKOV3', 'CellLine', 'CVCL:0532', (73, 78))	('migration', 'CPA', (41, 50))	('cell proliferation', 'CPA', (21, 39))	('MTF1', 'Gene', (8, 12))	('MTF1', 'Gene', '4520', (8, 12))	('reduced', 'NegReg', (13, 20))	('Loss', 'Var', (0, 4))	('invasion', 'CPA', (56, 64))
4618	30588241	Knockout of MTF1 upregulated the expression of the KLF4 transcription factor, and attenuated two cellular survival pathways, ERK1/2 and AKT.	('attenuated', 'NegReg', (82, 92))	('ERK1', 'molecular_function', 'GO:0004707', ('125', '129'))	('transcription', 'biological_process', 'GO:0006351', ('56', '69'))	('MTF1', 'Gene', (12, 16))	('upregulated', 'PosReg', (17, 28))	('KLF4', 'Gene', '9314', (51, 55))	('KLF4', 'Gene', (51, 55))	('AKT', 'Gene', '207', (136, 139))	('Knockout', 'Var', (0, 8))	('expression', 'MPA', (33, 43))	('ERK1/2', 'Pathway', (125, 131))	('transcription factor', 'molecular_function', 'GO:0000981', ('56', '76'))	('MTF1', 'Gene', '4520', (12, 16))	('cellular survival pathways', 'Pathway', (97, 123))	('AKT', 'Gene', (136, 139))
4634	30588241	MTF1 is regulated by zinc and copper, and the ratio of copper versus zinc and CA125 together have been used as biomarkers for ovarian cancer diagnosis.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('CA125', 'Var', (78, 83))	('MTF1', 'Gene', '4520', (0, 4))	('ovarian cancer', 'Disease', 'MESH:D010051', (126, 140))	('copper', 'Chemical', 'MESH:D003300', (55, 61))	('ovarian cancer', 'Disease', (126, 140))	('copper', 'Chemical', 'MESH:D003300', (30, 36))	('MTF1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
4636	30588241	In this study, we analyzed MTF1 expression in ovarian cancer patient samples and knocked out MTF1 in ovarian cancer SKOV3 and OVCAR3 cells using a lentiviral CRISPR/Cas9 nickase vector approach.	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('MTF1', 'Gene', (93, 97))	('patient', 'Species', '9606', (61, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('MTF1', 'Gene', '4520', (27, 31))	('knocked', 'Var', (81, 88))	('ovarian cancer', 'Disease', (46, 60))	('ovarian cancer', 'Disease', (101, 115))	('SKOV3', 'CellLine', 'CVCL:0532', (116, 121))	('MTF1', 'Gene', '4520', (93, 97))	('Cas', 'cellular_component', 'GO:0005650', ('165', '168'))	('MTF1', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (101, 115))
4637	30588241	We find that MTF1 is upregulated in ovarian cancer and knockout of MTF1 leads to inhibition of EMT in ovarian cancer cells, suggesting that MTF1 may contribute to ovarian tumor metastasis.	('ovarian cancer', 'Disease', 'MESH:D010051', (36, 50))	('upregulated', 'PosReg', (21, 32))	('MTF1', 'Gene', (140, 144))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('MTF1', 'Gene', '4520', (140, 144))	('MTF1', 'Gene', (67, 71))	('ovarian cancer', 'Disease', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('MTF1', 'Gene', '4520', (67, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('ovarian tumor', 'Phenotype', 'HP:0100615', (163, 176))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian tumor metastasis', 'Disease', (163, 187))	('EMT', 'biological_process', 'GO:0001837', ('95', '98'))	('knockout', 'Var', (55, 63))	('inhibition', 'NegReg', (81, 91))	('MTF1', 'Gene', (13, 17))	('ovarian cancer', 'Disease', (102, 116))	('EMT', 'CPA', (95, 98))	('contribute', 'Reg', (149, 159))	('MTF1', 'Gene', '4520', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('ovarian tumor metastasis', 'Disease', 'MESH:D009362', (163, 187))
4677	30588241	These data indicate that MTF1 is highly expressed in high-grade ovarian serous cancer, and high MTF1 expression is associated with poor patient survival and more frequent relapses in ovarian cancer.	('patient survival', 'CPA', (136, 152))	('MTF1', 'Gene', (25, 29))	('patient', 'Species', '9606', (136, 143))	('ovarian cancer', 'Disease', (183, 197))	('poor', 'NegReg', (131, 135))	('high', 'Var', (91, 95))	('MTF1', 'Gene', '4520', (25, 29))	('MTF1', 'Gene', '4520', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian cancer', 'Disease', 'MESH:D010051', (183, 197))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (64, 85))	('associated', 'Reg', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (64, 85))	('expression', 'MPA', (101, 111))	('MTF1', 'Gene', (96, 100))	('ovarian serous cancer', 'Disease', (64, 85))
4678	30588241	To investigate the function of MTF1 gene in ovarian cancer cells, we knocked out MTF1 gene by transducing SKOV3 and OVCAR3 cells using lentiviral CRISPR/Cas9 nickase, targeting a region of exon 2.	('MTF1', 'Gene', (31, 35))	('MTF1', 'Gene', '4520', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('MTF1', 'Gene', '4520', (31, 35))	('SKOV3', 'CellLine', 'CVCL:0532', (106, 111))	('Cas', 'cellular_component', 'GO:0005650', ('153', '156'))	('MTF1', 'Gene', (81, 85))	('ovarian cancer', 'Disease', (44, 58))	('transducing', 'Reg', (94, 105))	('knocked', 'Var', (69, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))
4682	30588241	Knockout of MTF1 led to the upregulation of epithelial cell markers E-cadherin and cytokeratin 7, and downregulation of mesenchymal markers Snai2 and beta-catenin in both MTF1 KO cell lines compared to control cells (Fig.	('beta-catenin', 'Gene', '1499', (150, 162))	('MTF1', 'Gene', '4520', (171, 175))	('mesenchymal markers', 'CPA', (120, 139))	('Snai2', 'Gene', (140, 145))	('Snai2', 'Gene', '6591', (140, 145))	('MTF1', 'Gene', (12, 16))	('downregulation', 'NegReg', (102, 116))	('cytokeratin 7', 'Gene', '3855', (83, 96))	('epithelial cell', 'CPA', (44, 59))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('MTF1', 'Gene', '4520', (12, 16))	('Knockout', 'Var', (0, 8))	('MTF1', 'Gene', (171, 175))	('cytokeratin 7', 'Gene', (83, 96))	('beta-catenin', 'Gene', (150, 162))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))	('upregulation', 'PosReg', (28, 40))
4687	30588241	As shown by these western blot and immunofluorescent staining experiments, loss of MTF1 inhibited EMT in ovarian cancer cells.	('inhibited', 'NegReg', (88, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MTF1', 'Gene', '4520', (83, 87))	('ovarian cancer', 'Disease', (105, 119))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('EMT in', 'CPA', (98, 104))	('EMT', 'biological_process', 'GO:0001837', ('98', '101'))	('loss', 'Var', (75, 79))	('MTF1', 'Gene', (83, 87))
4690	30588241	Knockout of MTF1 significantly reduced cell proliferation in both SKOV3 and OVCAR3 cells compared to control cells at all three time points (24, 48, and 72 h) (Fig.	('reduced', 'NegReg', (31, 38))	('MTF1', 'Gene', (12, 16))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('Knockout', 'Var', (0, 8))	('SKOV3', 'CellLine', 'CVCL:0532', (66, 71))	('cell proliferation', 'CPA', (39, 57))	('MTF1', 'Gene', '4520', (12, 16))
4691	30588241	We also examined cell survival using cell colony formation assays; knockout of MTF1 led to significant inhibition of colony formation in both SKOV3 (Fig.	('knockout', 'Var', (67, 75))	('MTF1', 'Gene', '4520', (79, 83))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('SKOV3', 'CellLine', 'CVCL:0532', (142, 147))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('MTF1', 'Gene', (79, 83))	('colony formation', 'CPA', (117, 133))	('inhibition', 'NegReg', (103, 113))
4692	30588241	Our data indicate that knockout of MTF1 in ovarian cancer cells led to inhibition of cell proliferation and colony formation.	('cell proliferation', 'CPA', (85, 103))	('MTF1', 'Gene', (35, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (43, 57))	('knockout', 'Var', (23, 31))	('ovarian cancer', 'Disease', (43, 57))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('71', '103'))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('inhibition', 'NegReg', (71, 81))	('MTF1', 'Gene', '4520', (35, 39))	('formation', 'biological_process', 'GO:0009058', ('115', '124'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))	('colony formation', 'CPA', (108, 124))
4694	30588241	We found that loss of MTF1 led to the inhibition of EMT.	('loss', 'Var', (14, 18))	('EMT', 'CPA', (52, 55))	('MTF1', 'Gene', (22, 26))	('EMT', 'biological_process', 'GO:0001837', ('52', '55'))	('inhibition', 'NegReg', (38, 48))	('MTF1', 'Gene', '4520', (22, 26))
4695	30588241	We tested whether loss of MTF1 affects cell motility and invasion.	('MTF1', 'Gene', '4520', (26, 30))	('invasion', 'CPA', (57, 65))	('loss', 'Var', (18, 22))	('cell motility', 'biological_process', 'GO:0048870', ('39', '52'))	('MTF1', 'Gene', (26, 30))	('tested', 'Reg', (3, 9))	('cell motility', 'CPA', (39, 52))
4704	30588241	Loss of MTF1 led to attenuation of phospho-ERK1/2 and phospho-AKT in both cell lines, but total ERK1/2 and AKT were not significantly altered, as compared to control cells (Fig.	('AKT', 'Gene', (62, 65))	('AKT', 'Gene', '207', (107, 110))	('AKT', 'Gene', (107, 110))	('MTF1', 'Gene', (8, 12))	('ERK1', 'molecular_function', 'GO:0004707', ('43', '47'))	('attenuation', 'NegReg', (20, 31))	('AKT', 'Gene', '207', (62, 65))	('MTF1', 'Gene', '4520', (8, 12))	('ERK1', 'molecular_function', 'GO:0004707', ('96', '100'))	('Loss', 'Var', (0, 4))	('phospho-ERK1/2', 'MPA', (35, 49))
4709	30588241	Knockout of MTF1 expression inhibited EMT in ovarian cancer cells.	('MTF1', 'Gene', (12, 16))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('inhibited', 'NegReg', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Knockout', 'Var', (0, 8))	('ovarian cancer', 'Disease', 'MESH:D010051', (45, 59))	('EMT', 'biological_process', 'GO:0001837', ('38', '41'))	('MTF1', 'Gene', '4520', (12, 16))	('ovarian cancer', 'Disease', (45, 59))
4714	30588241	We examined the function of MTF1 in ovarian cancer SKOV3 and OVCAR3 KO and control cells by performing cell functional assays, and found that knockout of MTF1 resulted in reduced cell proliferation, colony formation, migration, and invasion in both SKOV3 and OVCAR3 cells.	('MTF1', 'Gene', (28, 32))	('cell proliferation', 'CPA', (179, 197))	('ovarian cancer', 'Disease', 'MESH:D010051', (36, 50))	('SKOV3', 'CellLine', 'CVCL:0532', (249, 254))	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('MTF1', 'Gene', '4520', (154, 158))	('invasion', 'CPA', (232, 240))	('MTF1', 'Gene', '4520', (28, 32))	('ovarian cancer', 'Disease', (36, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('reduced', 'NegReg', (171, 178))	('MTF1', 'Gene', (154, 158))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('SKOV3', 'CellLine', 'CVCL:0532', (51, 56))	('migration', 'CPA', (217, 226))	('knockout', 'Var', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('colony formation', 'CPA', (199, 215))
4718	30588241	However, we found that knockout of MTF1 resulted in upregulation of KLF4 expression in both ovarian cancer SKOV3 and OVCAR3 cells (Fig.	('ovarian cancer', 'Disease', 'MESH:D010051', (92, 106))	('upregulation', 'PosReg', (52, 64))	('MTF1', 'Gene', (35, 39))	('KLF4', 'Gene', (68, 72))	('ovarian cancer', 'Disease', (92, 106))	('knockout', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('MTF1', 'Gene', '4520', (35, 39))	('expression', 'MPA', (73, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('SKOV3', 'CellLine', 'CVCL:0532', (107, 112))	('KLF4', 'Gene', '9314', (68, 72))
4726	30588241	Our studies indicated that knockout of MTF1 attenuated the ERK1/2 and PI3K/AKT pathways in both SKOV3 and OVCAR3 ovarian cancer cells.	('MTF1', 'Gene', '4520', (39, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('AKT', 'Gene', '207', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('MTF1', 'Gene', (39, 43))	('ovarian cancer', 'Disease', (113, 127))	('knockout', 'Var', (27, 35))	('AKT', 'Gene', (75, 78))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('ERK1', 'molecular_function', 'GO:0004707', ('59', '63'))	('SKOV3', 'CellLine', 'CVCL:0532', (96, 101))	('attenuated', 'NegReg', (44, 54))
4729	30588241	In conclusion, we demonstrated that MTF1 is highly expressed in ovarian cancer, and high MTF1 expression is associated with poor ovarian cancer patient survival and disease relapse.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('high', 'Var', (84, 88))	('MTF1', 'Gene', (36, 40))	('ovarian cancer', 'Disease', 'MESH:D010051', (64, 78))	('MTF1', 'Gene', '4520', (89, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('patient', 'Species', '9606', (144, 151))	('ovarian cancer', 'Disease', (129, 143))	('disease relapse', 'CPA', (165, 180))	('associated', 'Reg', (108, 118))	('MTF1', 'Gene', '4520', (36, 40))	('ovarian cancer', 'Disease', (64, 78))	('expression', 'MPA', (94, 104))	('MTF1', 'Gene', (89, 93))	('poor', 'NegReg', (124, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
4730	30588241	We found that disrupting MTF1 expression inhibited EMT, proliferation, survival, migration, and invasion of ovarian cancer SKOV3 and OVCAR3 cells.	('EMT', 'CPA', (51, 54))	('survival', 'CPA', (71, 79))	('invasion of ovarian cancer', 'Disease', (96, 122))	('MTF1', 'Gene', '4520', (25, 29))	('EMT', 'biological_process', 'GO:0001837', ('51', '54'))	('disrupting', 'Var', (14, 24))	('proliferation', 'CPA', (56, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('SKOV3', 'CellLine', 'CVCL:0532', (123, 128))	('inhibited', 'NegReg', (41, 50))	('invasion of ovarian cancer', 'Disease', 'MESH:D010051', (96, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('MTF1', 'Gene', (25, 29))	('migration', 'CPA', (81, 90))
4731	30588241	Also, knockout of MTF1 upregulated KLF4 expression and attenuated both the ERK1/2 and AKT pathways, indicating that MTF1 may contribute to ovarian tumor metastasis by promoting EMT in ovarian cancer.	('upregulated', 'PosReg', (23, 34))	('AKT', 'Gene', (86, 89))	('MTF1', 'Gene', (116, 120))	('ERK1', 'molecular_function', 'GO:0004707', ('75', '79'))	('ovarian cancer', 'Disease', 'MESH:D010051', (184, 198))	('MTF1', 'Gene', '4520', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('KLF4', 'Gene', (35, 39))	('ovarian tumor metastasis', 'Disease', 'MESH:D009362', (139, 163))	('EMT', 'biological_process', 'GO:0001837', ('177', '180'))	('KLF4', 'Gene', '9314', (35, 39))	('AKT', 'Gene', '207', (86, 89))	('MTF1', 'Gene', (18, 22))	('expression', 'MPA', (40, 50))	('ovarian cancer', 'Disease', (184, 198))	('ovarian tumor', 'Phenotype', 'HP:0100615', (139, 152))	('attenuated', 'NegReg', (55, 65))	('EMT', 'CPA', (177, 180))	('MTF1', 'Gene', '4520', (18, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (184, 198))	('promoting', 'PosReg', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('knockout', 'Var', (6, 14))	('contribute', 'Reg', (125, 135))	('ovarian tumor metastasis', 'Disease', (139, 163))
4740	30926680	In addition, high SFN expression is associated with significantly worse overall survival in patients who received chemotherapy contains gemcitabine, taxol, taxol+platin, paclitaxel and avastin.	('avastin', 'Chemical', 'MESH:D000068258', (185, 192))	('high', 'Var', (13, 17))	('overall survival', 'MPA', (72, 88))	('SFN', 'Gene', '2810', (18, 21))	('worse', 'NegReg', (66, 71))	('patients', 'Species', '9606', (92, 100))	('SFN', 'Gene', (18, 21))	('taxol', 'Chemical', 'MESH:D017239', (149, 154))	('paclitaxel', 'Chemical', 'MESH:D017239', (170, 180))	('taxol', 'Chemical', 'MESH:D017239', (156, 161))	('platin', 'Chemical', 'MESH:D010984', (162, 168))	('gemcitabine', 'Chemical', 'MESH:C056507', (136, 147))
4799	30926680	As shown in Figures 5 and 6, high SFN expression is associated with significantly worse OS in patients who received chemotherapy contains gemcitabine, taxol, taxol+platin, paclitaxel and avastin (P<0.05).	('high', 'Var', (29, 33))	('SFN', 'Gene', '2810', (34, 37))	('paclitaxel', 'Chemical', 'MESH:D017239', (172, 182))	('patients', 'Species', '9606', (94, 102))	('SFN', 'Gene', (34, 37))	('platin', 'Chemical', 'MESH:D010984', (164, 170))	('taxol', 'Chemical', 'MESH:D017239', (151, 156))	('avastin', 'Chemical', 'MESH:D000068258', (187, 194))	('gemcitabine', 'Chemical', 'MESH:C056507', (138, 149))	('taxol', 'Chemical', 'MESH:D017239', (158, 163))
4806	30926680	In addition, by log-rank tests in the Kaplan-Meier plots, we also discovered that ovarian serous adenocarcinoma cases with alterations in SFN gene had worse OS (P=0.0461).	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (82, 111))	('SFN', 'Gene', '2810', (138, 141))	('SFN', 'Gene', (138, 141))	('ovarian serous adenocarcinoma', 'Disease', (82, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('alterations', 'Var', (123, 134))
4812	30926680	The results indicated that a high expression of MICB mRNA was significantly associated with poor PFS in ovarian cancer patients, including ovarian serous carcinoma and ovarian endometrioid adenocarcinoma patients (Figure 8).	('high', 'Var', (29, 33))	('MICB', 'Gene', '4277', (48, 52))	('patients', 'Species', '9606', (204, 212))	('ovarian serous carcinoma and ovarian endometrioid adenocarcinoma', 'Disease', 'MESH:D010051', (139, 203))	('ovarian cancer', 'Disease', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('PFS', 'Disease', (97, 100))	('patients', 'Species', '9606', (119, 127))	('poor', 'NegReg', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('associated', 'Reg', (76, 86))	('MICB', 'Gene', (48, 52))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (176, 203))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
4817	30926680	Furthermore, they found that SFN enhances receptor tyrosine kinases stabilization by aberrant ubiquitin-specific protease 8 (USPB) regulation in lung adenocarcinoma, implying that SFN could be an appropriate therapeutic target for lung adenocarcinoma than USP8.	('regulation', 'MPA', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('USPB', 'Gene', (125, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (231, 250))	('SFN', 'Gene', '2810', (180, 183))	('SFN', 'Gene', '2810', (29, 32))	('lung adenocarcinoma', 'Disease', (145, 164))	('enhances', 'PosReg', (33, 41))	('USP', 'molecular_function', 'GO:0051748', ('256', '259'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (145, 164))	('ubiquitin', 'molecular_function', 'GO:0031386', ('94', '103'))	('lung adenocarcinoma', 'Disease', (231, 250))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('aberrant', 'Var', (85, 93))	('USP8', 'Gene', (256, 260))	('USP8', 'Gene', '9101', (256, 260))	('receptor tyrosine kinases stabilization', 'MPA', (42, 81))	('SFN', 'Gene', (180, 183))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (231, 250))	('SFN', 'Gene', (29, 32))
4830	30926680	As a result, high SFN expression is associated with significantly worse OS in patients who received chemotherapy contains gemcitabine, taxol, taxol+platin, paclitaxel, and avastin.	('gemcitabine', 'Chemical', 'MESH:C056507', (122, 133))	('taxol', 'Chemical', 'MESH:D017239', (142, 147))	('high', 'Var', (13, 17))	('SFN', 'Gene', '2810', (18, 21))	('taxol', 'Chemical', 'MESH:D017239', (135, 140))	('patients', 'Species', '9606', (78, 86))	('SFN', 'Gene', (18, 21))	('paclitaxel', 'Chemical', 'MESH:D017239', (156, 166))	('platin', 'Chemical', 'MESH:D010984', (148, 154))	('expression', 'MPA', (22, 32))	('avastin', 'Chemical', 'MESH:D000068258', (172, 179))
4840	30926680	In addition, the survival analysis revealed that a high expression of MICB mRNA was significantly associated with poor PFS in ovarian cancer patients, including ovarian serous carcinoma and ovarian endometrioid adenocarcinoma patients, which was also similar with SFN' survival analysis in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (198, 225))	('ovarian cancer', 'Disease', 'MESH:D010051', (290, 304))	('high expression', 'Var', (51, 66))	('patients', 'Species', '9606', (141, 149))	('MICB', 'Gene', '4277', (70, 74))	('ovarian cancer', 'Disease', (290, 304))	('SFN', 'Gene', (264, 267))	('patients', 'Species', '9606', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MICB', 'Gene', (70, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (290, 304))	('poor', 'NegReg', (114, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (126, 140))	('SFN', 'Gene', '2810', (264, 267))	('ovarian serous carcinoma and ovarian endometrioid adenocarcinoma', 'Disease', 'MESH:D010051', (161, 225))	('ovarian cancer', 'Disease', (126, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('PFS', 'Disease', (119, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
4846	30926680	Besides, high expression of MICB predicted worse PFS in both ovarian serous carcinoma and ovarian endometrioid adenocarcinoma patients.	('MICB', 'Gene', '4277', (28, 32))	('PFS', 'Disease', (49, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (98, 125))	('ovarian serous carcinoma and ovarian endometrioid adenocarcinoma', 'Disease', 'MESH:D010051', (61, 125))	('MICB', 'Gene', (28, 32))	('patients', 'Species', '9606', (126, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('high', 'Var', (9, 13))
4854	29668586	The mean serum CA19-9 and CA125 concentration was significantly higher in the patients with ovarian malignant epithelial tumors (CA19-9, 514.0 +- 104.8 U/mL; CA125, 440.0 +- 154.8 U/mL) than that in the patients with ovarian serous carcinoma (CA19-9, 58.0 +- 14.3 U/mL; CA125, 63.0 +- 25.8 U/mL).	('CA125', 'Gene', '94025', (26, 31))	('higher', 'PosReg', (64, 70))	('ovarian malignant epithelial tumors', 'Phenotype', 'HP:0025318', (92, 127))	('patients', 'Species', '9606', (78, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('CA125', 'Gene', '94025', (270, 275))	('CA125', 'Gene', '94025', (158, 163))	('patients', 'Species', '9606', (203, 211))	('CA19-9', 'Chemical', 'MESH:C086528', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('CA125', 'Gene', (26, 31))	('ovarian malignant epithelial tumors', 'Disease', 'MESH:D002277', (92, 127))	('CA19-9', 'Chemical', 'MESH:C086528', (243, 249))	('ovarian serous carcinoma', 'Disease', (217, 241))	('ovarian malignant epithelial tumors', 'Disease', (92, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CA19-9', 'Var', (129, 135))	('malignant epithelial tumors', 'Phenotype', 'HP:0031492', (100, 127))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (217, 241))	('CA125', 'Gene', (270, 275))	('CA125', 'Gene', (158, 163))	('CA19-9', 'Chemical', 'MESH:C086528', (129, 135))
4866	29668586	Previous study demonstrated that the serum concentration of CA19-9 and CA125 was lower in the patients with OSC than that in the patients with OMEC.	('lower', 'NegReg', (81, 86))	('patients', 'Species', '9606', (94, 102))	('OMEC', 'Phenotype', 'HP:0025318', (143, 147))	('OSC', 'Disease', (108, 111))	('CA19-9', 'Var', (60, 66))	('OMEC', 'Chemical', '-', (143, 147))	('patients', 'Species', '9606', (129, 137))	('CA125', 'Gene', (71, 76))	('CA19-9', 'Chemical', 'MESH:C086528', (60, 66))	('OSC', 'molecular_function', 'GO:0000250', ('108', '111'))	('CA125', 'Gene', '94025', (71, 76))	('serum concentration', 'MPA', (37, 56))
4884	29668586	The mean serum CA19-9 and CA125 concentration was significantly higher in the patients with ovarian malignant epithelial tumors (CA19-9, 514.0 +- 104.8 U/mL; CA125, 440.0 +- 154.8 U/mL) than that in the patients with ovarian serous carcinoma (CA19-9, 58.0 +- 14.3 U/mL; CA125, 63.0 +- 25.8 U/mL) (Fig.	('CA125', 'Gene', '94025', (26, 31))	('higher', 'PosReg', (64, 70))	('ovarian malignant epithelial tumors', 'Phenotype', 'HP:0025318', (92, 127))	('patients', 'Species', '9606', (78, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('CA125', 'Gene', '94025', (270, 275))	('CA125', 'Gene', '94025', (158, 163))	('patients', 'Species', '9606', (203, 211))	('CA19-9', 'Chemical', 'MESH:C086528', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('CA125', 'Gene', (26, 31))	('ovarian malignant epithelial tumors', 'Disease', 'MESH:D002277', (92, 127))	('CA19-9', 'Chemical', 'MESH:C086528', (243, 249))	('ovarian serous carcinoma', 'Disease', (217, 241))	('ovarian malignant epithelial tumors', 'Disease', (92, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CA19-9', 'Var', (129, 135))	('malignant epithelial tumors', 'Phenotype', 'HP:0031492', (100, 127))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (217, 241))	('CA125', 'Gene', (270, 275))	('CA125', 'Gene', (158, 163))	('CA19-9', 'Chemical', 'MESH:C086528', (129, 135))
4893	29668586	The specificities were 72% for CEUS plus CA125, and 73% for using the CEUS plus CA19-9 information (Table 3).	('CA19-9', 'Chemical', 'MESH:C086528', (80, 86))	('CEUS', 'Var', (31, 35))	('CEUS', 'Chemical', '-', (31, 35))	('CA125', 'Gene', '94025', (41, 46))	('CEUS', 'Chemical', '-', (70, 74))	('CA125', 'Gene', (41, 46))
4941	31396367	They are genetically stable, characterized by mutations in different genes: KRAS, BRAF, PTEN, ss-catenin, and others.	('mutations', 'Var', (46, 55))	('BRAF', 'Gene', '673', (82, 86))	('KRAS', 'Gene', (76, 80))	('BRAF', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (76, 80))	('PTEN', 'Gene', (88, 92))	('ss-catenin', 'Gene', (94, 104))	('PTEN', 'Gene', '5728', (88, 92))
4942	31396367	High grade ovarian serous carcinoma, on the other hand, has a high level of genetic instability and is characterized by TP53 mutation, and loss of BRCA1 and BRCA2 function.	('TP53', 'Gene', '7157', (120, 124))	('BRCA1', 'Gene', '672', (147, 152))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (11, 35))	('loss', 'NegReg', (139, 143))	('BRCA1', 'Gene', (147, 152))	('BRCA2', 'Gene', (157, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('function', 'MPA', (163, 171))	('TP53', 'Gene', (120, 124))	('ovarian serous carcinoma', 'Disease', (11, 35))	('BRCA2', 'Gene', '675', (157, 162))	('mutation', 'Var', (125, 133))
4983	31396367	Interestingly, in a few cases, only non-proliferating stems or CSCs (SSEA4+/KI67- or ALDH1/2+/KI67-), or only proliferating (KI67+) cells were observed, which indicates a dynamic process in which different populations of cells are involved forming fascinating cellular hierarchy.	('SSEA4+/KI67-', 'Var', (69, 81))	('ALDH1', 'Gene', (85, 90))	('CSCs', 'CPA', (63, 67))	('ALDH1', 'Gene', '216', (85, 90))	('ALDH', 'molecular_function', 'GO:0004030', ('85', '89'))
5006	31396367	Cancer stemness seems to be more associated with partial-EMT phenotype than fully-driven EMT.	('partial-EMT', 'Var', (49, 60))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer stemness', 'Disease', (0, 15))	('Cancer stemness', 'Disease', 'MESH:D009369', (0, 15))	('EMT', 'biological_process', 'GO:0001837', ('89', '92'))	('EMT', 'biological_process', 'GO:0001837', ('57', '60'))
5035	31396367	Conversely, inhibition of ALDH1A1 in a mouse model sensitized the tumors to treatment.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('inhibition', 'Var', (12, 22))	('ALDH1A1', 'Gene', '11668', (26, 33))	('sensitized', 'Reg', (51, 61))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('ALDH', 'molecular_function', 'GO:0004030', ('26', '30'))	('ALDH1A1', 'Gene', (26, 33))	('mouse', 'Species', '10090', (39, 44))
5041	31396367	Its knockdown by let-7d increases ovarian cancer cell sensitivity to a genistein analog.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ovarian cancer', 'Phenotype', 'HP:0100615', (34, 48))	('increases ovarian cancer', 'Disease', 'MESH:D010051', (24, 48))	('let-7d', 'Gene', '406886', (17, 23))	('let-7d', 'Gene', (17, 23))	('increases ovarian cancer', 'Disease', (24, 48))	('knockdown', 'Var', (4, 13))
5045	31396367	Although CSCs can cause different processes such as tumor initiation, malignant proliferation, relapse and multi-drug resistance, the way to eliminate CSCs remains unknown.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('relapse', 'CPA', (95, 102))	('cause', 'Reg', (18, 23))	('drug resistance', 'biological_process', 'GO:0009315', ('113', '128'))	('drug resistance', 'biological_process', 'GO:0042493', ('113', '128'))	('multi-drug resistance', 'CPA', (107, 128))	('CSCs', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('malignant proliferation', 'CPA', (70, 93))	('drug resistance', 'Phenotype', 'HP:0020174', (113, 128))
5050	31396367	About 50% of these tumors showed defective homologous recombination due to germline and somatic BRCA mutations, epigenetic inactivation of BRCA and abnormalities of DNA repair genes.	('homologous recombination', 'MPA', (43, 67))	('epigenetic inactivation', 'Var', (112, 135))	('tumors', 'Disease', (19, 25))	('abnormalities', 'Var', (148, 161))	('defective', 'NegReg', (33, 42))	('mutations', 'Var', (101, 110))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('BRCA', 'Gene', '672', (96, 100))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('BRCA', 'Gene', (96, 100))	('homologous recombination', 'biological_process', 'GO:0035825', ('43', '67'))	('DNA repair', 'Gene', (165, 175))	('DNA repair', 'biological_process', 'GO:0006281', ('165', '175'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BRCA', 'Gene', '672', (139, 143))	('BRCA', 'Gene', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('abnormalities of DNA repair', 'Phenotype', 'HP:0003254', (148, 175))
5053	31396367	Other subtypes of ovarian cancer were characterised by a different mutational spectrum: Low grade ovarian serous carcinoma has increased frequency of BRAF and RAS mutations, mucinous cancers have a mutation in ARID1A, PIK3CA, PTEN, CTNNB1 and in RAS genes.	('ARID1A', 'Gene', (210, 216))	('CTNNB1', 'Gene', '1499', (232, 238))	('mucinous cancers', 'Disease', (174, 190))	('PTEN', 'Gene', (226, 230))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('PIK3CA', 'Gene', (218, 224))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('ARID1A', 'Gene', '8289', (210, 216))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('PTEN', 'Gene', '5728', (226, 230))	('ovarian cancer', 'Disease', 'MESH:D010051', (18, 32))	('CTNNB1', 'Gene', (232, 238))	('ovarian serous carcinoma', 'Disease', (98, 122))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (98, 122))	('mutation', 'Var', (198, 206))	('ovarian cancer', 'Disease', (18, 32))	('mutations', 'Var', (163, 172))	('PIK3CA', 'Gene', '5290', (218, 224))	('RAS', 'Gene', (159, 162))	('mucinous cancers', 'Disease', 'MESH:D002288', (174, 190))	('RAS genes', 'Gene', (246, 255))	('ovarian cancer', 'Phenotype', 'HP:0100615', (18, 32))
5149	23762804	Anthracyclines, oxaliplatin and X-rays exemplify the stimuli that trigger bona fide immunogenic cell death.	('rays', 'Species', '255564', (34, 38))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (16, 27))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('oxaliplatin', 'Var', (16, 27))	('Anthracyclines', 'Var', (0, 14))
5156	23762804	Of note, antibodies against SPAG9 were detected in patients affected by all stages of epithelial ovarian cancer but not in healthy donors.	('SPAG9', 'Gene', (28, 33))	('epithelial ovarian cancer', 'Disease', (86, 111))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (86, 111))	('SPAG9', 'Gene', '9043', (28, 33))	('detected', 'Reg', (39, 47))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('antibodies', 'Var', (9, 19))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (86, 111))
5227	30233254	Immunohistochemical examination yielded the following results: CK (+++) (Figure 1A), Ki-67 (+++) (Figure 1B), P53 (+++) (Figure 1C), S-100 (-), and villin (-) (Figure 1D).	('P53', 'Gene', '7157', (110, 113))	('S-100', 'Var', (133, 138))	('CK (+++', 'Var', (63, 70))	('P53', 'Gene', (110, 113))	('Ki-67 (+++', 'Var', (85, 95))
5407	24245968	The aberrant expression of the claudin proteins has been related to various human carcinomas.	('expression', 'MPA', (13, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('aberrant', 'Var', (4, 12))	('related', 'Reg', (57, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('human', 'Species', '9606', (76, 81))	('claudin proteins', 'Protein', (31, 47))	('carcinomas', 'Disease', (82, 92))	('carcinomas', 'Disease', 'MESH:D002277', (82, 92))
5456	24245968	Currently the possibility that abnormalities in TJ s protein expression relate to the invasion and metastasis of ovarian cancer has not been widely examined.	('abnormalities', 'Var', (31, 44))	('TJ s', 'Gene', (48, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (99, 127))	('metastasis of ovarian cancer', 'Disease', (99, 127))	('relate', 'Reg', (72, 78))	('invasion', 'CPA', (86, 94))
5475	24245968	We speculated that aberrant expression of claudin-6 protein may play a key role in the invasion and metastasis of ovarian cancer and other cancers.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (100, 128))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('play', 'Reg', (64, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('claudin-6', 'Gene', '9074', (42, 51))	('claudin-6', 'Gene', (42, 51))	('invasion', 'CPA', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('metastasis of ovarian cancer', 'Disease', (100, 128))	('aberrant expression', 'Var', (19, 38))
5479	24245968	These changes may regulate tumor cell proliferation, differentiation, survival and apoptosis though some signal transduction pathways, which play a role in occurrence, invasion and metastasis of tumor.	('metastasis of tumor', 'Disease', (181, 200))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('cell proliferation', 'biological_process', 'GO:0008283', ('33', '51'))	('tumor', 'Disease', (195, 200))	('signal transduction', 'biological_process', 'GO:0007165', ('105', '124'))	('signal transduction pathways', 'Pathway', (105, 133))	('tumor', 'Disease', (27, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('metastasis of tumor', 'Disease', 'MESH:D009362', (181, 200))	('differentiation', 'CPA', (53, 68))	('changes', 'Var', (6, 13))	('regulate', 'Reg', (18, 26))	('apoptosis', 'CPA', (83, 92))	('survival', 'CPA', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
5487	24245968	It has been suggested that inhibition of occludin may act on TJs directly or indirectly to bind with factors that regulate cell proliferation, differentiation and cell cycle, receiving and imparting PKC and Rho protein etc.	('occludin', 'Gene', (41, 49))	('PKC', 'molecular_function', 'GO:0004697', ('199', '202'))	('cell proliferation', 'CPA', (123, 141))	('cell cycle', 'biological_process', 'GO:0007049', ('163', '173'))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('cell cycle', 'CPA', (163, 173))	('inhibition', 'Var', (27, 37))	('bind', 'Interaction', (91, 95))	('occludin', 'Gene', '100506658', (41, 49))	('differentiation', 'CPA', (143, 158))
5518	20508725	Similar to change in protein level, the FASN transcript level in SKOV3 cells was significantly reduced by N130 induction or by NAC1 knockdown.	('knockdown', 'Var', (132, 141))	('N130', 'Gene', (106, 110))	('NAC1', 'Gene', (127, 131))	('SKOV3', 'CellLine', 'CVCL:0532', (65, 70))	('NAC1', 'Gene', '112939', (127, 131))	('reduced', 'NegReg', (95, 102))	('NAC', 'cellular_component', 'GO:0005854', ('127', '130'))	('FASN transcript level', 'MPA', (40, 61))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
5522	20508725	Finally, C93, a new FASN inhibitor, induced massive apoptosis in carboplatin/paclitaxel resistant ovarian cancer cells.	('ovarian cancer', 'Disease', 'MESH:D010051', (98, 112))	('ovarian cancer', 'Disease', (98, 112))	('C93', 'Var', (9, 12))	('carboplatin', 'Chemical', 'MESH:D016190', (65, 76))	('apoptosis', 'CPA', (52, 61))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
5523	20508725	In conclusion, we show that NAC1 is essential for FASN expression in ovarian serous carcinomas and the expression of FASN significantly correlates with tumor recurrence and disease aggressiveness.	('NAC1', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('aggressiveness', 'Disease', 'MESH:D001523', (181, 195))	('NAC', 'cellular_component', 'GO:0005854', ('28', '31'))	('aggressiveness', 'Disease', (181, 195))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ovarian serous carcinomas', 'Disease', (69, 94))	('correlates with', 'Reg', (136, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('tumor', 'Disease', (152, 157))	('aggressiveness', 'Phenotype', 'HP:0000718', (181, 195))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (69, 94))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (69, 94))	('expression', 'Var', (103, 113))	('NAC1', 'Gene', '112939', (28, 32))
5534	20508725	Ectopic expression of NAC1 increased paclitaxel resistance while knockdown of NAC1 or disruption of NAC1 homodimerization sensitized cancer cells to chemotherapeutic drugs.	('sensitized', 'Reg', (122, 132))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('paclitaxel resistance', 'MPA', (37, 58))	('NAC1', 'Gene', '112939', (78, 82))	('disruption', 'Var', (86, 96))	('NAC1', 'Gene', '112939', (100, 104))	('NAC', 'cellular_component', 'GO:0005854', ('100', '103'))	('NAC', 'cellular_component', 'GO:0005854', ('22', '25'))	('NAC1', 'Gene', (78, 82))	('NAC1', 'Gene', '112939', (22, 26))	('knockdown', 'Var', (65, 74))	('NAC1', 'Gene', (100, 104))	('homodimerization', 'Protein', (105, 121))	('increased', 'PosReg', (27, 36))	('cancer', 'Disease', (133, 139))	('NAC1', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('paclitaxel', 'Chemical', 'MESH:D017239', (37, 47))	('NAC', 'cellular_component', 'GO:0005854', ('78', '81'))	('Ectopic expression', 'MPA', (0, 18))
5535	20508725	In order to understand how NAC1 contributes to drug resistance, we previously compared the gene expression profiles of SKOV3 ovarian cancer cells to those of NAC1 inactivated SKOV3 cells where the inactivation was induced by expression of N130, a mutant protein containing only the BTB/POZ domain of NAC1 that competitively inhibits NAC1 homodimerization.	('drug resistance', 'Phenotype', 'HP:0020174', (47, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('NAC', 'cellular_component', 'GO:0005854', ('27', '30'))	('NAC1', 'Gene', '112939', (333, 337))	('N130', 'Var', (239, 243))	('NAC1', 'Gene', '112939', (158, 162))	('NAC1', 'Gene', '112939', (300, 304))	('NAC', 'cellular_component', 'GO:0005854', ('333', '336'))	('SKOV3', 'CellLine', 'CVCL:0532', (175, 180))	('inhibits', 'NegReg', (324, 332))	('NAC1', 'Gene', (333, 337))	('NAC1', 'Gene', (158, 162))	('BTB', 'Chemical', '-', (282, 285))	('NAC1', 'Gene', '112939', (27, 31))	('NAC', 'cellular_component', 'GO:0005854', ('300', '303'))	('NAC1', 'Gene', (300, 304))	('SKOV3 ovarian cancer', 'Disease', 'MESH:D010051', (119, 139))	('gene expression', 'biological_process', 'GO:0010467', ('91', '106'))	('SKOV3', 'CellLine', 'CVCL:0532', (119, 124))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('NAC1', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('NAC', 'cellular_component', 'GO:0005854', ('158', '161'))	('drug resistance', 'biological_process', 'GO:0009315', ('47', '62'))	('drug resistance', 'biological_process', 'GO:0042493', ('47', '62'))	('SKOV3 ovarian cancer', 'Disease', (119, 139))
5537	20508725	However, suppressing the Gadd45 tumor suppressor pathway did not completely rescue ovarian cancer cells after NAC1 inactivation, thus suggesting that other mechanisms also play a role.	('NAC1', 'Gene', '112939', (110, 114))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('ovarian cancer', 'Disease', (83, 97))	('NAC', 'cellular_component', 'GO:0005854', ('110', '113'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('Gadd45', 'Gene', (25, 31))	('inactivation', 'Var', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Gadd45', 'Gene', '1647', (25, 31))	('tumor', 'Disease', (32, 37))	('NAC1', 'Gene', (110, 114))	('suppressing', 'NegReg', (9, 20))
5573	20508725	To detect early apoptotic cells, we grew ovarian cancer cell lines in 6 well plates (5 x 105 cells/well) and treated them with C93 at their IC50 and with DMSO of equal concentration.	('ovarian cancer', 'Disease', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('DMSO', 'Chemical', 'MESH:D004121', (154, 158))	('C93', 'Var', (127, 130))
5583	20508725	To determine the possible mechanism by which NAC1 promotes drug resistance, we used the quantitative proteomics to compare the proteomes of N130-induced and-noninduced SKOV3 ovarian cancer cells using tandem mass spectrometry (MS/MS) and spectral count.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('ovarian cancer', 'Phenotype', 'HP:0100615', (174, 188))	('SKOV3 ovarian cancer', 'Disease', (168, 188))	('N130-induced', 'Var', (140, 152))	('NAC', 'cellular_component', 'GO:0005854', ('45', '48'))	('drug resistance', 'Phenotype', 'HP:0020174', (59, 74))	('drug resistance', 'biological_process', 'GO:0042493', ('59', '74'))	('drug resistance', 'biological_process', 'GO:0009315', ('59', '74'))	('drug resistance', 'MPA', (59, 74))	('SKOV3 ovarian cancer', 'Disease', 'MESH:D010051', (168, 188))	('NAC1', 'Gene', '112939', (45, 49))	('NAC1', 'Gene', (45, 49))	('promotes', 'PosReg', (50, 58))
5587	20508725	The levels of FASN are less abundant in N130 induced cells than in N130-noninduced cells, suggesting that NAC1 inactivation by N130 suppresses FASN protein expression in SKOV3 cells.	('suppresses', 'NegReg', (132, 142))	('N130', 'Var', (127, 131))	('SKOV3', 'CellLine', 'CVCL:0532', (170, 175))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('inactivation', 'NegReg', (111, 123))	('NAC1', 'Gene', (106, 110))	('NAC1', 'Gene', '112939', (106, 110))	('FASN', 'Protein', (143, 147))	('NAC', 'cellular_component', 'GO:0005854', ('106', '109'))
5588	20508725	In our first system, we used the same NAC1 dominant negative (N130) cell model that was used in the proteomic analysis to assess whether disruption of NAC1 homodimerization by N130 leads to a decrease in FASN mRNA level.	('FASN mRNA level', 'MPA', (204, 219))	('decrease', 'NegReg', (192, 200))	('disruption', 'Var', (137, 147))	('NAC', 'cellular_component', 'GO:0005854', ('38', '41'))	('N130', 'Var', (176, 180))	('homodimerization', 'Protein', (156, 172))	('NAC', 'cellular_component', 'GO:0005854', ('151', '154'))	('NAC1', 'Gene', '112939', (151, 155))	('NAC1', 'Gene', (151, 155))	('NAC1', 'Gene', '112939', (38, 42))	('NAC1', 'Gene', (38, 42))
5589	20508725	At these same time points, SKOV3 cells with N130 induction exhibit a downregulation of FASN mRNA.	('FASN mRNA', 'MPA', (87, 96))	('N130', 'Var', (44, 48))	('downregulation', 'NegReg', (69, 83))	('SKOV3', 'CellLine', 'CVCL:0532', (27, 32))
5590	20508725	In our second system, we knocked down NAC1 in SKOV3 cells to determine the FASN levels.	('SKOV3', 'CellLine', 'CVCL:0532', (46, 51))	('FASN levels', 'MPA', (75, 86))	('knocked down', 'Var', (25, 37))	('NAC', 'cellular_component', 'GO:0005854', ('38', '41'))	('NAC1', 'Gene', '112939', (38, 42))	('NAC1', 'Gene', (38, 42))	('determine', 'Reg', (61, 70))
5613	20508725	Thus, to determine if FASN expression is essential for cell growth and survival of high-grade serous carcinoma cells (including those that are resistant to paclitaxel or carboplatin), we applied C93, a second generation FASN inhibitor, to ovarian cancer cell lines (including SKOV3, A2780, and OVCAR3).	('SKOV3', 'CellLine', 'CVCL:0532', (276, 281))	('cell growth', 'biological_process', 'GO:0016049', ('55', '66'))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('ovarian cancer', 'Disease', 'MESH:D010051', (239, 253))	('serous carcinoma', 'Disease', (94, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('serous carcinoma', 'Disease', 'MESH:D018284', (94, 110))	('ovarian cancer', 'Disease', (239, 253))	('paclitaxel', 'Chemical', 'MESH:D017239', (156, 166))	('carboplatin', 'Chemical', 'MESH:D016190', (170, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (239, 253))	('C93', 'Var', (195, 198))
5616	20508725	When applied to each cell line at its IC50 concentration, C93 significantly increases the percentage of annexin V stained cells (representing the early phase of apoptosis) and the sub-G1 fraction in cell cycle analyses (representing the late phase) (Figure 4).	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('sub-G1 fraction', 'CPA', (180, 195))	('annexin V', 'Gene', '308', (104, 113))	('annexin V', 'Gene', (104, 113))	('increases', 'PosReg', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('C93', 'Var', (58, 61))	('cell cycle analyses', 'CPA', (199, 218))	('cell cycle', 'biological_process', 'GO:0007049', ('199', '209'))
5617	20508725	Thus, C93 induces apoptosis in all three ovarian cancer cell lines.	('ovarian cancer', 'Disease', (41, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('18', '27'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('induces', 'Reg', (10, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('apoptosis', 'CPA', (18, 27))	('apoptosis', 'biological_process', 'GO:0097194', ('18', '27'))	('C93', 'Var', (6, 9))
5620	20508725	In all three cell lines, the C93-treated group shows a significantly higher percentage of sub-G1 cells than the DMSO-treated group (P < .01).	('C93-treated', 'Var', (29, 40))	('DMSO', 'Chemical', 'MESH:D004121', (112, 116))	('higher', 'PosReg', (69, 75))	('sub-G1 cells', 'CPA', (90, 102))
5621	20508725	C93 fails to affect cell cycle progression in SKOV3 and OVCAR3 cells by 96 hours after treatment but it arrests A2780 cells in the G1 phase as early as 24 hours after treatment (data not shown).	('cell cycle', 'biological_process', 'GO:0007049', ('20', '30'))	('A2780 cells', 'Var', (112, 123))	('G1 phase', 'biological_process', 'GO:0051318', ('131', '139'))	('SKOV3', 'CellLine', 'CVCL:0532', (46, 51))	('arrests', 'NegReg', (104, 111))	('C93', 'Var', (0, 3))
5649	20508725	The first generation of FASN inhibitors, including C75 and Orlistat, potently inhibited tumor growth in a mouse xenograft model but the adverse effects associated with these drugs prevented their further consideration for clinical applications.	('FASN', 'Protein', (24, 28))	('inhibited', 'NegReg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('C75', 'Var', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('mouse', 'Species', '10090', (106, 111))
5650	20508725	On the other hand, C93, the second generation FASN inhibitor used in this study, pharmacologically eliminates concomitant CPT-1 stimulation and does not induce the anorexia and feeding behavior changes in mice that were caused by earlier generation FASN inhibitors.	('CPT-1', 'Gene', (122, 127))	('anorexia', 'Disease', 'MESH:D000855', (164, 172))	('eliminates', 'NegReg', (99, 109))	('anorexia', 'Phenotype', 'HP:0002039', (164, 172))	('CPT', 'molecular_function', 'GO:0004142', ('122', '125'))	('stimulation', 'MPA', (128, 139))	('anorexia', 'Disease', (164, 172))	('CPT-1', 'Gene', '12894', (122, 127))	('CPT', 'molecular_function', 'GO:0004095', ('122', '125'))	('feeding behavior', 'biological_process', 'GO:0007631', ('177', '193'))	('C93', 'Var', (19, 22))	('feeding behavior changes', 'Phenotype', 'HP:0011968', (177, 201))	('mice', 'Species', '10090', (205, 209))
5651	20508725	Our in vitro studies demonstrate that C93 affects both carboplatin and paclitaxel resistant ovarian cancer cells.	('ovarian cancer', 'Disease', 'MESH:D010051', (92, 106))	('C93', 'Var', (38, 41))	('ovarian cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('carboplatin', 'Chemical', 'MESH:D016190', (55, 66))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('affects', 'Reg', (42, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))
5654	20508725	The antitumor effects of FASN inhibitors, like C93, are thought to result from depletion of end product fatty acids with accumulation of toxic intracellular malonyl-CoA and altered production of phospholipids with diminished membrane synthesis.	('synthesis', 'biological_process', 'GO:0009058', ('234', '243'))	('production of phospholipids', 'MPA', (181, 208))	('membrane', 'cellular_component', 'GO:0016020', ('225', '233'))	('fatty acids', 'Chemical', 'MESH:D005227', (104, 115))	('depletion of end product fatty acids', 'MPA', (79, 115))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('intracellular', 'cellular_component', 'GO:0005622', ('143', '156'))	('altered', 'Reg', (173, 180))	('malonyl-CoA', 'Chemical', 'MESH:D008316', (157, 168))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('membrane synthesis', 'MPA', (225, 243))	('accumulation', 'PosReg', (121, 133))	('tumor', 'Disease', (8, 13))	('C93', 'Var', (47, 50))	('phospholipids', 'Chemical', 'MESH:D010743', (195, 208))
5656	20508725	For example, FASN inhibition has been shown to selectively activate AMP-activated protein kinase (AMPK) in ovarian cancer cells causing cytotoxicity while sparing most normal human tissues from these pleiotropic effects of AMPK activation.	('human', 'Species', '9606', (175, 180))	('AMPK', 'molecular_function', 'GO:0047322', ('98', '102'))	('AMPK', 'molecular_function', 'GO:0050405', ('223', '227'))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('AMPK', 'molecular_function', 'GO:0004691', ('223', '227'))	('cytotoxicity', 'Disease', (136, 148))	('activate', 'PosReg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('AMPK', 'molecular_function', 'GO:0047322', ('223', '227'))	('AMPK', 'molecular_function', 'GO:0050405', ('98', '102'))	('inhibition', 'Var', (18, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (136, 148))	('AMPK', 'molecular_function', 'GO:0004691', ('98', '102'))	('AMP-activated', 'Enzyme', (68, 81))	('FASN', 'Protein', (13, 17))	('ovarian cancer', 'Disease', (107, 121))
5660	20508725	Thus, the C93-induced apoptosis in ovarian cancer cells may be related to FASN inactivation and/or suppression of AKT activity.	('C93-induced', 'Var', (10, 21))	('AKT', 'Gene', '207', (114, 117))	('inactivation', 'NegReg', (79, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('apoptosis', 'CPA', (22, 31))	('AKT', 'Gene', (114, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('FASN', 'Protein', (74, 78))	('suppression', 'NegReg', (99, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))	('ovarian cancer', 'Disease', (35, 49))
5661	20508725	It has been demonstrated that FASN inhibition initiates apoptosis more effectively in neoplastic cells with mutant TP53 than in those with wild-type TP53.	('TP53', 'Gene', '7157', (115, 119))	('TP53', 'Gene', '7157', (149, 153))	('mutant', 'Var', (108, 114))	('TP53', 'Gene', (115, 119))	('TP53', 'Gene', (149, 153))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('FASN', 'Protein', (30, 34))
5662	20508725	Our current finding supports this view as the A2780 cell line that harbors wild-type TP53  responds to C93 with cell cycle arrest in the G1 phase in addition to apoptosis, while both the SKOV3 and OVCAR3 cell lines with their deleted and mutated TP53, respectively, respond to C93 with massive apoptosis.	('SKOV3', 'CellLine', 'CVCL:0532', (187, 192))	('TP53', 'Gene', (85, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('apoptosis', 'biological_process', 'GO:0097194', ('294', '303'))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('mutated', 'Var', (238, 245))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (112, 129))	('TP53', 'Gene', '7157', (85, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('294', '303'))	('G1 phase', 'biological_process', 'GO:0051318', ('137', '145'))	('TP53', 'Gene', '7157', (246, 250))	('cell cycle arrest', 'CPA', (112, 129))	('TP53', 'Gene', (246, 250))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('112', '129'))
5663	20508725	Since mutated TP53 appears in the majority of ovarian high-grade serous carcinomas, it is likely that apoptosis is the predominant antitumor mechanism of FASN inhibition.	('ovarian high', 'Phenotype', 'HP:0008209', (46, 58))	('TP53', 'Gene', '7157', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('TP53', 'Gene', (14, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('serous carcinomas', 'Disease', 'MESH:D018284', (65, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('serous carcinomas', 'Disease', (65, 82))	('tumor', 'Disease', (135, 140))	('mutated', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
5677	20508725	Proteins that are differentially expressed in N130-induced and-noninduced SKOV3 cells.	('SKOV3', 'CellLine', 'CVCL:0532', (74, 79))	('Proteins', 'Protein', (0, 8))	('N130-induced', 'Var', (46, 58))
5716	29459674	The further functional enrichment on 889 genes with frequent copy number gains (CNGs) revealed that these genes were significantly associated with cancer pathways including regulation of cell cycle, cell differentiation and mitogen-activated protein kinase (MAPK) cascade.	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('173', '197'))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('copy number', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cell differentiation', 'biological_process', 'GO:0030154', ('199', '219'))	('MAPK', 'molecular_function', 'GO:0004707', ('258', '262'))	('associated', 'Reg', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cell cycle', 'CPA', (187, 197))	('MAPK) cascade', 'biological_process', 'GO:0000165', ('258', '271'))	('cancer', 'Disease', (147, 153))	('cell differentiation', 'CPA', (199, 219))
5720	29459674	This study provides the first observation of CNV in prognosis-related genes across pan-cancer.	('cancer', 'Disease', (87, 93))	('prognosis-related genes', 'Gene', (52, 75))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CNV', 'Var', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
5723	29459674	Examples of prognostic biomarkers are Prostate-Specific Antigen (PSA) in prostate cancer and the phosphatidylinositol 3-kinase (PIK3CA) mutation status of tumours - which are associated with human epidermal growth factor receptor 2 (HER2) in women with positive metastatic breast cancer.	('Prostate-Specific Antigen', 'Gene', (38, 63))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('197', '220'))	('PIK3CA', 'Gene', '5290', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('HER2', 'Gene', (233, 237))	('human', 'Species', '9606', (191, 196))	('prostate cancer', 'Disease', (73, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('mutation', 'Var', (136, 144))	('PIK3CA', 'Gene', (128, 134))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('epidermal growth factor receptor 2', 'Gene', '2064', (197, 231))	('breast cancer', 'Disease', (273, 286))	('tumours', 'Disease', (155, 162))	('women', 'Species', '9606', (242, 247))	('Prostate-Specific Antigen', 'Gene', '354', (38, 63))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('HER2', 'Gene', '2064', (233, 237))	('epidermal growth factor receptor 2', 'Gene', (197, 231))
5731	29459674	Cancer progression involves a series of genetic alterations involving mutations and copy number of variants (CNVs) in human genomes.	('mutations', 'Var', (70, 79))	('copy number of variants', 'Var', (84, 107))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('human', 'Species', '9606', (118, 123))
5740	29459674	Cancer results from a single somatic cell that has accumulated multiple DNA mutations and result in cell proliferation caused by mutations in genes that control proliferation and the cell cycle.	('mutations', 'Var', (76, 85))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('mutations', 'Var', (129, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell proliferation', 'CPA', (100, 118))	('caused by', 'Reg', (119, 128))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cell cycle', 'biological_process', 'GO:0007049', ('183', '193'))	('result in', 'Reg', (90, 99))
5745	29459674	Overexpression of BCL-2 and related anti-apoptotic proteins has been demonstrated to inhibit cell death induced by growth factor deprivation, hypoxia and oxidative stress.	('BCL-2', 'Gene', '596', (18, 23))	('growth', 'CPA', (115, 121))	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('BCL-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('inhibit', 'NegReg', (85, 92))	('BCL-2', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('hypoxia', 'Disease', (142, 149))	('cell death', 'CPA', (93, 103))	('cell death', 'biological_process', 'GO:0008219', ('93', '103'))
5750	29459674	For example, the frequency of genetic alterations in TCGA oesophageal carcinoma that exhibited at least one copy number change for each gene was the highest with 157 cases (85.3%).	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (58, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('genetic alterations', 'Var', (30, 49))	('oesophageal carcinoma', 'Disease', (58, 79))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (58, 79))
5753	29459674	More than 80.0% of oesophagus-stomach cancer patients involved gene amplifications.	('oesophagus-stomach cancer', 'Disease', 'MESH:D013274', (19, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (45, 53))	('stomach cancer', 'Phenotype', 'HP:0012126', (30, 44))	('gene amplifications', 'Var', (63, 82))	('oesophagus-stomach cancer', 'Disease', (19, 44))	('involved', 'Reg', (54, 62))
5754	29459674	The same proportion of copy number changes in both CNGs and CNLs with more than 60.0% cases were identified in 14 cancer datasets from six types of cancer, including breast cancer, head and neck squamous cell carcinoma, lung cancer, bladder urothelial carcinoma, sarcoma and uterine carcinosarcoma.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('carcinosarcoma', 'Disease', (283, 297))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (181, 218))	('cancer', 'Disease', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('neck', 'cellular_component', 'GO:0044326', ('190', '194'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (166, 179))	('carcinosarcoma', 'Disease', 'MESH:D002296', (283, 297))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('sarcoma', 'Disease', 'MESH:D012509', (290, 297))	('lung cancer', 'Disease', (220, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('sarcoma', 'Disease', (290, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (173, 179))	('copy number changes', 'Var', (23, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (275, 297))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('cancer', 'Disease', (148, 154))	('bladder urothelial carcinoma', 'Disease', (233, 261))	('sarcoma', 'Disease', 'MESH:D012509', (263, 270))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('sarcoma', 'Disease', (263, 270))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (233, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Disease', (114, 120))
5757	29459674	In addition to the sample analysis, we explored the genomic alterations in multiple genes across several tumour samples to further elaborate the prognosis-related genes (Fig.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('genomic alterations', 'Var', (52, 71))	('tumour', 'Disease', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
5788	29459674	Most studies show that the KRAS gene mutations are poor prognostic factors but that the upregulation of metadherin (MTDH) is associated with tumour progression in female reproductive system cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('KRAS', 'Gene', '3845', (27, 31))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('system cancers', 'Disease', (183, 197))	('system cancers', 'Disease', 'MESH:D009369', (183, 197))	('metadherin', 'Gene', '92140', (104, 114))	('upregulation', 'PosReg', (88, 100))	('mutations', 'Var', (37, 46))	('metadherin', 'Gene', (104, 114))	('MTDH', 'Gene', '92140', (116, 120))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', (141, 147))	('MTDH', 'Gene', (116, 120))	('KRAS', 'Gene', (27, 31))
5813	29459674	The frequency of the oncogenes with CNGs and overexpression across the tumour samples suggested that this could be a common mechanism in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CNGs', 'Var', (36, 40))	('cancer', 'Disease', (137, 143))	('oncogenes', 'Gene', (21, 30))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('overexpression', 'PosReg', (45, 59))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
5814	29459674	Using cBioPortal, the overall survival rates of patients in these cancer types was compared between tumour samples with or without alterations in each gene, and those which contained the highest number of tumour samples (Fig.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumour', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (131, 142))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (100, 106))	('patients', 'Species', '9606', (48, 56))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', (66, 72))
5815	29459674	Those patients with TCGA uterine corpus endometrial carcinoma had significant overall survival rates with p-value 1.930e-6.	('endometrial carcinoma', 'Disease', (40, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (40, 61))	('patients', 'Species', '9606', (6, 14))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (40, 61))	('TCGA', 'Var', (20, 24))
5816	29459674	We observed that TCGA uterine corpus endometrial carcinoma patients with genetic alterations in BIRC5 had significantly better overall survival rates when compared to TCGA sarcoma and ovarian serous cystadenocarcinoma patients with gene amplification in BIRC5 and EZH2.	('endometrial carcinoma', 'Disease', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('EZH2', 'Gene', (264, 268))	('EZH2', 'Gene', '2146', (264, 268))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('ovarian serous cystadenocarcinoma', 'Disease', (184, 217))	('sarcoma', 'Disease', (172, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('genetic alterations', 'Var', (73, 92))	('patients', 'Species', '9606', (59, 67))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (184, 217))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (37, 58))	('overall', 'MPA', (127, 134))	('better', 'PosReg', (120, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('patients', 'Species', '9606', (218, 226))	('BIRC5', 'Gene', '332', (254, 259))	('BIRC5', 'Gene', '332', (96, 101))	('BIRC5', 'Gene', (254, 259))	('BIRC5', 'Gene', (96, 101))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (192, 217))
5817	29459674	The median month survival for sarcoma patients with genetic alterations was 32.13 while that of patients without genetic alterations was 76.35.	('genetic alterations', 'Var', (52, 71))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('sarcoma', 'Disease', (30, 37))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
5826	29459674	The desired Affymetrix was valid: 202666_s_at (ACTL6A), 226463_at (ATP6V1C1), 203140_at (BCL6), 204274_at (EBAG9), 204010_s_at (KRAS), 212248_at (MTDH), 216071_x_at (OPA1) and 213184_at (SENP5).	('203140_at', 'Var', (78, 87))	('EBAG9', 'Gene', '9166', (107, 112))	('EBAG9', 'Gene', (107, 112))	('204010_s_at', 'Var', (115, 126))	('MTDH', 'Gene', (146, 150))	('202666_s_at', 'Var', (34, 45))	('SENP5', 'Gene', (187, 192))	('MTDH', 'Gene', '92140', (146, 150))	('ATP6V1C1', 'Gene', '528', (67, 75))	('ACTL6A', 'Gene', (47, 53))	('KRAS', 'Gene', '3845', (128, 132))	('BCL6', 'Gene', '604', (89, 93))	('212248_at', 'Var', (135, 144))	('ACTL6A', 'Gene', '86', (47, 53))	('OPA1', 'Gene', '4976', (166, 170))	('KRAS', 'Gene', (128, 132))	('OPA1', 'Gene', (166, 170))	('ATP6V1C1', 'Gene', (67, 75))	('226463_at', 'Var', (56, 65))	('213184_at', 'Var', (176, 185))	('204274_at', 'Var', (96, 105))	('216071_x_at', 'Var', (153, 164))	('SENP5', 'Gene', '205564', (187, 192))	('BCL6', 'Gene', (89, 93))
5829	29459674	Interestingly, we identified that MTDH was not statistically associated with RFS in ovarian cancer (P = 0.59); however, the high expression of MTDH was associated with a poor prognosis in other three cancer types - breast (P = 3.5e-10), lung (P = 2.1e-06) and gastric (P = 3.5e-10; Sup Fig.	('ovarian cancer', 'Disease', (84, 98))	('MTDH', 'Gene', (34, 38))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('lung', 'Disease', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('gastric', 'Disease', (260, 267))	('MTDH', 'Gene', '92140', (143, 147))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('MTDH', 'Gene', '92140', (34, 38))	('breast', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (200, 206))	('high', 'Var', (124, 128))	('MTDH', 'Gene', (143, 147))
5841	29459674	The cases with more than 40.0% genetic alterations and including both CNLs and CNGs were identified in six cancer datasets from four cancer types: ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, oesophageal carcinoma and uterine carcinosarcoma.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (238, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (212, 233))	('genetic alterations', 'Var', (31, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (182, 210))	('lung squamous cell carcinoma', 'Disease', (182, 210))	('cancer', 'Disease', (133, 139))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (155, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (212, 233))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinosarcoma', 'Disease', (246, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('ovarian serous cystadenocarcinoma', 'Disease', (147, 180))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('oesophageal carcinoma', 'Disease', (212, 233))	('carcinosarcoma', 'Disease', 'MESH:D002296', (246, 260))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (147, 180))
5842	29459674	For example, the TCGA ovarian serous cystadenocarcinoma patients had more than 60.0% (360 cases) genetic alteration in CNGs.	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (30, 55))	('patients', 'Species', '9606', (56, 64))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (22, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('ovarian serous cystadenocarcinoma', 'Disease', (22, 55))	('genetic alteration', 'Var', (97, 115))
5844	29459674	The median month survival for ovarian serous cystadenocarcinoma patients with genetic alterations was 48.72, while that of patients without genetic mutation was 39.55.	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (38, 63))	('patients', 'Species', '9606', (64, 72))	('ovarian serous cystadenocarcinoma', 'Disease', (30, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('patients', 'Species', '9606', (123, 131))	('genetic alterations', 'Var', (78, 97))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (30, 63))
5846	29459674	This study has revealed some significant somatic mutational characteristics of prognosis-related genes in multiple cancer types, particularly with respect to the CNVs and their effects on gene expression.	('mutational', 'Var', (49, 59))	('multiple cancer', 'Disease', (106, 121))	('prognosis-related genes', 'Gene', (79, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene expression', 'biological_process', 'GO:0010467', ('188', '203'))	('effects', 'Reg', (177, 184))	('multiple cancer', 'Disease', 'MESH:D009369', (106, 121))
5870	31554806	Cancers arise through the accumulation of genetic and epigenetic alterations that lead to widespread gene expression changes.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('lead', 'Reg', (82, 86))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('epigenetic alterations', 'Var', (54, 76))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	(' wid', 'Gene', '51523', (89, 93))	('gene expression', 'biological_process', 'GO:0010467', ('101', '116'))	(' wid', 'Gene', (89, 93))
5871	31554806	Transcription factors (TFs) are instrumental in driving these gene expression programs, and the aberrant activity of TFs:induced downstream of activated oncogenic signaling or in concert with epigenetic modifiers:often underlies the altered developmental state of cancer cells and acquisition of cancer-related cellular phenotypes.	('nal', 'Gene', (166, 169))	('tat', 'Gene', '6898', (256, 259))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('tat', 'Gene', (256, 259))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('aberrant', 'Var', (96, 104))	('TFs', 'Gene', (117, 120))	('nal', 'Gene', '80896', (166, 169))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('underlies', 'Reg', (219, 228))	('cancer', 'Disease', (296, 302))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
5878	31554806	Extensive pan-cancer genomic analyses have shown that the same genes and pathways are targeted by somatic alterations across multiple tumor types.	('cancer', 'Disease', (14, 20))	('nal', 'Gene', (30, 33))	('nal', 'Gene', '80896', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('nes', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('nes', 'Gene', '10763', (65, 68))	('alterations', 'Var', (106, 117))	('tumor', 'Disease', (134, 139))
5906	31554806	Interestingly, for the two uterine carcinosarcoma cell lines, the copy number high SNU685 cell line clustered with ovarian and basal breast cancer cell lines, whereas JHUCS1 clustered with uterine endometrioid cell lines.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('nes', 'Gene', (154, 157))	('nes', 'Gene', (57, 60))	('basal breast cancer', 'Disease', 'MESH:D001943', (127, 146))	('carcinosarcoma', 'Disease', 'MESH:D002296', (35, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('nes', 'Gene', '10763', (154, 157))	('nes', 'Gene', '10763', (57, 60))	('copy number high SNU685', 'Var', (66, 89))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (27, 49))	('nes', 'Gene', (217, 220))	('ovarian and basal', 'Disease', 'MESH:D010049', (115, 132))	('carcinosarcoma', 'Disease', (35, 49))	('basal breast cancer', 'Disease', (127, 146))	('nes', 'Gene', '10763', (217, 220))
5994	31554806	Indeed, tissue microarray analyses in clinically annotated primary basal breast tumor samples (n = 45) validated MITF positivity in tumor cells and revealed a significant association between MITF expression and patient survival (P < 0.006, log-rank test), with median survival of 1208 and 2406 days for the positive and negative staining groups, respectively (see Kaplan-Meier survival curve and representative MITF-positive staining in basal breast cancer patients in Fig.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tat', 'Gene', '6898', (53, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (443, 456))	('tumor', 'Disease', (132, 137))	('breast tumor', 'Phenotype', 'HP:0100013', (73, 85))	('positivity', 'Var', (118, 128))	('MITF', 'Gene', (191, 195))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('breast tumor', 'Disease', (73, 85))	('tat', 'Gene', (404, 407))	('basal breast cancer', 'Disease', 'MESH:D001943', (437, 456))	('patients', 'Species', '9606', (457, 465))	('clinical', 'Species', '191496', (38, 46))	('basal breast cancer', 'Disease', (437, 456))	('breast tumor', 'Disease', 'MESH:D061325', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('nal', 'Gene', (27, 30))	('tumor', 'Disease', (80, 85))	('tat', 'Gene', (53, 56))	('nal', 'Gene', '80896', (27, 30))	('patient', 'Species', '9606', (211, 218))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tat', 'Gene', '6898', (404, 407))	('cancer', 'Phenotype', 'HP:0002664', (450, 456))	('patient', 'Species', '9606', (457, 464))
6000	31554806	RNA-seq following MITF silencing revealed an effect on gene expression with 58 consistently down-regulated and 103 consistently upregulated genes (adjusted P < 0.05 and fold change > 2) in MDA-MB-436 cells transduced with two independent MITF shRNAs (Fig.	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('nes', 'Gene', '10763', (142, 145))	('silencing', 'Var', (23, 32))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('gene expression', 'MPA', (55, 70))	('nes', 'Gene', (142, 145))	('upregulated', 'PosReg', (128, 139))	('down-regulated', 'NegReg', (92, 106))
6025	31554806	Importantly, inhibition of MTF1 induces the expression of tumor suppressor factor Kruppel like factor 4 (KLF4).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('expression', 'MPA', (44, 54))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('MTF1', 'Gene', (27, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('induces', 'Reg', (32, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
6032	31554806	Possible future validation experiments to confirm the tumor-promoting roles of ETV6 in uterine serous cancer, expression levels of ETV6 can be manipulated in cultured cells through overexpression or silencing and the effects of ETV6 on cancer cell proliferation, survival, motility, and invasion potential can be evaluated.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('ETV6', 'Gene', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Disease', (54, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('243', '261'))	('silencing', 'Var', (199, 208))	('survival', 'CPA', (263, 271))
6033	31554806	Ultimately, in vivo validation of the roles of ETV6 expression on uterine cancer progression can be studied using uterine serous cancer-bearing mouse models through in vivo silencing of ETV6 using siRNAs.	('tim', 'Gene', '26762', (2, 5))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mouse', 'Species', '10090', (144, 149))	('uterine cancer', 'Phenotype', 'HP:0010784', (66, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (129, 135))	('silencing', 'Var', (173, 182))	('ETV6', 'Gene', (186, 190))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tim', 'Gene', (2, 5))	('ETV6', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
6037	31554806	Moreover, many of the factors de-repressed upon MITF knockdown are important players that activate anti-tumor immunity (e.g.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('knockdown', 'Var', (53, 62))	('tumor', 'Disease', (104, 109))	('activate', 'PosReg', (90, 98))	('MITF', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
6057	31554806	CAOV3 and OVCAR8 possess TP53 mutations and substantial copy-number changes, key characteristics of high grade serous ovarian cancer (HGSOC).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TP53', 'Gene', (25, 29))	('tat', 'Gene', (32, 35))	('serous ovarian cancer', 'Disease', (111, 132))	('copy-number changes', 'Var', (56, 75))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (111, 132))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('TP53', 'Gene', '7157', (25, 29))	('tat', 'Gene', '6898', (32, 35))
6082	31554806	The model vector wt represents the inferred global role of these TFs in driving gene expression; the event's true gene expression is denoted by yt; and the predicted gene expression is given by wtXt (treating both as row vectors for notational convenience).	('gene expression', 'biological_process', 'GO:0010467', ('166', '181'))	('driving gene expression', 'MPA', (72, 95))	('tat', 'Gene', '6898', (235, 238))	('TFs', 'Var', (65, 68))	('tat', 'Gene', (235, 238))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('nal', 'Gene', (240, 243))	('nal', 'Gene', '80896', (240, 243))	('gene expression', 'biological_process', 'GO:0010467', ('114', '129'))
6173	31222668	Endoscopic retrograde cholangiography (ERC) revealed the defect at the bifurcation of the common hepatic duct (Bismuth-Corlette classification type II) and endoscopic nasobiliary drainage was performed for obstructive jaundice (Fig.	('jaundice', 'Phenotype', 'HP:0000952', (218, 226))	('ER', 'Gene', '2099', (39, 41))	('ERC', 'cellular_component', 'GO:0055037', ('39', '42'))	('defect', 'Var', (57, 63))	('obstructive jaundice', 'Disease', 'MESH:D041781', (206, 226))	('obstructive jaundice', 'Disease', (206, 226))
6233	28611294	We used microarray analysis to determine alterations in the level of expression of genes in cisplatin- (CisPt), doxorubicin- (Dox), topotecan- (Top), and paclitaxel- (Pac) resistant variants of W1 and A2780 ovarian cancer cell lines.	('level', 'MPA', (60, 65))	('Pac', 'Chemical', 'MESH:D017239', (167, 170))	('CisPt', 'Chemical', 'MESH:D002945', (104, 109))	('Pac', 'Phenotype', 'HP:0006699', (167, 170))	('A2780 ovarian cancer', 'Disease', (201, 221))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('variants', 'Var', (182, 190))	('expression', 'MPA', (69, 79))	('topotecan', 'Chemical', 'MESH:D019772', (132, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('paclitaxel', 'Chemical', 'MESH:D017239', (154, 164))	('A2780 ovarian cancer', 'Disease', 'MESH:D010051', (201, 221))	('Dox', 'Chemical', 'MESH:D004317', (126, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))
6247	28611294	Other mechanisms underlying cytostatic-drug resistance include the following: inactivating the drugs using detoxification enzymes, inactivating the drugs through metallothionein or glutathione binding, repairing damaged DNA, developing point mutations in the genes that encode proteins that bind cytostatic drugs, and increasing the activity of anti-apoptotic or pro-survival pathways as well as disrupting apoptotic signaling pathways.	('developing point mutations', 'Var', (225, 251))	('drugs', 'MPA', (148, 153))	('apoptotic signaling pathways', 'Pathway', (407, 435))	('drug resistance', 'biological_process', 'GO:0009315', ('39', '54'))	('drug resistance', 'biological_process', 'GO:0042493', ('39', '54'))	('activity', 'MPA', (333, 341))	('disrupting', 'NegReg', (396, 406))	('inactivating', 'Var', (78, 90))	('detoxification', 'biological_process', 'GO:0098754', ('107', '121'))	('anti-apoptotic or pro-survival pathways', 'Pathway', (345, 384))	('N', 'Chemical', 'MESH:D009584', (221, 222))	('signaling', 'biological_process', 'GO:0023052', ('417', '426'))	('increasing', 'PosReg', (318, 328))	('DNA', 'cellular_component', 'GO:0005574', ('220', '223'))	('pro-survival', 'biological_process', 'GO:0043066', ('363', '375'))	('inactivating', 'NegReg', (131, 143))	('glutathione', 'Chemical', 'MESH:D005978', (181, 192))	('glutathione binding', 'molecular_function', 'GO:0043295', ('181', '200'))	('drug resistance', 'Phenotype', 'HP:0020174', (39, 54))
6262	28611294	The other most important mechanisms underlying Pac resistance are the development of tubulin mutations and the expression of the less common tubulin isotypes.	('tubulin', 'Protein', (85, 92))	('Pac', 'Phenotype', 'HP:0006699', (47, 50))	('Pac', 'Chemical', 'MESH:D017239', (47, 50))	('mutations', 'Var', (93, 102))
6268	28611294	Inhibiting DNA topoisomerase activities using poisons such as Dox and Top causes the formation of irreversible covalent cross-links between the topoisomerase and DNA, leading to DNA breakage and consequently, to cell death.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('Inhibiting', 'Var', (0, 10))	('topoisomerase', 'molecular_function', 'GO:0003917', ('15', '28'))	('topoisomerase', 'molecular_function', 'GO:0003917', ('144', '157'))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('DNA', 'MPA', (178, 181))	('topoisomerase', 'molecular_function', 'GO:0003918', ('15', '28'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('144', '157'))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('cell death', 'biological_process', 'GO:0008219', ('212', '222'))	('N', 'Chemical', 'MESH:D009584', (179, 180))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('breakage', 'NegReg', (182, 190))	('cell death', 'CPA', (212, 222))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('Dox', 'Chemical', 'MESH:D004317', (62, 65))	('N', 'Chemical', 'MESH:D009584', (163, 164))
6279	28611294	In addition to the four genes that were underexpressed in all three of the Cis-resistant cell lines, six genes were overexpressed and 13 genes were underexpressed in both the A2780CR1 and A2780CR2 cell lines.	('underexpressed', 'NegReg', (148, 162))	('overexpressed', 'PosReg', (116, 129))	('CR2', 'Species', '2498238', (193, 196))	('A2780CR1', 'Var', (175, 183))	('A2780CR2', 'Var', (188, 196))
6280	28611294	In addition to the three genes that were overexpressed and the six genes that were underexpressed in all three of the Pac-resistant cell lines, 14 genes were overexpressed and eight genes were underexpressed in both the A2780PR1 and A2780PR2 cell lines.	('A2780PR2', 'Var', (233, 241))	('overexpressed', 'PosReg', (158, 171))	('A2780PR1', 'Var', (220, 228))	('Pac', 'Chemical', 'MESH:D017239', (118, 121))	('Pac', 'Phenotype', 'HP:0006699', (118, 121))
6292	28611294	IFI16 expression was increased in all of the Dox-resistant cell lines but was also increased more than four-hundred-fold in the A2780PR1 Pac-resistant cell line.	('Pac', 'Phenotype', 'HP:0006699', (137, 140))	('Dox', 'Chemical', 'MESH:D004317', (45, 48))	('increased', 'PosReg', (21, 30))	('IFI16', 'Gene', (0, 5))	('increased', 'PosReg', (83, 92))	('expression', 'MPA', (6, 16))	('A2780PR1', 'Var', (128, 136))	('IFI16', 'Gene', '3428', (0, 5))	('Pac', 'Chemical', 'MESH:D017239', (137, 140))
6293	28611294	We observed the increased expression of IFIH1 in three Top-resistant cell lines and in the A2780DR1 and A2780PR1 cell lines that were resistant to Dox and Pac, respectively.	('expression', 'MPA', (26, 36))	('Pac', 'Chemical', 'MESH:D017239', (155, 158))	('A2780DR1', 'Var', (91, 99))	('Pac', 'Phenotype', 'HP:0006699', (155, 158))	('IFIH1', 'Gene', '64135', (40, 45))	('increased', 'PosReg', (16, 25))	('IFIH1', 'Gene', (40, 45))	('A2780PR1', 'Var', (104, 112))	('Dox', 'Chemical', 'MESH:D004317', (147, 150))
6371	28611294	In hepatocellular carcinoma (HCC) cells, the loss of PCDH9 expression facilitated tumour-cell migration and epithelial-mesenchymal transition (EMT).	('PCDH9', 'Gene', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('108', '141'))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('epithelial-mesenchymal transition', 'CPA', (108, 141))	('tumour', 'Disease', (82, 88))	('cell migration', 'biological_process', 'GO:0016477', ('89', '103'))	('PCDH9', 'Gene', '5101', (53, 58))	('facilitated', 'PosReg', (70, 81))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('loss', 'Var', (45, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
6380	28611294	Decreased levels of PTPRK expression or the loss of PTPRK activity due to mutation led to increased tyrosine-phosphorylation-based signalling, which is a major driving force in the development and progression of tumours.	('mutation', 'Var', (74, 82))	('tyrosine-phosphorylation-based signalling', 'MPA', (100, 141))	('activity', 'MPA', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('PTPRK', 'Gene', (20, 25))	('increased', 'PosReg', (90, 99))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('Decreased', 'NegReg', (0, 9))	('PTPRK', 'Gene', '5796', (20, 25))	('signalling', 'biological_process', 'GO:0023052', ('131', '141'))	('loss', 'NegReg', (44, 48))	('PTPRK', 'Gene', (52, 57))	('tumours', 'Disease', 'MESH:D009369', (212, 219))	('PTPRK', 'Gene', '5796', (52, 57))	('tumours', 'Disease', (212, 219))	('increased tyrosine-', 'Phenotype', 'HP:0003231', (90, 109))	('tyrosine', 'Chemical', 'MESH:D014443', (100, 108))	('phosphorylation', 'biological_process', 'GO:0016310', ('109', '124'))
6386	28611294	It was suggested that lower levels of SEMA3A may promote pleural and vascular invasion and lymph-node metastasis.	('pleural', 'Disease', (57, 64))	('lower levels of SEMA3A', 'Phenotype', 'HP:0032429', (22, 44))	('SEMA3A', 'Gene', (38, 44))	('promote', 'PosReg', (49, 56))	('SEMA3A', 'Gene', '10371', (38, 44))	('lower', 'Var', (22, 27))	('pleural', 'Disease', 'MESH:D010995', (57, 64))	('lymph-node metastasis', 'CPA', (91, 112))
6402	28611294	The main mechanism underlying Top resistance includes its efflux by the drug transporter ABCG2 and mutations in DNA topoisomerase I.	('DNA', 'Gene', (112, 115))	('ABCG2', 'Gene', '9429', (89, 94))	('Top resistance', 'Disease', (30, 44))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('efflux', 'biological_process', 'GO:0140115', ('58', '64'))	('efflux', 'biological_process', 'GO:0140352', ('58', '64'))	('mutations', 'Var', (99, 108))	('efflux', 'MPA', (58, 64))	('topoisomerase', 'molecular_function', 'GO:0003917', ('116', '129'))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('116', '129'))	('ABCG2', 'Gene', (89, 94))
6445	28611294	A2780 sublines that were resistant to CisPt [A2780CR1 and A2780CR2 (A2780 cisplatin resistant)], Pac [A2780PR1 and A2780PR2 (A2780 paclitaxel resistant)], Dox [A2780DR1 and A2780DR2 (A2780 doxorubicin resistant)] and Top [A2780TR1 and A2780TR2 (A2780 topotecan resistant)] were generated by exposing A2780 cells to the relevant drugs at incrementally increased concentrations.	('A2780CR2', 'Var', (58, 66))	('paclitaxel', 'Chemical', 'MESH:D017239', (131, 141))	('Dox', 'Chemical', 'MESH:D004317', (155, 158))	('topotecan', 'Chemical', 'MESH:D019772', (251, 260))	('A2780', 'Var', (300, 305))	('A2780PR2', 'Var', (115, 123))	('Pac', 'Chemical', 'MESH:D017239', (97, 100))	('A2780TR2', 'Var', (235, 243))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('Pac', 'Phenotype', 'HP:0006699', (97, 100))	('doxorubicin', 'Chemical', 'MESH:D004317', (189, 200))	('CisPt', 'Chemical', 'MESH:D002945', (38, 43))	('CR2', 'Species', '2498238', (63, 66))
6485	20154587	They displayTP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('type I tumors', 'Disease', 'MESH:D005776', (102, 115))	('TP53', 'Gene', '7157', (12, 16))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TP53', 'Gene', (12, 16))	('type I tumors', 'Disease', (102, 115))
6504	20154587	Type I tumors include low- grade serous, low-grade endometrioid, clear cell and mucinous carcinomas.	('low-grade', 'Var', (41, 50))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (80, 99))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('low- grade serous', 'Disease', (22, 39))	('clear cell', 'Disease', (65, 75))	('mucinous carcinomas', 'Disease', (80, 99))	('Type I tumors', 'Disease', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
6513	20154587	Thus, KRAS, BRAF, and ERBB2 mutations occur in approximately two thirds of low-grade serous carcinomas whereas TP53 mutations are rare in these tumors.	('tumors', 'Disease', (144, 150))	('ERBB2', 'Gene', '2064', (22, 27))	('serous carcinomas', 'Disease', 'MESH:D018284', (85, 102))	('KRAS', 'Gene', '3845', (6, 10))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('ERBB2', 'Gene', (22, 27))	('BRAF', 'Gene', (12, 16))	('serous carcinomas', 'Disease', (85, 102))	('occur', 'Reg', (38, 43))	('BRAF', 'Gene', '673', (12, 16))	('TP53', 'Gene', '7157', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('TP53', 'Gene', (111, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('KRAS', 'Gene', (6, 10))	('mutations', 'Var', (28, 37))
6514	20154587	Low-grade endometrioid carcinomas have aberrations in the Wnt signaling pathway involving somatic mutations of CTNNB1 (encoding beta-catenin), PTEN and PIK3CA.	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('58', '79'))	('PIK3CA', 'Gene', '5290', (152, 158))	('beta-catenin', 'Gene', (128, 140))	('endometrioid carcinomas', 'Disease', (10, 33))	('Wnt signaling pathway', 'Pathway', (58, 79))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (10, 33))	('PTEN', 'Gene', '5728', (143, 147))	('beta-catenin', 'Gene', '1499', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('mutations', 'Var', (98, 107))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (10, 33))	('CTNNB1', 'Gene', (111, 117))	('PTEN', 'Gene', (143, 147))	('PIK3CA', 'Gene', (152, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('CTNNB1', 'Gene', '1499', (111, 117))
6515	20154587	Mucinous carcinomas have KRAS mutations in more than 50% of specimens.	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (9, 19))	('Mucinous carcinomas', 'Disease', (0, 19))	('mutations', 'Var', (30, 39))	('Mucinous carcinomas', 'Disease', 'MESH:D002288', (0, 19))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
6516	20154587	Clear cell carcinoma is unique in that it has a high percentage of PIK3CA activating mutations when purified tumor samples and cell lines are analyzed.	('PIK3CA', 'Gene', '5290', (67, 73))	('activating', 'PosReg', (74, 84))	('Clear cell carcinoma', 'Disease', 'MESH:C538614', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutations', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Clear cell carcinoma', 'Disease', (0, 20))	('PIK3CA', 'Gene', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('tumor', 'Disease', (109, 114))
6518	20154587	High-grade serous carcinoma, the prototypic type II tumor, is characterized by very frequent TP53 mutations (>80% of cases) and CCNE1 (endcoding cyclin E1) amplification but rarely mutations that characterize most type I tumors such as KRAS, BRAF, ERBB2, PTEN, CTNNB1 and PIK3CA.	('CCNE1', 'Gene', (128, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('type I tumors', 'Disease', 'MESH:D005776', (214, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('TP53', 'Gene', (93, 97))	('ERBB2', 'Gene', '2064', (248, 253))	('amplification', 'PosReg', (156, 169))	('KRAS', 'Gene', (236, 240))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('CCNE1', 'Gene', '898', (128, 133))	('serous carcinoma', 'Disease', (11, 27))	('type II tumor', 'Disease', 'MESH:D009369', (44, 57))	('cyclin E1', 'Gene', (145, 154))	('PIK3CA', 'Gene', (272, 278))	('PTEN', 'Gene', (255, 259))	('type I tumors', 'Disease', (214, 227))	('CTNNB1', 'Gene', '1499', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('serous carcinoma', 'Disease', 'MESH:D018284', (11, 27))	('TP53', 'Gene', '7157', (93, 97))	('PTEN', 'Gene', '5728', (255, 259))	('BRAF', 'Gene', '673', (242, 246))	('BRAF', 'Gene', (242, 246))	('mutations', 'Var', (98, 107))	('PIK3CA', 'Gene', '5290', (272, 278))	('type II tumor', 'Disease', (44, 57))	('CTNNB1', 'Gene', (261, 267))	('ERBB2', 'Gene', (248, 253))	('KRAS', 'Gene', '3845', (236, 240))	('cyclin E1', 'Gene', '898', (145, 154))	('cyclin', 'molecular_function', 'GO:0016538', ('145', '151'))
6520	20154587	In summary, type I tumors, as a group, are genetically more stable than type II tumors and display a distinctive pattern of mutations that occur in specific cell types (low-grade serous, low-grade endometrioid, clear cell and mucinous).	('mutations', 'Var', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('low-grade serous', 'Disease', (169, 185))	('type I tumors', 'Disease', 'MESH:D005776', (12, 25))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('type II tumors', 'Disease', (72, 86))	('occur', 'Reg', (139, 144))	('type II tumors', 'Disease', 'MESH:D009369', (72, 86))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('type I tumors', 'Disease', (12, 25))
6551	20154587	This led to fallopian tube carcinoma being included as part of the cancer spectrum associated with inherited BRCA mutations.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA', 'Gene', '672', (109, 113))	('fallopian tube carcinoma', 'Phenotype', 'HP:0030394', (12, 36))	('fallopian tube carcinoma', 'Disease', 'MESH:D005185', (12, 36))	('fallopian tube carcinoma', 'Disease', (12, 36))	('BRCA', 'Gene', (109, 113))
6554	20154587	This observation gave substantial support to the proposal that STICs, which almost always are detected in the fimbria, may be the source of ovarian high-grade serous carcinoma in both women with hereditary mutations in BRCA as well as women who did not have a known genetic predisposition for ovarian cancer.	('TIC', 'Phenotype', 'HP:0100033', (64, 67))	('mutations', 'Var', (206, 215))	('ovarian cancer', 'Disease', (293, 307))	('women', 'Species', '9606', (184, 189))	('BRCA', 'Gene', '672', (219, 223))	('women', 'Species', '9606', (235, 240))	('serous carcinoma', 'Disease', 'MESH:D018284', (159, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('BRCA', 'Gene', (219, 223))	('ovarian cancer', 'Disease', 'MESH:D010051', (293, 307))	('TIC', 'Disease', 'None', (64, 67))	('source', 'Reg', (130, 136))	('TIC', 'Disease', (64, 67))	('ovarian high', 'Phenotype', 'HP:0008209', (140, 152))	('ovarian cancer', 'Phenotype', 'HP:0100615', (293, 307))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('fimbria', 'cellular_component', 'GO:0009289', ('110', '117'))	('serous carcinoma', 'Disease', (159, 175))
6558	20154587	Laser capture microdissection studies of these lesions have demonstrated that they harbor mutated TP53.	('TP53', 'Gene', '7157', (98, 102))	('mutated', 'Var', (90, 97))	('TP53', 'Gene', (98, 102))
6559	20154587	In addition, STICs associated with a concomitant ovarian carcinoma share not only morphologic features but also identical TP53 mutations indicating a clonal relationship between them.	('associated', 'Reg', (19, 29))	('ovarian carcinoma', 'Disease', (49, 66))	('TP53', 'Gene', (122, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('TIC', 'Phenotype', 'HP:0100033', (14, 17))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (49, 66))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (49, 66))	('TIC', 'Disease', 'None', (14, 17))	('mutations', 'Var', (127, 136))	('TP53', 'Gene', '7157', (122, 126))	('TIC', 'Disease', (14, 17))
6563	20154587	A recent finding has been the identification of benign tubal epithelium, specifically secretory as opposed to ciliated cells, that express p53 and in which laser capture microdissection studies have reported TP53 mutations in 57% of cases.	('p53', 'Gene', (139, 142))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))	('p53', 'Gene', '7157', (139, 142))	('mutations', 'Var', (213, 222))
6565	20154587	Like STICs, p53 signatures express gamma-H2AX which localizes to areas of DNA damage in nuclei.	('gamma-H2AX', 'Var', (35, 45))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('TIC', 'Phenotype', 'HP:0100033', (6, 9))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('TIC', 'Disease', 'None', (6, 9))	('TIC', 'Disease', (6, 9))
6567	20154587	Based on these findings, a sequence of pathogenetic events has been proposed, beginning with genotoxic DNA damage, followed by TP53 mutation and progressive loss of cell cycle control, which then eventuates in the development of carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (229, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('cell cycle control', 'CPA', (165, 183))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('TP53', 'Gene', (127, 131))	('loss', 'NegReg', (157, 161))	('carcinoma', 'Disease', (229, 238))	('eventuates', 'Reg', (196, 206))	('cell cycle control', 'biological_process', 'GO:1901987', ('165', '183'))	('TP53', 'Gene', '7157', (127, 131))	('mutation', 'Var', (132, 140))
6568	20154587	First, as noted in some instances, TP53 mutations, when present in the p53 signature, are not always identical with the mutations in the STICs and carcinomas in the same specimen.	('carcinomas', 'Disease', 'MESH:D002277', (147, 157))	('carcinomas', 'Disease', (147, 157))	('TIC', 'Phenotype', 'HP:0100033', (138, 141))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('p53', 'Gene', (71, 74))	('mutations', 'Var', (40, 49))	('TIC', 'Disease', 'None', (138, 141))	('p53', 'Gene', '7157', (71, 74))	('TIC', 'Disease', (138, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
6571	20154587	It is conceivable that p53 signatures reflect an appropriate and physiological upregulation of p53 in response to DNA damage, based on the observation that TP53 mutations are absent in nearly half of p53 signatures.	('response to DNA damage', 'MPA', (102, 124))	('p53', 'Gene', (200, 203))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('p53', 'Gene', '7157', (200, 203))	('p53', 'Gene', (95, 98))	('p53', 'Gene', (23, 26))	('mutations', 'Var', (161, 170))	('p53', 'Gene', '7157', (95, 98))	('p53', 'Gene', '7157', (23, 26))	('upregulation', 'PosReg', (79, 91))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
6585	20154587	In these cases the high-grade tumors have had KRAS mutations identical to those in the serous borderline tumors and lacked TP53 mutations.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', (30, 36))	('serous borderline tumors', 'Disease', (87, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (51, 60))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('KRAS', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TP53', 'Gene', '7157', (123, 127))	('serous borderline tumors', 'Disease', 'MESH:D012569', (87, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', (123, 127))
6586	20154587	This finding suggests that some high-grade serous carcinomas arise from low-grade serous tumors and not by the usual (type II) pathway that begins with a TP53 mutation.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('TP53', 'Gene', (154, 158))	('serous carcinomas', 'Disease', (43, 60))	('serous tumors', 'Disease', 'MESH:D018284', (82, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('mutation', 'Var', (159, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('serous tumors', 'Disease', (82, 95))	('serous carcinomas', 'Disease', 'MESH:D018284', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('TP53', 'Gene', '7157', (154, 158))
6596	20154587	In the case of a low-grade serous carcinoma the process develops slowly from a serous cystadenoma and then a serous borderline tumor after a KRAS or BRAF mutation whereas in the case of a high-grade serous carcinoma the process evolves rapidly, presumably from a cortical inclusion cyst after a TP53 mutation with the development of an intraepithelial carcinoma as an intermediate step.	('KRAS', 'Gene', (141, 145))	('serous cystadenoma', 'Disease', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('TP53', 'Gene', '7157', (295, 299))	('serous carcinoma', 'Disease', 'MESH:D018284', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutation', 'Var', (154, 162))	('intraepithelial carcinoma', 'Disease', (336, 361))	('serous carcinoma', 'Disease', (199, 215))	('serous cystadenoma', 'Phenotype', 'HP:0012887', (79, 97))	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cortical inclusion cyst', 'Phenotype', 'HP:0000803', (263, 286))	('TP53', 'Gene', (295, 299))	('serous carcinoma', 'Disease', 'MESH:D018284', (199, 215))	('serous carcinoma', 'Disease', (27, 43))	('tumor', 'Disease', (127, 132))	('KRAS', 'Gene', '3845', (141, 145))	('serous cystadenoma', 'Disease', 'MESH:D018293', (79, 97))	('mutation', 'Var', (300, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('intraepithelial carcinoma', 'Disease', 'MESH:D002278', (336, 361))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
6652	20154587	Mutations in these genes constitutively activate the signaling pathways they control, and tumor cells with mutations become dependent on those mutations for progression.	('signaling pathways', 'Pathway', (53, 71))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Mutations', 'Var', (0, 9))	('activate', 'PosReg', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
6653	20154587	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))
6657	20154587	A precedent exists for this approach as women with hereditary BRCA mutations are treated based on that information only.	('women', 'Species', '9606', (40, 45))	('BRCA', 'Gene', '672', (62, 66))	('BRCA', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
6665	20154587	The 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', (86, 95))	('BRCA1/2', 'Gene', (121, 128))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (78, 95))	('mutations', 'Var', (129, 138))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (78, 95))	('women', 'Species', '9606', (47, 52))	('BRCA1/2', 'Gene', '672;675', (121, 128))	('ovarian carcinoma', 'Disease', (78, 95))
6669	20154587	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 all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (296, 307))	('bilateral oophorectomy', 'Var', (136, 158))	('all-cause', 'Disease', (228, 237))	('women', 'Species', '9606', (47, 52))	('lung cancer', 'Disease', (296, 307))	('nonfatal coronary heart disease', 'Disease', 'MESH:D003324', (259, 290))	('lung cancer', 'Phenotype', 'HP:0100526', (296, 307))	('coronary heart disease', 'Phenotype', 'HP:0001677', (268, 290))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('nonfatal coronary heart disease', 'Disease', (259, 290))	('nonfatal coronary heart disease', 'Phenotype', 'HP:0012436', (259, 290))
6676	20154587	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))
6678	20154587	For example, clear cell carcinoma is classified as a type I tumor based on having a characteristic PIKC3CA mutation, relative genetic stability, frequent presentation in stage I and association with endometriosis, a well established precursor lesion.	('clear cell carcinoma', 'Disease', (13, 33))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (13, 33))	('association', 'Interaction', (182, 193))	('endometriosis', 'Disease', 'MESH:D004715', (199, 212))	('mutation', 'Var', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('endometriosis', 'Disease', (199, 212))	('endometriosis', 'Phenotype', 'HP:0030127', (199, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('PIKC3CA', 'Gene', (99, 106))
6701	28178720	Median rates of OS were 18, 22, and 58 months among high-, intermediate-, and low-expression tumors, respectively.	('low-expression', 'Var', (78, 92))	('intermediate-', 'Var', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('high-', 'Var', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))
6720	28178720	By contrast, mutations of ERBB4 have also been associated with multiple cancer types.	('ERBB4', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (13, 22))	('associated', 'Reg', (47, 57))	('ERBB4', 'Gene', '2066', (26, 31))	('cancer', 'Disease', (72, 78))
6743	28178720	Chi-square tests were performed on low (0-100), intermediate (101-200), and high (201-300) ERBB4 expression for tumor and control tissues as well as the CR and IR samples.	('201-300', 'Var', (82, 89))	('ERBB4', 'Gene', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('101-200', 'Var', (62, 69))	('0-100', 'Var', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('ERBB4', 'Gene', '2066', (91, 96))
6757	28178720	High-level ERBB4 expression (201-300) was observed in 37% of ovarian serous carcinoma specimens compared with 10% of control tissue (P = .013).	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (61, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ERBB4', 'Gene', '2066', (11, 16))	('ovarian serous carcinoma', 'Disease', (61, 85))	('ERBB4', 'Gene', (11, 16))	('201-300', 'Var', (29, 36))
6770	28178720	In addition, no survival difference was observed among low- and high-level ERBB4-expressing tumors within the CR and IR groups.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('high-level', 'Var', (64, 74))	('low-', 'NegReg', (55, 59))	('ERBB4', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('ERBB4', 'Gene', '2066', (75, 80))	('tumors', 'Disease', (92, 98))
6776	28178720	ERBB4 expression was observed to be an adverse prognostic factor in some studies but a favorable factor in others, even when studying the same tumor type.	('ERBB4', 'Gene', '2066', (0, 5))	('tumor', 'Disease', (143, 148))	('ERBB4', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
6783	28178720	In addition, the insertion and overexpression of 4ICD has been shown to suppress the cell cycle and proliferation in neuroblastoma cell lines.	('4ICD', 'Var', (49, 53))	('cell cycle', 'CPA', (85, 95))	('suppress', 'NegReg', (72, 80))	('neuroblastoma', 'Phenotype', 'HP:0003006', (117, 130))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('insertion', 'Var', (17, 26))	('neuroblastoma', 'Disease', 'MESH:D009447', (117, 130))	('overexpression', 'PosReg', (31, 45))	('neuroblastoma', 'Disease', (117, 130))
6794	28178720	High ERBB4 expression was also correlated with a low mitosis/karyorrhexis index, which is an indicator of mitosis activity, and also in clinical high-risk groups, metastasis, and poor rates of survival.	('mitosis', 'biological_process', 'GO:0000278', ('106', '113'))	('High', 'Var', (0, 4))	('ERBB4', 'Gene', (5, 10))	('mitosis', 'biological_process', 'GO:0000278', ('53', '60'))	('expression', 'MPA', (11, 21))	('low mitosis', 'Disease', (49, 60))	('low mitosis', 'Disease', 'MESH:D009800', (49, 60))	('ERBB4', 'Gene', '2066', (5, 10))
6795	28178720	These results may lead some to conclude that tumors growing more slowly are more difficult to treat and ERBB4 overexpression may reduce proliferation, thus rendering a refractory phenotype.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('refractory', 'MPA', (168, 178))	('reduce', 'NegReg', (129, 135))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('overexpression', 'Var', (110, 124))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('ERBB4', 'Gene', '2066', (104, 109))	('ERBB4', 'Gene', (104, 109))	('proliferation', 'CPA', (136, 149))
6865	28502078	The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer.	('liver metastases', 'Disease', 'MESH:D009362', (60, 76))	('metastases of colorectal cancer', 'Disease', (66, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('metastases of colorectal cancer', 'Disease', 'MESH:D009362', (66, 97))	('DYRK2', 'Var', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('regulates', 'Reg', (50, 59))	('liver metastases', 'Disease', (60, 76))
6872	28502078	Dual-specificity tyrosine-regulated kinase 2 (DYRK2) is a protein kinase that phosphorylates its substrates on serine/thereonine residues.14 Initially, DYRK2 was found to phosphorylate p53 at Ser46 to regulate apoptotic cell death in response to DNA damage.15, 16 Recent studies have shown that DYRK2-mediated phosphorylation initiates the degradation of several proteins through the ubiquitin-proteasome system.	('DYRK2-mediated', 'Var', (295, 309))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('phosphorylation', 'biological_process', 'GO:0016310', ('310', '325'))	('ubiquitin-proteasome system', 'MPA', (384, 411))	('degradation', 'biological_process', 'GO:0009056', ('340', '351'))	('serine', 'Chemical', 'MESH:D012694', (111, 117))	('proteasome', 'cellular_component', 'GO:0000502', ('394', '404'))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('proteasome', 'molecular_function', 'GO:0004299', ('394', '404'))	('Ser46', 'Chemical', '-', (192, 197))	('ubiquitin', 'molecular_function', 'GO:0031386', ('384', '393'))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('210', '230'))	('degradation of several proteins', 'MPA', (340, 371))	('Ser', 'cellular_component', 'GO:0005790', ('192', '195'))	('death', 'Disease', 'MESH:D003643', (225, 230))	('DNA', 'cellular_component', 'GO:0005574', ('246', '249'))	('death', 'Disease', (225, 230))
6874	28502078	EMT is characteristic of embryonic development, tissue remodeling, and wound healing.22 During EMT, epithelial cells show reduced intercellular adhesion.23, 24 Aberrant activation of this process has been hypothesized to promote tumor progression, especially invasion and metastasis.	('promote', 'PosReg', (221, 228))	('invasion', 'CPA', (259, 267))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('activation', 'PosReg', (169, 179))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('tissue remodeling', 'biological_process', 'GO:0048771', ('48', '65'))	('tumor', 'Disease', (229, 234))	('EMT', 'biological_process', 'GO:0001837', ('95', '98'))	('wound healing', 'biological_process', 'GO:0042060', ('71', '84'))	('Aberrant', 'Var', (160, 168))
6878	28502078	In this study, we found that DYRK2 regulates liver metastases of colorectal cancer cells through the activation of EMT, and that patients with low DYRK2-expressing colorectal cancer liver metastases had worse outcomes than those with high DYRK2-expressing metastases.	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('liver metastases', 'Disease', 'MESH:D009362', (182, 198))	('metastases of colorectal cancer', 'Disease', 'MESH:D009362', (51, 82))	('metastases', 'Disease', 'MESH:D009362', (256, 266))	('metastases', 'Disease', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('colorectal cancer liver metastases', 'Disease', (164, 198))	('metastases of colorectal cancer', 'Disease', (51, 82))	('metastases', 'Disease', (256, 266))	('liver metastases', 'Disease', 'MESH:D009362', (45, 61))	('regulates', 'Reg', (35, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('patients', 'Species', '9606', (129, 137))	('DYRK2', 'Var', (29, 34))	('EMT', 'CPA', (115, 118))	('EMT', 'biological_process', 'GO:0001837', ('115', '118'))	('colorectal cancer liver metastases', 'Disease', 'MESH:D009362', (164, 198))	('metastases', 'Disease', 'MESH:D009362', (188, 198))	('liver metastases', 'Disease', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('low DYRK2-expressing', 'Var', (143, 163))	('metastases', 'Disease', (188, 198))
6885	28502078	HCT116 cells were transduced with retroviral vector encoding E2-Crimson, Flag vector, Flag-DYRK2-WT, or Flag-DYRK2-KR.	('E2-Crimson', 'Var', (61, 71))	('Flag-DYRK2-KR', 'Var', (104, 117))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))
6898	28502078	To investigate the metastatic properties of these cell lines, the animals were injected with HCT116-E2 cells (HCT116-E2), HCT116-E2-Flag cells (Flag), HCT116-E2-Flag-DYRK2-WT cells (WT), or HCT116-E2-Flag-DYRK2-KR cells (KR).	('HCT116-E2', 'CellLine', 'CVCL:0291', (151, 160))	('HCT116-E2', 'CellLine', 'CVCL:0291', (93, 102))	('HCT116-E2', 'CellLine', 'CVCL:0291', (110, 119))	('HCT116-E2', 'CellLine', 'CVCL:0291', (190, 199))	('HCT116-E2-Flag-DYRK2-WT', 'Var', (151, 174))	('HCT116-E2', 'CellLine', 'CVCL:0291', (122, 131))	('HCT116-E2-Flag', 'Var', (122, 136))
6915	28502078	These sorting and selection procedures were undertaken twice to obtain HCT116-E2 with substantial fluorescence intensity (Fig.	('HCT116-E2', 'Var', (71, 80))	('HCT116-E2', 'CellLine', 'CVCL:0291', (71, 80))	('fluorescence intensity', 'MPA', (98, 120))
6917	28502078	In this study, we aimed to determine whether DYRK2 contributes to the liver metastases of colorectal cancer.	('DYRK2', 'Var', (45, 50))	('liver metastases', 'Disease', (70, 86))	('metastases of colorectal cancer', 'Disease', (76, 107))	('contributes', 'Reg', (51, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('metastases of colorectal cancer', 'Disease', 'MESH:D009362', (76, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('liver metastases', 'Disease', 'MESH:D009362', (70, 86))
6919	28502078	HCT116-E2 was injected into the spleen of male nude mice (BALB/c nu/nu) to generate liver metastases as described.	('liver metastases', 'Disease', 'MESH:D009362', (84, 100))	('nude mice', 'Species', '10090', (47, 56))	('HCT116-E2', 'Var', (0, 9))	('liver metastases', 'Disease', (84, 100))	('HCT116-E2', 'CellLine', 'CVCL:0291', (0, 9))
6922	28502078	Cells labeled with E2-Crimson were isolated and collected from liver tumor cells using the MoFlo XDP cell sorter (Fig.	('liver tumor', 'Phenotype', 'HP:0002896', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('E2-Crimson', 'Var', (19, 29))	('liver tumor', 'Disease', (63, 74))	('liver tumor', 'Disease', 'MESH:D008113', (63, 74))
6928	28502078	We used Flag-tagged WT DYRK2 (Flag-DYRK2-WT), kinase-dead DYRK2 mutant (K178R) (Flag-DYRK2-KR), or Flag vector as a vehicle control.	('DYRK2', 'Gene', (58, 63))	('K178R', 'Var', (72, 77))	('K178R', 'Mutation', 'p.K178R', (72, 77))
6931	28502078	reported that DYRK2 regulates E-cadherin and Snail expression in breast cancer cells.20 As expected, we similarly observed an increase or decrease of E-cadherin or Snail in Flag-DYRK2-WT, but not in KR or control cells, respectively (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('Flag-DYRK2-WT', 'Var', (173, 186))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('E-cadherin', 'Gene', (150, 160))	('E-cadherin', 'Gene', (30, 40))	('breast cancer', 'Disease', (65, 78))	('E-cadherin', 'Gene', '999', (150, 160))	('E-cadherin', 'Gene', '999', (30, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('decrease', 'NegReg', (138, 146))	('Snail', 'Protein', (164, 169))	('increase', 'PosReg', (126, 134))	('cadherin', 'molecular_function', 'GO:0008014', ('32', '40'))
6932	28502078	These results indicated that DYRK2 induces upregulation of E-cadherin.	('cadherin', 'molecular_function', 'GO:0008014', ('61', '69'))	('DYRK2', 'Var', (29, 34))	('upregulation', 'PosReg', (43, 55))	('E-cadherin', 'Gene', (59, 69))	('E-cadherin', 'Gene', '999', (59, 69))
6934	28502078	In this regard, as previously shown in breast cancer cells, c-Myc was suppressed by the expression of DYRK2 in a kinase activity-dependent manner (Fig.	('DYRK2', 'Gene', (102, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('expression', 'Var', (88, 98))	('suppressed', 'NegReg', (70, 80))	('c-Myc', 'Gene', '4609', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('kinase activity', 'molecular_function', 'GO:0016301', ('113', '128'))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('c-Myc', 'Gene', (60, 65))	('breast cancer', 'Disease', (39, 52))
6935	28502078	Given the finding that DYRK2 expression was downregulated in liver metastases, it is plausible that DYRK2 inhibits cell migration and invasion.	('liver metastases', 'Disease', (61, 77))	('inhibits', 'NegReg', (106, 114))	('DYRK2', 'Var', (100, 105))	('liver metastases', 'Disease', 'MESH:D009362', (61, 77))	('downregulated', 'NegReg', (44, 57))	('cell migration', 'biological_process', 'GO:0016477', ('115', '129'))	('DYRK2', 'Gene', (23, 28))	('expression', 'MPA', (29, 39))
6942	28502078	To extend this finding, Flag vector or Flag-DYRK2-KR cells formed liver metastases in three animals.	('liver metastases', 'Disease', (66, 82))	('Flag-DYRK2-KR cells', 'Var', (39, 58))	('liver metastases', 'Disease', 'MESH:D009362', (66, 82))
6950	28502078	Patients with high DYRK2 expression in their liver metastasis showed significantly better OS and DFS in the univariate analysis (Fig.	('high DYRK2 expression', 'Var', (14, 35))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (83, 89))	('DFS', 'CPA', (97, 100))
6954	28502078	Recently, our studies have suggested that DYRK2 plays an important role in cancer growth, invasion, and chemosensitivity.19, 20, 21 In this study, we aimed to determine whether DYRK2 contributes to liver metastases of colorectal cancer, and showed that the invasion and migration abilities of cancer cells are attenuated by DYRK2 (Fig.	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('liver metastases', 'Disease', 'MESH:D009362', (198, 214))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (75, 81))	('attenuated', 'NegReg', (310, 320))	('metastases of colorectal cancer', 'Disease', (204, 235))	('DYRK2', 'Var', (324, 329))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('metastases of colorectal cancer', 'Disease', 'MESH:D009362', (204, 235))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('colorectal cancer', 'Phenotype', 'HP:0003003', (218, 235))	('contributes', 'Reg', (183, 194))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('liver metastases', 'Disease', (198, 214))
6955	28502078	In a mouse model, liver metastatic lesions were decreased by the ectopic expression of DYRK2 (Fig.	('DYRK2', 'Gene', (87, 92))	('decreased', 'NegReg', (48, 57))	('liver metastatic lesions', 'CPA', (18, 42))	('mouse', 'Species', '10090', (5, 10))	('ectopic expression', 'Var', (65, 83))
6957	28502078	This result supports that DYRK2 inhibits EMT ability in colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('EMT ability', 'CPA', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('EMT', 'biological_process', 'GO:0001837', ('41', '44'))	('inhibits', 'NegReg', (32, 40))	('DYRK2', 'Var', (26, 31))
6961	28502078	In a mouse model, stable expression of DYRK2 inhibited liver metastases (Fig.	('liver metastases', 'Disease', (55, 71))	('liver metastases', 'Disease', 'MESH:D009362', (55, 71))	('mouse', 'Species', '10090', (5, 10))	('inhibited', 'NegReg', (45, 54))	('expression', 'Var', (25, 35))	('DYRK2', 'Gene', (39, 44))
6964	28502078	In this study, we showed that DYRK2 could be a potential prognostic marker of liver metastases originated from colorectal cancer.	('liver metastases', 'Disease', 'MESH:D009362', (78, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('DYRK2', 'Var', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('liver metastases', 'Disease', (78, 94))
6971	28502078	Dual-specificity tyrosine-regulated kinase 2 plays an important role in inhibiting the migration and invasion of colorectal cancer cells.	('colorectal cancer', 'Disease', (113, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('inhibiting', 'NegReg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Dual-specificity', 'Var', (0, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('invasion', 'CPA', (101, 109))
6981	29901154	There was additional evidence that KCNN3 expression is mediated by microRNA-892b.	('mediated by', 'Reg', (55, 66))	('expression', 'MPA', (41, 51))	('KCNN3', 'Gene', (35, 40))	('KCNN3', 'Gene', '3782', (35, 40))	('microRNA-892b', 'Var', (67, 80))
7000	29901154	GSE14764, GSE15622, GSE18520, GSE19829, GSE23554, GSE26193, GSE26712, GSE27651, GSE30161, GSE3149, GSE51373, GSE63885, GSE65986 and GSE9891) from the Gene Expression Omnibus (GEO) profiles and TCGA ovarian cohort.	('GSE30161', 'Var', (80, 88))	('ovarian cohort', 'Disease', 'MESH:D010051', (198, 212))	('GSE14764', 'Var', (0, 8))	('GSE27651', 'Var', (70, 78))	('GSE51373', 'Var', (99, 107))	('GSE18520', 'Var', (20, 28))	('ovarian cohort', 'Disease', (198, 212))	('GSE15622', 'Var', (10, 18))	('GSE19829', 'Var', (30, 38))	('Gene Expression', 'biological_process', 'GO:0010467', ('150', '165'))	('GSE23554', 'Var', (40, 48))	('GSE3149', 'Var', (90, 97))	('GSE26193', 'Var', (50, 58))	('GSE26712', 'Var', (60, 68))
7046	29901154	DNA methylation with KCNN3 mRNA expression levels in 489 OC tissues (including 197 sensitive tissues and 90 resistant tissues) was additionally analyzed; however, no correlation was observed, although DNA methylation of KCNN3 was negatively correlated with mRNA expression (data not shown).	('negatively', 'NegReg', (230, 240))	('DNA methylation', 'biological_process', 'GO:0006306', ('201', '216'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('KCNN3', 'Gene', (21, 26))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('KCNN3', 'Gene', (220, 225))	('mRNA expression', 'MPA', (257, 272))	('KCNN3', 'Gene', '3782', (21, 26))	('KCNN3', 'Gene', '3782', (220, 225))	('methylation', 'Var', (205, 216))
7065	19835627	Chemotherapy resistance in ovarian cancer has been studied thoroughly and several non-overlapping single genes, gene profiles and copy number alterations have been suggested as potential markers.	('ovarian cancer', 'Disease', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('copy number alterations', 'Var', (130, 153))
7070	19835627	We identified gain in 3q26.2, and losses in 6q11.2-12, 9p22.3, 9p22.2-22.1, 9p22.1-21.3, Xp22.2-22.12, Xp22.11-11.3, and Xp11.23-11.1 to be significantly associated with chemotherapy resistance.	('Xp22.11-11.3', 'Var', (103, 115))	('gain', 'PosReg', (14, 18))	('Xp22.2-22.12', 'CellLine', 'CVCL:6262', (89, 101))	('Xp22.2-22.12', 'Var', (89, 101))	('Xp11.23-11.1', 'Var', (121, 133))	('losses', 'NegReg', (34, 40))	('3q26.2', 'Gene', (22, 28))	('chemotherapy resistance', 'Disease', (170, 193))	('associated', 'Reg', (154, 164))
7072	19835627	In conclusion, we detected specific genetic alterations associated with resistance, of which some might be potential predictive markers of chemotherapy resistance in advanced ovarian serous carcinomas.	('ovarian serous carcinomas', 'Disease', (175, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (175, 200))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (175, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (190, 200))	('associated', 'Reg', (56, 66))	('genetic alterations', 'Var', (36, 55))	('resistance', 'Disease', (72, 82))
7083	19835627	Genetic changes such as copy number alterations (CNAs) are important in tumor development, and therefore most likely of importance for chemotherapy resistance as well.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('copy number alterations', 'Var', (24, 47))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('important', 'Reg', (59, 68))
7118	19835627	Using high-resolution whole genome array CGH, we explored copy number alterations in 40 stage III ovarian serous carcinomas in relation to chemotherapy response.	('III ovarian serous carcinomas', 'Disease', 'MESH:D010051', (94, 123))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (98, 123))	('III ovarian serous carcinomas', 'Disease', (94, 123))	('copy number alterations', 'Var', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))
7123	19835627	Further, losses in three regions in chromosome arm Xp (Xp22.2-22.12, Xp22.11-11.3, Xp11.23-11.1) were significantly more frequent in resistant cases than sensitive cases (Table 2).	('losses', 'NegReg', (9, 15))	('Xp11.23-11.1', 'Var', (83, 95))	('Xp22.2-22.12', 'CellLine', 'CVCL:6262', (55, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))	('Xp22.11-11.3', 'Var', (69, 81))
7143	19835627	Using array CGH, we detected specific genetic alterations associated with resistance, of which some might be potential predictive markers of chemotherapy resistance in advanced ovarian cancer.	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('ovarian cancer', 'Disease', (177, 191))	('resistance', 'Disease', (74, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (177, 191))	('genetic alterations', 'Var', (38, 57))	('ovarian cancer', 'Disease', 'MESH:D010051', (177, 191))
7152	19835627	In concordance with our results, Nanjundan and colleagues identified the ~2 Mbp wide region at 3q26.2 containing EVI1 and MDS1 to be the most frequent region of copy number gain in an ovarian tumor material.	('EVI1', 'Gene', (113, 117))	('ovarian tumor', 'Disease', 'MESH:D010051', (184, 197))	('Mbp', 'Gene', (76, 79))	('Mbp', 'Gene', '4155', (76, 79))	('ovarian tumor', 'Phenotype', 'HP:0100615', (184, 197))	('MDS1', 'Gene', '2122', (122, 126))	('copy number', 'Var', (161, 172))	('gain', 'PosReg', (173, 177))	('EVI1', 'Gene', '2122', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('ovarian tumor', 'Disease', (184, 197))	('MDS1', 'Gene', (122, 126))
7156	19835627	Interestingly, Liu and colleagues showed that the protein Evi1 inhibited paclitaxel-mediated apoptosis, thus causing resistance.	('Evi1', 'Gene', '2122', (58, 62))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('Evi1', 'Gene', (58, 62))	('paclitaxel-mediated apoptosis', 'CPA', (73, 102))	('paclitaxel', 'Chemical', 'MESH:D017239', (73, 83))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('inhibited', 'NegReg', (63, 72))	('causing', 'Reg', (109, 116))	('protein', 'Var', (50, 57))	('resistance', 'Disease', (117, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
7157	19835627	Further, Sunde and colleagues found a significant correlation between gene copy number and EVI1 gene expression, and suggested that enhanced expression of EVI1 can partly be explained by increased gene copy number.	('EVI1', 'Gene', '2122', (91, 95))	('EVI1', 'Gene', (91, 95))	('gene expression', 'biological_process', 'GO:0010467', ('96', '111'))	('gene copy number', 'Var', (70, 86))	('increased', 'PosReg', (187, 196))	('expression', 'MPA', (141, 151))	('enhanced', 'PosReg', (132, 140))	('gene copy number', 'Var', (197, 213))	('EVI1', 'Gene', '2122', (155, 159))	('expression', 'MPA', (101, 111))	('correlation', 'Interaction', (50, 61))	('EVI1', 'Gene', (155, 159))
7159	19835627	Additionally, among the tumors exhibiting gains in 3q26, some display a gain peak specifically in the significant region 3q26.2, whereas others display gains extending over a larger region, and a few exhibit peaks in the surrounding regions.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('gains', 'Var', (42, 47))	('gain', 'PosReg', (72, 76))
7160	19835627	MDS1 was first identified as a component of the AML1-MDS1-EVI1 fusion transcript in myeloid leukemia, and very little is known about the gene product when not in a fusion transcript.	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('myeloid leukemia', 'Disease', 'MESH:D007951', (84, 100))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (84, 100))	('MDS1', 'Gene', (0, 4))	('MDS1', 'Gene', '2122', (53, 57))	('MDS1', 'Gene', (53, 57))	('AML1', 'Gene', '861', (48, 52))	('EVI1', 'Gene', '2122', (58, 62))	('EVI1', 'Gene', (58, 62))	('fusion', 'Var', (63, 69))	('MDS1', 'Gene', '2122', (0, 4))	('myeloid leukemia', 'Disease', (84, 100))	('AML1', 'Gene', (48, 52))
7162	19835627	Losses in three regions in chromosome arm Xp (Xp22.2-22.12, Xp22.11-11.3, Xp11.23-11.1) were associated with chemotherapy resistance in the current study.	('Losses', 'NegReg', (0, 6))	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('Xp22.11-11.3', 'Var', (60, 72))	('associated', 'Reg', (93, 103))	('Xp22.2-22.12', 'CellLine', 'CVCL:6262', (46, 58))	('Xp11.23-11.1', 'Var', (74, 86))	('chemotherapy resistance', 'CPA', (109, 132))	('Xp22.2-22.12', 'Var', (46, 58))
7165	19835627	Loss of the SH3KBP1 locus as found in our investigation could be a form of resistance mechanism by inhibiting EGFR endocytosis and thus increasing EGFR signaling, which might reduce sensitivity to paclitaxel and/or platinum drugs.	('EGFR', 'Gene', (147, 151))	('sensitivity to', 'MPA', (182, 196))	('EGFR', 'Gene', '1956', (110, 114))	('inhibiting', 'NegReg', (99, 109))	('EGFR', 'Gene', (110, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('endocytosis', 'biological_process', 'GO:0006897', ('115', '126'))	('increasing', 'PosReg', (136, 146))	('reduce', 'NegReg', (175, 181))	('platinum', 'Chemical', 'MESH:D010984', (215, 223))	('paclitaxel', 'Chemical', 'MESH:D017239', (197, 207))	('SH3KBP1', 'Gene', (12, 19))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('EGFR', 'Gene', '1956', (147, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('Loss', 'Var', (0, 4))	('SH3KBP1', 'Gene', '30011', (12, 19))
7168	19835627	In ovarian cancer, allelic imbalances are commonly detected in 9p, but the region have to our knowledge not been associated with chemotherapy resistance earlier.	('detected', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('imbalances', 'Phenotype', 'HP:0002172', (27, 37))	('allelic imbalances', 'Var', (19, 37))	('ovarian cancer', 'Disease', (3, 17))
7183	19835627	This elevated frequency of genetic alterations might present an advantage for the resistant tumors, and help them to adapt in the hostile chemotherapy environment.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('advantage', 'PosReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('help', 'Reg', (104, 108))	('genetic alterations', 'Var', (27, 46))	('tumors', 'Disease', (92, 98))
7195	23029043	The Genomic Landscape of TP53 and p53 Annotated High Grade Ovarian Serous Carcinomas from a Defined Founder Population Associated with Patient Outcome High-grade ovarian serous carcinomas (HGSC) are characterized by TP53 mutations and non-random patterns of chromosomal anomalies, where the nature of the TP53 mutation may correlate with clinical outcome.	('p53', 'Gene', '7157', (34, 37))	('Serous Carcinomas', 'Disease', 'MESH:D018284', (67, 84))	('Patient', 'Species', '9606', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('TP53', 'Gene', '7157', (305, 309))	('p53', 'Gene', (34, 37))	('mutations', 'Var', (221, 230))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (162, 187))	('chromosomal anomalies', 'Disease', (258, 279))	('TP53', 'Gene', (216, 220))	('TP53', 'Gene', (305, 309))	('TP53', 'Gene', (25, 29))	('Ovarian Serous Carcinomas', 'Phenotype', 'HP:0012887', (59, 84))	('Serous Carcinomas', 'Disease', (67, 84))	('ovarian serous carcinomas', 'Disease', (162, 187))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (258, 279))	('Carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('TP53', 'Gene', '7157', (216, 220))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (162, 187))	('TP53', 'Gene', '7157', (25, 29))
7197	23029043	TP53 mutations were identified in 91% of HGSCs.	('TP53', 'Gene', '7157', (0, 4))	('HGSCs', 'Disease', (41, 46))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
7199	23029043	The subgroup expressing mutant p53 protein exhibited significantly prolonged overall and disease-free survival as compared with the p53 protein null subgroup.	('mutant', 'Var', (24, 30))	('p53', 'Gene', (31, 34))	('overall', 'CPA', (77, 84))	('p53', 'Gene', '7157', (31, 34))	('disease-free survival', 'CPA', (89, 110))	('protein', 'Protein', (35, 42))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('prolonged', 'PosReg', (67, 76))
7200	23029043	Interestingly, a comparative analysis of genomic landscapes revealed a significant enrichment of gains involving 1q, 8q, and 12p intervals in the subgroup expressing mutant p53 protein as compared with the p53 protein null subgroup.	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('gains', 'PosReg', (97, 102))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('p53', 'Gene', (173, 176))	('p53', 'Gene', '7157', (173, 176))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('protein', 'Protein', (177, 184))	('mutant', 'Var', (166, 172))
7201	23029043	Although the findings show that the frequency of TP53 mutations and the genomic landscapes observed in French Canadian samples were similar to those reported for samples from unselected populations, there were differences in the magnitude of global gains/losses of specific chromosomal arms and in the spectrum of amplifications and deletions involving focal regions in individual samples.	('gains/losses', 'NegReg', (249, 261))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('gains/losses', 'PosReg', (249, 261))	('mutations', 'Var', (54, 63))	('deletions', 'Var', (333, 342))
7202	23029043	The findings from our comparative genomic analyses also support the notion that there may be biological differences between HGSCs that could be related to the nature of the TP53 mutation.	('TP53', 'Gene', (173, 177))	('mutation', 'Var', (178, 186))	('TP53', 'Gene', '7157', (173, 177))
7206	23029043	The etiology of HGSCs is unknown, though about 10% have been associated with inherited mutations in the BRCA1/BRCA2 cancer susceptibility genes.	('HGSCs', 'Disease', (16, 21))	('BRCA1/BRCA2 cancer', 'Disease', 'OMIM:604370', (104, 122))	('BRCA1/BRCA2 cancer', 'Disease', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('associated', 'Reg', (61, 71))	('mutations', 'Var', (87, 96))
7207	23029043	HGSCs frequently exhibit somatic TP53 mutations that have been reported in more than 90% of cases.	('mutations', 'Var', (38, 47))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))
7209	23029043	These findings not only have important implications in clinical management but may reflect biological differences in HGSCs based on the consequences of the nature of the TP53 mutation in the cancer sample as also suggested by recent gene expression profiling of ovarian cancer cases, which showed differences in transcriptome profiles in samples stratified based on the absence or the nature of the TP53 mutation.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('mutation', 'Var', (175, 183))	('gene expression', 'biological_process', 'GO:0010467', ('233', '248'))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('ovarian cancer', 'Disease', 'MESH:D010051', (262, 276))	('TP53', 'Gene', '7157', (170, 174))	('TP53', 'Gene', '7157', (399, 403))	('TP53', 'Gene', (170, 174))	('TP53', 'Gene', (399, 403))	('ovarian cancer', 'Phenotype', 'HP:0100615', (262, 276))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('ovarian cancer', 'Disease', (262, 276))
7210	23029043	The heterogeneity of HGSC is also reflected by the high frequency of chromosomal anomalies involving copy number gains and losses, loss of heterozygosity (LOH), and complex intrachromosomal rearrangements.	('copy number', 'Var', (101, 112))	('chromosomal anomalies', 'Disease', (69, 90))	('HGSC', 'Disease', (21, 25))	('gains', 'PosReg', (113, 118))	('loss of heterozygosity', 'Var', (131, 153))	('losses', 'NegReg', (123, 129))	('high frequency of chromosomal anomalies', 'Phenotype', 'HP:0040012', (51, 90))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (69, 90))
7211	23029043	For example, LOH of a chromosome 17 contig is common in HGSC and this has been attributed to the disruption of TP53 (17p13.1), BRCA1 (17q12) (in some cases), and most recently other candidate tumour suppressor genes.	('disruption', 'Var', (97, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('22', '32'))	('BRCA1', 'Gene', '672', (127, 132))	('LOH', 'Var', (13, 16))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('TP53', 'Gene', '7157', (111, 115))	('BRCA1', 'Gene', (127, 132))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('TP53', 'Gene', (111, 115))	('tumour', 'Disease', (192, 198))	('HGSC', 'Disease', (56, 60))
7213	23029043	We recently reported an unusual excess of copy number neutral regions of homozygosity involving chromosome 3 in borderline ovarian serous tumours.	('ovarian serous tumours', 'Disease', 'MESH:D010051', (123, 145))	('excess', 'PosReg', (32, 38))	('copy number neutral regions', 'Var', (42, 69))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('ovarian serous tumours', 'Disease', (123, 145))
7215	23029043	While regions of homozygosity may have an impact on complex diseases, including cancer, their significance is unknown.	('regions', 'Var', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('impact', 'Reg', (42, 48))	('complex diseases', 'Disease', (52, 68))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
7217	23029043	Here we describe, for the first time, whole genome SNP array, TP53 mutation, and TP53 gene and protein expression analyses in HGSC samples with defined clinical correlates from the demographically unique French Canadian population, and compare our findings with independent reports describing similar analyses of cancer specimens from unselected populations.	('TP53', 'Gene', '7157', (62, 66))	('mutation', 'Var', (67, 75))	('TP53', 'Gene', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer', 'Disease', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
7219	23029043	We also report that the TP53 mutation frequency is similar to that reported in independent studies and that p53 protein null mutation cases were associated with poorer overall and disease-free survival, comparable to a recent report.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('TP53', 'Gene', (24, 28))	('poorer', 'NegReg', (161, 167))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('disease-free survival', 'CPA', (180, 201))	('null mutation', 'Var', (120, 133))	('TP53', 'Gene', '7157', (24, 28))
7220	23029043	We also explored the possibility that differences in TP53 mutation type might be reflected in genomic landscapes, and report the unique finding that samples expressing mutant p53 protein, which were the cases associated with prolonged overall and disease-free survival, showed significant copy number gains of specific chromosomal regions, relative to TP53 mutation-positive, p53 protein null samples.	('protein', 'Protein', (179, 186))	('mutant', 'Var', (168, 174))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('p53', 'Gene', (376, 379))	('p53', 'Gene', '7157', (376, 379))	('protein', 'cellular_component', 'GO:0003675', ('380', '387'))	('gains', 'PosReg', (301, 306))	('TP53', 'Gene', '7157', (352, 356))	('TP53', 'Gene', '7157', (53, 57))	('p53', 'Gene', (175, 178))	('TP53', 'Gene', (352, 356))	('copy number', 'CPA', (289, 300))	('TP53', 'Gene', (53, 57))	('p53', 'Gene', '7157', (175, 178))
7225	23029043	Most of the variants identified (Table S1) are suspected to affect p53 function and have been reported in various cancer samples by the IARC TP53 Database.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('function', 'MPA', (71, 79))	('TP53', 'Gene', '7157', (141, 145))	('p53', 'Gene', (67, 70))	('TP53', 'Gene', (141, 145))	('p53', 'Gene', '7157', (67, 70))	('variants', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('affect', 'Reg', (60, 66))	('cancer', 'Disease', (114, 120))
7226	23029043	About 61% (48 of 79) of mutation-positive HGSCs had a missense mutation that is predicted to affect either the DNA binding (n = 47) or oligomerization (n = 1) domain of the encoded p53 protein (Table S1).	('p53', 'Gene', (181, 184))	('p53', 'Gene', '7157', (181, 184))	('DNA binding', 'molecular_function', 'GO:0003677', ('111', '122'))	('oligomerization', 'MPA', (135, 150))	('affect', 'Reg', (93, 99))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('DNA binding', 'Interaction', (111, 122))	('missense mutation', 'Var', (54, 71))	('mutation-positive', 'Reg', (24, 41))
7227	23029043	Both the spectrum and frequency of TP53 mutations observed in our HGSCs were consistent with independent reports where comprehensive DNA sequencing or exomic sequencing (as in TCGA study) was performed.	('mutations', 'Var', (40, 49))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))
7228	23029043	Somatic mutations in the oncogenes KRAS or BRAF usually occur as mutually exclusive events in epithelial ovarian cancer, have been reported in borderline ovarian serous carcinomas or low-grade ovarian serous carcinomas, and occur at a low frequency in HGSCs.	('ovarian serous carcinomas', 'Disease', (154, 179))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (154, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('reported', 'Reg', (131, 139))	('ovarian serous carcinomas', 'Disease', (193, 218))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (193, 218))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (94, 119))	('mutations', 'Var', (8, 17))	('occur', 'Reg', (56, 61))	('KRAS', 'Gene', '3845', (35, 39))	('KRAS', 'Gene', (35, 39))	('epithelial ovarian cancer', 'Disease', (94, 119))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (154, 179))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (94, 119))	('BRAF', 'Gene', '673', (43, 47))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (193, 218))	('BRAF', 'Gene', (43, 47))
7230	23029043	TP53 gene and protein expression was assessed in HGSCs to determine if the nature of the mutation affected mRNA expression levels by TP53 gene expression array analysis or nuclear p53 protein staining by immunohistochemistry of a tissue array.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('affected', 'Reg', (98, 106))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('p53', 'Gene', (180, 183))	('mutation', 'Var', (89, 97))	('p53', 'Gene', '7157', (180, 183))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('mRNA expression levels', 'MPA', (107, 129))	('TP53', 'Gene', '7157', (133, 137))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('TP53', 'Gene', (133, 137))
7231	23029043	TP53 expression showed a significantly higher average level of expression in missense mutation-containing samples (mean = 232.2) than samples harbouring frameshift-stop (mean = 67.6), splice (mean = 70.1) or nonsense (mean = 46.6) mutations (p<0.001) (Figure 1A).	('TP53', 'Gene', '7157', (0, 4))	('higher', 'PosReg', (39, 45))	('TP53', 'Gene', (0, 4))	('expression', 'MPA', (63, 73))	('missense mutation-containing', 'Var', (77, 105))
7233	23029043	Missense mutation-positive samples were more likely to express mutant p53 protein (42 of 45, 93%) than samples with other types of mutations (2 of 23, 9%).	('protein', 'Protein', (74, 81))	('mutant', 'Var', (63, 69))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (70, 73))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('Missense mutation-positive', 'Var', (0, 26))
7234	23029043	Not surprisingly, all samples with nonsense mutations exhibited no p53 staining (p53 protein null).	('nonsense mutations', 'Var', (35, 53))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
7235	23029043	Interestingly, three of the eight TP53 mutation-negative samples expressed p53 protein (see Figure 1B), suggesting the possibility of missed mutations in our sequencing analysis or the deregulation of other pathways that result in the stabilization of p53 protein.	('stabilization', 'MPA', (235, 248))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (141, 150))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('p53', 'Gene', (252, 255))	('deregulation', 'Reg', (185, 197))	('p53', 'Gene', '7157', (252, 255))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('TP53', 'Gene', '7157', (34, 38))
7236	23029043	Overall and disease-free survival were assessed for the TP53 mutation-positive HGSCs as recent evidence suggests improved survival in cases expressing mutant p53 protein.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('mutant', 'Var', (151, 157))	('p53', 'Gene', '7157', (158, 161))	('TP53', 'Gene', '7157', (56, 60))	('protein', 'Protein', (162, 169))	('TP53', 'Gene', (56, 60))	('improved', 'PosReg', (113, 121))	('p53', 'Gene', (158, 161))
7237	23029043	Kaplan-Meier survival curve analysis found that the subgroup expressing mutant p53 protein had significantly longer overall survival (p = 0.010) and disease-free interval (p = 0.010) than the p53 protein null subgroup (Figure 1C, D).	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('longer', 'PosReg', (109, 115))	('mutant', 'Var', (72, 78))	('protein', 'Protein', (83, 90))	('p53', 'Gene', '7157', (192, 195))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('disease-free interval', 'CPA', (149, 170))	('p53', 'Gene', (192, 195))	('overall survival', 'CPA', (116, 132))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
7239	23029043	Chromosomal anomalies were evident in all TP53 mutation-positive HGSCs (Table 1) but only in three of the eight TP53 mutation-negative HGSCs (Table 1).	('TP53', 'Gene', '7157', (42, 46))	('evident', 'Reg', (27, 34))	('mutation-positive', 'Var', (47, 64))	('TP53', 'Gene', (42, 46))	('Chromosomal anomalies', 'Disease', (0, 21))	('TP53', 'Gene', '7157', (112, 116))	('Chromosomal anomalies', 'Disease', 'MESH:D002869', (0, 21))	('TP53', 'Gene', (112, 116))
7240	23029043	We focused our analysis on the 79 TP53 mutation-positive HGSCs as there were too few TP53 mutation-negative samples for comparative analyses and only a small subset (3 of 8) exhibited evidence of chromosomal anomalies (Table 1).	('TP53', 'Gene', (85, 89))	('mutation-positive', 'Var', (39, 56))	('TP53', 'Gene', (34, 38))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (196, 217))	('TP53', 'Gene', '7157', (85, 89))	('chromosomal anomalies', 'Disease', (196, 217))	('TP53', 'Gene', '7157', (34, 38))
7242	23029043	To investigate the frequency of common anomalies, we applied GenoCNA analyses to the TP53 mutation-positive HGSCs.	('mutation-positive', 'Var', (90, 107))	('TP53', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (85, 89))
7243	23029043	The chromosome 17 profile was striking: though TP53 is located at 17p13.1, nearly all samples exhibited evidence of LOH across the entire chromosome, although copy number varied (Figure 4), as described in independent reports.	('LOH', 'Var', (116, 119))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('chromosome', 'cellular_component', 'GO:0005694', ('4', '14'))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
7244	23029043	Manual examination of the data for each TP53 mutation-positive sample identified 398 non-overlapping regions of amplification or homozygous deletion, where 178 amplifications involved known genes and 98 deletions were intragenic (Tables S2-S6).	('TP53', 'Gene', '7157', (40, 44))	('mutation-positive', 'Var', (45, 62))	('TP53', 'Gene', (40, 44))
7247	23029043	For example, only 35 focal regions of gain from the TCGA study and 78 such regions from the AOCS study overlapped the 178 gene-containing amplifications identified in our TP53 mutation-positive samples (Table S5).	('TP53', 'Gene', (171, 175))	('mutation-positive', 'Var', (176, 193))	('TP53', 'Gene', '7157', (171, 175))
7250	23029043	The differences observed in disease-free and overall survival based on p53-immunoreactivity suggested the possibility of biological differences related to the nature of the TP53 mutation and thus we questioned if they could also be reflected in the genomic landscapes.	('mutation', 'Var', (178, 186))	('p53', 'Gene', '7157', (71, 74))	('p53', 'Gene', (71, 74))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))
7252	23029043	Not surprisingly, the genomic landscapes of the subgroup expressing mutant p53 protein and that of the p53 protein null subgroup were remarkably similar (Figure 3B, C).	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('protein', 'Protein', (79, 86))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('mutant', 'Var', (68, 74))
7254	23029043	A statistical analysis of copy number variation between the two groups revealed significant (p>0.001) gains of specific regions of 1q, 8q and 12p intervals in the subgroup expressing mutant p53 protein as compared with the p53 protein null subgroup (Figure 5, Figure 3B, C).	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('mutant', 'Var', (183, 189))	('p53', 'Gene', (190, 193))	('p53', 'Gene', '7157', (190, 193))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('gains', 'PosReg', (102, 107))	('protein', 'Protein', (194, 201))
7257	23029043	Interestingly,CSMD3 and CDK12, found "significantly" mutated (2.8-6.0%) in HGSC by the TCGA, map to regions of amplification identified in our study.	('CSMD3', 'Gene', (14, 19))	('HGSC', 'Disease', (75, 79))	('CDK12', 'Gene', '51755', (24, 29))	('CDK', 'molecular_function', 'GO:0004693', ('24', '27'))	('mutated', 'Var', (53, 60))	('CDK12', 'Gene', (24, 29))	('CSMD3', 'Gene', '114788', (14, 19))
7260	23029043	NF1 defects may be emerging as a low frequency, but recurrent event in HGSC.	('NF1', 'Gene', '4763', (0, 3))	('defects', 'Var', (4, 11))	('NF1', 'Gene', (0, 3))
7265	23029043	The most well documented example involves the frequency of activating mutations in the EGFR oncogene and copy number differences of the EGFR locus for certain types of lung and breast carcinomas.	('breast carcinomas', 'Disease', (177, 194))	('EGFR', 'Gene', '1956', (87, 91))	('lung', 'Disease', (168, 172))	('copy number differences', 'Var', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('breast carcinomas', 'Phenotype', 'HP:0003002', (177, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('activating', 'PosReg', (59, 69))	('EGFR', 'Gene', (87, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('breast carcinomas', 'Disease', 'MESH:D001943', (177, 194))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('EGFR', 'Gene', (136, 140))
7269	23029043	The significant enrichment of gains involving specific 1q, 8q and 12p intervals in HGSCs expressing mutant p53 protein as compared with p53 protein null samples suggest that there are biological differences between these two groups.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('mutant', 'Var', (100, 106))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('p53', 'Gene', '7157', (136, 139))	('protein', 'Protein', (111, 118))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('gains', 'PosReg', (30, 35))	('p53', 'Gene', (136, 139))
7271	23029043	Studies that have evaluated the correlation of p53-immunoreactivity with clinical outcome have produced conflicting results, and this may have been due to analyses that included different histological subtypes of ovarian cancer as well as incomplete assessment of TP53 mutation status, where mutation status was inferred by immunohistochemistry or where mutation screening was limited to specific exons.	('TP53', 'Gene', '7157', (264, 268))	('ovarian cancer', 'Phenotype', 'HP:0100615', (213, 227))	('TP53', 'Gene', (264, 268))	('subtypes of ovarian cancer', 'Disease', 'MESH:D010051', (201, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('subtypes of ovarian cancer', 'Disease', (201, 227))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('mutation', 'Var', (269, 277))
7273	23029043	Furthermore, another independent study has shown that p53 null mutations were more common in ovarian cancer cases with distant metastasis.	('ovarian cancer', 'Disease', (93, 107))	('common', 'Reg', (83, 89))	('null mutations', 'Var', (58, 72))	('p53', 'Gene', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('p53', 'Gene', '7157', (54, 57))
7275	23029043	The TCGA study also did not appear to report on any associations with the nature of the TP53 mutations.	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('mutations', 'Var', (93, 102))
7276	23029043	An earlier, independent study reported differences in the transcriptomes of serous ovarian carcinomas grouped according to the presence, absence and nature of TP53 mutation.	('serous ovarian carcinomas', 'Disease', (76, 101))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (83, 101))	('transcriptomes', 'MPA', (58, 72))	('TP53', 'Gene', '7157', (159, 163))	('mutation', 'Var', (164, 172))	('TP53', 'Gene', (159, 163))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (76, 101))
7277	23029043	In this study LMNA expression was found to be significantly higher in samples with missense TP53 mutations relative to samples with null mutations, and this gene maps within an interval on 1q showing gain in our HGSCs expressing mutant p53 protein.	('LMNA', 'Gene', '4000', (14, 18))	('mutations', 'Var', (97, 106))	('higher', 'PosReg', (60, 66))	('missense', 'Var', (83, 91))	('p53', 'Gene', (236, 239))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('gain', 'PosReg', (200, 204))	('LMNA', 'Gene', (14, 18))	('p53', 'Gene', '7157', (236, 239))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))
7278	23029043	Furthermore, low LMNA protein expression was recently found associated with increased disease recurrence in colon cancer, a pattern consistent with our findings relating p53-immunoreactivity status and outcome of HGSC patients.	('colon cancer', 'Disease', (108, 120))	('increased', 'PosReg', (76, 85))	('patients', 'Species', '9606', (218, 226))	('LMNA', 'Gene', (17, 21))	('p53', 'Gene', (170, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('low', 'Var', (13, 16))	('LMNA', 'Gene', '4000', (17, 21))	('p53', 'Gene', '7157', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('disease', 'Disease', (86, 93))
7280	23029043	Amplification of the KRAS locus has been suggested as an alternative mechanism for deregulating KRAS-implicated pathways in HGSC given that oncogene-activating point mutations in this gene are infrequently observed.	('KRAS', 'Gene', '3845', (96, 100))	('Amplification', 'Var', (0, 13))	('KRAS', 'Gene', '3845', (21, 25))	('HGSC', 'Disease', (124, 128))	('deregulating', 'PosReg', (83, 95))	('KRAS', 'Gene', (21, 25))	('KRAS', 'Gene', (96, 100))
7281	23029043	Our findings relating clinical outcome to the nature of the TP53 mutation are not surprising given that alteration of p53 function, as a consequence of missense mutation, can result in a range of activities but not necessarily abolition of the transcriptional activity exhibited by wild-type protein.	('transcriptional', 'MPA', (244, 259))	('activities', 'MPA', (196, 206))	('result', 'Reg', (175, 181))	('alteration', 'Reg', (104, 114))	('p53', 'Gene', (118, 121))	('function', 'MPA', (122, 130))	('missense mutation', 'Var', (152, 169))	('p53', 'Gene', '7157', (118, 121))	('TP53', 'Gene', '7157', (60, 64))	('mutation', 'Var', (65, 73))	('protein', 'cellular_component', 'GO:0003675', ('292', '299'))	('TP53', 'Gene', (60, 64))
7282	23029043	For example, in vitro mutagenesis assays of codon 175 found different effects depending on the amino acid that replaced the wild-type arginine, ranging from wild-type function to mediating only cell cycle arrest.	('mutagenesis', 'biological_process', 'GO:0006280', ('22', '33'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (194, 211))	('arginine', 'Chemical', 'MESH:D001120', (134, 142))	('codon 175', 'Gene', (44, 53))	('mutagenesis', 'Var', (22, 33))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('194', '211'))
7284	23029043	In conclusion, our genomic analyses of TP53 mutation-positive HGSCs from French Canadians identified global anomalies in common with HGSCs examined from populations not selected for ethnicity.	('mutation-positive', 'Var', (44, 61))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
7285	23029043	Our findings are the first to define genomic landscapes based on mutant p53-immunoreactivity and clinical outcome and this warrants replication in independent samples from the French Canadian and other populations.	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))
7286	23029043	In particular, it would be interesting to investigate the genomic landscapes of the TCGA samples based on mutant p53 immunoreactivity and how they relate to the HGSC subtypes identified based various large-scale molecular analyses.	('mutant', 'Var', (106, 112))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', (113, 116))
7287	23029043	The association with clinical outcome warrants further investigation of the genes associated with the chromosomal regions showing gains in the cases expressing mutant p53 protein, as this may allow for patient stratification and ultimately improve disease management.	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('patient', 'Species', '9606', (202, 209))	('mutant', 'Var', (160, 166))	('p53', 'Gene', '7157', (167, 170))	('gains', 'PosReg', (130, 135))	('p53', 'Gene', (167, 170))	('protein', 'Protein', (171, 178))
7296	23029043	Mutation analysis of tumour DNA samples was designed to detect variants in the protein coding exons 2 to 11, and adjacent splice sites of TP53, as well as the common mutations in exon 2 of KRAS and exons 11 and 15 of BRAF.	('KRAS', 'Gene', (189, 193))	('KRAS', 'Gene', '3845', (189, 193))	('TP53', 'Gene', '7157', (138, 142))	('variants', 'Var', (63, 71))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('TP53', 'Gene', (138, 142))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('BRAF', 'Gene', '673', (217, 221))	('BRAF', 'Gene', (217, 221))	('tumour', 'Disease', (21, 27))
7299	23029043	Sequence chromatograms were compared with NCBI reference sequence (RefSeq) reported in GenBank: NM_000546.4 (TP53), NM_004985.3 (KRAS) and NM_004333.4 (BRAF), and the genomic structures available from the February 2009 GRCh37/hg19 assembly of the human reference genome.	('BRAF', 'Gene', (152, 156))	('human', 'Species', '9606', (247, 252))	('NM_004333.4', 'Var', (139, 150))	('TP53', 'Gene', '7157', (109, 113))	('KRAS', 'Gene', (129, 133))	('NM_000546.4', 'Var', (96, 107))	('KRAS', 'Gene', '3845', (129, 133))	('TP53', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (152, 156))	('NM_004985.3', 'Var', (116, 127))
3008	23029043	In addition, TP53 variants were evaluated based on information in the International Agency for Research on Cancer (IARC) TP53 Database (www-p53.iarc.fr).	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('variants', 'Var', (18, 26))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TP53', 'Gene', '7157', (13, 17))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))
7308	23029043	These two cores were from TP53 mutation-positive HGSCs.	('TP53', 'Gene', (26, 30))	('mutation-positive', 'Var', (31, 48))	('TP53', 'Gene', '7157', (26, 30))
7314	23029043	Using the copy numbers estimated by GenoCNA for each individual, we calculated the mean and standard deviation of the copy numbers, at each SNP, for the samples expressing mutant p53 protein and those that were p53 protein null.	('mutant', 'Var', (172, 178))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('p53', 'Gene', (211, 214))	('protein', 'Protein', (183, 190))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('p53', 'Gene', '7157', (211, 214))
7454	19427017	Alterations in the phosphatidylinositol-3-kinase (PI-3 kinase) signaling pathway are commonly found in human cancers.	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('human', 'Species', '9606', (103, 108))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('Alterations', 'Var', (0, 11))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
7456	19427017	In ovarian carcinoma, PIK3CA amplification may even contribute to the development of cisplatin resistance.	('development', 'MPA', (70, 81))	('ovarian carcinoma', 'Disease', (3, 20))	('cisplatin resistance', 'MPA', (85, 105))	('amplification', 'Var', (29, 42))	('PIK3CA', 'Gene', '5290', (22, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (3, 20))	('contribute', 'Reg', (52, 62))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (3, 20))	('PIK3CA', 'Gene', (22, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
7457	19427017	Excessive signaling through the PI-3 kinase pathway can also result from loss of PTEN, the phosphatase that negatively regulates PI-3 kinase signaling by converting PIP3 to PIP2.	('signaling', 'biological_process', 'GO:0023052', ('10', '19'))	('loss', 'Var', (73, 77))	('PIP3 to PIP2', 'MPA', (165, 177))	('Excessive', 'PosReg', (0, 9))	('PIP3', 'Chemical', '-', (165, 169))	('signaling', 'MPA', (10, 19))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('PIP2', 'Chemical', 'MESH:D019269', (173, 177))	('PTEN', 'Gene', (81, 85))	('PI-3 kinase pathway', 'Pathway', (32, 51))	('phosphatase', 'molecular_function', 'GO:0016791', ('91', '102'))	('PTEN', 'Gene', '5728', (81, 85))
7460	19427017	AKT2 amplification has been demonstrated in some cancers including high-grade serous carcinomas of the ovary.	('demonstrated', 'Reg', (28, 40))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('serous carcinomas of the ovary', 'Disease', 'MESH:D010051', (78, 108))	('amplification', 'Var', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('carcinomas of the ovary', 'Phenotype', 'HP:0100615', (85, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('serous carcinomas of the ovary', 'Disease', (78, 108))	('AKT2', 'Gene', (0, 4))	('AKT2', 'Gene', '208', (0, 4))	('cancers', 'Disease', (49, 56))
7469	19427017	Inhibition of PRK1 has been demonstrated to decrease AR-induced proliferation in cultured cells, suggesting PRK1 is an important effector of androgen signaling.	('PRK1', 'Gene', '5585', (108, 112))	('PRK', 'molecular_function', 'GO:0008974', ('14', '17'))	('decrease', 'NegReg', (44, 52))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('AR', 'Gene', '367', (53, 55))	('PRK', 'molecular_function', 'GO:0008974', ('108', '111'))	('Inhibition', 'Var', (0, 10))	('PRK1', 'Gene', (14, 18))	('PRK1', 'Gene', '5585', (14, 18))	('PRK1', 'Gene', (108, 112))
7506	19427017	The tumor material was then resuspended in five volumes (weight:volume) of ice cold tumor extraction buffer (50mM Tris pH 8, 250mM sucrose, 50mM NaCl, 1mM EDTA, 1mM EGTA, 1 mM DTT) containing phosphatase inhibitor cocktails 1 and 2 (P2850 & P5726, Sigma, St. Louis, MO) and a protease inhibitor tablet (11873580001, Roche, Mannheim, Germany).	('tumor', 'Disease', (4, 9))	('P5726', 'Chemical', '-', (241, 246))	('DTT', 'Chemical', 'MESH:D004229', (176, 179))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('P2850', 'Chemical', '-', (233, 238))	('EDTA', 'Chemical', 'MESH:D004492', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('phosphatase', 'molecular_function', 'GO:0016791', ('192', '203'))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('Tris', 'Chemical', '-', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('sucrose', 'Chemical', 'MESH:D013395', (131, 138))	('EGTA', 'Chemical', 'MESH:D004533', (165, 169))	('NaCl', 'Chemical', 'MESH:D012965', (145, 149))	('P2850 &', 'Var', (233, 240))
7556	19427017	At the protein level, we found a high level of positivity for PRK1 in nearly 90% of serous ovarian carcinomas.	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (84, 109))	('PRK1', 'Gene', '5585', (62, 66))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (91, 109))	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (91, 108))	('serous ovarian carcinomas', 'Disease', (84, 109))	('PRK', 'molecular_function', 'GO:0008974', ('62', '65'))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (84, 109))	('PRK1', 'Gene', (62, 66))	('positivity', 'Var', (47, 57))
7564	19427017	As PRK1 is downstream of PI-3 kinase, it is possible that in some cases amplification of PIK3CA leads to PRK1 overexpression.	('amplification', 'Var', (72, 85))	('PRK', 'molecular_function', 'GO:0008974', ('3', '6'))	('PIK3CA', 'Gene', (89, 95))	('leads to', 'Reg', (96, 104))	('PRK1', 'Gene', (105, 109))	('PRK1', 'Gene', '5585', (105, 109))	('PIK3CA', 'Gene', '5290', (89, 95))	('PRK1', 'Gene', (3, 7))	('PRK1', 'Gene', '5585', (3, 7))	('PRK', 'molecular_function', 'GO:0008974', ('105', '108'))	('overexpression', 'PosReg', (110, 124))
7565	19427017	In one study, amplification of PIK3CA occurred in 13% of high-grade serous carcinomas.	('amplification', 'Var', (14, 27))	('PIK3CA', 'Gene', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('PIK3CA', 'Gene', '5290', (31, 37))	('serous carcinomas', 'Disease', 'MESH:D018284', (68, 85))	('occurred', 'Reg', (38, 46))	('serous carcinomas', 'Disease', (68, 85))
7568	19427017	Thus, it is possible that tumors expressing higher levels of PI-3 kinase might promote PRK1 expression or protein stabilization as part of a feed forward mechanism.	('PI-3 kinase', 'Var', (61, 72))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('expression', 'MPA', (92, 102))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('PRK', 'molecular_function', 'GO:0008974', ('87', '90'))	('protein', 'MPA', (106, 113))	('protein stabilization', 'biological_process', 'GO:0050821', ('106', '127'))	('promote', 'PosReg', (79, 86))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PRK1', 'Gene', (87, 91))	('PRK1', 'Gene', '5585', (87, 91))	('tumors', 'Disease', (26, 32))
7625	31766991	In ascites, the Cyr61 level of ovarian serous cystadenocarcinoma (n = 66) and serous cystadenoma (n = 18) was 1624.33 +- 191.92 cf.	('Cyr61', 'Gene', (16, 21))	('serous cystadenoma', 'Disease', 'MESH:D018293', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('ascites', 'Disease', 'MESH:D001201', (3, 10))	('ascites', 'Disease', (3, 10))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (31, 64))	('ascites', 'Phenotype', 'HP:0001541', (3, 10))	('ovarian serous cystadenocarcinoma', 'Disease', (31, 64))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D010049', (31, 64))	('Cyr61', 'Gene', '3491', (16, 21))	('serous cystadenoma', 'Phenotype', 'HP:0012887', (78, 96))	('1624.33 +- 191.92', 'Var', (110, 127))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (39, 64))	('serous cystadenoma', 'Disease', (78, 96))
7714	27478834	We extracted a batch of 5 genes (GPR128, AGXT, CYTH3, C10orf76, and TSPAN9) (Table 2) with the largest AUROC using the following formula: risk score = (0.0796 x expression point of GPR128) + (0.3451 x expression point of AGXT) + (0.3402 x expression point of CYTH3) + (0.6198 x expression point of C10orf76) + (0.2534 x expression point of TSPAN9).	('CYTH3', 'Gene', '9265', (47, 52))	('AGXT', 'Gene', (41, 45))	('C10orf76', 'Gene', '79591', (298, 306))	('GPR128', 'Gene', (33, 39))	('AGXT', 'Gene', '189', (221, 225))	('C10orf76', 'Gene', (298, 306))	('CYTH3', 'Gene', '9265', (259, 264))	('CYTH3', 'Gene', (47, 52))	('TSPAN9', 'Gene', '10867', (340, 346))	('AGXT', 'Gene', (221, 225))	('0.0796', 'Var', (152, 158))	('TSPAN9', 'Gene', '10867', (68, 74))	('GPR128', 'Gene', '84873', (181, 187))	('CYTH3', 'Gene', (259, 264))	('TSPAN9', 'Gene', (340, 346))	('GPR128', 'Gene', (181, 187))	('C10orf76', 'Gene', '79591', (54, 62))	('AGXT', 'Gene', '189', (41, 45))	('GPR128', 'Gene', '84873', (33, 39))	('TSPAN9', 'Gene', (68, 74))	('C10orf76', 'Gene', (54, 62))
7735	26871282	In a previous study we demonstrated that impairment of estrogen receptor alpha (ERalpha)-mediated olfactomedin 4 (OLFM4) expression promotes the malignant progression of endometrioid adenocarcinoma, and we identified OLFM4 as a potential target of miR-486-5p.	('OLFM4', 'Gene', (217, 222))	('OLFM4', 'Gene', (114, 119))	('promotes', 'PosReg', (132, 140))	('estrogen receptor alpha', 'Gene', (55, 78))	('endometrioid adenocarcinoma', 'Disease', (170, 197))	('malignant progression', 'CPA', (145, 166))	('miR-486', 'Gene', '619554', (248, 255))	('ERalpha', 'Gene', (80, 87))	('olfactomedin 4', 'Gene', (98, 112))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (170, 197))	('5p', 'Chemical', '-', (256, 258))	('OLFM4', 'Gene', '10562', (217, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('ERalpha', 'Gene', '2099', (80, 87))	('OLFM4', 'Gene', '10562', (114, 119))	('estrogen receptor alpha', 'Gene', '2099', (55, 78))	('impairment', 'Var', (41, 51))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (170, 197))	('olfactomedin 4', 'Gene', '10562', (98, 112))	('miR-486', 'Gene', (248, 255))
7741	26871282	OLFM4 knockdown enhanced proliferation, migration, and invasion by ovarian cancer cells.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('proliferation', 'CPA', (25, 38))	('ovarian cancer', 'Disease', (67, 81))	('OLFM4', 'Gene', '10562', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('invasion', 'CPA', (55, 63))	('migration', 'CPA', (40, 49))	('knockdown', 'Var', (6, 15))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('enhanced', 'PosReg', (16, 24))	('OLFM4', 'Gene', (0, 5))
7751	26871282	High ERalpha expression is associated with reduced apoptosis in poorly-differentiated ovarian cancer.	('ERalpha', 'Gene', (5, 12))	('ovarian cancer', 'Disease', (86, 100))	('High', 'Var', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('reduced', 'NegReg', (43, 50))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('apoptosis', 'CPA', (51, 60))	('ERalpha', 'Gene', '2099', (5, 12))
7757	26871282	Patients with well-differentiated gastric cancer and higher OLFM4 expression have a five-year survival rate higher than patients with poorly differentiated cancer.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('higher', 'PosReg', (108, 114))	('OLFM4', 'Gene', '10562', (60, 65))	('expression', 'MPA', (66, 76))	('gastric cancer', 'Disease', (34, 48))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (42, 48))	('patients', 'Species', '9606', (120, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('survival', 'CPA', (94, 102))	('OLFM4', 'Gene', (60, 65))	('higher', 'Var', (53, 59))
7760	26871282	We previously demonstrated that aberrant OLFM4 expression also occurs in gynecological tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('OLFM4', 'Gene', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('occurs', 'Reg', (63, 69))	('tumors', 'Disease', (87, 93))	('aberrant', 'Var', (32, 40))	('OLFM4', 'Gene', '10562', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
7762	26871282	Impairment of ERalpha-mediated OLFM4 expression promotes the malignant progression of endometrioid adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('malignant progression', 'CPA', (61, 82))	('OLFM4', 'Gene', (31, 36))	('ERalpha', 'Gene', (14, 21))	('promotes', 'PosReg', (48, 56))	('ERalpha', 'Gene', '2099', (14, 21))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (86, 113))	('endometrioid adenocarcinoma', 'Disease', (86, 113))	('Impairment', 'Var', (0, 10))	('OLFM4', 'Gene', '10562', (31, 36))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (86, 113))
7770	26871282	The rates of OLFM4 high-expression in these tissues were 16.7, 34.3, 65.1, 72.2, 50.0, and 11.9%, respectively (Table S1 and Table S2).	('high-expression', 'Var', (19, 34))	('OLFM4', 'Gene', '10562', (13, 18))	('OLFM4', 'Gene', (13, 18))
7774	26871282	In a previous study we demonstrated that knockdown of OLFM4 enhances the proliferation, migration, and invasion of endometrial carcinoma cells.	('enhances', 'PosReg', (60, 68))	('proliferation', 'CPA', (73, 86))	('OLFM4', 'Gene', '10562', (54, 59))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (115, 136))	('migration', 'CPA', (88, 97))	('OLFM4', 'Gene', (54, 59))	('endometrial carcinoma', 'Disease', (115, 136))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (115, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('knockdown', 'Var', (41, 50))	('invasion', 'CPA', (103, 111))
7776	26871282	siRNA knockdown of OLFM4 promoted cell proliferation in both HO8910-pm and SKOV3 cells (Figure 2A), but had no effect on cell apoptosis (Figure 2D).	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('cell proliferation', 'CPA', (34, 52))	('OLFM4', 'Gene', '10562', (19, 24))	('SKOV3', 'CellLine', 'CVCL:0532', (75, 80))	('promoted', 'PosReg', (25, 33))	('HO8910', 'CellLine', 'CVCL:6868', (61, 67))	('knockdown', 'Var', (6, 15))	('OLFM4', 'Gene', (19, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))
7778	26871282	In a transwell migration assay, the mean number of invaded cells per one visual field (at 200X magnification) was greater with OLFM4 knockdown (mean number = 68) compared with the control group (mean number = 24) (Figure 2C).	('OLFM4', 'Gene', '10562', (127, 132))	('OLFM4', 'Gene', (127, 132))	('knockdown', 'Var', (133, 142))	('greater', 'PosReg', (114, 121))
7781	26871282	HO8910-pm cells with OLFM4 knockdown had decreased numbers of cells in G1 phase and increased numbers in S phase compared with control cells, demonstrating that OLFM4 facilitates cell cycle arrest at G1 (Figure 2E).	('knockdown', 'Var', (27, 36))	('facilitates', 'PosReg', (167, 178))	('G1 phase', 'biological_process', 'GO:0051318', ('71', '79'))	('OLFM4', 'Gene', (21, 26))	('decreased', 'NegReg', (41, 50))	('S phase', 'biological_process', 'GO:0051320', ('105', '112'))	('OLFM4', 'Gene', '10562', (161, 166))	('cell cycle arrest at G1', 'CPA', (179, 202))	('cells in G1 phase', 'CPA', (62, 79))	('HO8910', 'CellLine', 'CVCL:6868', (0, 6))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (179, 196))	('OLFM4', 'Gene', '10562', (21, 26))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('179', '196'))	('OLFM4', 'Gene', (161, 166))	('S phase', 'CPA', (105, 112))
7785	26871282	The cumulative survival rate was 84.8% in 46 cases with high expression of OLFM4, and 80.0% in patients with low-expression of OLFM4.	('OLFM4', 'Gene', (127, 132))	('patients', 'Species', '9606', (95, 103))	('OLFM4', 'Gene', '10562', (75, 80))	('OLFM4', 'Gene', (75, 80))	('OLFM4', 'Gene', '10562', (127, 132))	('high expression', 'Var', (56, 71))
7808	26871282	HO8910-pm and SKOV3 cells transfected with miR-486-5p mimics, had decreased OLFM4 mRNA levels, indicating that OLFM4 is a potential target of miR-486-5p in ovarian serous adenocarcinoma (Figure 6D, 6E).	('OLFM4', 'Gene', '10562', (111, 116))	('ovarian serous adenocarcinoma', 'Disease', (156, 185))	('miR-486', 'Gene', '619554', (142, 149))	('OLFM4', 'Gene', '10562', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('HO8910-pm', 'Var', (0, 9))	('decreased', 'NegReg', (66, 75))	('OLFM4', 'Gene', (111, 116))	('OLFM4', 'Gene', (76, 81))	('miR-486', 'Gene', (43, 50))	('5p', 'Chemical', '-', (150, 152))	('miR-486', 'Gene', '619554', (43, 50))	('SKOV3', 'CellLine', 'CVCL:0532', (14, 19))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (156, 185))	('5p', 'Chemical', '-', (51, 53))	('HO8910', 'CellLine', 'CVCL:6868', (0, 6))	('miR-486', 'Gene', (142, 149))
7810	26871282	The estrogen receptor antagonist ICI 182 780 or knockdown of ERalpha attenuated E2-induced changes in miR-486-5p expression in SKOV3 cells (Figure 6F), supporting a potential inhibitory effect of ERalpha signaling on miR-486-5p expression.	('ERalpha', 'Gene', (61, 68))	('estrogen receptor', 'Gene', (4, 21))	('5p', 'Chemical', '-', (110, 112))	('ERalpha', 'Gene', '2099', (61, 68))	('estrogen receptor', 'Gene', '2099', (4, 21))	('ERalpha', 'Gene', '2099', (196, 203))	('attenuated', 'NegReg', (69, 79))	('ERalpha', 'Gene', (196, 203))	('5p', 'Chemical', '-', (225, 227))	('miR-486', 'Gene', (102, 109))	('miR-486', 'Gene', (217, 224))	('E2', 'Chemical', 'MESH:D004958', (80, 82))	('miR-486', 'Gene', '619554', (217, 224))	('SKOV3', 'CellLine', 'CVCL:0532', (127, 132))	('miR-486', 'Gene', '619554', (102, 109))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('knockdown', 'Var', (48, 57))
7811	26871282	Aberrant expression of OLFM4 has been observed in some cancerous tissues, especially in those of the digestive system.	('cancerous', 'Disease', (55, 64))	('Aberrant', 'Var', (0, 8))	('OLFM4', 'Gene', '10562', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('expression', 'MPA', (9, 19))	('OLFM4', 'Gene', (23, 28))	('cancerous', 'Disease', 'MESH:D009369', (55, 64))	('observed', 'Reg', (38, 46))
7816	26871282	There were 58 patients with low OLFM4 expression in a total 93 metastasis patients, but only 35 patients with high OLFM4 expression.	('patients', 'Species', '9606', (74, 82))	('OLFM4', 'Gene', '10562', (32, 37))	('OLFM4', 'Gene', (115, 120))	('OLFM4', 'Gene', (32, 37))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (14, 22))	('low', 'Var', (28, 31))	('OLFM4', 'Gene', '10562', (115, 120))
7830	26871282	Our study suggests that the role of ER signaling in ovarian cancer may be partially due to the regulation of mi-486-5p and OLFM4.	('ovarian cancer', 'Disease', (52, 66))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('mi-486-5p', 'Var', (109, 118))	('OLFM4', 'Gene', (123, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('5p', 'Chemical', '-', (116, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (52, 66))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('OLFM4', 'Gene', '10562', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
7842	26871282	HO8910-pm, a poorly-differentiated ovarian serous adenocarcinoma cell line, was reserved in Department of Gynecology, the First Affiliated Hospital, Sun Yat-sen University.	('ovarian serous adenocarcinoma', 'Disease', (35, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('HO8910-pm', 'Var', (0, 9))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (35, 64))	('HO8910', 'CellLine', 'CVCL:6868', (0, 6))
7934	33336051	Previous studies indicated that high KLK7 expression was significantly associated with prolonged OS and PFS.	('high', 'Var', (32, 36))	('PFS', 'Disease', (104, 107))	('prolonged OS', 'Disease', (87, 99))	('expression', 'MPA', (42, 52))	('KLK7', 'Gene', '5650', (37, 41))	('KLK7', 'Gene', (37, 41))	('associated', 'Reg', (71, 81))
7936	33336051	In contrast to this result, our finding revealed that overexpressed KLK7 was significantly associated with worse FPS in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))	('overexpressed', 'Var', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('FPS in ovarian cancer', 'Disease', (113, 134))	('KLK7', 'Gene', '5650', (68, 72))	('KLK7', 'Gene', (68, 72))	('FPS', 'molecular_function', 'GO:0047221', ('113', '116'))	('FPS in ovarian cancer', 'Disease', 'MESH:D010051', (113, 134))	('associated', 'Reg', (91, 101))
7950	22833081	The presence of a high grade component significantly worsens patient outcomes.	('patient outcomes', 'CPA', (61, 77))	('presence', 'Var', (4, 12))	('worsens', 'NegReg', (53, 60))	('patient', 'Species', '9606', (61, 68))
7953	22833081	Low grade serous carcinomas often arise in a background of serous borderline tumors, particularly those with micropapillary features, and may show BRAF, KRAS and ERBB2 mutations.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('serous borderline tumors', 'Disease', (59, 83))	('serous carcinomas', 'Disease', 'MESH:D018284', (10, 27))	('serous carcinomas', 'Disease', (10, 27))	('KRAS', 'Gene', (153, 157))	('serous borderline tumors', 'Disease', 'MESH:D012569', (59, 83))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('KRAS', 'Gene', '3845', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ERBB2', 'Gene', '2064', (162, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('ERBB2', 'Gene', (162, 167))	('mutations', 'Var', (168, 177))
7954	22833081	Type II carcinomas are high grade neoplasms that frequently show p53 mutations, the prototype being high grade serous carcinoma.	('neoplasms', 'Disease', 'MESH:D009369', (34, 43))	('mutations', 'Var', (69, 78))	('p53', 'Gene', (65, 68))	('neoplasms', 'Disease', (34, 43))	('serous carcinoma', 'Disease', (111, 127))	('p53', 'Gene', '7157', (65, 68))	('neoplasm', 'Phenotype', 'HP:0002664', (34, 42))	('Type II carcinomas', 'Disease', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('serous carcinoma', 'Disease', 'MESH:D018284', (111, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('neoplasms', 'Phenotype', 'HP:0002664', (34, 43))	('Type II carcinomas', 'Disease', 'MESH:D016532', (0, 18))
8017	22833081	Irrespective of morphology, presence of a high grade component significantly worsens patient outcomes.	('worsens', 'NegReg', (77, 84))	('patient', 'Species', '9606', (85, 92))	('patient outcomes', 'CPA', (85, 101))	('presence', 'Var', (28, 36))
8022	22833081	Low grade serous tumors show mutations in BRAF/KRAS/ERBB2, while high grade serous carcinomas arise as a result of Tp53 mutations.	('BRAF', 'Gene', '673', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (29, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('serous carcinomas', 'Disease', 'MESH:D018284', (76, 93))	('KRAS', 'Gene', '3845', (47, 51))	('serous carcinomas', 'Disease', (76, 93))	('serous tumors', 'Disease', 'MESH:D018284', (10, 23))	('ERBB2', 'Gene', '2064', (52, 57))	('KRAS', 'Gene', (47, 51))	('Tp53', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('ERBB2', 'Gene', (52, 57))	('BRAF', 'Gene', (42, 46))	('Tp53', 'Gene', '7157', (115, 119))	('serous tumors', 'Disease', (10, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
8024	22833081	Dehari et al found identical KRAS mutations in the low and high grade components in 2 of their 6 combined high and low grade serous carcinomas, indicative of a clonal relationship.	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('KRAS', 'Gene', (29, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('serous carcinomas', 'Disease', 'MESH:D018284', (125, 142))	('KRAS', 'Gene', '3845', (29, 33))	('serous carcinomas', 'Disease', (125, 142))	('mutations', 'Var', (34, 43))
8026	22833081	This raises the possibility that unlike conventional high grade serous carcinomas, those that arise in this setting may not be associated with p53 mutations.	('mutations', 'Var', (147, 156))	('serous carcinomas', 'Disease', (64, 81))	('p53', 'Gene', '7157', (143, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('p53', 'Gene', (143, 146))	('serous carcinomas', 'Disease', 'MESH:D018284', (64, 81))
8027	22833081	However, Quddus et al reported the presence of strong and diffuse p53 staining (an immunohistochemical staining pattern that correlates with Tp53 mutation) in the high grade component of their combined low and high grade serous carcinoma.	('serous carcinoma', 'Disease', (221, 237))	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('serous carcinoma', 'Disease', 'MESH:D018284', (221, 237))	('Tp53', 'Gene', (141, 145))	('Tp53', 'Gene', '7157', (141, 145))	('mutation', 'Var', (146, 154))	('p53', 'Gene', (66, 69))
8035	22833081	The presence of this component is associated with aggressive behavior and poor clinical outcomes.	('aggressive behavior', 'Disease', (50, 69))	('associated', 'Reg', (34, 44))	('aggressive behavior', 'Disease', 'MESH:D001523', (50, 69))	('aggressive behavior', 'Phenotype', 'HP:0000718', (50, 69))	('aggressive behavior', 'biological_process', 'GO:0002118', ('50', '69'))	('presence', 'Var', (4, 12))
8052	33936678	Immunohistochemical reactions showed positivity for CK7, CK125, WT1, PAX-8, and negativity for CK20 (Figure 4D-F).	('CK7', 'Gene', (52, 55))	('CK125', 'Var', (57, 62))	('CK20', 'Gene', '54474', (95, 99))	('CK7', 'Gene', '3855', (52, 55))	('WT1', 'Gene', (64, 67))	('PAX-8', 'Gene', (69, 74))	('CK20', 'Gene', (95, 99))	('PAX-8', 'Gene', '7849', (69, 74))	('WT1', 'Gene', '7490', (64, 67))
8077	33936678	The immunohistochemical staining of cell block showed CK7, CK125, WT1, PAX-8 positive, and CK 20 negative, which is usually the case with ovarian serous adenocarcinoma.	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D000230', (138, 167))	('WT1', 'Gene', '7490', (66, 69))	('CK7', 'Gene', (54, 57))	('CK125', 'Var', (59, 64))	('CK 20', 'Gene', '54474', (91, 96))	('WT1', 'Gene', (66, 69))	('PAX-8', 'Gene', '7849', (71, 76))	('CK7', 'Gene', '3855', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('CK 20', 'Gene', (91, 96))	('PAX-8', 'Gene', (71, 76))	('ovarian serous adenocarcinoma', 'Disease', (138, 167))
8085	26775705	Moreover, pan-cancer mutation and network analysis also identified common cell aging mechanisms in cancers and uncovered a highly modular network structure.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutation', 'Var', (21, 29))	('cancers', 'Disease', (99, 106))	('cancer', 'Disease', (99, 105))	('cell aging', 'biological_process', 'GO:0007569', ('74', '84'))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
8091	26775705	On one hand, cell senescence contributes to eliminating damaged cells, and on the other hand, persistent senescence may cause loss of cell-proliferative and tissue-regenerative capacities and eventually lead to cell death.	('rat', 'Species', '10116', (146, 149))	('senescence', 'Var', (105, 115))	('death', 'Disease', 'MESH:D003643', (216, 221))	('death', 'Disease', (216, 221))	('rat', 'Species', '10116', (170, 173))	('cell death', 'biological_process', 'GO:0008219', ('211', '221'))	('senescence', 'biological_process', 'GO:0010149', ('105', '115'))	('lead to', 'Reg', (203, 210))	('loss', 'NegReg', (126, 130))	('senescence', 'biological_process', 'GO:0010149', ('18', '28'))
8103	26775705	To retrieve a comprehensive list of annotated genes from the Gene Ontology annotation database (GOA), we curated four GO terms related to cell senescence: cellular senescence (GO:0090398), stress-induced premature senescence (GO:0090400), oncogene-induced cell senescence (GO:0090402), and oxidative stress-induced premature senescence (GO:0090403).	('oxidative stress', 'Phenotype', 'HP:0025464', (290, 306))	('GOA', 'Gene', '91107', (96, 99))	('GO:0090403', 'Var', (337, 347))	('GO:0090402', 'Var', (273, 283))	('cellular senescence', 'biological_process', 'GO:0090398', ('155', '174'))	('oxidative stress-induced premature senescence', 'biological_process', 'GO:0090403', ('290', '335'))	('GOA', 'Gene', (96, 99))	('rat', 'Species', '10116', (107, 110))	('Gene Ontology', 'biological_process', 'GO:0003673', ('61', '74'))	('oncogene-induced cell senescence', 'biological_process', 'GO:0090402', ('239', '271'))	('GO:0090400', 'Var', (226, 236))	('senescence', 'biological_process', 'GO:0010149', ('143', '153'))	('GO:0090398', 'Var', (176, 186))	('stress-induced premature senescence', 'biological_process', 'GO:0090400', ('189', '224'))	('cellular', 'Disease', (155, 163))
8150	26775705	For example, the 100 genes have single-nucleotide mutations among 94.90% of 300 individuals with ovarian serous adenocarcinoma.	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (97, 126))	('single-nucleotide mutations', 'Var', (32, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ovarian serous adenocarcinoma', 'Disease', (97, 126))
8151	26775705	A similar prevalence of single-nucleotide mutations can be found in all top 13 mutated cancer studies for 7 cancer types: colorectal adenocarcinoma, esophageal squamous cell carcinoma (SCC), lung SCC, small-cell lung cancer, head and neck SCC, uterine carcinosarcoma, and ovarian serous adenocarcinoma.	('carcinosarcoma', 'Disease', (252, 266))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (122, 147))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (149, 183))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (272, 301))	('neck', 'cellular_component', 'GO:0044326', ('234', '238'))	('carcinosarcoma', 'Disease', 'MESH:D002296', (252, 266))	('SCC', 'Phenotype', 'HP:0002860', (239, 242))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('lung SCC', 'Disease', (191, 199))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (244, 266))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (201, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('small-cell lung cancer', 'Disease', (201, 223))	('cancer', 'Disease', (87, 93))	('SCC', 'Phenotype', 'HP:0002860', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian serous adenocarcinoma', 'Disease', (272, 301))	('esophageal squamous cell carcinoma', 'Disease', (149, 183))	('cancer', 'Disease', (108, 114))	('single-nucleotide mutations', 'Var', (24, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('colorectal adenocarcinoma', 'Disease', (122, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (217, 223))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (201, 223))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
8156	26775705	For cancers with abundant mutations in cell senescence genes, cellular senescence may provide a feasible tumor suppression mechanism in vivo that may be new avenue for developing novel therapeutics for these devastating cancers.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('senescence', 'biological_process', 'GO:0010149', ('44', '54'))	('cell senescence genes', 'Gene', (39, 60))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('mutations', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cellular senescence', 'biological_process', 'GO:0090398', ('62', '81'))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Disease', (220, 227))	('tumor', 'Disease', (105, 110))	('cancers', 'Disease', (4, 11))
8227	24005572	Overexpression of class III beta-tubulin in patients dispositioned to NACT may thus identify an intrinsically aggressive phenotype, and predict poor overall survival and paclitaxel resistance.	('patients', 'Species', '9606', (44, 52))	('paclitaxel resistance', 'MPA', (170, 191))	('overall', 'MPA', (149, 156))	('NACT', 'Chemical', '-', (70, 74))	('poor', 'NegReg', (144, 148))	('class III beta-tubulin', 'Gene', '10381', (18, 40))	('paclitaxel', 'Chemical', 'MESH:D017239', (170, 180))	('class III beta-tubulin', 'Gene', (18, 40))	('predict', 'Reg', (136, 143))	('Overexpression', 'Var', (0, 14))
8246	24005572	Class III beta-tubulin (Hs00964962_g1) specific primers were obtained (Applied Biosystems), with GAPDH (Hs99999905_m1) as an internal control.	('Class III beta-tubulin', 'Gene', '10381', (0, 22))	('GAPDH', 'Gene', '2597', (97, 102))	('Class III beta-tubulin', 'Gene', (0, 22))	('Hs00964962_g1', 'Var', (24, 37))	('GAPDH', 'Gene', (97, 102))	('Hs99999905_m1', 'Var', (104, 117))
8267	24005572	In this manuscript, reduced median crude overall survival (OS) was predicted by increased class III beta-tubulin staining by both tumor (high [2+,3+] vs low [0,1+]: 707 days vs not reached, HR 3.66 [1.11,12.1], p=0.03) (Figure 3a-left) and stroma (high [1+,2+,3+] vs low [0]: 649 vs 1494 days, HR 4.53 [1.28,16.1], p=0.02) (Figure 3a-right) at time of interval debulking.	('reduced', 'NegReg', (20, 27))	('high [2+,3+', 'Var', (137, 148))	('increased', 'PosReg', (80, 89))	('high [1+,2+,3+', 'Var', (248, 262))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('increased class III beta', 'Phenotype', 'HP:0001976', (80, 104))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('class III beta-tubulin', 'Gene', '10381', (90, 112))	('class III beta-tubulin', 'Gene', (90, 112))	('tumor', 'Disease', (130, 135))	('overall survival', 'CPA', (41, 57))
8271	24005572	Using a separate cohort of patients identified retrospectively and restricted to a laboratory database of those with stage IIIC/IV high-grade serous ovarian carcinoma for whom fresh-frozen tissue was available from time of debulking, we then compared class III beta-tubulin expression using qRT-PCR among those who received carboplatin and paclitaxel in neoadjuvant fashion against those who underwent primary debulking followed by chemotherapy.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (149, 166))	('compared', 'Reg', (242, 250))	('patients', 'Species', '9606', (27, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('serous ovarian carcinoma', 'Disease', (142, 166))	('qRT-PCR', 'Var', (291, 298))	('class III beta-tubulin', 'Gene', '10381', (251, 273))	('carboplatin', 'Chemical', 'MESH:D016190', (324, 335))	('class III beta-tubulin', 'Gene', (251, 273))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (142, 166))	('paclitaxel', 'Chemical', 'MESH:D017239', (340, 350))
8283	24005572	Mean +- SD for class III beta-tubulin expression values increased from baseline at 985.8 +- 219 to 2306 +- 550 (p = 0.039) (Figure 5a).	('class III beta-tubulin', 'Gene', (15, 37))	('985.8 +- 219', 'Var', (83, 95))	('increased', 'PosReg', (56, 65))	('expression', 'MPA', (38, 48))	('2306 +- 550', 'Var', (99, 110))	('class III beta-tubulin', 'Gene', '10381', (15, 37))
8286	24005572	As illustrated in Figure 5c, cell lines with class III beta-tubulin expression values ranging from 504-1653 were 16->100 times more sensitive to patupilone compared to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (168, 178))	('sensitive', 'MPA', (132, 141))	('expression', 'MPA', (68, 78))	('504-1653', 'Var', (99, 107))	('class III beta-tubulin', 'Gene', '10381', (45, 67))	('patupilone', 'Chemical', 'MESH:C093788', (145, 155))	('class III beta-tubulin', 'Gene', (45, 67))
8292	24005572	Similarly, we have also previously implicated class III beta-tubulin overexpression in the identification of a subset of chemo-naive patients with uterine serous and ovarian clear cell carcinoma at risk of poor outcome secondary to paclitaxel resistance, with retention of responsiveness to epothilones.	('overexpression', 'PosReg', (69, 83))	('class III beta-tubulin', 'Gene', '10381', (46, 68))	('secondary', 'Reg', (219, 228))	('class III beta-tubulin', 'Gene', (46, 68))	('uterine serous', 'Disease', (147, 161))	('paclitaxel resistance', 'Var', (232, 253))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (166, 194))	('patients', 'Species', '9606', (133, 141))	('epothilones', 'Chemical', 'MESH:D034261', (291, 302))	('retention', 'biological_process', 'GO:0051235', ('260', '269'))	('paclitaxel', 'Chemical', 'MESH:D017239', (232, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('ovarian clear cell carcinoma', 'Disease', (166, 194))
8294	24005572	We have shown the prognostic relevance of overexpression by both tumor (p=0.03) and stroma (p=0.04) on overall survival and have found that NACT may lead to decreased stromal expression (p=0.07), presumably coincident with restoration of normal tumor microenvironment or decreased tumor bulk as a result of therapy due to either the taxane or platinum component.	('stromal expression', 'MPA', (167, 185))	('decreased tumor', 'Disease', (271, 286))	('NACT', 'Chemical', '-', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('platinum', 'Chemical', 'MESH:D010984', (343, 351))	('decreased tumor', 'Disease', 'MESH:D009369', (271, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (245, 250))	('NACT', 'Var', (140, 144))	('taxane', 'Chemical', 'MESH:C080625', (333, 339))	('decreased', 'NegReg', (157, 166))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
8306	24005572	We have previously reported enhanced sensitivity of ovarian/uterine serous carcinoma cell lines to paclitaxel following siRNA-mediated knockdown of class III but not class II beta-tubulin.	('carcinoma cell lines', 'Disease', (75, 95))	('knockdown', 'Var', (135, 144))	('ovarian/uterine serous carcinoma', 'Disease', (52, 84))	('enhanced', 'PosReg', (28, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('ovarian/uterine serous carcinoma', 'Disease', 'MESH:D010051', (52, 84))	('carcinoma cell lines', 'Disease', 'MESH:C538614', (75, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (99, 109))	('sensitivity', 'MPA', (37, 48))
8316	24005572	In GOG-126M, an overall response rate of 14.3% and disease stabilization rate of 40.8% was achieved in 49 patients with platinum/taxane-resistant recurrent ovarian cancer using 20 mg/m2 on days 1, 8 and 15 of a 28 day cycle.	('ovarian cancer', 'Disease', 'MESH:D010051', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('ovarian cancer', 'Disease', (156, 170))	('GOG-126M', 'Var', (3, 11))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (146, 170))	('patients', 'Species', '9606', (106, 114))	('taxane', 'Chemical', 'MESH:C080625', (129, 135))	('platinum', 'Chemical', 'MESH:D010984', (120, 128))
8326	24005572	NACT neoadjuvant chemotherapy FIGO Federation Internationale de Gynecologie et d'Obstetrique qRT-PCR quantitative real time polymerase chain reaction OSPC ovarian serous papillary carcinoma USPC uterine serous papillary carcinoma OS overall survival DeltaIHC change in immunohistochemistry score	('NACT', 'Chemical', '-', (0, 4))	('ovarian serous papillary carcinoma', 'Disease', 'MESH:D002291', (155, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('serous papillary carcinoma', 'Disease', 'MESH:D002291', (203, 229))	('ovarian serous papillary carcinoma', 'Disease', (155, 189))	('serous papillary carcinoma', 'Disease', (203, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('DeltaIHC', 'Var', (250, 258))	('serous papillary carcinoma', 'Disease', 'MESH:D002291', (163, 189))	('ovarian serous papillary', 'Phenotype', 'HP:0012887', (155, 179))
8331	19700937	They evolve from adenofibromas or borderline tumors, have frequent mutations of the KRAS, BRAF, or ERBB2 genes, and lack TP53 mutations (Type I pathway).	('BRAF', 'Gene', (90, 94))	('lack', 'NegReg', (116, 120))	('adenofibromas', 'Disease', (17, 30))	('adenofibromas', 'Disease', 'MESH:D000232', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('borderline tumors', 'Disease', (34, 51))	('ERBB2', 'Gene', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', '7157', (121, 125))	('ERBB2', 'Gene', '2064', (99, 104))	('TP53', 'Gene', (121, 125))	('mutations', 'Var', (67, 76))	('KRAS', 'Gene', (84, 88))	('KRAS', 'Gene', '3845', (84, 88))	('BRAF', 'Gene', '673', (90, 94))	('borderline tumors', 'Disease', 'MESH:D012569', (34, 51))
8338	19700937	The vast majority are characterized by TP53 mutations and lack mutations of KRAS, BRAF, or ERBB2.	('ERBB2', 'Gene', '2064', (91, 96))	('BRAF', 'Gene', '673', (82, 86))	('KRAS', 'Gene', (76, 80))	('ERBB2', 'Gene', (91, 96))	('BRAF', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (76, 80))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
8355	19700937	Both low-grade serous carcinoma and APST/non-invasive MPSC are characterized by mutations of the KRAS, BRAF, or ERBB2 genes, in which approximately two thirds of tumors have a mutation of 1 of these genes.	('ERBB2', 'Gene', '2064', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('KRAS', 'Gene', (97, 101))	('mutations', 'Var', (80, 89))	('ERBB2', 'Gene', (112, 117))	('BRAF', 'Gene', '673', (103, 107))	('serous carcinoma', 'Disease', (15, 31))	('KRAS', 'Gene', '3845', (97, 101))	('serous carcinoma', 'Disease', 'MESH:D018284', (15, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('APST/non-invasive MPSC', 'Disease', (36, 58))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('BRAF', 'Gene', (103, 107))
8357	19700937	Mutations of each of these 3 genes are mutually exclusive; thus, a tumor with a KRAS mutation will not have a mutation of the other 2 genes, and vice versa.	('KRAS', 'Gene', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mutation', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('KRAS', 'Gene', '3845', (80, 84))	('tumor', 'Disease', (67, 72))
8359	19700937	In contrast to high grade serous carcinoma, TP53 mutations are uncommon (8%) in low-grade serous carcinoma.	('serous carcinoma', 'Disease', 'MESH:D018284', (90, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('mutations', 'Var', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('serous carcinoma', 'Disease', (26, 42))	('serous carcinoma', 'Disease', 'MESH:D018284', (26, 42))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('serous carcinoma', 'Disease', (90, 106))
8360	19700937	Identical mutations of either KRAS or BRAF have been observed in the epithelium of cystadenomas adjacent to the APSTs indicating a shared lineage and suggesting that mutation of KRAS or BRAF is an early event in the transition from a cystadenoma to an APST.	('KRAS', 'Gene', (178, 182))	('cystadenomas', 'Disease', (83, 95))	('BRAF', 'Gene', (186, 190))	('KRAS', 'Gene', '3845', (178, 182))	('KRAS', 'Gene', '3845', (30, 34))	('cystadenoma', 'Disease', 'MESH:D003537', (234, 245))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', '673', (186, 190))	('cystadenomas', 'Disease', 'MESH:D003537', (83, 95))	('cystadenoma', 'Disease', 'MESH:D003537', (83, 94))	('BRAF', 'Gene', (38, 42))	('cystadenoma', 'Disease', (234, 245))	('KRAS', 'Gene', (30, 34))	('mutation', 'Var', (166, 174))	('cystadenoma', 'Disease', (83, 94))
8361	19700937	Serous cystadenomas that do not contain APSTs do not harbor KRAS or BRAF mutations.	('BRAF', 'Gene', '673', (68, 72))	('Serous cystadenomas', 'Disease', (0, 19))	('BRAF', 'Gene', (68, 72))	('Serous cystadenomas', 'Disease', 'MESH:D018293', (0, 19))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (60, 64))	('Serous cystadenomas', 'Phenotype', 'HP:0012887', (0, 19))	('mutations', 'Var', (73, 82))
8368	19700937	Hemizygous ch1p36 deletion was common in low-grade serous carcinomas but rarely seen in serous borderline tumors.	('common', 'Reg', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('serous borderline tumors', 'Disease', 'MESH:D012569', (88, 112))	('ch1p36', 'Gene', (11, 17))	('serous borderline tumors', 'Disease', (88, 112))	('serous carcinomas', 'Disease', 'MESH:D018284', (51, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('serous carcinomas', 'Disease', (51, 68))	('deletion', 'Var', (18, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
8372	19700937	Unlike low-grade serous carcinoma, mutations of KRAS, BRAF, or ERBB2 occur very infrequently in high-grade carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('KRAS', 'Gene', (48, 52))	('carcinoma', 'Disease', (24, 33))	('BRAF', 'Gene', (54, 58))	('KRAS', 'Gene', '3845', (48, 52))	('BRAF', 'Gene', '673', (54, 58))	('ERBB2', 'Gene', '2064', (63, 68))	('carcinoma', 'Disease', (107, 116))	('ERBB2', 'Gene', (63, 68))	('carcinoma', 'Disease', 'MESH:D002277', (107, 116))	('serous carcinoma', 'Disease', (17, 33))	('serous carcinoma', 'Disease', 'MESH:D018284', (17, 33))	('carcinoma', 'Disease', 'MESH:D002277', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('mutations', 'Var', (35, 44))
8373	19700937	In contrast, TP53 mutation occurs in 80% of high-grade tumors, and up-regulation and down-regulation of numerous other genes and various DNA copy number changes have been described.	('TP53', 'Gene', (13, 17))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('up-regulation', 'PosReg', (67, 80))	('down-regulation', 'NegReg', (85, 100))	('regulation', 'biological_process', 'GO:0065007', ('90', '100'))	('tumors', 'Disease', (55, 61))	('mutation', 'Var', (18, 26))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('TP53', 'Gene', '7157', (13, 17))
8374	19700937	Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4%, and 4.3%, respectively, of 47 affinity-purified high-grade serous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('serous carcinomas', 'Disease', 'MESH:D018284', (189, 206))	('DOCK4', 'Gene', '9732', (70, 75))	('CDKN2A/B', 'Gene', (49, 57))	('DOCK4', 'Gene', (70, 75))	('deletions', 'Var', (17, 26))	('serous carcinomas', 'Disease', (189, 206))	('Rb1', 'Gene', (44, 47))	('CSMD1', 'Gene', (59, 64))	('CSMD1', 'Gene', '64478', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('CDKN2A/B', 'Gene', '1029;1030', (49, 57))	('Rb1', 'Gene', '5925', (44, 47))
8378	19700937	In an effort to detect putative precursors, investigators have focused on ovaries of women with a family history of ovarian cancer and women with BRCA mutations.	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('ovaries', 'Disease', (74, 81))	('BRCA', 'Gene', '672', (146, 150))	('ovarian cancer', 'Disease', (116, 130))	('BRCA', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('women', 'Species', '9606', (85, 90))	('ovaries', 'Disease', 'MESH:D010051', (74, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('mutations', 'Var', (151, 160))	('women', 'Species', '9606', (135, 140))
8380	19700937	Mutations and/or loss of heterozygosity of TP53 have been identified in early carcinomas and epithelial inclusions of the ovary, including identical mutations in the epithelium and adjacent carcinoma in the same cases.	('carcinomas', 'Disease', (78, 88))	('carcinoma', 'Disease', 'MESH:D002277', (190, 199))	('mutations', 'Var', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('carcinoma', 'Disease', 'MESH:D002277', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Disease', (190, 199))	('TP53', 'Gene', '7157', (43, 47))	('carcinoma', 'Disease', (78, 87))	('TP53', 'Gene', (43, 47))	('carcinomas', 'Disease', 'MESH:D002277', (78, 88))	('identified', 'Reg', (58, 68))	('loss of', 'NegReg', (17, 24))
8381	19700937	These molecular findings support to the role of TP53 mutation as an early event in the pathogenesis of high-grade serous carcinoma and that the origin for some tumors is the surface epithelium or epithelial inclusions of the ovary.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('serous carcinoma', 'Disease', (114, 130))	('TP53', 'Gene', '7157', (48, 52))	('mutation', 'Var', (53, 61))	('serous carcinoma', 'Disease', 'MESH:D018284', (114, 130))	('TP53', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('pathogenesis', 'biological_process', 'GO:0009405', ('87', '99'))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
8383	19700937	Of the hereditary carcinomas, most are related to BRCA mutations, which appear to play a role in the pathogenesis of ovarian carcinoma in this subset of tumors.	('hereditary carcinomas', 'Disease', (7, 28))	('ovarian carcinoma', 'Disease', (117, 134))	('hereditary carcinomas', 'Disease', 'MESH:C565972', (7, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('mutations', 'Var', (55, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('related', 'Reg', (39, 46))	('pathogenesis', 'biological_process', 'GO:0009405', ('101', '113'))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('BRCA', 'Gene', '672', (50, 54))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (117, 134))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('BRCA', 'Gene', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (117, 134))
8388	19700937	Also, loss of heterozygosity of BRCA has been demonstrated in epithelial inclusions/surface epithelium in ovaries from prophylactic oophorectomy specimens.	('loss', 'NegReg', (6, 10))	('ovaries', 'Disease', (106, 113))	('BRCA', 'Gene', '672', (32, 36))	('BRCA', 'Gene', (32, 36))	('heterozygosity', 'Var', (14, 28))	('ovaries', 'Disease', 'MESH:D010051', (106, 113))
8390	19700937	These studies suggest that loss of heterozygosity of BRCA is an early event in high-grade serous carcinoma for tumors with germline mutations.	('BRCA', 'Gene', '672', (53, 57))	('serous carcinoma for tumors', 'Disease', 'MESH:D009369', (90, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('serous carcinoma for tumors', 'Disease', (90, 117))	('loss of heterozygosity', 'Var', (27, 49))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('BRCA', 'Gene', (53, 57))
8392	19700937	Thus, patients inherit a germline mutation of BRCA, and with somatic loss of the wild-type allele, carcinoma develops.	('BRCA', 'Gene', '672', (46, 50))	('carcinoma', 'Disease', 'MESH:D002277', (99, 108))	('patients', 'Species', '9606', (6, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('BRCA', 'Gene', (46, 50))	('germline mutation', 'Var', (25, 42))	('carcinoma', 'Disease', (99, 108))
8393	19700937	The exact interaction between mutations of BRCA and TP53 in ovarian carcinoma is unclear.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (60, 77))	('TP53', 'Gene', '7157', (52, 56))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (60, 77))	('ovarian carcinoma', 'Disease', (60, 77))	('TP53', 'Gene', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('mutations', 'Var', (30, 39))	('BRCA', 'Gene', '672', (43, 47))	('BRCA', 'Gene', (43, 47))
8394	19700937	In addition to germline mutations, other molecular alterations leading to inactivation of BRCA include somatic mutation, promoter hypermethylation, and isolated loss of hetrerozygosity.	('promoter hypermethylation', 'Var', (121, 146))	('loss of hetrerozygosity', 'Var', (161, 184))	('BRCA', 'Gene', '672', (90, 94))	('BRCA', 'Gene', (90, 94))	('inactivation', 'NegReg', (74, 86))
8399	19700937	This is supported by the following: (1) early serous carcinomas in prophylactic bilateral salpingo-oophorectomy specimens from women with BRCA mutations (i.e., women who are at an increased risk for "ovarian" carcinoma) can be detected in the tube, especially the fimbriated end, in the absence of an ovarian tumor, (2) identical TP53 mutations have been reported in TIC and synchronous ovarian high-grade serous carcinomas, and (3) identical TP53 mutations have been reported in TICs and in small foci of histologically normal tubal epithelium that diffusely expresses p53, which has been termed "p53 signature".	('synchronous ovarian high-grade serous carcinomas', 'Disease', (375, 423))	('TP53', 'Gene', (443, 447))	('TIC', 'Disease', (480, 483))	('TP53', 'Gene', (330, 334))	('p53', 'Gene', (598, 601))	('ovarian tumor', 'Phenotype', 'HP:0100615', (301, 314))	('TIC', 'Disease', 'None', (367, 370))	('mutations', 'Var', (335, 344))	('serous carcinomas', 'Disease', (46, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (413, 422))	('"ovarian" carcinoma', 'Disease', 'MESH:D010051', (199, 218))	('BRCA', 'Gene', '672', (138, 142))	('women', 'Species', '9606', (160, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (413, 423))	('TIC', 'Disease', (367, 370))	('synchronous ovarian high', 'Phenotype', 'HP:0008209', (375, 399))	('ovarian high', 'Phenotype', 'HP:0008209', (387, 399))	('women', 'Species', '9606', (127, 132))	('TIC', 'Phenotype', 'HP:0100033', (480, 483))	('serous carcinomas', 'Disease', 'MESH:D018284', (406, 423))	('TP53', 'Gene', '7157', (330, 334))	('mutations', 'Var', (143, 152))	('p53', 'Gene', '7157', (570, 573))	('TICs', 'Phenotype', 'HP:0100033', (480, 484))	('TP53', 'Gene', '7157', (443, 447))	('ovarian tumor', 'Disease', (301, 314))	('BRCA', 'Gene', (138, 142))	('synchronous ovarian high-grade serous carcinomas', 'Disease', 'MESH:D009378', (375, 423))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('ovarian tumor', 'Disease', 'MESH:D010051', (301, 314))	('serous carcinomas', 'Disease', 'MESH:D018284', (46, 63))	('p53', 'Gene', (570, 573))	('TIC', 'Phenotype', 'HP:0100033', (367, 370))	('TIC', 'Disease', 'None', (480, 483))	('p53', 'Gene', '7157', (598, 601))	('mutations', 'Var', (448, 457))	('"ovarian" carcinoma', 'Disease', (199, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
8406	19700937	In summary, the pathogenesis of high-grade serous carcinoma (Type II pathway) is characterized by: (1) rapid development from what are now believed to be intraepithelial carcinomas very likely of tubal origin, (2) TP53 mutations, (3) a high level of chromosomal instability, (4) in hereditary tumors, BRCA germline mutations, and (5) absence of mutations of KRAS, BRAF, or ERBB2.	('pathogenesis', 'biological_process', 'GO:0009405', ('16', '28'))	('serous carcinoma', 'Disease', (43, 59))	('intraepithelial carcinomas', 'Disease', 'MESH:D002278', (154, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('BRCA', 'Gene', (301, 305))	('KRAS', 'Gene', '3845', (358, 362))	('intraepithelial carcinomas', 'Disease', (154, 180))	('hereditary tumors', 'Disease', 'MESH:D009386', (282, 299))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('BRAF', 'Gene', '673', (364, 368))	('ERBB2', 'Gene', (373, 378))	('TP53', 'Gene', '7157', (214, 218))	('serous carcinoma', 'Disease', 'MESH:D018284', (43, 59))	('BRAF', 'Gene', (364, 368))	('KRAS', 'Gene', (358, 362))	('ERBB2', 'Gene', '2064', (373, 378))	('chromosomal instability', 'Phenotype', 'HP:0040012', (250, 273))	('mutations', 'Var', (219, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('hereditary tumors', 'Disease', (282, 299))	('TP53', 'Gene', (214, 218))	('absence', 'NegReg', (334, 341))	('BRCA', 'Gene', '672', (301, 305))
8415	19700937	Two of the 6 cases contained identical KRAS mutations in both the low- and high-grade components.	('KRAS', 'Gene', '3845', (39, 43))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))
8417	19700937	The finding of identical KRAS mutations in both components establishes a clonal relationship between the low- and high-grade tumors in those 2 cases.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
8418	19700937	However, the lack of TP53 mutations in all 6 cases contrasts with the high frequency of mutations typically seen in high-grade serous carcinoma (80%).	('TP53', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('serous carcinoma', 'Disease', (127, 143))	('serous carcinoma', 'Disease', 'MESH:D018284', (127, 143))	('TP53', 'Gene', '7157', (21, 25))
8421	19700937	In particular, a high-grade serous carcinoma with a micropapillary pattern does not necessarily indicate origin from a low-grade tumor, as such tumors have been shown to lack KRAS mutations and exhibit TP53 mutations.	('tumors', 'Disease', (144, 150))	('TP53', 'Gene', (202, 206))	('tumor', 'Disease', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('mutations', 'Var', (180, 189))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('TP53', 'Gene', '7157', (202, 206))	('lack', 'NegReg', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (129, 134))	('KRAS', 'Gene', (175, 179))	('serous carcinoma', 'Disease', (28, 44))	('KRAS', 'Gene', '3845', (175, 179))	('serous carcinoma', 'Disease', 'MESH:D018284', (28, 44))
8446	19700937	A potential pitfall in the evaluation of low-grade serous tumors of the ovary is that some low-grade serous carcinomas exhibit an inverted "macropapillary" form of invasion which can be misdiagnosed as serous adenofibroma (Fig.	('serous tumors of the ovary', 'Disease', (51, 77))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('serous adenofibroma', 'Disease', 'MESH:D000232', (202, 221))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('serous tumors of the ovary', 'Disease', 'MESH:D010051', (51, 77))	('serous carcinomas', 'Disease', 'MESH:D018284', (101, 118))	('serous adenofibroma', 'Disease', (202, 221))	('serous carcinomas', 'Disease', (101, 118))	('low-grade', 'Var', (91, 100))
8453	19700937	Molecular analysis was performed on 7 tumors, and in 4, both the macropapillary and micropapillary components contained identical KRAS mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('mutations', 'Var', (135, 144))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('KRAS', 'Gene', (130, 134))	('contained', 'Reg', (110, 119))	('KRAS', 'Gene', '3845', (130, 134))
8455	19700937	In another tumor, identical BRAF mutations were present in the macropapillary and micropapillary components.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('BRAF', 'Gene', '673', (28, 32))	('tumor', 'Disease', (11, 16))	('mutations', 'Var', (33, 42))	('BRAF', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
8494	19700937	None contained KRAS, BRAF, or ERBB2 mutations, but TP53 mutations were identified in 10 (91%).	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('ERBB2', 'Gene', '2064', (30, 35))	('KRAS', 'Gene', (15, 19))	('ERBB2', 'Gene', (30, 35))	('mutations', 'Var', (36, 45))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('KRAS', 'Gene', '3845', (15, 19))	('TP53', 'Gene', '7157', (51, 55))
8500	19700937	In a study of high-grade serous carcinomas in which moderately differentiated and poorly differentiated were compared, there were no significant differences in the frequency of TP53 mutation or extreme drug resistance for each of 10 chemotherapeutic agents.	('drug resistance', 'biological_process', 'GO:0042493', ('202', '217'))	('drug resistance', 'Phenotype', 'HP:0020174', (202, 217))	('serous carcinomas', 'Disease', 'MESH:D018284', (25, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('serous carcinomas', 'Disease', (25, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('TP53', 'Gene', '7157', (177, 181))	('mutation', 'Var', (182, 190))	('TP53', 'Gene', (177, 181))	('drug resistance', 'biological_process', 'GO:0009315', ('202', '217'))
8503	19700937	The few studies that have compared outcome between both types of serous carcinomas using the 2-tier system have shown that patients with low-grade tumors have better survival.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('survival', 'MPA', (166, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('tumors', 'Disease', (147, 153))	('serous carcinomas', 'Disease', 'MESH:D018284', (65, 82))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('serous carcinomas', 'Disease', (65, 82))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('patients', 'Species', '9606', (123, 131))	('better', 'PosReg', (159, 165))	('low-grade', 'Var', (137, 146))
8506	19700937	The median survival was 1.7 years for patients with high-grade tumors compared to 4.2 years for women with low-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('high-grade', 'Var', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('patients', 'Species', '9606', (38, 46))	('women', 'Species', '9606', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
8523	19700937	In the endometrium, a diffuse pattern of expression, which is typically 90-100% positive cells, generally correlates with a TP53 mutation.	('TP53', 'Gene', '7157', (124, 128))	('TP53', 'Gene', (124, 128))	('mutation', 'Var', (129, 137))
8525	19700937	Among tumors with a TP53 mutation, 27% were negative by immunohistochemistry (<1% positive cells), 18% had 51-90% positive cells, and 55% had >90% positive cells.	('TP53', 'Gene', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (25, 33))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('TP53', 'Gene', '7157', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
8527	19700937	Of note, 26% of tumors with wild-type TP53 had 51-90% positive cells, and 13% had >90% positive cells.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('wild-type', 'Var', (28, 37))	('tumors', 'Disease', (16, 22))	('TP53', 'Gene', '7157', (38, 42))
8529	19700937	These findings demonstrate that although diffuse expression of p53 (>90% positive cells) indicates that the tumor is more likely to have a TP53 mutation, immunohistochemistry cannot accurately predict mutation status.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('TP53', 'Gene', '7157', (139, 143))	('tumor', 'Disease', (108, 113))	('mutation', 'Var', (144, 152))	('TP53', 'Gene', (139, 143))
8569	19700937	CI-1040 prevents MAPK activation, which plays a critical role in the development of low-grade serous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('serous carcinoma', 'Disease', (94, 110))	('CI-1040', 'Chemical', 'MESH:C120227', (0, 7))	('MAPK activation', 'biological_process', 'GO:0000187', ('17', '32'))	('serous carcinoma', 'Disease', 'MESH:D018284', (94, 110))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('MAPK', 'Protein', (17, 21))	('activation', 'PosReg', (22, 32))	('CI-1040', 'Var', (0, 7))
8570	19700937	In vitro and in vivo laboratory evidence has shown that CI-1040 inhibits growth of ovarian cancer cells containing a KRAS or BRAF mutation.	('KRAS', 'Gene', (117, 121))	('CI-1040', 'Chemical', 'MESH:C120227', (56, 63))	('mutation', 'Var', (130, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('KRAS', 'Gene', '3845', (117, 121))	('growth', 'CPA', (73, 79))	('BRAF', 'Gene', '673', (125, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('inhibits', 'NegReg', (64, 72))	('ovarian cancer', 'Disease', (83, 97))	('BRAF', 'Gene', (125, 129))	('CI-1040', 'Gene', (56, 63))
8571	19700937	Therefore, MAPK inhibitors could be used as potential therapeutic agents for low-grade serous carcinomas containing a KRAS or BRAF mutation and possibly the uncommon high-grade serous carcinomas with KRAS or BRAF mutations.	('serous carcinomas', 'Disease', (177, 194))	('BRAF', 'Gene', '673', (208, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('MAPK', 'molecular_function', 'GO:0004707', ('11', '15'))	('KRAS', 'Gene', (200, 204))	('BRAF', 'Gene', (208, 212))	('KRAS', 'Gene', (118, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('serous carcinomas', 'Disease', 'MESH:D018284', (87, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('serous carcinomas', 'Disease', (87, 104))	('KRAS', 'Gene', '3845', (200, 204))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('KRAS', 'Gene', '3845', (118, 122))	('serous carcinomas', 'Disease', 'MESH:D018284', (177, 194))	('mutation', 'Var', (131, 139))
8572	19700937	The GOG is currently performing a study of AZD6244, which is an inhibitor of the MAPK signaling pathway, in ovarian low-grade serous carcinoma, and it is hoped that the results will lead to more optimal treatment of patients with these tumors in the future.	('serous carcinoma', 'Disease', 'MESH:D018284', (126, 142))	('lead to', 'Reg', (182, 189))	('signaling pathway', 'biological_process', 'GO:0007165', ('86', '103'))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('patients', 'Species', '9606', (216, 224))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('AZD6244', 'Var', (43, 50))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('MAPK signaling', 'biological_process', 'GO:0000165', ('81', '95'))	('AZD6244', 'Chemical', 'MESH:C517975', (43, 50))	('serous carcinoma', 'Disease', (126, 142))	('tumors', 'Disease', (236, 242))	('tumors', 'Disease', 'MESH:D009369', (236, 242))
8577	19700937	They evolve from adenofibromas and APST/non-invasive MPSCs and have frequent mutations of the KRAS, BRAF, or ERBB2 genes.	('adenofibromas', 'Disease', (17, 30))	('adenofibromas', 'Disease', 'MESH:D000232', (17, 30))	('KRAS', 'Gene', (94, 98))	('ERBB2', 'Gene', '2064', (109, 114))	('ERBB2', 'Gene', (109, 114))	('BRAF', 'Gene', '673', (100, 104))	('KRAS', 'Gene', '3845', (94, 98))	('mutations', 'Var', (77, 86))	('BRAF', 'Gene', (100, 104))
8578	19700937	They rarely harbor TP53 mutations and are genetically stable.	('mutations', 'Var', (24, 33))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))
8580	19700937	High-grade serous carcinomas are characterized by TP53 mutations and genetic instability.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('mutations', 'Var', (55, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('serous carcinomas', 'Disease', 'MESH:D018284', (11, 28))	('TP53', 'Gene', '7157', (50, 54))	('serous carcinomas', 'Disease', (11, 28))	('TP53', 'Gene', (50, 54))
8693	31322247	Notably, the bevacizumab-induced decrease in MVD was significantly enhanced by PEGylated liposomal doxorubicin (Fig.	('MVD', 'MPA', (45, 48))	('decrease', 'NegReg', (33, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (99, 110))	('PEGylated liposomal', 'Var', (79, 98))	('bevacizumab', 'Chemical', 'MESH:D000068258', (13, 24))	('enhanced', 'PosReg', (67, 75))
8698	31322247	Although PEGylated liposomal doxorubicin alone and bevacizumab alone did not affect human IGFBP-3 expression, PEGylated liposomal doxorubicin plus bevacizumab treatment resulted in levels of human IGFBP-3 being significantly lower, compared with levels following PEGylated liposomal doxorubicin alone or bevacizumab alone treatment (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (283, 294))	('bevacizumab', 'Chemical', 'MESH:D000068258', (51, 62))	('doxorubicin', 'Chemical', 'MESH:D004317', (29, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	('IGFBP-3', 'Gene', (90, 97))	('bevacizumab', 'Chemical', 'MESH:D000068258', (304, 315))	('IGFBP-3', 'Gene', '3486', (197, 204))	('IGFBP-3', 'Gene', (197, 204))	('lower', 'NegReg', (225, 230))	('human', 'Species', '9606', (84, 89))	('bevacizumab', 'Chemical', 'MESH:D000068258', (147, 158))	('human', 'Species', '9606', (191, 196))	('PEGylated liposomal doxorubicin', 'Var', (110, 141))	('IGFBP-3', 'Gene', '3486', (90, 97))
8704	31322247	The precise mechanism by which the PEGylated liposomal doxorubicin plus bevacizumab combination reduces the IGFBP-3 level and its general contribution to tumor angiogenesis remains to be elucidated.	('tumor', 'Disease', (154, 159))	('reduces', 'NegReg', (96, 103))	('IGFBP-3', 'Gene', (108, 115))	('PEGylated', 'Var', (35, 44))	('angiogenesis', 'biological_process', 'GO:0001525', ('160', '172'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('doxorubicin', 'Chemical', 'MESH:D004317', (55, 66))	('bevacizumab', 'Chemical', 'MESH:D000068258', (72, 83))	('IGFBP-3', 'Gene', '3486', (108, 115))
8786	19525924	High-grade ovarian serous carcinomas were demonstrated to have p53 mutations and higher expression of bcl-2 and c-kit than low-grade carcinomas, which in many cases have BRAF and KRAS mutations.	('c-kit', 'Gene', '3815', (112, 117))	('KRAS', 'Gene', '3845', (179, 183))	('ovarian serous carcinomas', 'Disease', (11, 36))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (11, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('KRAS', 'Gene', (179, 183))	('carcinomas', 'Disease', 'MESH:D002277', (26, 36))	('expression', 'MPA', (88, 98))	('carcinomas', 'Disease', (133, 143))	('bcl-2', 'molecular_function', 'GO:0015283', ('102', '107'))	('p53', 'Gene', '7157', (63, 66))	('bcl-2', 'Gene', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('c-kit', 'Gene', (112, 117))	('p53', 'Gene', (63, 66))	('bcl-2', 'Gene', '596', (102, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('carcinomas', 'Disease', 'MESH:D002277', (133, 143))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (11, 36))	('BRAF', 'Gene', '673', (170, 174))	('carcinomas', 'Disease', (26, 36))	('BRAF', 'Gene', (170, 174))	('higher', 'PosReg', (81, 87))	('mutations', 'Var', (67, 76))
8798	19525924	Mutations in PAX2 have been associated with renal-coloboma syndrome, and unattenuated PAX2 expression has been found in various cancers, including ovarian, renal, prostate, and breast cancers, Wilms tumor, and Kaposi sarcoma.	('renal-coloboma syndrome', 'Disease', 'MESH:D007674', (44, 67))	('renal-coloboma syndrome', 'Disease', (44, 67))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('PAX2', 'Gene', (13, 17))	('Kaposi sarcoma', 'Disease', (210, 224))	('ovarian', 'Disease', (147, 154))	('Wilms tumor', 'Phenotype', 'HP:0002667', (193, 204))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancers', 'Disease', (184, 191))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (210, 224))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancers', 'Disease', 'MESH:D001943', (177, 191))	('breast cancers', 'Disease', (177, 191))	('found', 'Reg', (111, 116))	('Wilms tumor', 'Disease', (193, 204))	('associated', 'Reg', (28, 38))	('breast cancers', 'Phenotype', 'HP:0003002', (177, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('prostate', 'Disease', (163, 171))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('coloboma', 'Phenotype', 'HP:0000589', (50, 58))	('renal', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (210, 224))	('Wilms tumor', 'Disease', 'MESH:D009396', (193, 204))
8805	19525924	Studies have found that inhibition of PAX2 expression decreases proliferation of renal cancer cells.	('PAX2', 'Gene', (38, 42))	('renal cancer', 'Phenotype', 'HP:0009726', (81, 93))	('renal cancer', 'Disease', 'MESH:D007680', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('inhibition', 'Var', (24, 34))	('decreases', 'NegReg', (54, 63))	('renal cancer', 'Disease', (81, 93))
8807	19525924	Furthermore, deregulated PAX2 function has been found to block caspase-2 associated apoptosis.	('caspase-2', 'Gene', (63, 72))	('apoptosis', 'CPA', (84, 93))	('deregulated', 'Var', (13, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('block', 'NegReg', (57, 62))	('PAX2', 'Gene', (25, 29))	('caspase-2', 'Gene', '835', (63, 72))
8808	19525924	PAX2 overexpression has also been implicated in the resistance of renal cell carcinoma to cisplatin-induced apoptosis, and inhibition of PAX2 resulted in increased cisplatin sensitivity.	('resistance', 'MPA', (52, 62))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('inhibition', 'Var', (123, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('overexpression', 'PosReg', (5, 19))	('cisplatin sensitivity', 'MPA', (164, 185))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('PAX2', 'Gene', (137, 141))	('increased', 'PosReg', (154, 163))	('PAX2', 'Gene', (0, 4))	('renal cell carcinoma', 'Disease', (66, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
8820	30301218	In assessments of progression-free survival probability, high levels of FBXL7 transcript strongly predicted a poor prognosis and unfavorable response to PTX-based chemotherapy in patients with ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (193, 207))	('high', 'Var', (57, 61))	('PTX', 'Chemical', 'MESH:D017239', (153, 156))	('ovarian cancer', 'Disease', (193, 207))	('FBXL7', 'Gene', (72, 77))	('FBXL7', 'Gene', '23194', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (179, 187))	('predicted', 'Reg', (98, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))
8821	30301218	The knockdown of FBXL7 predominantly enhanced the cytotoxic effectiveness of PTX on the PTX-resistant KURAMOCHI cells.	('FBXL7', 'Gene', (17, 22))	('PTX', 'Chemical', 'MESH:D017239', (77, 80))	('FBXL7', 'Gene', '23194', (17, 22))	('PTX', 'Chemical', 'MESH:D017239', (88, 91))	('cytotoxic effectiveness', 'CPA', (50, 73))	('knockdown', 'Var', (4, 13))	('enhanced', 'PosReg', (37, 45))
8874	30301218	In the ovarian cancer patients with taxol adjuvant therapy, the other DGKH, except probes 227415_at and 1553300_a_at, and MFSD6 microarray probes displayed similar prognostic significance under PFS probability (Figure S3).	('ovarian cancer', 'Phenotype', 'HP:0100615', (7, 21))	('taxol', 'Chemical', 'MESH:D017239', (36, 41))	('MFSD6', 'Gene', '54842', (122, 127))	('patients', 'Species', '9606', (22, 30))	('ovarian cancer', 'Disease', 'MESH:D010051', (7, 21))	('DGKH', 'Gene', (70, 74))	('ovarian cancer', 'Disease', (7, 21))	('DGKH', 'Gene', '160851', (70, 74))	('MFSD6', 'Gene', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('1553300_a_at', 'Var', (104, 116))
8876	30301218	The data showed that the high-level transcripts determined by probe identifiers for DGKH (except probes 235952_at, 227415_at and 240145_at), FBXL7, and MFSD6 were associated with an unfavorable hazard ratio in the unclassified cohort (Figure 3C).	('MFSD6', 'Gene', (152, 157))	('DGKH', 'Gene', '160851', (84, 88))	('MFSD6', 'Gene', '54842', (152, 157))	('235952_at', 'Var', (104, 113))	('FBXL7', 'Gene', '23194', (141, 146))	('FBXL7', 'Gene', (141, 146))	('240145_at', 'Var', (129, 138))	('DGKH', 'Gene', (84, 88))	('227415_at', 'Var', (115, 124))
8877	30301218	Similarly, in the ovarian cancer patients receiving taxol adjuvant therapy, the elevated mRNA levels detected by probes for DGKH (except probes 235952_at and 240145_at), FBXL7, and MFSD6 appeared to be correlated with poor outcomes (Figure 3D).	('MFSD6', 'Gene', '54842', (181, 186))	('235952_at', 'Var', (144, 153))	('taxol', 'Chemical', 'MESH:D017239', (52, 57))	('ovarian cancer', 'Disease', (18, 32))	('elevated', 'PosReg', (80, 88))	('patients', 'Species', '9606', (33, 41))	('DGKH', 'Gene', (124, 128))	('FBXL7', 'Gene', '23194', (170, 175))	('FBXL7', 'Gene', (170, 175))	('DGKH', 'Gene', '160851', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (18, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (18, 32))	('mRNA levels', 'MPA', (89, 100))	('240145_at', 'Var', (158, 167))	('MFSD6', 'Gene', (181, 186))
8880	30301218	Under the condition of overall survival (OS), high levels of FBXL7 transcripts were significantly (p = 0.0017) associated with a poor survival rate and unfavorable hazard ratio (HR = 1.4, p = 0.0018) in ovarian cancer patients (Figure 4A,B).	('survival rate', 'CPA', (134, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (203, 217))	('poor', 'NegReg', (129, 133))	('patients', 'Species', '9606', (218, 226))	('associated', 'Reg', (111, 121))	('ovarian cancer', 'Disease', 'MESH:D010051', (203, 217))	('high levels', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('ovarian cancer', 'Disease', (203, 217))	('FBXL7', 'Gene', '23194', (61, 66))	('FBXL7', 'Gene', (61, 66))
8882	30301218	The data revealed that high levels of FBXL7 transcripts predict an increased risk for cancer recurrence, with a statistical significance at log-rank p = 0.00051; HR = 1.64, p = 0.00057 (Figure 4C,D).	('FBXL7', 'Gene', (38, 43))	('high levels', 'Var', (23, 34))	('FBXL7', 'Gene', '23194', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
8884	30301218	The data indicated that high levels of FBXL7 transcripts could be an independent factor for predicting an unfavorable risk for cancer recurrence after adjuvant chemotherapy in ovarian cancer patients (Table 1).	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('high', 'Var', (24, 28))	('FBXL7', 'Gene', '23194', (39, 44))	('cancer', 'Disease', (127, 133))	('FBXL7', 'Gene', (39, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('ovarian cancer', 'Disease', (176, 190))
8886	30301218	The IHC results revealed that high protein levels of FBXL7 refers to a poor overall survival rate and an increased hazard ratio in the enrolled ovarian cancer patients (Figure 4F).	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('overall survival rate', 'CPA', (76, 97))	('poor', 'NegReg', (71, 75))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('high', 'Var', (30, 34))	('ovarian cancer', 'Disease', (144, 158))	('FBXL7', 'Gene', '23194', (53, 58))	('increased', 'PosReg', (105, 114))	('FBXL7', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (159, 167))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('protein levels', 'MPA', (35, 49))
8894	30301218	Recent evidence shows that UBR5 (an E3 ubiquitin ligase) knockdown enhances Bax activation and sensitizes resistant cells to cisplatin-induced apoptosis.	('Bax', 'Gene', (76, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('UBR5', 'Gene', '51366', (27, 31))	('enhances', 'PosReg', (67, 75))	('knockdown', 'Var', (57, 66))	('sensitizes', 'Reg', (95, 105))	('Bax', 'Gene', '581', (76, 79))	('ubiquitin', 'molecular_function', 'GO:0031386', ('39', '48'))	('activation', 'MPA', (80, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('UBR5', 'Gene', (27, 31))
8895	30301218	Furthermore, UBR5 expression was higher in ovarian cancers from cisplatin-resistant patients than from cisplatin-responsive patients.	('UBR5', 'Gene', '51366', (13, 17))	('higher', 'PosReg', (33, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('cisplatin-resistant', 'Var', (64, 83))	('patients', 'Species', '9606', (84, 92))	('ovarian cancers', 'Phenotype', 'HP:0100615', (43, 58))	('ovarian cancers', 'Disease', (43, 58))	('ovarian cancers', 'Disease', 'MESH:D010051', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('UBR5', 'Gene', (13, 17))	('expression', 'MPA', (18, 28))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))	('patients', 'Species', '9606', (124, 132))
8904	30301218	Furthermore, high protein levels of FBXL7 refers to a poor OS and an increased hazard ratio in the enrolled ovarian cancer patients (Figure 4E,F).	('ovarian cancer', 'Disease', (108, 122))	('protein levels', 'MPA', (18, 32))	('increased', 'PosReg', (69, 78))	('high', 'Var', (13, 17))	('patients', 'Species', '9606', (123, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('FBXL7', 'Gene', '23194', (36, 41))	('FBXL7', 'Gene', (36, 41))
8906	30301218	Previous studies have demonstrated that a single nucleotide polymorphism (SNP) in FBXL7 showed the strongest associations in BRCA2 mutation carriers of breast cancer.	('BRCA2', 'Gene', (125, 130))	('BRCA2', 'Gene', '675', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('single nucleotide polymorphism', 'Var', (42, 72))	('breast cancer', 'Disease', (152, 165))	('associations', 'Interaction', (109, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('FBXL7', 'Gene', '23194', (82, 87))	('FBXL7', 'Gene', (82, 87))	('mutation', 'Var', (131, 139))
8907	30301218	Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers.	('BRCA2', 'Gene', '675', (64, 69))	('ovarian cancer', 'Disease', (18, 32))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA1', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('BRCA2', 'Gene', (64, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (18, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (18, 32))	('mutation', 'Var', (70, 78))
8929	30967995	Accumulative evidence indicates that aberrant expression or activation of E2Fs is a common phenomenon in malignances, and significant associations have been noted between E2Fs and tumorigenesis or progression in a wide range of cancers.	('E2Fs', 'Gene', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('aberrant expression', 'Var', (37, 56))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancers', 'Disease', (228, 235))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('tumor', 'Disease', (180, 185))	('activation', 'PosReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('E2Fs', 'Gene', (74, 78))	('associations', 'Interaction', (134, 146))	('progression', 'CPA', (197, 208))
8933	30967995	Aberrant expression of E2F2/5/7/8 was found to be associated with the clinical outcomes of patients with OC.	('Aberrant expression', 'Var', (0, 19))	('patients', 'Species', '9606', (91, 99))	('OC', 'Phenotype', 'HP:0100615', (105, 107))	('E2F2', 'Gene', (23, 27))	('E2F2', 'Gene', '1870', (23, 27))	('associated', 'Reg', (50, 60))
8940	30967995	Some of these markers include osteopontin, mesothelin, vascular cell adhesion molecule-1, kallikreins, B7-H4, human prostasin, apolipoprotein A1, interleukin-6/8, glutathione S-transferase polymorphisms, folate receptor alpha miRNA, and aldehyde dehydrogenase.	('folate receptor alpha', 'Gene', (204, 225))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('127', '141'))	('cell adhesion', 'biological_process', 'GO:0007155', ('64', '77'))	('apolipoprotein A1', 'Gene', (127, 144))	('osteopontin', 'Gene', '6696', (30, 41))	('interleukin-6/8', 'Gene', (146, 161))	('osteopontin', 'Gene', (30, 41))	('glutathione S-transferase', 'Gene', (163, 188))	('vascular cell adhesion molecule-1', 'Gene', (55, 88))	('mesothelin', 'Gene', (43, 53))	('folate receptor alpha', 'Gene', '2348', (204, 225))	('prostasin', 'Gene', '5652', (116, 125))	('apolipoprotein A1', 'Gene', '335', (127, 144))	('prostasin', 'Gene', (116, 125))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('64', '86'))	('interleukin-6/8', 'Gene', '3569;3576', (146, 161))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('127', '141'))	('aldehyde dehydrogenase', 'Enzyme', (237, 259))	('polymorphisms', 'Var', (189, 202))	('human', 'Species', '9606', (110, 115))	('mesothelin', 'Gene', '10232', (43, 53))	('vascular cell adhesion molecule-1', 'Gene', '7412', (55, 88))	('glutathione S-transferase', 'Gene', '373156', (163, 188))
8943	30967995	Increased aberrant expression or activation of E2Fs has been reported in several human malignancies; in some studies, E2Fs might act as promising biomarkers to predict tumor prognosis.	('tumor', 'Disease', (168, 173))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('aberrant expression', 'Var', (10, 29))	('human', 'Species', '9606', (81, 86))	('E2Fs', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('activation', 'MPA', (33, 43))	('malignancies', 'Disease', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
8945	30967995	Several E2Fs were shown to be deregulated in OC compared with that in normal tissues, and high expression levels of E2F1, E2F2, E2F4, E2F7, and E2F8 were found to be significantly associated with survival rate in OC.	('E2F8', 'Gene', (144, 148))	('E2F2', 'Gene', '1870', (122, 126))	('E2F7', 'Gene', (134, 138))	('survival rate', 'CPA', (196, 209))	('E2F4', 'Var', (128, 132))	('E2F8', 'Gene', '79733', (144, 148))	('OC', 'Phenotype', 'HP:0100615', (213, 215))	('E2F2', 'Gene', (122, 126))	('deregulated', 'Reg', (30, 41))	('OC', 'Phenotype', 'HP:0100615', (45, 47))	('E2F1', 'Gene', (116, 120))	('E2F7', 'Gene', '144455', (134, 138))	('expression levels', 'MPA', (95, 112))	('associated with', 'Reg', (180, 195))
8946	30967995	More importantly, E2F1 and E2F2 have attracted increasing attention as targeted molecular therapeutic genes for OC.	('OC', 'Phenotype', 'HP:0100615', (112, 114))	('E2F2', 'Gene', (27, 31))	('E2F2', 'Gene', '1870', (27, 31))	('E2F1', 'Var', (18, 22))
8953	30967995	The frequency of E2F family gene alterations (amplification, deep deletion, and missense mutations), copy number variance obtained from Genomic Identification of Significant Targets in Cancer(GISTC), and mRNA expression z-scores (RNA Seq V2 RSEM) were assessed using the cBioPortal for Cancer Genomics database and TCGA.	('RNA', 'cellular_component', 'GO:0005562', ('230', '233'))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Cancer', 'Disease', (185, 191))	('E2F family gene', 'Gene', (17, 32))	('deep deletion', 'Var', (61, 74))	('missense mutations', 'Var', (80, 98))	('Cancer', 'Disease', (286, 292))	('Cancer', 'Phenotype', 'HP:0002664', (286, 292))	('Cancer', 'Disease', 'MESH:D009369', (185, 191))	('Cancer', 'Disease', 'MESH:D009369', (286, 292))
8958	30967995	We compared the transcriptional levels of E2Fs in cancers with those in normal tissue samples by using ONCOMINE databases (Figure 1 and Table 1).	('E2Fs', 'Var', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ONCOMINE', 'Chemical', '-', (103, 111))
8959	30967995	ONCOMINE analysis revealed that the mRNA expression of E2F1, E2F4, E2F5, and E2F8 was upregulated in patients with OC.	('E2F5', 'Gene', '1875', (67, 71))	('E2F8', 'Gene', '79733', (77, 81))	('patients', 'Species', '9606', (101, 109))	('mRNA expression', 'MPA', (36, 51))	('ONCOMINE', 'Chemical', '-', (0, 8))	('E2F8', 'Gene', (77, 81))	('upregulated', 'PosReg', (86, 97))	('E2F1', 'Var', (55, 59))	('E2F4', 'Var', (61, 65))	('OC', 'Phenotype', 'HP:0100615', (115, 117))	('E2F5', 'Gene', (67, 71))
8968	30967995	The mRNA levels of E2F4 in ovarian carcinoma (fold change = 1.573 and p-value = 7.77E-04) and ovarian serous carcinoma (fold change = 2.574 and p-value = 1.01E-06) were significantly higher than those in the normal samples in Bonome's and Welsh's datasets.	('ovarian carcinoma', 'Disease', (27, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('higher', 'PosReg', (183, 189))	('mRNA levels', 'MPA', (4, 15))	('ovarian serous carcinoma', 'Disease', (94, 118))	('01E-06', 'CellLine', 'CVCL:S504', (156, 162))	('E2F4', 'Var', (19, 23))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (94, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (27, 44))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (27, 44))
8973	30967995	The results showed that the mRNA expression levels of E2F1, E2F2, E2F3, E2F5, and E2F8 were significantly higher in OC tissues than in normal ovarian tissues, whereas the transcription expression levels of E2F4, E2F6, and E2F7 were not significantly different between OC and normal tissues.	('E2F7', 'Gene', (222, 226))	('E2F1', 'Var', (54, 58))	('E2F6', 'Gene', '1876', (212, 216))	('OC', 'Phenotype', 'HP:0100615', (116, 118))	('E2F2', 'Gene', (60, 64))	('E2F2', 'Gene', '1870', (60, 64))	('higher', 'PosReg', (106, 112))	('E2F5', 'Gene', '1875', (72, 76))	('mRNA expression levels', 'MPA', (28, 50))	('E2F5', 'Gene', (72, 76))	('E2F8', 'Gene', (82, 86))	('E2F3', 'Var', (66, 70))	('E2F7', 'Gene', '144455', (222, 226))	('E2F6', 'Gene', (212, 216))	('OC', 'Phenotype', 'HP:0100615', (268, 270))	('transcription', 'biological_process', 'GO:0006351', ('171', '184'))	('E2F8', 'Gene', '79733', (82, 86))
8976	30967995	The results indicated a significant positive correlation among E2F1 and E2F3; E2F3 with E2F1, E2F4, and E2F7; E2F4 with E2F3 and E2F8; and E2F8 with E2F4.	('E2F3', 'Var', (72, 76))	('E2F1', 'Var', (88, 92))	('E2F4', 'Var', (110, 114))	('E2F7', 'Gene', '144455', (104, 108))	('E2F3', 'Var', (78, 82))	('E2F4', 'Var', (94, 98))	('E2F7', 'Gene', (104, 108))	('E2F8', 'Gene', (139, 143))	('E2F3', 'Var', (120, 124))	('E2F8', 'Gene', (129, 133))	('E2F8', 'Gene', '79733', (139, 143))	('E2F8', 'Gene', '79733', (129, 133))	('E2F1', 'Var', (63, 67))
8978	30967995	The results revealed relationships in co-expression between E2F1 and E2F2, E2F2 and E2F5, E2F3 and E2F2, E2F6 and E2F5, as well as E2F7 and E2F2.	('E2F2', 'Gene', '1870', (140, 144))	('E2F2', 'Gene', (75, 79))	('E2F2', 'Gene', (99, 103))	('E2F2', 'Gene', '1870', (75, 79))	('E2F2', 'Gene', '1870', (99, 103))	('relationships', 'Reg', (21, 34))	('E2F7', 'Gene', (131, 135))	('E2F5', 'Gene', '1875', (84, 88))	('E2F3', 'Var', (90, 94))	('E2F5', 'Gene', (114, 118))	('E2F2', 'Gene', (69, 73))	('E2F1', 'Var', (60, 64))	('co-expression', 'MPA', (38, 51))	('E2F2', 'Gene', '1870', (69, 73))	('E2F7', 'Gene', '144455', (131, 135))	('E2F6', 'Gene', '1876', (105, 109))	('E2F6', 'Gene', (105, 109))	('E2F2', 'Gene', (140, 144))	('E2F5', 'Gene', '1875', (114, 118))	('E2F5', 'Gene', (84, 88))
8979	30967995	Relationships were noted in co-localization between E2F1 and E2F3, as well as E2F3 and E2F2.	('localization', 'biological_process', 'GO:0051179', ('31', '43'))	('E2F3', 'Var', (78, 82))	('E2F2', 'Gene', '1870', (87, 91))	('E2F3', 'Var', (61, 65))	('E2F1', 'Var', (52, 56))	('E2F2', 'Gene', (87, 91))	('co-localization', 'Interaction', (28, 43))
8980	30967995	Further, relationships were noted between E2F3 and E2F4 in genetic interactions, and E2F1 and E2F2 participated in a network group.	('E2F2', 'Gene', (94, 98))	('relationships', 'Interaction', (9, 22))	('genetic interactions', 'Interaction', (59, 79))	('E2F2', 'Gene', '1870', (94, 98))	('E2F1', 'Var', (85, 89))	('E2F4', 'Var', (51, 55))	('E2F3', 'Var', (42, 46))	('participated', 'Reg', (99, 111))
8981	30967995	In addition, the same pathway was shared between E2F1 and E2F3, E2F1and E2F4, E2F3 and E2F4, as well as E2F4 and E2F2.	('E2F4', 'Var', (87, 91))	('E2F4', 'Var', (104, 108))	('E2F3', 'Var', (78, 82))	('E2F2', 'Gene', (113, 117))	('E2F1', 'Var', (49, 53))	('E2F2', 'Gene', '1870', (113, 117))	('E2F1and E2F4', 'Gene', (64, 76))	('E2F3', 'Var', (58, 62))	('E2F1and E2F4', 'Gene', '1869;1874', (64, 76))
8982	30967995	Physical interactions were noted between E2F1 and E2F4 as well as E2F7 and E2F2.	('E2F7', 'Gene', '144455', (66, 70))	('E2F4', 'Var', (50, 54))	('E2F2', 'Gene', (75, 79))	('E2F7', 'Gene', (66, 70))	('E2F1', 'Var', (41, 45))	('interactions', 'Interaction', (9, 21))	('E2F2', 'Gene', '1870', (75, 79))
8983	30967995	Moreover, relationships were noted between E2F1 with E2F4 and E2F5, E2F2 and E2F5, E2F3 and E2F4, E2F4 and E2F2, as well as E2F6 and E2F5.	('E2F5', 'Gene', (77, 81))	('E2F5', 'Gene', (133, 137))	('E2F5', 'Gene', '1875', (77, 81))	('E2F1', 'Var', (43, 47))	('E2F2', 'Gene', (68, 72))	('E2F2', 'Gene', '1870', (107, 111))	('E2F6', 'Gene', (124, 128))	('E2F6', 'Gene', '1876', (124, 128))	('E2F5', 'Gene', '1875', (62, 66))	('E2F4', 'Var', (92, 96))	('E2F4', 'Var', (98, 102))	('E2F4', 'Var', (53, 57))	('E2F5', 'Gene', (62, 66))	('E2F2', 'Gene', '1870', (68, 72))	('relationships', 'Interaction', (10, 23))	('E2F3', 'Var', (83, 87))	('E2F2', 'Gene', (107, 111))	('E2F5', 'Gene', '1875', (133, 137))
8984	30967995	Shared protein domains were noted among E2F1 with E2F5, E2F7, and E2F8; E2F2 with E2F6 and E2F8; E2F3 with E2F5, E2F6, E2F7, and E2F8; E2F4 with E2F5 and E2F8; E2F6 and E2F5; E2F7 with E2F4, E2F5, E2F6, and E2F8; as well as E2F8 with E2F5 and E2F6.	('E2F5', 'Gene', (234, 238))	('E2F8', 'Gene', (129, 133))	('E2F6', 'Gene', '1876', (160, 164))	('E2F6', 'Gene', (160, 164))	('E2F5', 'Gene', (107, 111))	('E2F8', 'Gene', (91, 95))	('E2F7', 'Gene', '144455', (119, 123))	('E2F8', 'Gene', (154, 158))	('E2F5', 'Gene', (50, 54))	('E2F8', 'Gene', (224, 228))	('E2F1', 'Var', (40, 44))	('E2F7', 'Gene', '144455', (175, 179))	('E2F8', 'Gene', (66, 70))	('E2F8', 'Gene', (207, 211))	('E2F5', 'Gene', '1875', (169, 173))	('E2F7', 'Gene', '144455', (56, 60))	('E2F5', 'Gene', (191, 195))	('E2F8', 'Gene', '79733', (129, 133))	('E2F5', 'Gene', (145, 149))	('E2F5', 'Gene', (169, 173))	('E2F2', 'Gene', (72, 76))	('E2F3', 'Var', (97, 101))	('E2F8', 'Gene', '79733', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('E2F8', 'Gene', '79733', (154, 158))	('E2F8', 'Gene', '79733', (224, 228))	('E2F5', 'Gene', '1875', (234, 238))	('E2F2', 'Gene', '1870', (72, 76))	('E2F8', 'Gene', '79733', (66, 70))	('E2F5', 'Gene', '1875', (107, 111))	('E2F8', 'Gene', '79733', (207, 211))	('E2F6', 'Gene', (243, 247))	('E2F6', 'Gene', '1876', (197, 201))	('E2F6', 'Gene', (197, 201))	('E2F5', 'Gene', '1875', (50, 54))	('E2F6', 'Gene', '1876', (243, 247))	('E2F7', 'Gene', (119, 123))	('E2F7', 'Gene', (175, 179))	('E2F6', 'Gene', '1876', (113, 117))	('E2F7', 'Gene', (56, 60))	('E2F6', 'Gene', (113, 117))	('E2F5', 'Gene', '1875', (145, 149))	('E2F5', 'Gene', '1875', (191, 195))	('E2F6', 'Gene', (82, 86))	('E2F6', 'Gene', '1876', (82, 86))
8985	30967995	E2F1 was shown to interact with E2F2, E2F4, and E2F8, and E2F7 was found to interact with E2F8 with regard to co-expression, text-mining, and protein homology.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('E2F8', 'Gene', (48, 52))	('E2F2', 'Gene', (32, 36))	('interact', 'Interaction', (18, 26))	('E2F7', 'Gene', '144455', (58, 62))	('E2F8', 'Gene', (90, 94))	('E2F8', 'Gene', '79733', (48, 52))	('E2F7', 'Gene', (58, 62))	('E2F8', 'Gene', '79733', (90, 94))	('E2F2', 'Gene', '1870', (32, 36))	('E2F1', 'Var', (0, 4))	('interact', 'Reg', (76, 84))
8987	30967995	The percentages of genetic alterations in E2F family members for OC varied from 3 to 14% for individual genes based on the TCGA Provisional dataset (E2F1, 9%; E2F2, 4%; E2F3, 16%; E2F4, 10%; E2F5, 14%; E2F6, 10%; E2F7, 3%; E2F8, 4%; Figure 5B).	('E2F2', 'Gene', (159, 163))	('E2F8', 'Gene', (223, 227))	('E2F1', 'Var', (149, 153))	('OC', 'Phenotype', 'HP:0100615', (65, 67))	('E2F3', 'Var', (169, 173))	('E2F7', 'Gene', '144455', (213, 217))	('E2F8', 'Gene', '79733', (223, 227))	('E2F4', 'Var', (180, 184))	('E2F7', 'Gene', (213, 217))	('E2F2', 'Gene', '1870', (159, 163))	('E2F5', 'Gene', (191, 195))	('E2F5', 'Gene', '1875', (191, 195))	('E2F6', 'Gene', '1876', (202, 206))	('E2F6', 'Gene', (202, 206))
8995	30967995	In addition, increased E2F1, E2F2, E2F4, and E2F7 mRNA expression levels were associated with poor PPS.	('E2F2', 'Gene', (29, 33))	('E2F7', 'Gene', '144455', (45, 49))	('increased E2F1', 'Phenotype', 'HP:0030269', (13, 27))	('E2F1', 'Var', (23, 27))	('PPS', 'Chemical', '-', (99, 102))	('E2F4', 'Var', (35, 39))	('poor PPS', 'Disease', (94, 102))	('E2F7', 'Gene', (45, 49))	('E2F2', 'Gene', '1870', (29, 33))	('increased', 'PosReg', (13, 22))
8996	30967995	The high mRNA expression levels of E2F1, E2F3, E2F7, and E2F8 were correlated to poor OS in serous OC patients, whereas increased E2F2 mRNA expression was associated with better OS in serous OC patients.	('serous OC', 'Disease', (92, 101))	('E2F7', 'Gene', (47, 51))	('patients', 'Species', '9606', (194, 202))	('E2F2', 'Gene', '1870', (130, 134))	('OS', 'Chemical', '-', (86, 88))	('patients', 'Species', '9606', (102, 110))	('E2F2', 'Gene', (130, 134))	('OC', 'Phenotype', 'HP:0100615', (99, 101))	('OC', 'Phenotype', 'HP:0100615', (191, 193))	('E2F8', 'Gene', (57, 61))	('high', 'PosReg', (4, 8))	('E2F3', 'Var', (41, 45))	('E2F8', 'Gene', '79733', (57, 61))	('mRNA expression levels', 'MPA', (9, 31))	('OS', 'Chemical', '-', (178, 180))	('E2F1', 'Var', (35, 39))	('E2F7', 'Gene', '144455', (47, 51))	('poor OS', 'Disease', (81, 88))
8997	30967995	Further, increased E2F2 and E2F4 mRNA expression levels were associated with poor PFS in serous OC patients.	('E2F4', 'Var', (28, 32))	('E2F2', 'Gene', (19, 23))	('serous OC', 'Disease', (89, 98))	('increased', 'PosReg', (9, 18))	('patients', 'Species', '9606', (99, 107))	('OC', 'Phenotype', 'HP:0100615', (96, 98))	('PFS', 'Disease', (82, 85))	('E2F2', 'Gene', '1870', (19, 23))	('poor PFS', 'Disease', (77, 85))
8998	30967995	High mRNA expression of E2F1, E2F2, E2F3, E2F4, and E2F7 was significantly associated with worse PPS.	('E2F4', 'Var', (42, 46))	('E2F3', 'Var', (36, 40))	('E2F2', 'Gene', '1870', (30, 34))	('PPS', 'Disease', (97, 100))	('E2F7', 'Gene', '144455', (52, 56))	('mRNA', 'MPA', (5, 9))	('E2F7', 'Gene', (52, 56))	('E2F1', 'Var', (24, 28))	('E2F2', 'Gene', (30, 34))	('associated', 'Reg', (75, 85))	('PPS', 'Chemical', '-', (97, 100))
9000	30967995	High E2F1, E2F3, and E2F8 mRNA expression levels were associated with poor PFS, whereas increased E2F2 and E2F5 mRNA expression levels were associated with superior PFS in endometrioid OC patients.	('E2F8', 'Gene', '79733', (21, 25))	('mRNA expression levels', 'MPA', (26, 48))	('E2F2', 'Gene', (98, 102))	('PFS', 'Disease', (75, 78))	('patients', 'Species', '9606', (188, 196))	('E2F5', 'Gene', '1875', (107, 111))	('OC', 'Phenotype', 'HP:0100615', (185, 187))	('E2F5', 'Gene', (107, 111))	('E2F1', 'MPA', (5, 9))	('endometrioid OC', 'Disease', (172, 187))	('E2F3', 'Var', (11, 15))	('E2F2', 'Gene', '1870', (98, 102))	('E2F8', 'Gene', (21, 25))
9003	30967995	Numerous studies have suggested that E2Fs are involved in not only proliferation and differentiation but also apoptosis and tumorigenesis.	('apoptosis', 'CPA', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('tumor', 'Disease', (124, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('involved', 'Reg', (46, 54))	('E2Fs', 'Var', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
9004	30967995	Accumulative evidence indicated that aberrant expression or activation of E2Fs is a common phenomenon in malignances, and significant associations between E2Fs and tumorigenesis or progression of patients with cancer has been partially confirmed.	('aberrant expression', 'Var', (37, 56))	('tumor', 'Disease', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('E2Fs', 'Var', (155, 159))	('patients', 'Species', '9606', (196, 204))	('activation', 'PosReg', (60, 70))	('E2Fs', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('cancer', 'Disease', (210, 216))	('associations', 'Interaction', (134, 146))
9006	30967995	E2F1 has been shown sto exhibit dual properties and can act as a tumor suppressor or oncogene in the same cancer.	('tumor', 'Disease', (65, 70))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('E2F1', 'Var', (0, 4))	('cancer', 'Disease', (106, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
9008	30967995	More and more studies revealed that E2F1 overexpression could produce more aggressive tumors with a high proliferation rate and chemoresistance.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('chemoresistance', 'CPA', (128, 143))	('overexpression', 'Var', (41, 55))	('aggressive tumors', 'Disease', 'MESH:D001523', (75, 92))	('E2F1', 'Gene', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('high proliferation rate', 'CPA', (100, 123))	('aggressive tumors', 'Disease', (75, 92))
9009	30967995	In our study, ONCOMINE and GEPIA datasets revealed that the expression of E2F1 was up-regulated in human OC, and E2F1 expression was linked with the clinical characteristics of patients with OC.	('expression', 'MPA', (60, 70))	('E2F1', 'Var', (113, 117))	('OC', 'Phenotype', 'HP:0100615', (105, 107))	('up-regulated', 'PosReg', (83, 95))	('patients', 'Species', '9606', (177, 185))	('E2F1', 'Gene', (74, 78))	('ONCOMINE', 'Chemical', '-', (14, 22))	('linked', 'Reg', (133, 139))	('human', 'Species', '9606', (99, 104))	('OC', 'Phenotype', 'HP:0100615', (191, 193))
9015	30967995	In addition, high E2F2 expression was significantly correlated with worse PPS in all patients with OC.	('PPS', 'Chemical', '-', (74, 77))	('high', 'Var', (13, 17))	('E2F2', 'Gene', '1870', (18, 22))	('OC', 'Phenotype', 'HP:0100615', (99, 101))	('patients', 'Species', '9606', (85, 93))	('PPS', 'Disease', (74, 77))	('E2F2', 'Gene', (18, 22))	('expression', 'MPA', (23, 33))
9017	30967995	Amplification and overexpression of E2F3 has been shown to be closely associated with clinical stage, pathological grading, proliferation index, and tumor aggression.	('tumor aggression', 'Disease', (149, 165))	('Amplification', 'Var', (0, 13))	('tumor aggression', 'Disease', 'MESH:D001523', (149, 165))	('aggression', 'biological_process', 'GO:0002118', ('155', '165'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('E2F3', 'Gene', (36, 40))	('proliferation index', 'CPA', (124, 143))	('associated', 'Reg', (70, 80))	('aggression', 'Phenotype', 'HP:0000718', (155, 165))	('overexpression', 'PosReg', (18, 32))
9018	30967995	Interestingly, E2F3a was found to be essential in EGFR-mediated proliferation in ovarian cancer cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('E2F3a', 'Var', (15, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('EGFR', 'Gene', '1956', (50, 54))	('ovarian cancer', 'Disease', (81, 95))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
9023	30967995	E2F4 is a key regulator of cell transformation, proliferation, and cell cycle progression, and a recent study showed that patients exhibiting high expression of E2F4 target genes exhibited more severe cancer and shorter survival.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('shorter', 'NegReg', (212, 219))	('cancer', 'Disease', (201, 207))	('cell cycle', 'biological_process', 'GO:0007049', ('67', '77'))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('E2F4', 'Gene', (161, 165))	('high expression', 'Var', (142, 157))
9024	30967995	In OC, E2F4 is involved in cell cycle arrest at the G0 phase in TOV21G and SKOV3 cells, and this role is enhanced by deregulated cyclin-dependent kinase inhibitors such as p27, p130/Rb2, and p130/Rb2.	('cyclin-dependent kinase inhibitors', 'MPA', (129, 163))	('SKOV3', 'CellLine', 'CVCL:0532', (75, 80))	('Rb2', 'Gene', (196, 199))	('cyclin', 'molecular_function', 'GO:0016538', ('129', '135'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('p27', 'Gene', '3429', (172, 175))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('27', '44'))	('p27', 'Gene', (172, 175))	('Rb2', 'Gene', '5934', (182, 185))	('OC', 'Phenotype', 'HP:0100615', (3, 5))	('p130', 'Gene', '5934', (191, 195))	('G0 phase', 'biological_process', 'GO:0044838', ('52', '60'))	('p130', 'Gene', '5934', (177, 181))	('Rb2', 'Gene', '5934', (196, 199))	('cell cycle arrest', 'CPA', (27, 44))	('Rb2', 'Gene', (182, 185))	('p130', 'Gene', (191, 195))	('deregulated', 'PosReg', (117, 128))	('p130', 'Gene', (177, 181))	('E2F4', 'Var', (7, 11))	('enhanced', 'PosReg', (105, 113))
9041	30967995	revealed that BRCA2-deficient cells are less sensitive to PARP inhibitor and cisplatin treatment after E2F7 depletion, thereby indicating that E2F7 could be a putative biomarker for tumor response to PARP inhibitor therapy.	('PARP', 'Gene', '142', (58, 62))	('sensitive to', 'MPA', (45, 57))	('E2F7', 'Gene', (143, 147))	('tumor', 'Disease', (182, 187))	('BRCA2', 'Gene', '675', (14, 19))	('less', 'NegReg', (40, 44))	('depletion', 'Var', (108, 117))	('E2F7', 'Gene', '144455', (103, 107))	('PARP', 'Gene', '142', (200, 204))	('E2F7', 'Gene', (103, 107))	('PARP', 'Gene', (58, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('PARP', 'Gene', (200, 204))	('BRCA2', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('E2F7', 'Gene', '144455', (143, 147))
9043	30967995	Further, high E2F7 expression was significantly correlated with poor PFS and PPS in all and serous OC patients, indicating its oncogenic role in OC.	('serous OC', 'Disease', (92, 101))	('expression', 'MPA', (19, 29))	('PPS', 'Chemical', '-', (77, 80))	('E2F7', 'Gene', '144455', (14, 18))	('E2F7', 'Gene', (14, 18))	('patients', 'Species', '9606', (102, 110))	('OC', 'Phenotype', 'HP:0100615', (99, 101))	('poor', 'NegReg', (64, 68))	('PFS', 'MPA', (69, 72))	('PPS', 'MPA', (77, 80))	('OC', 'Phenotype', 'HP:0100615', (145, 147))	('high', 'Var', (9, 13))
9049	30967995	Interestingly, high E2F8 expression was significantly correlated with poor OS and PFS in all patients with OC.	('high', 'Var', (15, 19))	('poor OS', 'Disease', (70, 77))	('patients', 'Species', '9606', (93, 101))	('expression', 'MPA', (25, 35))	('E2F8', 'Gene', '79733', (20, 24))	('OS', 'Chemical', '-', (75, 77))	('correlated', 'Reg', (54, 64))	('PFS', 'Disease', (82, 85))	('OC', 'Phenotype', 'HP:0100615', (107, 109))	('E2F8', 'Gene', (20, 24))
9051	30967995	For example, E2F1 and E2F3 were shown to be target genes involved in the p53 and p73 pathways for inducing apoptosis in a transgenic mouse model.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('E2F1', 'Var', (13, 17))	('E2F3', 'Var', (22, 26))	('transgenic', 'Species', '10090', (122, 132))	('inducing', 'PosReg', (98, 106))	('p73', 'Gene', (81, 84))	('mouse', 'Species', '10090', (133, 138))	('apoptosis', 'CPA', (107, 116))	('p73', 'Gene', '22062', (81, 84))
9052	30967995	showed that deregulation of both proliferation-promoting and proliferation-inhibiting E2F transcription factors and their cross-talk is crucial for tumor progression of OC and influence clinical outcome; thus, they could be possible useful targets in anti-cancer therapy.	('OC', 'Phenotype', 'HP:0100615', (169, 171))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('proliferation-promoting', 'CPA', (33, 56))	('tumor', 'Disease', (148, 153))	('cancer', 'Disease', (256, 262))	('deregulation', 'Var', (12, 24))	('proliferation-inhibiting', 'CPA', (61, 85))	('influence', 'Reg', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('E2F transcription', 'Gene', (86, 103))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))
9054	30967995	Further, cases with alterations in one of the query gene had worse OS and DFS than those without any alterations in the query genes, but the difference was not statistically significant.	('OS', 'Chemical', '-', (67, 69))	('alterations', 'Var', (20, 31))	('worse', 'NegReg', (61, 66))	('DFS', 'MPA', (74, 77))
9056	30967995	In summary, our results indicated that the mRNA expression levels of E2F1, E2F3, E2F5, and E2F8 were significantly upregulated, and obvious and negatively associated with tumor stage for OC.	('E2F8', 'Gene', '79733', (91, 95))	('E2F8', 'Gene', (91, 95))	('mRNA expression levels', 'MPA', (43, 65))	('OC', 'Phenotype', 'HP:0100615', (187, 189))	('E2F5', 'Gene', (81, 85))	('E2F5', 'Gene', '1875', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('associated', 'Reg', (155, 165))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('E2F3', 'Var', (75, 79))	('E2F1', 'Var', (69, 73))	('tumor', 'Disease', (171, 176))	('negatively', 'NegReg', (144, 154))	('upregulated', 'PosReg', (115, 126))
9057	30967995	Furthermore, aberrant expression of E2F2, E2F5, E2F7, and E2F8 were found to be associated with the clinical outcomes of patients with OC.	('E2F8', 'Gene', (58, 62))	('E2F2', 'Gene', (36, 40))	('aberrant expression', 'Var', (13, 32))	('E2F7', 'Gene', '144455', (48, 52))	('E2F5', 'Gene', '1875', (42, 46))	('E2F8', 'Gene', '79733', (58, 62))	('E2F7', 'Gene', (48, 52))	('E2F5', 'Gene', (42, 46))	('associated', 'Reg', (80, 90))	('E2F2', 'Gene', '1870', (36, 40))	('patients', 'Species', '9606', (121, 129))	('OC', 'Phenotype', 'HP:0100615', (135, 137))
9130	20091184	HES genes are thought to prevent cellular differentiation and maintain the population of undifferentiated precursor cells (Jensen et al.).	('HES', 'Gene', (0, 3))	('genes', 'Var', (4, 9))	('prevent', 'NegReg', (25, 32))	('HES', 'Gene', '43161', (0, 3))	('maintain', 'PosReg', (62, 70))	('cellular differentiation', 'CPA', (33, 57))
9132	20091184	Recent studies have shown mis-expressions of HES1 and HES5 in human malignancies such as lung cancer, cholangiocarcinoma, murine leukemia, and others (Ishimura et al.	('leukemia', 'Disease', (129, 137))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (102, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('leukemia', 'Disease', 'MESH:D007938', (129, 137))	('lung cancer', 'Disease', (89, 100))	('malignancies', 'Disease', (68, 80))	('human', 'Species', '9606', (62, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('murine', 'Species', '10090', (122, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('HES1', 'Gene', (45, 49))	('mis-expressions', 'Var', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('HES5', 'Gene', (54, 58))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('cholangiocarcinoma', 'Disease', (102, 120))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))
9133	20091184	For instance, activation of HES1 expression induced the differentiation of neuroblastoma cells, the process of which was probably inhibited by Notch1 (Axelson), induction of HES1 led to suppression of proliferation in carcinoid tumor cells (Kunnimalaiyaan et al.)	('induction', 'Var', (161, 170))	('neuroblastoma', 'Disease', 'MESH:D009447', (75, 88))	('carcinoid tumor', 'Disease', 'MESH:D002276', (218, 233))	('carcinoid tumor', 'Disease', (218, 233))	('proliferation', 'CPA', (201, 214))	('differentiation', 'CPA', (56, 71))	('neuroblastoma', 'Disease', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('HES1', 'Gene', (174, 178))	('suppression', 'NegReg', (186, 197))	('HES1', 'Gene', (28, 32))	('neuroblastoma', 'Phenotype', 'HP:0003006', (75, 88))	('carcinoid', 'Phenotype', 'HP:0100570', (218, 227))
9142	20091184	Nefedova and colleagues found that activation of Notch-1 resulted in protection of myeloma and malignant lymphoid cells from melphalan- and mitoxantrone-induced apoptosis and this protection was associated with up-regulation of p21 (WAF/Cip) and growth inhibition of cells (Nefedova et al.).	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('growth inhibition', 'CPA', (246, 263))	('up-regulation', 'PosReg', (211, 224))	('myeloma', 'Disease', 'MESH:D009101', (83, 90))	('activation', 'Var', (35, 45))	('WAF', 'Disease', 'None', (233, 236))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('WAF', 'Disease', (233, 236))	('Notch-1', 'Gene', (49, 56))	('regulation', 'biological_process', 'GO:0065007', ('214', '224'))	('mitoxantrone', 'Chemical', 'MESH:D008942', (140, 152))	('protection', 'CPA', (69, 79))	('myeloma', 'Disease', (83, 90))	('Notch-1', 'Gene', '18128', (49, 56))
9144	20091184	A clinical study showed that activating Notch1 mutations could predict favorable early chemotherapy response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia (Breit et al.).	('leukemia', 'Phenotype', 'HP:0001909', (175, 183))	('T-cell lymphoblastic leukemia', 'Disease', (154, 183))	('mutations', 'Var', (47, 56))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (161, 183))	('Notch1', 'Gene', (40, 46))	('T-cell lymphoblastic leukemia', 'Disease', 'MESH:D054218', (154, 183))	('activating', 'PosReg', (29, 39))
9146	20091184	A recent study in vitro and in mice model by Nefedova and colleagues showed that inhibition of Notch signaling prevented drug resistance and sensitizes myeloma to chemotherapy, and HES1 mediated this procedure (Nefedova et al.).	('myeloma', 'Disease', (152, 159))	('sensitizes', 'Reg', (141, 151))	('drug resistance', 'biological_process', 'GO:0042493', ('121', '136'))	('Notch', 'Protein', (95, 100))	('inhibition', 'Var', (81, 91))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('myeloma', 'Disease', 'MESH:D009101', (152, 159))	('mice', 'Species', '10090', (31, 35))	('prevented', 'NegReg', (111, 120))	('drug resistance', 'MPA', (121, 136))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('drug resistance', 'biological_process', 'GO:0009315', ('121', '136'))
9155	32823589	By using human CD83 stable overexpression and knockdown sublines of several ovarian cancer cells, we observed that CD83 advanced the growth proliferation, colony formation ability, spheroid formation, and in vivo tumorigenicity of ovarian cancer cells; surprisingly, CD83 limited their migration and invasion potentials.	('CD83', 'Var', (267, 271))	('human', 'Species', '9606', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('ovarian cancer', 'Disease', (76, 90))	('colony formation ability', 'CPA', (155, 179))	('tumorigenicity of ovarian cancer', 'Disease', 'MESH:D002471', (213, 245))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('growth proliferation', 'CPA', (133, 153))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('formation', 'biological_process', 'GO:0009058', ('190', '199'))	('ovarian cancer', 'Disease', 'MESH:D010051', (231, 245))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('spheroid formation', 'CPA', (181, 199))	('tumorigenicity of ovarian cancer', 'Disease', (213, 245))	('limited', 'NegReg', (272, 279))	('invasion potentials', 'CPA', (300, 319))	('ovarian cancer', 'Disease', 'MESH:D010051', (76, 90))	('formation', 'biological_process', 'GO:0009058', ('162', '171'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (231, 245))
9183	32823589	Immunostaining analysis further indicated the ectopically activated CD83 expression in human ovarian serous adenocarcinoma, as compared with that in para-cancer tissues (Figure 1c).	('para-cancer', 'Disease', (149, 160))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D000230', (93, 122))	('human', 'Species', '9606', (87, 92))	('CD83', 'Gene', (68, 72))	('expression', 'MPA', (73, 83))	('para-cancer', 'Disease', 'MESH:D009369', (149, 160))	('ectopically', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ovarian serous adenocarcinoma', 'Disease', (93, 122))
9188	32823589	Taken together, CD83 was associated with poor survival of ovarian cancer patients, and CD83 might determine the fate of ovarian cancer cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (58, 72))	('CD83', 'Var', (16, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ovarian cancer', 'Disease', 'MESH:D010051', (58, 72))	('ovarian cancer', 'Disease', (120, 134))	('poor', 'NegReg', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ovarian cancer', 'Disease', (58, 72))	('determine', 'Reg', (98, 107))	('patients', 'Species', '9606', (73, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
9193	32823589	Compared with the control group, the proliferation behavior of SKOV3 cells was significantly attenuated in the CD83-KD group, whereas the accelerated proliferation of CD83-OV cells was observed (Figure 2a).	('proliferation behavior of SKOV3 cells', 'CPA', (37, 74))	('CD83-KD', 'Var', (111, 118))	('SKOV3', 'CellLine', 'CVCL:0532', (63, 68))	('attenuated', 'NegReg', (93, 103))
9195	32823589	On the other hand, apoptosis rates of CD83-KD, CD83-OV, and control SKOV3 cells were almost identical in vitro, as revealed by a TUNEL staining (Figure S4).	('apoptosis', 'CPA', (19, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('19', '28'))	('SKOV3', 'CellLine', 'CVCL:0532', (68, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('19', '28'))	('CD83-KD', 'Var', (38, 45))
9199	32823589	Notably, CD83 knockdown significantly reduced the spheroid formation ability of the single SKOV3, OVCAR3, and Caov3 cells, while forced expression of CD83 boosted the growth of spheroids (Figure 2c, Figure S3c,d).	('Caov3', 'CellLine', 'CVCL:0201', (110, 115))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('reduced', 'NegReg', (38, 45))	('boosted', 'PosReg', (155, 162))	('spheroid formation ability', 'CPA', (50, 76))	('SKOV3', 'CellLine', 'CVCL:0532', (91, 96))	('CD83', 'Gene', (9, 13))	('OVCAR3', 'Gene', '761', (98, 104))	('growth', 'CPA', (167, 173))	('knockdown', 'Var', (14, 23))	('CD83', 'Gene', (150, 154))	('OVCAR3', 'Gene', (98, 104))
9204	32823589	The total tumor weights for CD83-OV groups (n = 9) were significantly higher than that for the control (n = 8) and CD83-KD groups (n = 8), suggesting that the expression of CD83 was tightly linked to tumor burden (Figure 2e).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (10, 15))	('linked', 'Reg', (190, 196))	('CD83', 'Gene', (173, 177))	('tumor', 'Disease', (200, 205))	('CD83-OV', 'Var', (28, 35))	('higher', 'PosReg', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
9210	32823589	To explore the downstream targets and regulatory network of transmembrane CD83 in ovarian cancer cells without bias, an integrated study of transcriptome and proteome was performed using CD83-OV, CD83-KD, and control SKOV3 cells (Figure S6, Tables S1-4).	('CD83-OV', 'Var', (187, 194))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('S1-4', 'Gene', '6208', (248, 252))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('transmembrane', 'cellular_component', 'GO:0044214', ('60', '73'))	('ovarian cancer', 'Disease', (82, 96))	('transmembrane', 'cellular_component', 'GO:0016021', ('60', '73'))	('S1-4', 'Gene', (248, 252))	('SKOV3', 'CellLine', 'CVCL:0532', (217, 222))	('CD83-KD', 'Var', (196, 203))
9212	32823589	We found that CD83-KD ovarian cancer cells exhibited elevated transcriptional expression of matrix metallopeptidases (MMPs) and transforming growth factor (TGF)-beta family members (Figure 4b); in contrast, cell cycle regulators (e.g., cyclins-CDKs) and stemness factors (e.g., CD24, CD44, and KIT) were upregulated in CD83-OV and negative control (NC) ovarian cancer cells (Figure 4c).	('elevated', 'PosReg', (53, 61))	('KIT', 'Gene', '3815', (294, 297))	('transcriptional expression', 'MPA', (62, 88))	('KIT', 'molecular_function', 'GO:0005020', ('294', '297'))	('cell cycle', 'biological_process', 'GO:0007049', ('207', '217'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('cyclins', 'Gene', (236, 243))	('(NC) ovarian cancer', 'Disease', 'OMIM:617025', (348, 367))	('CDKs', 'Gene', '1017', (244, 248))	('CD24', 'Gene', '100133941', (278, 282))	('cell cycle', 'CPA', (207, 217))	('CD44', 'Gene', '960', (284, 288))	('MMPs', 'Gene', (118, 122))	('upregulated', 'PosReg', (304, 315))	('ovarian cancer', 'Phenotype', 'HP:0100615', (353, 367))	('CD44', 'Gene', (284, 288))	('MMPs', 'Gene', '4312;4316;4319', (118, 122))	('CDKs', 'Gene', (244, 248))	('KIT', 'Gene', (294, 297))	('stemness factors', 'CPA', (254, 270))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('CD83-OV', 'Var', (319, 326))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('CD24', 'Gene', (278, 282))	('cyclins', 'Gene', '891;9133', (236, 243))
9215	32823589	In addition to MMPs, expression of a disintegrin and metallopeptidases (ADAMs), ADAM metallopeptidase with thrombospondin type 1 motifs (ADAMTSs), and tissue inhibitor of metallopeptidases (TIMPs) also showed differential expression between CD83-KD and other two groups (Figure S7).	('MMPs', 'Gene', (15, 19))	('MMPs', 'Gene', '4312;4316;4319', (15, 19))	('expression', 'MPA', (21, 31))	('CD83-KD', 'Var', (241, 248))	('expression', 'MPA', (222, 232))
9217	32823589	Taken together, transcriptome and proteome strongly indicated the positive regulation of proliferation/stemness factors and negative regulation of matrix metallopeptidases by CD83, partially explaining why CD83 advanced the growth proliferation and spheroid formation but limited the migration and invasion of ovarian cancer cells.	('growth proliferation', 'CPA', (224, 244))	('formation', 'biological_process', 'GO:0009058', ('258', '267'))	('limited', 'NegReg', (272, 279))	('migration', 'CPA', (284, 293))	('spheroid formation', 'CPA', (249, 267))	('ovarian cancer', 'Phenotype', 'HP:0100615', (310, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('CD83', 'Var', (206, 210))	('regulation', 'biological_process', 'GO:0065007', ('75', '85'))	('advanced', 'PosReg', (211, 219))	('regulation', 'biological_process', 'GO:0065007', ('133', '143'))	('CD83', 'Gene', (175, 179))	('invasion of ovarian cancer', 'Disease', (298, 324))	('invasion of ovarian cancer', 'Disease', 'MESH:D009362', (298, 324))
9222	32823589	Given that TAK1 and TAB1 are preassociated on the cell membrane, as well as the membrane localization of CD83, we hypothesized that CD83 forms a complex with TAK1-TAB1 to activate the MAPK signaling pathway.	('activate', 'PosReg', (171, 179))	('TAK1', 'Gene', '6885', (11, 15))	('signaling pathway', 'biological_process', 'GO:0007165', ('189', '206'))	('TAK1', 'Gene', (158, 162))	('cell membrane', 'cellular_component', 'GO:0005886', ('50', '63'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('184', '198'))	('TAK1', 'Gene', (11, 15))	('localization', 'biological_process', 'GO:0051179', ('89', '101'))	('MAPK', 'Gene', (184, 188))	('complex', 'Interaction', (145, 152))	('TAK1', 'Gene', '6885', (158, 162))	('MAPK', 'Gene', '4216', (184, 188))	('CD83', 'Var', (132, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('184', '188'))	('membrane', 'cellular_component', 'GO:0016020', ('80', '88'))
9224	32823589	Interestingly, CD83 further promoted the stability of TAB1 when SKOV3 cells were treated by cycloheximide, a protein synthesis inhibitor (Figure 5d).	('CD83', 'Var', (15, 19))	('stability', 'MPA', (41, 50))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('protein synthesis', 'biological_process', 'GO:0006412', ('109', '126'))	('SKOV3', 'CellLine', 'CVCL:0532', (64, 69))	('cycloheximide', 'Chemical', 'MESH:D003513', (92, 105))	('promoted', 'PosReg', (28, 36))	('TAB1', 'Gene', (54, 58))
9232	32823589	We generated a truncation mutant of the CD83 intracellular domain (termed CD83DeltaID) with a Flag tag and found that the deletion of the intracellular domain significantly blocked the interaction of CD83 with TAK1 and TAB1 in a Co-IP assay (Figure 6b).	('TAK1', 'Gene', (210, 214))	('intracellular', 'cellular_component', 'GO:0005622', ('138', '151'))	('interaction', 'Interaction', (185, 196))	('CD83', 'Gene', (200, 204))	('deletion', 'Var', (122, 130))	('intracellular', 'cellular_component', 'GO:0005622', ('45', '58'))	('blocked', 'NegReg', (173, 180))	('TAK1', 'Gene', '6885', (210, 214))
9233	32823589	As expected, SKOV3 cells transfected with CD83DeltaID expressed a lower level of p-TAK1, p-MEK1/2, and p-ERK1/2 as compared with those in the wild-type CD83-transfected SKOV3 cells (Figure 6c).	('TAK1', 'Gene', '6885', (83, 87))	('SKOV3', 'CellLine', 'CVCL:0532', (169, 174))	('MEK1', 'molecular_function', 'GO:0004708', ('91', '95'))	('ERK', 'Gene', '5594', (105, 108))	('TAK1', 'Gene', (83, 87))	('lower', 'NegReg', (66, 71))	('SKOV3', 'CellLine', 'CVCL:0532', (13, 18))	('ERK', 'Gene', (105, 108))	('ERK1', 'molecular_function', 'GO:0004707', ('105', '109'))	('MEK', 'Gene', (91, 94))	('MEK', 'Gene', '5609', (91, 94))	('CD83DeltaID', 'Var', (42, 53))
9234	32823589	Importantly, CD83-mediated stimulation of cell proliferation and spheroid formation was significantly inhibited in CD83DeltaID-transfected SKOV3 cells (Figure 6d,e).	('CD83DeltaID-transfected', 'Var', (115, 138))	('spheroid formation', 'CPA', (65, 83))	('SKOV3', 'CellLine', 'CVCL:0532', (139, 144))	('inhibited', 'NegReg', (102, 111))	('cell proliferation', 'CPA', (42, 60))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('27', '60'))
9235	32823589	Moreover, the deletion of the intracellular domain interrupted the stimulations of CDK2, CCNB1, and STAT3, as well as inhibitions of FOXO1, p21, and DKK1 by CD83 (Figure 6f).	('FOXO1', 'Gene', (133, 138))	('stimulations', 'MPA', (67, 79))	('FOXO1', 'Gene', '2308', (133, 138))	('STAT3', 'Gene', (100, 105))	('CDK2', 'Gene', (83, 87))	('CCNB1', 'Gene', '891', (89, 94))	('intracellular', 'cellular_component', 'GO:0005622', ('30', '43'))	('p21', 'Gene', '644914', (140, 143))	('interrupted', 'NegReg', (51, 62))	('inhibitions', 'NegReg', (118, 129))	('CDK', 'molecular_function', 'GO:0004693', ('83', '86'))	('CCNB1', 'Gene', (89, 94))	('CDK2', 'Gene', '1017', (83, 87))	('deletion', 'Var', (14, 22))	('DKK1', 'Gene', '22943', (149, 153))	('STAT3', 'Gene', '6774', (100, 105))	('DKK1', 'Gene', (149, 153))	('p21', 'Gene', (140, 143))
9236	32823589	Taken together, our findings demonstrated that the CD83 intracellular domain was important for its association with TAK1/TAB1 and activation of the MAPK signaling pathway, as well as CD83 function in ovarian cancer cells.	('ovarian cancer', 'Disease', (200, 214))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('CD83', 'Gene', (183, 187))	('intracellular', 'cellular_component', 'GO:0005622', ('56', '69'))	('activation', 'PosReg', (130, 140))	('MAPK', 'Gene', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('MAPK signaling', 'biological_process', 'GO:0000165', ('148', '162'))	('MAPK', 'Gene', '4216', (148, 152))	('CD83', 'Var', (51, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('TAK1', 'Gene', '6885', (116, 120))	('association', 'Interaction', (99, 110))	('TAK1', 'Gene', (116, 120))	('signaling pathway', 'biological_process', 'GO:0007165', ('153', '170'))
9244	32823589	Cancer is characterized by uncontrolled tumor cell proliferation resulting from the aberrant activity of cell cycle proteins.	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	('cell cycle proteins', 'Protein', (105, 124))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('aberrant activity', 'Var', (84, 101))
9247	32823589	Monoclonal antibodies of anti-CSC markers may be a potential strategy for the treatment of human ovarian cancer (reviewed in).	('Monoclonal', 'Var', (0, 10))	('human ovarian cancer', 'Disease', (91, 111))	('human ovarian cancer', 'Disease', 'MESH:D010051', (91, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))
9250	32823589	Accordingly, there is positive regulation of above cell cycle/stemness factors and negative regulation of MMPs by CD83, partially explaining why CD83 advances the growth proliferation and spheroid formation but limits invasion of ovarian cancer cells.	('CD83', 'Var', (145, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (230, 244))	('formation', 'biological_process', 'GO:0009058', ('197', '206'))	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('growth proliferation', 'CPA', (163, 183))	('MMPs', 'Gene', (106, 110))	('CD83', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cell cycle', 'biological_process', 'GO:0007049', ('51', '61'))	('MMPs', 'Gene', '4312;4316;4319', (106, 110))	('invasion of ovarian cancer', 'Disease', (218, 244))	('limits', 'NegReg', (211, 217))	('advances', 'PosReg', (150, 158))	('invasion of ovarian cancer', 'Disease', 'MESH:D009362', (218, 244))	('spheroid formation', 'CPA', (188, 206))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))
9258	32823589	FOXO1 is known as a tumor suppressor, and dysregulation of FOXO1 is involved in a variety of tumorigenesis.	('involved', 'Reg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('FOXO1', 'Gene', '2308', (59, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('tumor', 'Disease', (93, 98))	('dysregulation', 'Var', (42, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('FOXO1', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
9309	30588099	Distinct expression and prognostic value of members of the epidermal growth factor receptor family in ovarian cancer Increased aberrant expression or activation of the epidermal growth factor receptor (EGFR) family members has been reported in a wide range of cancers, and the EGFR family of tyrosine kinases has emerged as an important therapeutic target in malignancies.	('EGFR', 'Gene', (202, 206))	('EGFR', 'molecular_function', 'GO:0005006', ('202', '206'))	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('EGFR', 'Gene', '1956', (277, 281))	('malignancies', 'Disease', 'MESH:D009369', (359, 371))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('168', '191'))	('malignancies', 'Disease', (359, 371))	('expression', 'MPA', (136, 146))	('aberrant', 'Var', (127, 135))	('EGFR', 'Gene', '1956', (202, 206))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('activation', 'PosReg', (150, 160))	('epidermal growth factor receptor', 'Gene', (59, 91))	('cancers', 'Disease', (260, 267))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('epidermal growth factor receptor', 'Gene', '1956', (59, 91))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('EGFR', 'Gene', (277, 281))	('epidermal growth factor receptor', 'Gene', (168, 200))	('EGFR', 'molecular_function', 'GO:0005006', ('277', '281'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('59', '82'))	('epidermal growth factor receptor', 'Gene', '1956', (168, 200))	('ovarian cancer', 'Disease', (102, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))
9313	30588099	Aberrant EGFR expression and ERBB2/3/4 mRNA levels were associated with OC prognosis.	('ERBB2/3/4', 'Gene', (29, 38))	('ERBB2/3/4', 'Gene', '2064;2065;2066', (29, 38))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (56, 66))	('expression', 'MPA', (14, 24))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('OC', 'Phenotype', 'HP:0100615', (72, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
9322	30588099	In the past three decades, increased aberrant expression or activation of the EGFR family members has been reported in a wide range of cancers, and in some studies, has also been associated with poor prognosis and resistance to therapeutic options.	('aberrant expression', 'Var', (37, 56))	('increased', 'PosReg', (27, 36))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('activation', 'PosReg', (60, 70))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))
9356	30588099	As shown in Table 2, high ERBB2 mRNA expression was correlated to longer OS in serous OC patients.	('mRNA expression', 'MPA', (32, 47))	('OC', 'Phenotype', 'HP:0100615', (86, 88))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('OS', 'Chemical', '-', (73, 75))	('high', 'Var', (21, 25))	('serous OC', 'Disease', (79, 88))	('patients', 'Species', '9606', (89, 97))	('longer OS', 'Disease', (66, 75))
9359	30588099	In endometrioid OC, high ERBB4 mRNA expression level was associated with better OS.	('OC', 'Phenotype', 'HP:0100615', (16, 18))	('OS', 'Chemical', '-', (80, 82))	('ERBB4', 'Gene', '2066', (25, 30))	('endometrioid OC', 'Disease', (3, 18))	('high', 'Var', (20, 24))	('better OS', 'Disease', (73, 82))	('ERBB4', 'Gene', (25, 30))
9362	30588099	As shown in Table 3, high mRNA expression of ERBB4 was associated with better OS and PFS in pathological grade I OC patients.	('OC', 'Phenotype', 'HP:0100615', (113, 115))	('PFS', 'CPA', (85, 88))	('high mRNA', 'Var', (21, 30))	('patients', 'Species', '9606', (116, 124))	('ERBB4', 'Gene', '2066', (45, 50))	('OS', 'Chemical', '-', (78, 80))	('better', 'PosReg', (71, 77))	('ERBB4', 'Gene', (45, 50))
9369	30588099	However, high mRNA expression level of ERBB4 was associated with better PFS in this subgroup.	('ERBB4', 'Gene', (39, 44))	('mRNA expression level', 'MPA', (14, 35))	('PFS', 'Disease', (72, 75))	('better', 'PosReg', (65, 71))	('ERBB4', 'Gene', '2066', (39, 44))	('high', 'Var', (9, 13))
9372	30588099	The percentages of genetic alterations in EGFR family members for OC varied from 2.7% to 5.0% for individual genes (EGFR, 2.7%; ERBB2, 4%; ERBB3, 5%; and ERBB4, 5%) (Figure 4B).	('ERBB2', 'Gene', '2064', (128, 133))	('EGFR', 'Gene', '1956', (42, 46))	('ERBB4', 'Gene', (154, 159))	('EGFR', 'Gene', (42, 46))	('genetic alterations', 'Var', (19, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('OC', 'Phenotype', 'HP:0100615', (66, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('ERBB3', 'Gene', '2065', (139, 144))	('ERBB4', 'Gene', '2066', (154, 159))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('ERBB3', 'Gene', (139, 144))	('ERBB2', 'Gene', (128, 133))
9373	30588099	After cBioPortal, Kaplan-Meier plotter and log-rank test, the results indicated that there are no significant difference in OS and disease-free survival (DFS) in cases with or without alterations in one of the EFGR family genes (P-values, 0.454 and 0.321, respectively) (Figure 4C, D).	('disease-free survival', 'CPA', (131, 152))	('OS', 'Chemical', '-', (124, 126))	('alterations', 'Var', (184, 195))	('EFGR family', 'Gene', (210, 221))
9389	30588099	Accumulative studies have determined that aberrant expression or activation of the EGFR family members is a common feature in human cancers, and the functions of different EGFR family members are associated with tumorigenesis and progression of solid tumors.	('solid tumors', 'Disease', (245, 257))	('tumor', 'Disease', (251, 256))	('EGFR', 'Gene', (172, 176))	('EGFR', 'Gene', (83, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('aberrant', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('solid tumors', 'Disease', 'MESH:D009369', (245, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('progression', 'CPA', (230, 241))	('activation', 'PosReg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', '1956', (172, 176))	('human', 'Species', '9606', (126, 131))	('associated', 'Reg', (196, 206))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('tumor', 'Disease', (212, 217))	('cancers', 'Disease', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))
9393	30588099	Till date, various cancer cells are characterized by EGFR hyper-activation, overexpression, or mutants with dysregulated signaling.	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('hyper-activation', 'Var', (58, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('EGFR', 'Gene', '1956', (53, 57))	('mutants', 'Var', (95, 102))	('EGFR', 'Gene', (53, 57))	('overexpression', 'PosReg', (76, 90))
9395	30588099	Recent studies confirmed that amplification and overexpression of EGFR have been reported in several solid cancers, and a growing body of research interests has focused on the prognostic value and therapeutic potential of EGFR for OC.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('EGFR', 'Gene', '1956', (66, 70))	('OC', 'Phenotype', 'HP:0100615', (231, 233))	('EGFR', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('222', '226'))	('amplification', 'Var', (30, 43))	('EGFR', 'Gene', '1956', (222, 226))	('overexpression', 'PosReg', (48, 62))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('EGFR', 'Gene', (222, 226))	('reported', 'Reg', (81, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
9402	30588099	Previous studies have demonstrated that ERBB2 overexpression or mutations in human malignant cancers correlate with poor prognosis and chemo-resistance.	('malignant cancers', 'Disease', 'MESH:D009369', (83, 100))	('chemo-resistance', 'CPA', (135, 151))	('overexpression', 'PosReg', (46, 60))	('ERBB2', 'Gene', '2064', (40, 45))	('ERBB2', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('malignant cancers', 'Disease', (83, 100))	('mutations', 'Var', (64, 73))	('poor prognosis', 'CPA', (116, 130))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (77, 82))
9406	30588099	Interestingly, high expression of ERBB2 was associated with poor PFS in clinical stage III and IV OC patients and with poor OS and PFS in mutated-TP53-type OC patients.	('high', 'Var', (15, 19))	('patients', 'Species', '9606', (101, 109))	('OC', 'Phenotype', 'HP:0100615', (156, 158))	('TP53', 'Gene', '7157', (146, 150))	('expression', 'MPA', (20, 30))	('OS', 'Chemical', '-', (124, 126))	('OC', 'Phenotype', 'HP:0100615', (98, 100))	('IV OC', 'Disease', (95, 100))	('PFS', 'MPA', (65, 68))	('ERBB2', 'Gene', (34, 39))	('TP53', 'Gene', (146, 150))	('ERBB2', 'Gene', '2064', (34, 39))	('patients', 'Species', '9606', (159, 167))
9410	30588099	ERBB3 has been shown to be overexpressed in several human carcinomas, and somatic mutations have been found scattered throughout the ERBB3 gene in subsets of breast cancers, gastric cancers, and OC.	('carcinomas', 'Disease', 'MESH:D002277', (58, 68))	('OC', 'Phenotype', 'HP:0100615', (195, 197))	('ERBB3', 'Gene', (0, 5))	('overexpressed', 'PosReg', (27, 40))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('ERBB3', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('carcinomas', 'Disease', (58, 68))	('gastric cancers', 'Disease', (174, 189))	('gastric cancers', 'Disease', 'MESH:D013274', (174, 189))	('gastric cancers', 'Phenotype', 'HP:0012126', (174, 189))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('ERBB3', 'Gene', '2065', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancers', 'Disease', 'MESH:D001943', (158, 172))	('breast cancers', 'Disease', (158, 172))	('human', 'Species', '9606', (52, 57))	('mutations', 'Var', (82, 91))	('ERBB3', 'Gene', '2065', (133, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('breast cancers', 'Phenotype', 'HP:0003002', (158, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
9417	30588099	ERBB4 is necessary for the development of the heart, mammary gland, and the central nervous system, and mutations in ERBB4 have been identified in various cancer types including melanoma, lung adenocarcinoma, and medulloblastoma.	('medulloblastoma', 'Disease', 'MESH:D008527', (213, 228))	('ERBB4', 'Gene', '2066', (0, 5))	('medulloblastoma', 'Phenotype', 'HP:0002885', (213, 228))	('ERBB4', 'Gene', (0, 5))	('medulloblastoma', 'Disease', (213, 228))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (188, 207))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('mutations', 'Var', (104, 113))	('ERBB4', 'Gene', '2066', (117, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('ERBB4', 'Gene', (117, 122))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('cancer', 'Disease', (155, 161))	('identified', 'Reg', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung adenocarcinoma', 'Disease', (188, 207))
9420	30588099	Mutations, gene amplification, and protein overexpression of EGFR family members are all linked to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('protein', 'Protein', (35, 42))	('linked', 'Reg', (89, 95))	('gene amplification', 'Var', (11, 29))	('overexpression', 'PosReg', (43, 57))	('carcinogenesis', 'Disease', (99, 113))	('Mutations', 'Var', (0, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
9421	30588099	Mutant EGFR family members cause a gain-of-function phenotype and are involved in tumorigenesis, invasion, and metastasis.	('metastasis', 'CPA', (111, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('7', '11'))	('EGFR', 'Gene', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('gain-of-function', 'PosReg', (35, 51))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('involved', 'Reg', (70, 78))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', (82, 87))	('invasion', 'CPA', (97, 105))	('EGFR', 'Gene', '1956', (7, 11))
9422	30588099	In our current analysis, we found that the percentages of alterations in EGFR family members among OC varied from 2.7% to 5.0% for individual genes, but there is no significant difference in OS and DFS in cases with or without alterations in one of the EFGR family genes (P-values, 0.454 and 0.321, respectively).	('EGFR', 'Gene', '1956', (73, 77))	('OC', 'Phenotype', 'HP:0100615', (99, 101))	('OS', 'Chemical', '-', (191, 193))	('EGFR', 'Gene', (73, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('alterations', 'Var', (58, 69))
9429	30588099	Aberrant EGFR expression and ERBB2/3/4 mRNA levels were all found to be associated with the prognosis of OC.	('ERBB2/3/4', 'Gene', (29, 38))	('ERBB2/3/4', 'Gene', '2064;2065;2066', (29, 38))	('Aberrant', 'Var', (0, 8))	('OC', 'Phenotype', 'HP:0100615', (105, 107))	('associated', 'Reg', (72, 82))	('expression', 'MPA', (14, 24))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
9441	31208449	PD-L1 immunostaining using SP263 was observed in tumor cells as well as intraepithelial and stromal tumor-infiltrating lymphocytes.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('SP263', 'Var', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('SP263', 'Chemical', '-', (27, 32))
9453	31208449	Clinical trials for these drugs showed that the level of PD-L1 immunostaining in tumor cells or tumor-infiltrating lymphocytes determined using specific clones such as 22C3, 28-8, SP263, and SP142, was correlated with drug efficacy and patient survival rate.	('SP263', 'Chemical', '-', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SP263', 'Var', (180, 185))	('SP142', 'Chemical', '-', (191, 196))	('PD-L1', 'Gene', (57, 62))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('SP142', 'Var', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('correlated', 'Reg', (202, 212))	('patient', 'Species', '9606', (236, 243))	('tumor', 'Disease', (81, 86))
9482	31208449	Spanning all histologic types of ovarian epithelial cancers, high PD-L1 expression in stromal tumor-infiltrating lymphocytes, tumor cells, and intraepithelial tumor-infiltrating lymphocytes was detected in 42 (16.9%), 21 (8.5%), and 26 (10.5%) patients of total 248 patients with ovarian epithelial cancers, respectively.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ovarian epithelial cancer', 'Phenotype', 'HP:0025318', (33, 58))	('patients', 'Species', '9606', (244, 252))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (266, 274))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('epithelial cancer', 'Phenotype', 'HP:0031492', (288, 305))	('detected', 'Reg', (194, 202))	('expression', 'MPA', (72, 82))	('epithelial cancer', 'Phenotype', 'HP:0031492', (41, 58))	('ovarian epithelial cancers', 'Phenotype', 'HP:0025318', (33, 59))	('intraepithelial tumor', 'Phenotype', 'HP:0032187', (143, 164))	('ovarian epithelial cancers', 'Phenotype', 'HP:0025318', (280, 306))	('intraepithelial tumor', 'Disease', 'MESH:D002278', (143, 164))	('high', 'Var', (61, 65))	('tumor', 'Disease', (159, 164))	('intraepithelial tumor', 'Disease', (143, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('tumor', 'Disease', (126, 131))	('ovarian epithelial cancers', 'Disease', (33, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian epithelial cancers', 'Disease', (280, 306))	('ovarian epithelial cancer', 'Phenotype', 'HP:0025318', (280, 305))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Disease', (94, 99))	('ovarian epithelial cancers', 'Disease', 'MESH:D000077216', (33, 59))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PD-L1', 'Gene', (66, 71))	('ovarian epithelial cancers', 'Disease', 'MESH:D000077216', (280, 306))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
9486	31208449	In ovarian serous carcinoma, high PD-L1 expression in stromal tumor-infiltrating lymphocytes, tumor cells, and intraepithelial tumor-infiltrating lymphocytes was noted in 29 (20.7%), 13 (9.3%), and 19 (13.6%) patients of total 140 patients with ovarian serous carcinoma, respectively.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('ovarian serous carcinoma', 'Disease', (245, 269))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (245, 269))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ovarian serous carcinoma', 'Disease', (3, 27))	('high', 'Var', (29, 33))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (3, 27))	('intraepithelial tumor', 'Phenotype', 'HP:0032187', (111, 132))	('intraepithelial tumor', 'Disease', 'MESH:D002278', (111, 132))	('patients', 'Species', '9606', (209, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('patients', 'Species', '9606', (231, 239))	('tumor', 'Disease', (127, 132))	('intraepithelial tumor', 'Disease', (111, 132))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (94, 99))	('PD-L1', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
9490	31208449	The results showed that only the high stromal PD-L1 expression group was associated with increased overall survival rate (p-value = 0.02) in all histologic types of ovarian epithelial cancers (Fig.	('ovarian epithelial cancers', 'Disease', 'MESH:D000077216', (165, 191))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('high', 'Var', (33, 37))	('ovarian epithelial cancers', 'Phenotype', 'HP:0025318', (165, 191))	('epithelial cancer', 'Phenotype', 'HP:0031492', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian epithelial cancers', 'Disease', (165, 191))	('increased', 'PosReg', (89, 98))	('ovarian epithelial cancer', 'Phenotype', 'HP:0025318', (165, 190))
9492	31208449	When the same analyses were performed on patients with ovarian serous carcinoma, only high expression of stromal PD-L1 was associated with increased overall survival rate and acted as an independent prognostic factor with residual tumor and tumor stage (Fig.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('tumor', 'Disease', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('increased', 'PosReg', (139, 148))	('PD-L1', 'Gene', (113, 118))	('overall survival', 'MPA', (149, 165))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (55, 79))	('tumor', 'Disease', (231, 236))	('patients', 'Species', '9606', (41, 49))	('high expression', 'Var', (86, 101))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('ovarian serous carcinoma', 'Disease', (55, 79))	('stromal', 'Gene', (105, 112))
9504	31208449	They classified patients with PD-L1 expression in more than one cell as a PD-L1 positive group and showed that PD-L1 positivity in high grade serous carcinoma was a favorable independent prognostic factor for disease-specific survival.	('serous carcinoma', 'Disease', (142, 158))	('serous carcinoma', 'Disease', 'MESH:D018284', (142, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('positivity', 'Var', (117, 127))	('patients', 'Species', '9606', (16, 24))	('PD-L1', 'Gene', (111, 116))
9507	31208449	The results showed that only PD-L1 expression on stromal tumor-infiltrating lymphocytes was significantly associated with overall survival rate and acted as a favorable independent prognostic factor in all histologic types of ovarian cancers and ovarian serous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('ovarian serous carcinoma', 'Disease', (246, 270))	('PD-L1', 'Gene', (29, 34))	('associated', 'Reg', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ovarian cancers', 'Phenotype', 'HP:0100615', (226, 241))	('ovarian cancers', 'Disease', (226, 241))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('ovarian cancers', 'Disease', 'MESH:D010051', (226, 241))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (246, 270))	('tumor', 'Disease', (57, 62))	('expression', 'Var', (35, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (226, 240))
9511	31208449	also showed that the majority of PD-L1-positive immune cells were CD68-positive macrophages and that they improved the overall survival rate and acted as a favorable prognostic factor in hepatocellular carcinoma.	('CD68', 'Gene', (66, 70))	('improved', 'PosReg', (106, 114))	('PD-L1-positive', 'Var', (33, 47))	('CD68', 'Gene', '968', (66, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (187, 211))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (187, 211))	('hepatocellular carcinoma', 'Disease', (187, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
9521	31208449	showed that patients with high PD-L1 expression of tumor-infiltrating lymphocytes but not tumor as determined by immunostaining using the SP142 clone, were more responsive to atezolizumab compared to the patients with low PD-L1 expression of tumor-infiltrating lymphocyte.	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high', 'Var', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('atezolizumab', 'Chemical', 'MESH:C000594389', (175, 187))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (51, 56))	('responsive to atezolizumab', 'MPA', (161, 187))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('SP142', 'Chemical', '-', (138, 143))	('PD-L1', 'Gene', (31, 36))	('more', 'PosReg', (156, 160))
9529	31208449	Actually, high PD-L1 expression on intraepithelial tumor-infiltrating lymphocytes was also associated with increased overall survival with a looser cutoff value in this study and could be a prognostic factor for the response to immunotherapy.	('overall survival', 'MPA', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PD-L1', 'Gene', (15, 20))	('intraepithelial tumor', 'Phenotype', 'HP:0032187', (35, 56))	('intraepithelial tumor', 'Disease', (35, 56))	('increased', 'PosReg', (107, 116))	('intraepithelial tumor', 'Disease', 'MESH:D002278', (35, 56))	('expression', 'MPA', (21, 31))	('high', 'Var', (10, 14))
9536	19461510	In contrast, 10 (90.9%) of 11 cases contained non-synonymous TP53 mutations characteristic of high-grade serous carcinomas.	('mutations', 'Var', (66, 75))	('non-synonymous', 'Var', (46, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('serous carcinomas', 'Disease', 'MESH:D018284', (105, 122))	('serous carcinomas', 'Disease', (105, 122))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
9545	19461510	Molecular genetic studies have demonstrated that low-grade micropapillary serous carcinomas contain either KRAS, BRAF or ERBB2 mutations in approximately two thirds of cases but only rarely harbor TP53 mutations.	('BRAF', 'Gene', '673', (113, 117))	('KRAS', 'Gene', (107, 111))	('BRAF', 'Gene', (113, 117))	('micropapillary serous carcinomas', 'Disease', 'MESH:D018284', (59, 91))	('KRAS', 'Gene', '3845', (107, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('TP53', 'Gene', '7157', (197, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('micropapillary serous carcinomas', 'Disease', (59, 91))	('ERBB2', 'Gene', '2064', (121, 126))	('mutations', 'Var', (127, 136))	('ERBB2', 'Gene', (121, 126))	('TP53', 'Gene', (197, 201))
9547	19461510	High-grade serous carcinomas frequently contain TP53 mutations (>80%) but on rare occasion harbor mutations in KRAS, BRAF and ERBB2 genes.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('TP53', 'Gene', '7157', (48, 52))	('KRAS', 'Gene', (111, 115))	('ERBB2', 'Gene', '2064', (126, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('serous carcinomas', 'Disease', 'MESH:D018284', (11, 28))	('TP53', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (111, 115))	('ERBB2', 'Gene', (126, 131))	('serous carcinomas', 'Disease', (11, 28))	('mutations', 'Var', (53, 62))	('BRAF', 'Gene', '673', (117, 121))	('contain', 'Reg', (40, 47))	('BRAF', 'Gene', (117, 121))
9551	19461510	In this study, we analyzed a small group of serous carcinomas displaying these intermediate features corresponding to what would be classified as moderately differentiated (nuclear grade 2) carcinomas for mutations of TP53, KRAS, BRAF and ERBB2 genes in order to determine whether these tumors displayed a molecular genetic profile that paralleled the genotype of low or high-grade serous carcinomas.	('ERBB2', 'Gene', (239, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('carcinomas', 'Disease', 'MESH:D002277', (51, 61))	('BRAF', 'Gene', '673', (230, 234))	('BRAF', 'Gene', (230, 234))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('serous carcinomas', 'Disease', 'MESH:D018284', (44, 61))	('ERBB2', 'Gene', '2064', (239, 244))	('KRAS', 'Gene', '3845', (224, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (389, 398))	('carcinomas', 'Phenotype', 'HP:0030731', (389, 399))	('carcinomas', 'Disease', 'MESH:D002277', (389, 399))	('carcinomas', 'Phenotype', 'HP:0030731', (190, 200))	('carcinomas', 'Disease', 'MESH:D002277', (190, 200))	('serous carcinomas', 'Disease', 'MESH:D018284', (382, 399))	('TP53', 'Gene', (218, 222))	('KRAS', 'Gene', (224, 228))	('carcinomas', 'Disease', (51, 61))	('mutations', 'Var', (205, 214))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('serous carcinomas', 'Disease', (44, 61))	('carcinomas', 'Disease', (389, 399))	('carcinomas', 'Disease', (190, 200))	('TP53', 'Gene', '7157', (218, 222))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('serous carcinomas', 'Disease', (382, 399))	('tumors', 'Disease', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
9575	19461510	We found no KRAS, BRAF, ERBB2, mutations in any of the grade 2 tumors while 10 of the 11 tumors carried non-synonymous TP53 mutations (Table 3 and 4).	('tumors', 'Disease', (89, 95))	('mutations', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('ERBB2', 'Gene', (24, 29))	('KRAS', 'Gene', (12, 16))	('ERBB2', 'Gene', '2064', (24, 29))	('tumors', 'Disease', (63, 69))	('KRAS', 'Gene', '3845', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('BRAF', 'Gene', '673', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TP53', 'Gene', '7157', (119, 123))	('BRAF', 'Gene', (18, 22))	('TP53', 'Gene', (119, 123))
9581	19461510	Specifically, the aggressive behavior of the tumors, the high proportion of TP53 mutations (90%) and the absence of KRAS, BRAF, ERBB2 mutations are similar to tumors with grade 3 nuclei as compared to tumors with grade 1 nuclei.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('KRAS', 'Gene', (116, 120))	('mutations', 'Var', (81, 90))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('ERBB2', 'Gene', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('ERBB2', 'Gene', '2064', (128, 133))	('aggressive behavior', 'biological_process', 'GO:0002118', ('18', '37'))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('aggressive behavior', 'Phenotype', 'HP:0000718', (18, 37))	('BRAF', 'Gene', '673', (122, 126))	('TP53', 'Gene', '7157', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('BRAF', 'Gene', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('KRAS', 'Gene', '3845', (116, 120))
9590	19461510	Mutations of KRAS, BRAF and ERBB2 which characterize most low-grade serous carcinomas were not identified in any of them.	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('ERBB2', 'Gene', '2064', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Mutations', 'Var', (0, 9))	('ERBB2', 'Gene', (28, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('KRAS', 'Gene', (13, 17))	('serous carcinomas', 'Disease', 'MESH:D018284', (68, 85))	('KRAS', 'Gene', '3845', (13, 17))	('serous carcinomas', 'Disease', (68, 85))
9591	19461510	In contrast, 10 (90%) of 11 tumors contained non-synonymous TP53 mutations characteristic of high-grade serous carcinoma.	('serous carcinoma', 'Disease', 'MESH:D018284', (104, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('non-synonymous', 'Var', (45, 59))	('mutations', 'Var', (65, 74))	('serous carcinoma', 'Disease', (104, 120))
9593	26754874	The chromosome 3q26 OncCassette: a multigenic driver of human cancer Recurrent copy number variations (CNVs) are genetic alterations commonly observed in human tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('human', 'Species', '9606', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('4', '14'))	('human', 'Species', '9606', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Disease', (160, 166))	('copy number', 'Var', (79, 90))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
9594	26754874	One of the most frequent CNVs in human tumors involves copy number gains (CNGs) at chromosome 3q26, which is estimated to occur in >20% of human tumors.	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('CNG', 'Chemical', '-', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('copy number gains', 'Var', (55, 72))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('human', 'Species', '9606', (33, 38))	('human', 'Species', '9606', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (39, 45))
9595	26754874	The high prevalence and frequent occurrence of 3q26 CNG suggest that it drives the biology of tumors harboring this genetic alteration.	('3q26 CNG', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('CNG', 'Chemical', '-', (52, 55))
9600	26754874	Integration of available genetic, genomic, biochemical and functional data demonstrates that SOX2, ECT2, PRKCI and PIK3CA are cooperating oncogenes that function within an integrated cell signaling network that drives a highly aggressive, stem-like phenotype in LSCC tumors harboring 3q26 amplification.	('drives', 'PosReg', (211, 217))	('SCC', 'Gene', '6317', (263, 266))	('SOX2', 'Gene', (93, 97))	('SOX2', 'Gene', '6657', (93, 97))	('PRKCI', 'Gene', '5584', (105, 110))	('PRKCI', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('3q26 amplification', 'Var', (284, 302))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('PIK3CA', 'Gene', (115, 121))	('SCC', 'Gene', (263, 266))	('tumors', 'Disease', (267, 273))	('PIK3CA', 'Gene', '5290', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
9602	26754874	Genomic analysis indicates that the 3q26 OncCassette also operates in other major tumor types that exhibit frequent 3q26 CNGs, including head and neck squamous cell carcinoma (HNSCC), ovarian serous cancer and cervical cancer.	('neck squamous cell carcinoma (HNSCC), ovarian serous cancer', 'Disease', 'MESH:D000077195', (146, 205))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (184, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('neck', 'cellular_component', 'GO:0044326', ('146', '150'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('3q26 CNGs', 'Var', (116, 125))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (137, 174))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cervical cancer', 'Disease', 'MESH:D002583', (210, 225))	('CNG', 'Chemical', '-', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cervical cancer', 'Disease', (210, 225))	('tumor', 'Disease', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
9604	26754874	Cancer is a disease of progressive genetic alterations that conspire to drive a cellular phenotype characterized by uncontrolled growth, aggressive invasive behavior, enhanced survival, evasion of immune surveillance, and resistance to therapeutic interventions.	('enhanced', 'PosReg', (167, 175))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('alterations', 'Var', (43, 54))	('aggressive invasive behavior', 'Phenotype', 'HP:0000718', (137, 165))	('survival', 'CPA', (176, 184))
9606	26754874	In M-type tumors, somatic mutations that either activate oncogenes or inactivate tumor suppressor genes are the predominant genetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('M-type tumors', 'Disease', 'MESH:C566367', (3, 16))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('tumor', 'Disease', (10, 15))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('activate', 'PosReg', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (26, 35))	('oncogenes', 'Protein', (57, 66))	('M-type tumors', 'Disease', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('inactivate', 'NegReg', (70, 80))	('tumor', 'Disease', (81, 86))
9607	26754874	In contrast, in C-type tumors recurrent gene copy number variations (CNVs) are the predominant genetic alterations.	('C-type tumors', 'Disease', 'MESH:D019698', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('C-type tumors', 'Disease', (16, 29))	('gene copy number variations', 'Var', (40, 67))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
9608	26754874	Many of the key oncogenic driver mutations occurring in M-type tumors have been identified, molecularly characterized, functionally validated, and in some cases therapeutically targeted; prominent examples include EGFR, BRAF and PI3KCA mutations that are key drivers of oncogenic phenotypes.	('M-type tumors', 'Disease', (56, 69))	('M-type tumors', 'Disease', 'MESH:C566367', (56, 69))	('PI3', 'Gene', (229, 232))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('EGFR', 'Gene', '1956', (214, 218))	('EGFR', 'molecular_function', 'GO:0005006', ('214', '218'))	('BRAF', 'Gene', '673', (220, 224))	('mutations', 'Var', (236, 245))	('EGFR', 'Gene', (214, 218))	('BRAF', 'Gene', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PI3', 'Gene', '5266', (229, 232))
9609	26754874	Likewise, prevalent recurring inactivating mutations in tumor suppressor genes, including those in TP53, CDKN2A (p16), PTEN and APC, have been well-documented and molecularly characterized.	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('TP53', 'Gene', (99, 103))	('p16', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('APC', 'cellular_component', 'GO:0005680', ('128', '131'))	('CDKN2A', 'Gene', (105, 111))	('tumor', 'Disease', (56, 61))	('CDKN2A', 'Gene', '1029', (105, 111))	('p16', 'Gene', '1029', (113, 116))	('APC', 'Disease', 'MESH:D011125', (128, 131))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('TP53', 'Gene', '7157', (99, 103))	('APC', 'Disease', (128, 131))	('inactivating mutations', 'Var', (30, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
9611	26754874	Comparative Genomic Hybridization (CGH) studies and more recent global genomic initiatives, such as The Cancer Genome Atlas (TCGA) project, have revealed that C-type tumors exhibit frequent and recurrent CNVs, both CNGs, or deletions, often encompassing large chromosomal regions (including, in some cases, entire chromosomal arms).	('C-type tumors', 'Disease', 'MESH:D019698', (159, 172))	('CNG', 'Chemical', '-', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('C-type tumors', 'Disease', (159, 172))	('CNGs', 'Disease', (215, 219))	('CNVs', 'Var', (204, 208))	('deletions', 'Var', (224, 233))	('Cancer', 'Disease', (104, 110))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
9613	26754874	Recurrent CNVs involving loss of specific chromosomal regions are in some cases associated with loss of specific tumor suppressor genes; the most prevalent CNV in human tumors involves loss of chromosome 9p21 containing the prominent tumor suppressor target CDKN2A (reviewed in).	('tumor', 'Disease', (234, 239))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('234', '250'))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('CDKN2A', 'Gene', '1029', (258, 264))	('tumor suppressor', 'biological_process', 'GO:0051726', ('234', '250'))	('chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('loss', 'Var', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('human', 'Species', '9606', (163, 168))	('CDKN2A', 'Gene', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (169, 175))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))
9614	26754874	However, for many recurrent CNVs involving chromosome loss, the relevant tumor suppressor(s) remain to be conclusively identified and functionally validated.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('tumor', 'Disease', (73, 78))	('chromosome loss', 'Var', (43, 58))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))
9617	26754874	Examples of CNGs driving oncogene activation through increased expression include amplification of CMYC at chromosome 8q24, cyclin D1 (CCND1) at chromosome 11q23, and EGFR at chromosome 7p11.	('cyclin D1', 'Gene', '595', (124, 133))	('increased', 'PosReg', (53, 62))	('activation', 'PosReg', (34, 44))	('amplification', 'Var', (82, 95))	('CMYC', 'Gene', (99, 103))	('CCND1', 'Gene', '595', (135, 140))	('cyclin', 'molecular_function', 'GO:0016538', ('124', '130'))	('EGFR', 'Gene', (167, 171))	('CCND1', 'Gene', (135, 140))	('expression', 'MPA', (63, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('oncogene', 'Gene', (25, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('145', '155'))	('cyclin D1', 'Gene', (124, 133))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('CMYC', 'Gene', '4609', (99, 103))	('EGFR', 'Gene', '1956', (167, 171))	('CNG', 'Chemical', '-', (12, 15))
9618	26754874	However, unlike the situation involving specific oncogenic somatic mutations, in which a distinct mutation specifically defines the molecular target of the genetic alteration, the relevant target(s) of many recurrent cancer-associated CNGs are not readily apparent in the context of tumor biology.	('CNG', 'Chemical', '-', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('mutation', 'Var', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('tumor', 'Disease', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
9619	26754874	Herein, we describe the genomic, genetic and functional characterization of the most common CNG event in human tumors, 3q26 amplification.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CNG', 'Chemical', '-', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('3q26 amplification', 'Var', (119, 137))	('human', 'Species', '9606', (105, 110))
9623	26754874	A GISTIC score of +1 or +2 was considered to indicate the presence of significant CNG in that gene.	('TIC', 'Disease', (5, 8))	('TIC', 'Disease', 'None', (5, 8))	('CNG', 'Chemical', '-', (82, 85))	('CNG', 'Var', (82, 85))	('TIC', 'Phenotype', 'HP:0100033', (5, 8))
9630	26754874	Tumors were segregated into two groups; those exhibiting CNG at the locus for the gene being interrogated and those exhibiting no CNG at that locus.	('CNG', 'Chemical', '-', (57, 60))	('CNG', 'Var', (57, 60))	('CNG', 'Chemical', '-', (130, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
9632	26754874	35 of the 50 genes were found to exhibit expression that was significantly higher in tumors harboring CNG at that gene than in those not exhibiting CNG.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('expression', 'MPA', (41, 51))	('higher', 'PosReg', (75, 81))	('CNG', 'Chemical', '-', (102, 105))	('CNG', 'Var', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('CNG', 'Chemical', '-', (148, 151))	('tumors', 'Disease', (85, 91))
9636	26754874	Independent CGH analyses revealed prevalent 3q26 CNVs in cervical (77-90%), esophageal (50-69%), HNSCC (50-91%), LSCC (77-85%), ovarian serous (36-51%) and endometrial serous cancers (50%).	('cervical', 'Disease', (57, 65))	('3q26', 'Gene', (44, 48))	('SCC', 'Gene', '6317', (99, 102))	('endometrial serous cancers', 'Disease', (156, 182))	('SCC', 'Gene', (114, 117))	('esophageal', 'Disease', (76, 86))	('endometrial serous cancers', 'Disease', 'MESH:D016889', (156, 182))	('SCC', 'Gene', '6317', (114, 117))	('ovarian serous', 'Disease', 'MESH:D010051', (128, 142))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ovarian serous', 'Disease', (128, 142))	('SCC', 'Gene', (99, 102))	('CNVs', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
9637	26754874	3q26 CNGs were also observed in 76% of small cell lung cancers (SCLC), though the estimate of prevalence in SCLC must be considered tentative given the extremely small sample size of these studies.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (39, 62))	('3q26', 'Var', (0, 4))	('small cell lung cancers', 'Disease', (39, 62))	('lung cancers', 'Phenotype', 'HP:0100526', (50, 62))	('CNG', 'Chemical', '-', (5, 8))	('SCLC', 'Disease', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('SCLC', 'Disease', 'MESH:D018288', (64, 68))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (39, 61))	('small cell lung cancers', 'Disease', 'MESH:D055752', (39, 62))	('observed', 'Reg', (20, 28))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('SCLC', 'Disease', (108, 112))	('SCLC', 'Disease', 'MESH:D018288', (108, 112))
9641	26754874	Analysis revealed extremely prevalent chromosome 3q26 CNGs in LSCC (85%), esophageal (85%), ovarian serous (85%), cervical (78%), HNSCC (75%) and bladder (60%) cancers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('CNG', 'Chemical', '-', (54, 57))	('bladder', 'Disease', (146, 153))	('chromosome', 'Var', (38, 48))	('SCC', 'Gene', (63, 66))	('cancers', 'Disease', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('SCC', 'Gene', (132, 135))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('cervical', 'Disease', (114, 122))	('CNGs', 'Var', (54, 58))	('SCC', 'Gene', '6317', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian serous', 'Disease', (92, 106))	('prevalent', 'Reg', (28, 37))	('ovarian serous', 'Disease', 'MESH:D010051', (92, 106))	('SCC', 'Gene', '6317', (132, 135))	('esophageal', 'Disease', (74, 84))
9642	26754874	3q26 CNGs were of intermediate prevalence (20-35%) in stomach, lung adenocarcinoma, breast, uterine and liver cancers, and of lower, but significant, prevalence (10-18%) in prostate, pancreatic, sarcoma, glioblastoma, kidney and colorectal cancers (Figure 1).	('glioblastoma', 'Disease', 'MESH:D005909', (204, 216))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('CNG', 'Chemical', '-', (5, 8))	('breast', 'Disease', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('glioblastoma', 'Disease', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('kidney and colorectal cancers', 'Disease', 'MESH:D015179', (218, 247))	('uterine', 'Disease', (92, 99))	('liver cancers', 'Disease', 'MESH:D006528', (104, 117))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('pancreatic', 'Disease', 'MESH:D010195', (183, 193))	('sarcoma', 'Disease', (195, 202))	('3q26', 'Var', (0, 4))	('prostate', 'Disease', (173, 181))	('liver cancers', 'Phenotype', 'HP:0002896', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung adenocarcinoma', 'Disease', (63, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('pancreatic', 'Disease', (183, 193))	('stomach', 'Disease', (54, 61))	('liver cancers', 'Disease', (104, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
9643	26754874	Our analysis confirms earlier CGH studies demonstrating very high frequency 3q26 CNGs in many tumors types (i.e.	('CNG', 'Chemical', '-', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('3q26 CNGs', 'Var', (76, 85))
9647	26754874	Several lines of experimental evidence indicate that 3q26 CNG is an oncogenic driver in affected tumors.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CNG', 'Chemical', '-', (58, 61))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('3q26 CNG', 'Var', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
9648	26754874	First, 3q26 CNGs are observed in precancerous lesions, demonstrating that this is an early event in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('precancerous lesions', 'Disease', 'MESH:D011230', (33, 53))	('precancerous lesions', 'Disease', (33, 53))	('3q26 CNGs', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('CNG', 'Chemical', '-', (12, 15))
9650	26754874	Both the CIS and the subsequent LSCC lesion harbored specific 3q26 CNG, indicating occurrence of this event prior to progression to malignant LSCC.	('SCC', 'Gene', (143, 146))	('SCC', 'Gene', '6317', (33, 36))	('3q26 CNG', 'Var', (62, 70))	('SCC', 'Gene', '6317', (143, 146))	('SCC', 'Gene', (33, 36))	('CNG', 'Chemical', '-', (67, 70))
9651	26754874	Similarly, 3q26 CNGs were found to be present in both early stage pre-invasive lung squamous cell lesions and in invasive LSCCs, albeit at a higher frequency in the more advanced lesions.	('CNG', 'Chemical', '-', (16, 19))	('lung squamous cell lesions', 'Disease', (79, 105))	('pre', 'molecular_function', 'GO:0003904', ('66', '69'))	('3q26', 'Var', (11, 15))	('SCC', 'Gene', '6317', (123, 126))	('squamous cell lesions', 'Phenotype', 'HP:0002860', (84, 105))	('lung squamous cell lesions', 'Disease', 'MESH:D002294', (79, 105))	('SCC', 'Gene', (123, 126))
9653	26754874	Since 3q26 CNGs are detected in pre-invasive lesions that progress to LSCC, 3q26 CNG, and/or increased expression of 3q26 target genes, has been proposed as a biomarker of early pre-cancerous lesions with a high potential for progression to invasive LSCC.	('cancerous lesions', 'Disease', 'MESH:D009062', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CNG', 'Chemical', '-', (81, 84))	('pre', 'molecular_function', 'GO:0003904', ('178', '181'))	('cancerous lesions', 'Disease', (182, 199))	('pre', 'molecular_function', 'GO:0003904', ('32', '35'))	('SCC', 'Gene', '6317', (251, 254))	('increased', 'PosReg', (93, 102))	('expression', 'MPA', (103, 113))	('3q26 CNG', 'Var', (76, 84))	('CNG', 'Chemical', '-', (11, 14))	('SCC', 'Gene', '6317', (71, 74))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', (251, 254))
9654	26754874	Similar findings of 3q26 CNGs in early malignant or preneoplastic lesions have been observed in cervical cancer and HNSCC.	('preneoplastic lesions', 'CPA', (52, 73))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (55, 73))	('SCC', 'Gene', (118, 121))	('CNG', 'Chemical', '-', (25, 28))	('3q26 CNGs', 'Var', (20, 29))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SCC', 'Gene', '6317', (118, 121))	('cervical cancer', 'Disease', (96, 111))
9655	26754874	CGH analysis of normal cervical epithelium, dysplasias (subcategorized as mild, moderate and severe), and stage I invasive carcinomas, revealed that 3q26 CNGs are the most consistent chromosomal aberration occurring in dysplastic cells that progress to invasive cervical carcinoma.	('3q26 CNGs', 'Var', (149, 158))	('dysplastic', 'Disease', 'MESH:D004416', (219, 229))	('carcinomas', 'Disease', (123, 133))	('CNG', 'Chemical', '-', (154, 157))	('dysplastic', 'Disease', (219, 229))	('invasive cervical carcinoma', 'Disease', 'MESH:D002575', (253, 280))	('invasive cervical carcinoma', 'Disease', (253, 280))	('dysplasias', 'Disease', (44, 54))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (183, 205))	('progress', 'PosReg', (241, 249))	('dysplasias', 'Disease', 'MESH:D004476', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('carcinomas', 'Disease', 'MESH:D002277', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
9656	26754874	Likewise, a study of HNSCC found 3q26 CNGs in 3% of normal mucosa, 25% of premalignant tissue, and 56% of invasive HNSCCs, while a second report found frequent 3q CNGs in low grade HNSCCs.	('3q26 CNGs', 'Var', (33, 42))	('SCC', 'Gene', '6317', (23, 26))	('SCC', 'Gene', (117, 120))	('SCC', 'Gene', (183, 186))	('SCC', 'Gene', '6317', (183, 186))	('invasive HNSCCs', 'Disease', 'MESH:D000077195', (106, 121))	('CNG', 'Chemical', '-', (38, 41))	('SCC', 'Gene', '6317', (117, 120))	('SCC', 'Gene', (23, 26))	('CNG', 'Chemical', '-', (163, 166))	('invasive HNSCCs', 'Disease', (106, 121))
9659	26754874	In primary HNSCC tumors, 3q26 CNG is associated with significantly higher rates of tumor recurrence and cancer-related death, and with shorter disease-specific survival when compared to tumors not harboring 3q26 CNG.	('tumor', 'Disease', (83, 88))	('tumors', 'Disease', (17, 23))	('tumor', 'Disease', (186, 191))	('cancer', 'Disease', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (11, 23))	('3q26 CNG', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('HNSCC tumors', 'Disease', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (17, 22))	('higher', 'PosReg', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('disease-specific survival', 'CPA', (143, 168))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('CNG', 'Chemical', '-', (30, 33))	('CNG', 'Chemical', '-', (212, 215))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('shorter', 'NegReg', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
9660	26754874	Consistent with this observation, 3q26 CNG is more frequently observed in high grade ovarian serous tumors when compared to low grade tumors, suggesting an association with disease progression and acquisition of an aggressive phenotype in ovarian cancer.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('ovarian serous tumors', 'Disease', 'MESH:D010051', (85, 106))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('3q26 CNG', 'Var', (34, 42))	('tumors', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('association', 'Interaction', (156, 167))	('ovarian serous tumors', 'Disease', (85, 106))	('observed', 'Reg', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('ovarian cancer', 'Disease', 'MESH:D010051', (239, 253))	('ovarian serous tumors', 'Phenotype', 'HP:0012887', (85, 106))	('tumors', 'Disease', (100, 106))	('CNG', 'Chemical', '-', (39, 42))	('ovarian cancer', 'Disease', (239, 253))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (239, 253))
9661	26754874	Similarly, 3q26 CNGs were found at significantly higher frequencies in metastatic esophageal squamous cell carcinomas when compared to those tumors that did not metastasize.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal squamous cell carcinomas', 'Disease', (82, 117))	('CNG', 'Chemical', '-', (16, 19))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (82, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('higher frequencies', 'PosReg', (49, 67))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (93, 117))	('3q26 CNGs', 'Var', (11, 20))
9662	26754874	These findings support a role for 3q26 CNG in tumor aggressiveness, progression and/or clinical outcome in essentially all of the major tumor types that frequently harbor this alteration.	('3q26 CNG', 'Var', (34, 42))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (46, 66))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CNG', 'Chemical', '-', (39, 42))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor aggressiveness', 'Disease', (46, 66))	('aggressiveness', 'Phenotype', 'HP:0000718', (52, 66))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
9663	26754874	The third line of evidence that 3q26 CNG is an oncogenic driver comes from a genetic analysis of strain-specific differences in susceptibility to tobacco smoke carcinogen-induced LSCC in the mouse.	('CNG', 'Chemical', '-', (37, 40))	('SCC', 'Gene', (180, 183))	('3q26', 'Var', (32, 36))	('mouse', 'Species', '10090', (191, 196))	('SCC', 'Gene', '6317', (180, 183))	('tobacco', 'Species', '4097', (146, 153))
9675	26754874	We further reasoned that the most critical target genes within this group would exhibit expression that is driven by 3q26 CNG in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('3q26 CNG', 'Var', (117, 125))	('CNG', 'Chemical', '-', (122, 125))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (129, 134))	('expression', 'MPA', (88, 98))
9681	26754874	The genomic analysis above indicates that 3q26 CNG drives tumorigenesis by coordinately overexpressing a set of core genes that functionally interact within a signaling network.	('core', 'cellular_component', 'GO:0019013', ('112', '116'))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('3q26 CNG', 'Var', (42, 50))	('CNG', 'Chemical', '-', (47, 50))	('overexpressing', 'PosReg', (88, 102))	('drives', 'PosReg', (51, 57))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
9689	26754874	Likewise, ectopic expression of SOX2 in HNSCC cells promotes "stemness" while SOX2 knockdown (KD) in HNSCC TICs reduces self-renewal, chemoresistance and tumorigenicity, demonstrating a functional role for SOX2 in 3q26 amplified cancers.	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', (154, 159))	('TIC', 'Disease', (107, 110))	('SOX2', 'Gene', '6657', (32, 36))	('SOX2', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('promotes', 'PosReg', (52, 60))	('SCC', 'Gene', '6317', (42, 45))	('KD', 'Disease', 'MESH:C537017', (94, 96))	('TICs', 'Phenotype', 'HP:0100033', (107, 111))	('ectopic expression', 'Var', (10, 28))	('SOX2', 'Gene', (206, 210))	('reduces', 'NegReg', (112, 119))	('SOX2', 'Gene', '6657', (206, 210))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('SCC', 'Gene', (42, 45))	('cancers', 'Disease', (229, 236))	('TIC', 'Phenotype', 'HP:0100033', (107, 110))	('SOX2', 'Gene', '6657', (78, 82))	('SCC', 'Gene', '6317', (103, 106))	('SOX2', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('self-renewal', 'CPA', (120, 132))	('SCC', 'Gene', (103, 106))	('chemoresistance', 'CPA', (134, 149))	('TIC', 'Disease', 'None', (107, 110))
9692	26754874	Gene amplification drives SOX2 expression in lung, esophageal and other squamous cell cancers.	('lung', 'Disease', (45, 49))	('squamous cell cancers', 'Disease', (72, 93))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('drives', 'Reg', (19, 25))	('esophageal', 'Disease', (51, 61))	('Gene amplification', 'Var', (0, 18))	('expression', 'MPA', (31, 41))	('squamous cell cancers', 'Disease', 'MESH:D002294', (72, 93))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('SOX2', 'Gene', '6657', (26, 30))	('SOX2', 'Gene', (26, 30))
9693	26754874	ShRNA-mediated knockdown of SOX2 expression and candidate neighboring genes in 3q26 amplified and non-amplified cancer cell lines revealed that inhibition of SOX2 expression had the largest differential anti-proliferative effect on 3q26 amplified SCC cell lines.	('SOX2', 'Gene', '6657', (28, 32))	('SCC', 'Gene', (247, 250))	('SOX2', 'Gene', (28, 32))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('inhibition', 'Var', (144, 154))	('SCC', 'Gene', '6317', (247, 250))	('anti-proliferative effect', 'CPA', (203, 228))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SOX2', 'Gene', (158, 162))	('SOX2', 'Gene', '6657', (158, 162))
9708	26754874	These findings are consistent with the prevalence of chromosome 3q26 CNGs in LSCCs and the relatively rare occurrence of 3q26 CNGs in LADCs.	('SCC', 'Gene', '6317', (78, 81))	('chromosome 3q26 CNGs', 'Var', (53, 73))	('CNG', 'Chemical', '-', (126, 129))	('CNG', 'Chemical', '-', (69, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('SCC', 'Gene', (78, 81))
9710	26754874	In addition to LSCC, ovarian tumors also show tumor-specific amplification at 3q26.	('ovarian tumors', 'Disease', 'MESH:D010051', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (46, 51))	('SCC', 'Gene', (16, 19))	('amplification', 'Var', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('SCC', 'Gene', '6317', (16, 19))	('ovarian tumors', 'Disease', (21, 35))	('ovarian tumors', 'Phenotype', 'HP:0100615', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
9711	26754874	Ect2 is overexpressed in ovarian tumors harboring ECT2 amplification compared to whole normal ovary indicating that tumor-specific ECT2 amplification also drives Ect2 expression in ovarian tumors.	('amplification', 'Var', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('ECT2', 'Gene', (131, 135))	('ovarian tumors', 'Phenotype', 'HP:0100615', (181, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('expression', 'MPA', (167, 177))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (33, 38))	('ovarian tumors', 'Disease', (25, 39))	('ovarian tumors', 'Disease', 'MESH:D010051', (25, 39))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Ect2', 'Gene', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('ovarian tumors', 'Disease', (181, 195))	('ovarian tumors', 'Disease', 'MESH:D010051', (181, 195))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (116, 121))	('ovarian tumors', 'Phenotype', 'HP:0100615', (25, 39))
9712	26754874	Thus, a major mechanism driving Ect2 expression is tumor-specific amplification of ECT2 as part of the 3q26 amplicon.	('amplification', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('ECT2', 'Gene', (83, 87))	('Ect2', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
9715	26754874	PIK3CA is frequently targeted for oncogenic activation either by somatic mutation or CNG as part of the 3q26 amplicon.	('CNG', 'Chemical', '-', (85, 88))	('PIK3CA', 'Gene', '5290', (0, 6))	('CNG', 'Var', (85, 88))	('PIK3CA', 'Gene', (0, 6))
9716	26754874	PIK3CA is frequently mutated in breast, endometrial, colorectal, urinary tract and ovarian cancers (reviewed in).	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('urinary tract and ovarian cancers', 'Disease', 'MESH:D014571', (65, 98))	('colorectal', 'Disease', (53, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('endometrial', 'Disease', (40, 51))	('PIK3CA', 'Gene', (0, 6))	('ovarian cancers', 'Phenotype', 'HP:0100615', (83, 98))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast', 'Disease', (32, 38))	('mutated', 'Var', (21, 28))	('colorectal', 'Disease', 'MESH:D015179', (53, 63))
9717	26754874	These "hot spot" mutations, H1047R, E545K and E542K, are non-synonymous missense mutations that confer constitutive kinase activity.	('E545K', 'Var', (36, 41))	('E542K', 'Var', (46, 51))	('H1047R', 'Mutation', 'rs121913279', (28, 34))	('constitutive kinase activity', 'MPA', (103, 131))	('E542K', 'Mutation', 'rs121913273', (46, 51))	('H1047R', 'Var', (28, 34))	('E545K', 'Mutation', 'rs104886003', (36, 41))
9718	26754874	Amplification of PIK3CA has been found in primary ovarian tumors and ovarian cancer cell lines, primary cervical tumors and cervical cancer cell lines, HNSCC primary tumors and LSCC.	('SCC', 'Gene', '6317', (154, 157))	('primary ovarian tumors', 'Disease', (42, 64))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SCC', 'Gene', '6317', (178, 181))	('PIK3CA', 'Gene', '5290', (17, 23))	('primary ovarian tumors', 'Disease', 'MESH:D010051', (42, 64))	('SCC', 'Gene', (154, 157))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('primary cervical tumors', 'Disease', 'MESH:D002583', (96, 119))	('HNSCC primary tumors', 'Disease', (152, 172))	('SCC', 'Gene', (178, 181))	('ovarian cancer', 'Disease', (69, 83))	('found', 'Reg', (33, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('cervical cancer', 'Disease', (124, 139))	('cervical cancer', 'Disease', 'MESH:D002583', (124, 139))	('HNSCC primary tumors', 'Disease', 'MESH:D000077195', (152, 172))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('PIK3CA', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cervical tumors', 'Phenotype', 'HP:0030159', (104, 119))	('Amplification', 'Var', (0, 13))	('primary cervical tumors', 'Disease', (96, 119))	('ovarian tumors', 'Phenotype', 'HP:0100615', (50, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))
9721	26754874	CNGs in PIK3CA have been shown to correlate with its mRNA expression in HNSCC cell primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CNGs', 'Var', (0, 4))	('primary tumors', 'Disease', (83, 97))	('primary tumors', 'Disease', 'MESH:D009369', (83, 97))	('CNG', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SCC', 'Gene', (74, 77))	('PIK3CA', 'Gene', (8, 14))	('mRNA expression', 'MPA', (53, 68))	('SCC', 'Gene', '6317', (74, 77))	('PIK3CA', 'Gene', '5290', (8, 14))
9722	26754874	CNGs in PIK3CA are prevalent in thyroid cancer, particularly follicular thyroid carcinoma (FTC) and anaplastic thyroid carcinoma (ATC) sub-types which exhibit 24% and 42% CNG, respectively.	('CNGs', 'Var', (0, 4))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (72, 89))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (111, 128))	('CNG', 'Chemical', '-', (171, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (32, 46))	('follicular thyroid carcinoma', 'Disease', (61, 89))	('PIK3CA', 'Gene', '5290', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (100, 128))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (100, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('thyroid cancer', 'Disease', (32, 46))	('CNG', 'Chemical', '-', (0, 3))	('PIK3CA', 'Gene', (8, 14))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (61, 89))	('prevalent', 'Reg', (19, 28))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (61, 89))	('thyroid cancer', 'Disease', 'MESH:D013964', (32, 46))	('anaplastic thyroid carcinoma', 'Disease', (100, 128))
9723	26754874	Several studies have shown that PIK3CA amplification is associated with overexpression of p110alpha in thyroid tumors.	('PIK3CA', 'Gene', '5290', (32, 38))	('p110alpha', 'Gene', (90, 99))	('p110alpha', 'Gene', '5290', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('amplification', 'Var', (39, 52))	('thyroid tumors', 'Disease', (103, 117))	('thyroid tumors', 'Disease', 'MESH:D013959', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (56, 66))	('overexpression', 'MPA', (72, 86))	('PIK3CA', 'Gene', (32, 38))
9724	26754874	Endometrial tumors with 3q amplification overexpress PIK3CA when compared with unamplified tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Endometrial tumors', 'Disease', 'MESH:D016889', (0, 18))	('PIK3CA', 'Gene', '5290', (53, 59))	('3q amplification', 'Var', (24, 40))	('overexpress', 'PosReg', (41, 52))	('PIK3CA', 'Gene', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('Endometrial tumors', 'Disease', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
9725	26754874	In a separate study, 9 of 15 (60.0%) gastric cancer cell lines and 17 of 55 (30.9%) primary gastric carcinomas harbored PIK3CA amplification, whereas no normal and benign tumor tissues showed abnormal amplification.	('PIK3CA', 'Gene', (120, 126))	('gastric carcinomas', 'Disease', 'MESH:D013274', (92, 110))	('gastric carcinomas', 'Disease', (92, 110))	('gastric cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('PIK3CA', 'Gene', '5290', (120, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('amplification', 'Var', (127, 140))
9726	26754874	In addition, amplification of PIK3CA in gastric tumor cell lines was strongly associated with increased transcript level.	('PIK3CA', 'Gene', (30, 36))	('transcript level', 'MPA', (104, 120))	('increased', 'PosReg', (94, 103))	('PIK3CA', 'Gene', '5290', (30, 36))	('gastric tumor', 'Disease', (40, 53))	('amplification', 'Var', (13, 26))	('gastric tumor', 'Disease', 'MESH:D013274', (40, 53))	('gastric tumor', 'Phenotype', 'HP:0006753', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
9732	26754874	PKCiota expression is predictive of poor outcome in patients with bile duct, lung, ovarian, pancreatic and prostate cancers.	('PKCiota expression', 'Var', (0, 18))	('pancreatic', 'Disease', 'MESH:D010195', (92, 102))	('ovarian', 'Disease', (83, 90))	('ovarian', 'Disease', 'MESH:D010051', (83, 90))	('pancreatic', 'Disease', (92, 102))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('bile duct', 'Disease', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('lung', 'Disease', (77, 81))	('prostate cancers', 'Phenotype', 'HP:0012125', (107, 123))	('patients', 'Species', '9606', (52, 60))
9737	26754874	PRKCI is frequently amplified in NSCLC, and amplification drives PKCiota expression in NSCLC primary tumors and established cell lines.	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('amplification', 'Var', (44, 57))	('PRKCI', 'Gene', (0, 5))	('expression', 'MPA', (73, 83))	('PRKCI', 'Gene', '5584', (0, 5))	('NSCLC', 'Disease', (33, 38))	('NSCLC primary tumors', 'Disease', (87, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('NSCLC primary tumors', 'Disease', 'MESH:D009369', (87, 107))	('PKCiota', 'Gene', (65, 72))
9738	26754874	Disruption of PKCiota signaling blocks transformed growth of NSCLC cell lines with PRKCI amplification, demonstrating that PKCiota is a critical target of 3q26 amplification in NSCLC.	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', (61, 66))	('amplification', 'Var', (89, 102))	('PRKCI', 'Gene', '5584', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('PRKCI', 'Gene', (83, 88))	('Disruption', 'Var', (0, 10))
9739	26754874	PRKCI amplification is associated with lymph node metastases in ESCC, and PKCiota promotes metastasis of ESCC cell lines.	('SCC', 'Gene', (65, 68))	('promotes', 'PosReg', (82, 90))	('SCC', 'Gene', '6317', (106, 109))	('metastases', 'Disease', (50, 60))	('metastasis', 'CPA', (91, 101))	('PRKCI', 'Gene', (0, 5))	('SCC', 'Gene', '6317', (65, 68))	('PRKCI', 'Gene', '5584', (0, 5))	('amplification', 'Var', (6, 19))	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('associated', 'Reg', (23, 33))	('SCC', 'Gene', (106, 109))
9741	26754874	PRKCI is frequently amplified and overexpressed in ovarian serous cancer and PRKCI amplification predicts poor patient survival.	('ovarian serous cancer', 'Disease', 'MESH:D010051', (51, 72))	('PRKCI', 'Gene', '5584', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('poor', 'NegReg', (106, 110))	('PRKCI', 'Gene', (77, 82))	('ovarian serous cancer', 'Disease', (51, 72))	('PRKCI', 'Gene', (0, 5))	('PRKCI', 'Gene', '5584', (0, 5))	('patient', 'Species', '9606', (111, 118))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (51, 72))	('amplification', 'Var', (83, 96))	('overexpressed', 'PosReg', (34, 47))
9744	26754874	As described above, each of the four 3q26 nodal genes, SOX2, ECT2, PIK3CA and PRKCI, have individually been shown to function in the establishment and maintenance of the transformed phenotype of 3q26 driven tumors.	('PIK3CA', 'Gene', '5290', (67, 73))	('SOX2', 'Gene', (55, 59))	('ECT2', 'Gene', (61, 65))	('SOX2', 'Gene', '6657', (55, 59))	('PRKCI', 'Gene', '5584', (78, 83))	('PIK3CA', 'Gene', (67, 73))	('PRKCI', 'Gene', (78, 83))	('function', 'Reg', (117, 125))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('3q26', 'Var', (195, 199))
9745	26754874	It is also quite evident that these genes operate in a tumor environment in which they are coordinately amplified and overexpressed in tumors harboring 3q26 CNGs, demonstrating that these genes are genetically integrated with the oncogenic behavior of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CNG', 'Chemical', '-', (157, 160))	('tumor', 'Disease', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Disease', (55, 60))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('3q26 CNGs', 'Var', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
9749	26754874	SKIL/SNO, which resides at 3q26, was found to be consistently over-expressed in ESCC cell lines and primary tumors that exhibit 3q26 amplification, suggesting that this gene is a potential target of 3q26 amplification.	('SCC', 'Gene', '6317', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SNO', 'Gene', (5, 8))	('primary tumors', 'Disease', (100, 114))	('over-expressed', 'PosReg', (62, 76))	('amplification', 'Var', (133, 146))	('SKIL', 'Gene', (0, 4))	('SNO', 'molecular_function', 'GO:0033784', ('5', '8'))	('primary tumors', 'Disease', 'MESH:D009369', (100, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('3q26', 'Gene', (128, 132))	('SCC', 'Gene', (81, 84))	('SKIL', 'Gene', '6498', (0, 4))	('SNO', 'Gene', '22904', (5, 8))
9755	26754874	Like PKCiota and Par6, RNAi-mediated knockdown of Ect2 in NSCLC cells inhibits Rac1 activation and transformation.	('NSCLC', 'Disease', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('knockdown', 'Var', (37, 46))	('inhibits', 'NegReg', (70, 78))	('Par6', 'Gene', (17, 21))	('Rac1', 'Gene', '5879', (79, 83))	('Ect2', 'Gene', (50, 54))	('Par6', 'Gene', '50855', (17, 21))	('RNAi', 'biological_process', 'GO:0016246', ('23', '27'))	('Rac1', 'Gene', (79, 83))
9767	26754874	This study led us to hypothesize that the oncogenic function of PKCiota is to establish and maintain a TIC phenotype in LSCC tumors harboring 3q26 CNG as well.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('3q26 CNG', 'Var', (142, 150))	('SCC', 'Gene', (121, 124))	('tumors', 'Disease', (125, 131))	('CNG', 'Chemical', '-', (147, 150))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('TIC', 'Phenotype', 'HP:0100033', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('SCC', 'Gene', '6317', (121, 124))	('TIC', 'Disease', 'None', (103, 106))	('TIC', 'Disease', (103, 106))
9776	26754874	The realization that 3q26 CNG drives oncogenesis through coordinated overexpression of biochemically and functionally linked genes presents both challenges and opportunities for therapeutic intervention.	('overexpression', 'PosReg', (69, 83))	('drives', 'PosReg', (30, 36))	('oncogenesis', 'CPA', (37, 48))	('3q26 CNG', 'Var', (21, 29))	('CNG', 'Chemical', '-', (26, 29))	('oncogenesis', 'biological_process', 'GO:0007048', ('37', '48'))
9786	26754874	Our initial clinical experience with these agents has demonstrated proof of principle for PKCiota inhibition using ATM or ANF as a viable therapeutic approach in both LSCC and ovarian serous cancer, tumor types exhibiting frequent 3q26 CNGs.	('tumor', 'Disease', (199, 204))	('SCC', 'Gene', (168, 171))	('CNG', 'Chemical', '-', (236, 239))	('3q26 CNGs', 'Var', (231, 240))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (176, 197))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (176, 197))	('SCC', 'Gene', '6317', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('ovarian serous cancer', 'Disease', (176, 197))	('ANF', 'Chemical', 'MESH:D001310', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('PKCiota', 'Enzyme', (90, 97))
9794	26754874	Further functional characterization of the 3q26 OncCassette holds considerable promise of revealing further opportunities for development of novel combined therapeutic intervention strategies that target unique vulnerabilities of 3q26 CNG driven tumors.	('3q26', 'Var', (230, 234))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('CNG', 'Chemical', '-', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumors', 'Disease', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))
9828	23685873	Additionally, germline mutations in these genes can lead to familial diseases such as the autosomal recessive form of non-syndromic sensorineural deafness which results from a defect in the claudin-14 gene.	('familial diseases', 'Disease', 'MESH:D030342', (60, 77))	('defect', 'Var', (176, 182))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (132, 154))	('non-syndromic sensorineural deafness', 'Disease', (118, 154))	('deafness', 'Phenotype', 'HP:0000365', (146, 154))	('claudin-14', 'Gene', (190, 200))	('claudin-14', 'Gene', '23562', (190, 200))	('familial diseases', 'Disease', (60, 77))	('lead to', 'Reg', (52, 59))	('non-syndromic sensorineural deafness', 'Disease', 'MESH:C537845', (118, 154))	('germline mutations', 'Var', (14, 32))
9830	23685873	Tight junction disruption in premalignant tissues can increase the likelihood of progression to a frankly invasive tumor due to passage of large solutes across epithelial barriers allowing growth factors (usually in luminal fluids in epithelial tissues) to now bind to their growth factor receptors (usually on the baso-lateral surface facing interstitial fluid and the bloodstream) and this interaction may lead to continuous stimulation of premalignant cells.	('bind', 'Interaction', (261, 265))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('progression', 'CPA', (81, 92))	('invasive tumor', 'Disease', 'MESH:D009369', (106, 120))	('lead to', 'Reg', (408, 415))	('invasive tumor', 'Disease', (106, 120))	('Tight junction', 'cellular_component', 'GO:0070160', ('0', '14'))	('disruption', 'Var', (15, 25))	('stimulation', 'PosReg', (427, 438))
9862	23685873	Consistent with this view the expression of claudin-3 and -4 in ovarian epithelial cells is thought to enhance neoplastic cell invasion and has been found to be associated with increased matrix metalloproteinase-2-activity and angiogenic effects.	('matrix metalloproteinase-2', 'Gene', (187, 213))	('matrix metalloproteinase-2', 'Gene', '4313', (187, 213))	('expression', 'Var', (30, 40))	('enhance', 'PosReg', (103, 110))	('increased', 'PosReg', (177, 186))	('neoplastic cell invasion', 'CPA', (111, 135))	('matrix metalloproteinase-2-activity', 'molecular_function', 'GO:0004228', ('187', '222'))	('claudin-3', 'Gene', (44, 53))	('angiogenic effects', 'CPA', (227, 245))
9867	23685873	The mechanism of the increased claudin-3 and-4 expression in ovarian carcinoma is thought to be the result of epigenetic modifications of the claudin promoter regions in the cancer cells resulting in increased cell survival, invasion and motility.	('invasion', 'CPA', (225, 233))	('increased', 'PosReg', (21, 30))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (61, 78))	('motility', 'CPA', (238, 246))	('claudin-3 and-4', 'Gene', (31, 46))	('increased', 'PosReg', (200, 209))	('cell survival', 'CPA', (210, 223))	('cancer', 'Disease', (174, 180))	('claudin-3 and-4', 'Gene', '1365;1364', (31, 46))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (61, 78))	('epigenetic modifications', 'Var', (110, 134))	('ovarian carcinoma', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('expression', 'MPA', (47, 57))
9885	23685873	In this study knockdown of claudin-3 and -4 increased the in vivo growth rate and metastatic potential of the xenografted tumors and reduced expression of these claudin proteins enhanced cell migration and invasion in in vitro assays.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('cell migration', 'biological_process', 'GO:0016477', ('187', '201'))	('enhanced', 'PosReg', (178, 186))	('growth rate', 'CPA', (66, 77))	('invasion', 'CPA', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('expression', 'MPA', (141, 151))	('knockdown', 'Var', (14, 23))	('increased', 'PosReg', (44, 53))	('cell migration', 'CPA', (187, 201))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('reduced', 'NegReg', (133, 140))	('claudin-3', 'Gene', (27, 36))
9886	23685873	study, the loss of either claudin-3 or -4 resulted in the down-regulation of E-cadherin mRNA and protein as well as activation of beta-catenin pathway signaling and as such claudin-3 and -4 may mediate interactions with other cells in vivo that result in reduced growth and metastatic potential through the maintenance of E-cadherin expression and by limiting beta-catenin signaling.	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('E-cadherin', 'Gene', (322, 332))	('limiting', 'NegReg', (351, 359))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('interactions', 'Interaction', (202, 214))	('claudin-3 or -4', 'Gene', '1365;1364', (26, 41))	('beta-catenin', 'Gene', '1499', (360, 372))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (322, 332))	('E-cadherin', 'Gene', '999', (77, 87))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('reduced', 'NegReg', (255, 262))	('claudin-3 or -4', 'Gene', (26, 41))	('expression', 'MPA', (333, 343))	('signaling', 'biological_process', 'GO:0023052', ('373', '382'))	('down-regulation', 'NegReg', (58, 73))	('cadherin', 'molecular_function', 'GO:0008014', ('324', '332'))	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('loss', 'Var', (11, 15))	('activation', 'PosReg', (116, 126))	('beta-catenin', 'Gene', (130, 142))	('beta-catenin', 'Gene', (360, 372))	('beta-catenin', 'Gene', '1499', (130, 142))
9887	23685873	E-cadherin is the major structural protein of the adherens junctions and loss of E-cadherin is declared as a hallmark of the epithelial-to-mesenchymal transition through which it is speculated that cells must pass before becoming metastatic.	('loss', 'Var', (73, 77))	('E-cadherin', 'Gene', (81, 91))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('E-cadherin', 'Gene', '999', (81, 91))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('125', '161'))	('E-cadherin', 'Gene', (0, 10))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('E-cadherin', 'Gene', '999', (0, 10))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))
9890	23685873	Of interest, low-level expression of claudin-3 and claudin-4 in other human solid tumors has also been linked to a mesenchymal pattern and, as such, correlates to an overall poor survival in breast, esophageal, colon and pancreatic carcinoma.	('low-level', 'Var', (13, 22))	('esophageal', 'Disease', (199, 209))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('colon and pancreatic carcinoma', 'Disease', 'MESH:D003110', (211, 241))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('claudin-4', 'Gene', (51, 60))	('claudin-3', 'Gene', (37, 46))	('human', 'Species', '9606', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast', 'Disease', (191, 197))	('mesenchymal pattern', 'CPA', (115, 134))	('solid tumors', 'Disease', (76, 88))	('poor', 'NegReg', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('linked to', 'Reg', (103, 112))	('expression', 'MPA', (23, 33))
9894	23685873	This same group has recently demonstrated in a single cell line that knockdown of claudin-3 and -4 resulted in marked changes in the phenotype of ovarian cells including an increased resistance to cisplatin by regulating the expression of the copper influx transporter CTR1.	('changes', 'Reg', (118, 125))	('CTR1', 'Gene', (269, 273))	('copper influx transporter', 'MPA', (243, 268))	('resistance to cisplatin', 'MPA', (183, 206))	('claudin-3', 'Gene', (82, 91))	('phenotype', 'MPA', (133, 142))	('regulating', 'Reg', (210, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (197, 206))	('increased', 'PosReg', (173, 182))	('copper', 'Chemical', 'MESH:D003300', (243, 249))	('knockdown', 'Var', (69, 78))	('expression', 'MPA', (225, 235))	('CTR1', 'Gene', '799', (269, 273))
9895	23685873	Taken together the results of these latter studies are consistent with the conclusion that the effect of claudin-3/-4 knockdown on cisplatin resistance may be the consequence of promoting an epithelial to mesenchymal transition after the downregulation of the claudin proteins.	('epithelial to mesenchymal transition', 'CPA', (191, 227))	('claudin-3/-4', 'Gene', (105, 117))	('knockdown', 'Var', (118, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('191', '227'))	('cisplatin resistance', 'MPA', (131, 151))	('claudin-3/-4', 'Gene', '100288814;1365;1364', (105, 117))	('promoting', 'PosReg', (178, 187))
9903	23685873	The survival analysis in this study revealed that serous adenocarcinoma patients with high claudin-3 expression had a substantially shorter survival and multivariate analysis showed claudin-3 overexpression to be an independent negative prognostic factor.	('serous adenocarcinoma', 'Disease', (50, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('serous adenocarcinoma', 'Disease', 'MESH:D000230', (50, 71))	('claudin-3', 'Gene', (91, 100))	('shorter', 'NegReg', (132, 139))	('expression', 'MPA', (101, 111))	('survival', 'MPA', (140, 148))	('high', 'Var', (86, 90))	('patients', 'Species', '9606', (72, 80))
9904	23685873	Consistent with these results claudin-3 gene silencing with small interfering RNA has been shown in mouse models to suppress ovarian tumor growth and metastasis.	('small interfering', 'Var', (60, 77))	('silencing', 'NegReg', (45, 54))	('ovarian tumor', 'Phenotype', 'HP:0100615', (125, 138))	('ovarian tumor', 'Disease', 'MESH:D010051', (125, 138))	('mouse', 'Species', '10090', (100, 105))	('RNA', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('gene silencing', 'biological_process', 'GO:0016458', ('40', '54'))	('suppress', 'NegReg', (116, 124))	('ovarian tumor', 'Disease', (125, 138))	('claudin-3 gene', 'Gene', (30, 44))
9925	23685873	These high VEGF levels are theorized to increase local permeability and result in fluid extravasation (third spacing) and thus ascites formation.	('VEGF', 'Gene', (11, 15))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('ascites', 'Disease', 'MESH:D001201', (127, 134))	('ascites', 'Disease', (127, 134))	('ascites', 'Phenotype', 'HP:0001541', (127, 134))	('increase', 'PosReg', (40, 48))	('VEGF', 'Gene', '7422', (11, 15))	('high', 'Var', (6, 10))	('fluid extravasation', 'MPA', (82, 101))	('result in', 'Reg', (72, 81))	('local permeability', 'MPA', (49, 67))
9936	23685873	Only 25%-30% of claudin-5 positive patients were alive at 5 years follow-up compared to 60% of claudin-5 negative patients.	('claudin-5', 'Gene', (16, 25))	('positive', 'Var', (26, 34))	('claudin-5', 'Gene', (95, 104))	('claudin-5', 'Gene', '7122', (16, 25))	('claudin-5', 'Gene', '7122', (95, 104))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (114, 122))
9941	23685873	Consistent with this view, UCI-101, an ovarian cancer cell line highly sensitive to CPE, does not express claudin-3/4 and knockdown of claudin-6 in these cells decreases CPE sensitivity.	('ovarian cancer', 'Disease', 'MESH:D010051', (39, 53))	('ovarian cancer', 'Disease', (39, 53))	('CPE', 'Gene', (170, 173))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('knockdown', 'Var', (122, 131))	('CPE', 'Gene', '10874406', (170, 173))	('decreases', 'NegReg', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CPE', 'Gene', '10874406', (84, 87))	('CPE', 'Gene', (84, 87))	('claudin-6', 'Gene', (135, 144))
9946	23685873	High claudin-7 expression has been associated with a poor response to platinum-based chemotherapy in epithelial ovarian cancer.	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (101, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('response to platinum', 'biological_process', 'GO:0070541', ('58', '78'))	('High', 'Var', (0, 4))	('epithelial ovarian cancer', 'Disease', (101, 126))	('platinum', 'Chemical', 'MESH:D010984', (70, 78))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (101, 126))	('associated', 'Reg', (35, 45))	('claudin-7', 'Gene', '1366', (5, 14))	('claudin-7', 'Gene', (5, 14))	('expression', 'MPA', (15, 25))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))
9951	23685873	The gene for claudin-7 was found to be upregulated in all tumor samples studied and small-interfering RNA-mediated knockdown of claudin-7 in ovarian cancer cells led to significant changes in the expression of other genes as determined by microarrays.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('claudin-7', 'Gene', (13, 22))	('upregulated', 'PosReg', (39, 50))	('claudin-7', 'Gene', '1366', (128, 137))	('expression', 'MPA', (196, 206))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('changes', 'Reg', (181, 188))	('ovarian cancer', 'Phenotype', 'HP:0100615', (141, 155))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('claudin-7', 'Gene', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (141, 155))	('claudin-7', 'Gene', '1366', (13, 22))	('ovarian cancer', 'Disease', (141, 155))	('knockdown', 'Var', (115, 124))
9952	23685873	Analyses of the genes differentially expressed revealed that the genes altered in response to claudin-7 knockdown were associated with pathways implicated in various molecular and cellular functions including cell cycle growth and proliferation, cell death and development.	('cell death', 'CPA', (246, 256))	('claudin-7', 'Gene', '1366', (94, 103))	('development', 'CPA', (261, 272))	('claudin-7', 'Gene', (94, 103))	('proliferation', 'CPA', (231, 244))	('cell cycle', 'biological_process', 'GO:0007049', ('209', '219'))	('cell cycle growth', 'CPA', (209, 226))	('cell death', 'biological_process', 'GO:0008219', ('246', '256'))	('knockdown', 'Var', (104, 113))	('associated', 'Reg', (119, 129))
9958	23685873	In this study claudin-7 was found to be expressed in 69/71 (97.1%) epithelial ovarian cancers but not in normal ovaries (p < 0.001) and high claudin-7 expression in primary tumors correlated with shorter progression-free survival (PFS) of patients and poor sensitivity to platinum based chemotherapy.	('claudin-7', 'Gene', '1366', (141, 150))	('shorter', 'NegReg', (196, 203))	('epithelial ovarian cancers', 'Disease', (67, 93))	('high', 'Var', (136, 140))	('progression-free survival', 'CPA', (204, 229))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('platinum', 'Chemical', 'MESH:D010984', (272, 280))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('claudin-7', 'Gene', (14, 23))	('claudin-7', 'Gene', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (67, 93))	('tumors', 'Disease', (173, 179))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (151, 161))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('ovarian cancers', 'Phenotype', 'HP:0100615', (78, 93))	('patients', 'Species', '9606', (239, 247))	('claudin-7', 'Gene', '1366', (14, 23))
10004	23685873	Cytotoxicity of up to 100% was observed 72 h after gene transfer and was restricted to claudin-3 and -4 expressing tumor lines.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Cytotoxicity', 'Disease', (0, 12))	('gene', 'Var', (51, 55))	('tumor', 'Disease', (115, 120))	('Cytotoxicity', 'Disease', 'MESH:D064420', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
10040	32169072	Our lab previously demonstrated that phosphorylation of PHB at Y259 (phospho-PHBY259) and T258 (phospho-PHBT258) in the lipid raft of the plasma membrane activates Raf-1, which subsequently activates ERK and promotes cancer development.	('activates', 'PosReg', (190, 199))	('phosphorylation', 'Var', (37, 52))	('ERK', 'Protein', (200, 203))	('PHBY259', 'Chemical', '-', (77, 84))	('ERK', 'molecular_function', 'GO:0004707', ('200', '203'))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('lipid', 'Chemical', 'MESH:D008055', (120, 125))	('PHBT258', 'Chemical', '-', (104, 111))	('T258', 'Var', (90, 94))	('Raf-1', 'Gene', (164, 169))	('activates', 'PosReg', (154, 163))	('PHB', 'Gene', (56, 59))	('promotes', 'PosReg', (208, 216))	('Raf-1', 'Gene', '5894', (164, 169))	('plasma membrane', 'cellular_component', 'GO:0005886', ('138', '153'))	('cancer', 'Disease', (217, 223))	('lipid raft', 'cellular_component', 'GO:0045121', ('120', '130'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
10044	32169072	There is a positive correlation between c-Kit and phospho-PHBY259 in advanced serous ovarian carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('serous ovarian carcinoma', 'Disease', (78, 102))	('PHBY259', 'Chemical', '-', (58, 65))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (78, 102))	('phospho-PHBY259', 'Var', (50, 65))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (85, 102))	('c-Kit', 'Protein', (40, 45))
10045	32169072	Phosphorylation of PHB by c-Kit promotes ovarian cancer stem cell survival and proliferation through activation of not only the beta-catenin signaling pathway but also the Notch3 signaling pathway.	('ovarian cancer', 'Disease', (41, 55))	('proliferation', 'CPA', (79, 92))	('PHB', 'Gene', (19, 22))	('beta-catenin', 'Gene', (128, 140))	('c-Kit', 'Gene', (26, 31))	('Phosphorylation', 'Var', (0, 15))	('activation', 'PosReg', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('beta-catenin', 'Gene', '1499', (128, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('signaling pathway', 'biological_process', 'GO:0007165', ('179', '196'))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Notch3 signaling pathway', 'Pathway', (172, 196))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('promotes', 'PosReg', (32, 40))
10047	32169072	Chloroquine diphosphate (S4157, Selleckchem) was dissolved in double-distilled H2O to produce a 50 mM stock solution and used to treat cells at 25 muMu for 24 h. MG132 (M7449, MilliporeSigma) was dissolved in DMSO to produce a 10 mM stock solution and used to treat cells at 20 muMu for 7 h. Primary antibodies against the following antigens were used in western blot analysis: c-Kit (3074, Cell Signaling Technology, Danvers, MA, USA), PHB (GTX101105, GeneTex, Irvine, CA, USA), phospho-PHBY259 (11,587, SAB; Signalway Antibody, College Park, MD, USA), phospho-PHBT258 (11,588, SAB; Signalway Antibody), caveolin 1 (GTX100205, GeneTex), clathrin heavy chain (2410, Cell Signaling Technology), E-cadherin (20874-1-AP, Proteintech, Chicago, IL, USA), N-cadherin (GTX127345, GeneTex), ZEB1 (GTX105278, GeneTex), Notch3 (5276, Cell Signaling Technology), PBX1 (GTX113242, GeneTex), beta-catenin (GTX101435, GeneTex), ABCG2 (GTX100437, GeneTex) and beta-actin (E1C605, EnoGene, Nanjing, China).	('PHBT258', 'Chemical', '-', (562, 569))	('PBX1', 'Gene', (852, 856))	('cadherin', 'molecular_function', 'GO:0008014', ('696', '704'))	('N-cadherin', 'Gene', (750, 760))	('N-cadherin', 'Gene', '1000', (750, 760))	('beta-actin', 'Gene', '728378', (945, 955))	('E1C605', 'Var', (957, 963))	('caveolin 1', 'Gene', '857', (605, 615))	('clathrin heavy chain', 'Gene', '1213', (638, 658))	('PBX1', 'Gene', '5087', (852, 856))	('MG132', 'Chemical', 'MESH:C072553', (162, 167))	('cadherin', 'molecular_function', 'GO:0008014', ('752', '760'))	('GTX101435', 'Var', (893, 902))	('ZEB1', 'Gene', (783, 787))	('E-cadherin', 'Gene', (694, 704))	('E-cadherin', 'Gene', '999', (694, 704))	('beta-catenin', 'Gene', (879, 891))	('ABCG2', 'Gene', (914, 919))	('clathrin heavy chain', 'Gene', (638, 658))	('beta-catenin', 'Gene', '1499', (879, 891))	('PHBY259', 'Chemical', '-', (488, 495))	('ABCG2', 'Gene', '9429', (914, 919))	('Signaling', 'biological_process', 'GO:0023052', ('396', '405'))	('GTX100437', 'Var', (921, 930))	('Signaling', 'biological_process', 'GO:0023052', ('829', '838'))	('caveolin 1', 'Gene', (605, 615))	('beta-actin', 'Gene', (945, 955))	('Signaling', 'biological_process', 'GO:0023052', ('671', '680'))	('ZEB1', 'Gene', '6935', (783, 787))
10082	32169072	Human ovarian cancer tissue microarray (TMA) slides OV807 and OV803b were purchased from US Biomax (Rockville, MD, USA).	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (6, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (6, 20))	('OV803b', 'Var', (62, 68))	('ovarian cancer', 'Disease', (6, 20))
10084	32169072	Here, we selected normal ovarian tissues from OV807 and serous-type ovarian carcinoma from OV803b for analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('serous-type ovarian carcinoma', 'Disease', 'MESH:D010051', (56, 85))	('OV803b', 'Var', (91, 97))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (68, 85))	('serous-type ovarian carcinoma', 'Disease', (56, 85))
10099	32169072	According to the MS/MS spectrum, we found that tyrosine 259 of PHB was indeed phosphorylated by c-Kit (Suppl.	('tyrosine 259', 'Var', (47, 59))	('c-Kit', 'Protein', (96, 101))	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('PHB', 'Gene', (63, 66))
10104	32169072	Furthermore, both plasma membrane-associated PHB and abnormal c-Kit expression have been demonstrated to be associated with cancer invasiveness.	('cancer invasiveness', 'Disease', 'MESH:D009362', (124, 143))	('cancer invasiveness', 'Disease', (124, 143))	('expression', 'MPA', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('c-Kit', 'Protein', (62, 67))	('associated', 'Reg', (108, 118))	('abnormal', 'Var', (53, 61))	('plasma membrane', 'cellular_component', 'GO:0005886', ('18', '33'))
10113	32169072	The expression levels of c-Kit, phospho-PHBY259 and phospho-PHBT258 in the KURAMOCHI lipid raft domain were higher than those in the SKOV3 lipid raft domain (Fig.	('expression levels', 'MPA', (4, 21))	('lipid', 'Chemical', 'MESH:D008055', (85, 90))	('phospho-PHBY259', 'Var', (32, 47))	('lipid raft', 'cellular_component', 'GO:0045121', ('139', '149'))	('c-Kit', 'Protein', (25, 30))	('phospho-PHBT258', 'Var', (52, 67))	('PHBY259', 'Chemical', '-', (40, 47))	('PHBT258', 'Chemical', '-', (60, 67))	('lipid', 'Chemical', 'MESH:D008055', (139, 144))	('lipid raft', 'cellular_component', 'GO:0045121', ('85', '95'))	('higher', 'PosReg', (108, 114))
10115	32169072	3c) but also increased phospho-PHBY259, phospho-PHBT258, and PHB expression in the lipid raft domain (Fig.	('lipid raft', 'cellular_component', 'GO:0045121', ('83', '93'))	('PHB', 'Gene', (61, 64))	('lipid', 'Chemical', 'MESH:D008055', (83, 88))	('PHBY259', 'Chemical', '-', (31, 38))	('PHBT258', 'Chemical', '-', (48, 55))	('expression', 'MPA', (65, 75))	('phospho-PHBT258', 'Var', (40, 55))	('phospho-PHBY259', 'MPA', (23, 38))	('increased', 'PosReg', (13, 22))
10120	32169072	SKOV3 cells expressing green fluorescent protein and luciferase (SKOV3GL) were used as parental cells in this murine ascitic model to generate several generations of metastatic phenotypes of SKOV3, namely, SKOV3GL-G1, SKOV3GL-G2, SKOV3GL-G3 and SKOV3GL-G4 (Fig.	('ascitic', 'Disease', (117, 124))	('GL', 'Chemical', 'MESH:C015905', (70, 72))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('metastatic', 'CPA', (166, 176))	('SKOV3GL-G1', 'Var', (206, 216))	('SKOV3GL-G2', 'Var', (218, 228))	('GL', 'Chemical', 'MESH:C015905', (250, 252))	('GL', 'Chemical', 'MESH:C015905', (211, 213))	('GL', 'Chemical', 'MESH:C015905', (235, 237))	('ascitic', 'Disease', 'MESH:D001201', (117, 124))	('GL', 'Chemical', 'MESH:C015905', (223, 225))	('SKOV3GL-G4', 'Var', (245, 255))	('murine', 'Species', '10090', (110, 116))
10121	32169072	Migration ability significantly increased in SKOV3GL-G3 and SKOV3GL-G4 cells compared to other SKOV3 cells (Fig.	('SKOV3GL-G3', 'Var', (45, 55))	('GL', 'Chemical', 'MESH:C015905', (50, 52))	('Migration ability', 'CPA', (0, 17))	('increased', 'PosReg', (32, 41))	('GL', 'Chemical', 'MESH:C015905', (65, 67))
10123	32169072	As phospho-PHB at Y259 and T258 in the cell membrane correlated with the invasiveness of cervical and lung cancer, we then examined the expression of phospho-PHB in SKOV3GL-G1 to -G4 cells.	('cell membrane', 'cellular_component', 'GO:0005886', ('39', '52'))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('correlated', 'Reg', (53, 63))	('lung cancer', 'Disease', (102, 113))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('T258', 'Var', (27, 31))
10124	32169072	The levels of phospho-PHBY259, phospho-PHBT258, and PHB in the lipid raft domain of the plasma membrane gradually increased from SKOV3GL to SKOV3GL-G4 cells (Fig.	('PHBY259', 'Chemical', '-', (22, 29))	('phospho-PHBT258', 'Var', (31, 46))	('lipid', 'Chemical', 'MESH:D008055', (63, 68))	('GL', 'Chemical', 'MESH:C015905', (145, 147))	('increased', 'PosReg', (114, 123))	('GL', 'Chemical', 'MESH:C015905', (134, 136))	('PHB', 'Gene', (52, 55))	('plasma membrane', 'cellular_component', 'GO:0005886', ('88', '103'))	('PHBT258', 'Chemical', '-', (39, 46))	('lipid raft', 'cellular_component', 'GO:0045121', ('63', '73'))
10127	32169072	Moreover, knockdown of c-Kit in SKOV3GL-G4 cells reduced phospho-PHBY259, phospho-PHBT258, PHB, and Notch3 (FL & NTM) protein expression (Fig.	('c-Kit', 'Gene', (23, 28))	('reduced', 'NegReg', (49, 56))	('phospho-PHBY259', 'MPA', (57, 72))	('Notch3', 'Gene', (100, 106))	('PHBT258', 'Chemical', '-', (82, 89))	('PHBY259', 'Chemical', '-', (65, 72))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('PHB', 'MPA', (91, 94))	('knockdown', 'Var', (10, 19))	('phospho-PHBT258', 'MPA', (74, 89))
10130	32169072	Moreover, SKOV3GL-G4 spheroids expressed higher levels of the stem cell markers Oct4, Nanog and SOX2 than did SKOV3GL parental cells (Fig.	('Oct4', 'MPA', (80, 84))	('GL', 'Chemical', 'MESH:C015905', (115, 117))	('levels of', 'MPA', (48, 57))	('GL', 'Chemical', 'MESH:C015905', (15, 17))	('higher', 'PosReg', (41, 47))	('SOX2', 'MPA', (96, 100))	('SKOV3GL-G4', 'Var', (10, 20))	('Nanog', 'MPA', (86, 91))
10132	32169072	Respective subcutaneous injections of the same amount of sphere cells derived from SKOV3GL and SKOV3GL-G4 into the right flank and left flank of female nude mice showed that SKOV3GL-G4 cells formed tumors more easily than SKOV3GL cells, as indicated by bioluminescence imaging quantification (Fig.	('nude mice', 'Species', '10090', (152, 161))	('GL', 'Chemical', 'MESH:C015905', (100, 102))	('SKOV3GL-G4', 'Var', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('GL', 'Chemical', 'MESH:C015905', (88, 90))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Disease', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('bioluminescence', 'biological_process', 'GO:0008218', ('253', '268'))	('GL', 'Chemical', 'MESH:C015905', (179, 181))	('GL', 'Chemical', 'MESH:C015905', (227, 229))
10139	32169072	Transfection of SKOV3 cells with the pD-PHBWT-HA plasmid that expressed exogenous PHB and phospho-PHB in the membrane raft increased Notch3 (FL & NTM) and PBX1 protein expression, whereas transfection with the mutant pD-PHBY259F-HA plasmid did not (Fig.	('increased', 'PosReg', (123, 132))	('phospho-PHB', 'Var', (90, 101))	('Notch3', 'Protein', (133, 139))	('protein', 'MPA', (160, 167))	('PBX1', 'Gene', '5087', (155, 159))	('and', 'Gene', (151, 154))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('membrane raft', 'cellular_component', 'GO:0045121', ('109', '122'))	('PHBY259', 'Chemical', '-', (220, 227))	('PBX1', 'Gene', (155, 159))
10141	32169072	Interestingly, transfection with pD-PHBY259F-HA in SKOV3_c-Kit or SKOV3GL-G4 cells suppressed stemness-related protein expression regardless of c-Kit overexpression in these cells (Fig.	('PHBY259', 'Chemical', '-', (36, 43))	('pD-PHBY259F-HA', 'Var', (33, 47))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('stemness-related protein expression', 'MPA', (94, 129))	('suppressed', 'NegReg', (83, 93))
10146	32169072	Notch3 protein was stable over a course of 24 h in SKOV3 cells transfected with pD-PHBWT-HA, whereas the stability of Notch3 was significantly decreased in raft-phospho-PHBY259-depleted cells (Fig.	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('decreased', 'NegReg', (143, 152))	('pD-PHBWT-HA', 'Var', (80, 91))	('PHBY259', 'Chemical', '-', (169, 176))	('stability', 'MPA', (105, 114))
10149	32169072	Moreover, cells expressing wild-type raft-PHB protein or Y259F mutant raft-PHB protein were subjected to a coimmunoprecipitation assay.	('Y259F', 'Mutation', 'p.Y259F', (57, 62))	('raft-PHB', 'Gene', (70, 78))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('Y259F', 'Var', (57, 62))
10153	32169072	Our results showed that the levels of beta-catenin and ABCG2 in SKOV3_c-Kit cells were higher than those in control cells (SKOV3_vector) (Fig.	('levels', 'MPA', (28, 34))	('beta-catenin', 'Gene', (38, 50))	('ABCG2', 'Gene', (55, 60))	('beta-catenin', 'Gene', '1499', (38, 50))	('SKOV3_c-Kit', 'Var', (64, 75))	('ABCG2', 'Gene', '9429', (55, 60))	('higher', 'PosReg', (87, 93))
10154	32169072	To examine whether this effect of c-Kit was dependent on phospho-PHB, SKOV3 cells were transfected with pD-PHBWT-HA and pD-PHBY259F-HA plasmids.	('pD-PHBWT-HA', 'Var', (104, 115))	('pD-PHBY259F-HA', 'Var', (120, 134))	('PHBY259', 'Chemical', '-', (123, 130))
10156	32169072	In comparison, suppression of phospho-PHBY259 by transfection with pD-PHBY259F-HA in c-Kit-overexpressing tumor cells, such as SKOV3_c-Kit, SKOV3GL-G4 or KURAMOCHI cells, reduced the levels of beta-catenin and ABCG2 (Fig.	('Y259F', 'Mutation', 'p.Y259F', (73, 78))	('ABCG2', 'Gene', (210, 215))	('beta-catenin', 'Gene', (193, 205))	('PHBY259', 'Chemical', '-', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('pD-PHBY259F-HA', 'Var', (67, 81))	('ABCG2', 'Gene', '9429', (210, 215))	('PHBY259', 'Chemical', '-', (38, 45))	('suppression', 'NegReg', (15, 26))	('beta-catenin', 'Gene', '1499', (193, 205))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('reduced', 'NegReg', (171, 178))
10158	32169072	To determine the effects of phospho-PHBY259 on CSC phenotypes and tumorigenicity, SKOV3_c-Kit and SKOV3GL-G4 cells were transfected with pD-PHBY259F-HA and empty vector control.	('PHBY259', 'Chemical', '-', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PHBY259', 'Chemical', '-', (140, 147))	('tumor', 'Disease', (66, 71))	('pD-PHBY259F-HA', 'Var', (137, 151))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
10160	32169072	Since chemoresistance is a hallmark of CSCs, we then evaluated whether changes in phospho-PHBY259 expression in the membrane raft can affect the responses of ovarian cancer cells to carboplatin, a chemotherapeutic drug commonly used in treating ovarian cancer patients.	('membrane raft', 'cellular_component', 'GO:0045121', ('116', '129'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('changes', 'Var', (71, 78))	('ovarian cancer', 'Disease', (245, 259))	('carboplatin', 'Chemical', 'MESH:D016190', (182, 193))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('responses', 'MPA', (145, 154))	('patients', 'Species', '9606', (260, 268))	('PHBY259', 'Chemical', '-', (90, 97))	('affect', 'Reg', (134, 140))	('ovarian cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ovarian cancer', 'Phenotype', 'HP:0100615', (245, 259))	('ovarian cancer', 'Disease', 'MESH:D010051', (245, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
10162	32169072	On the other hand, downregulating phospho-PHBY259 by transfection of SKOV3_c-Kit and SKOV3GL-G4 cells with mutant pD-PHBY259F-HA reduced their resistance to carboplatin, as indicated by a decrease in IC50 (Fig.	('mutant', 'Var', (107, 113))	('resistance to carboplatin', 'MPA', (143, 168))	('decrease', 'NegReg', (188, 196))	('carboplatin', 'Chemical', 'MESH:D016190', (157, 168))	('downregulating', 'NegReg', (19, 33))	('PHBY259', 'Chemical', '-', (42, 49))	('IC50', 'MPA', (200, 204))	('PHBY259', 'Chemical', '-', (117, 124))	('pD-PHBY259F-HA', 'Gene', (114, 128))	('reduced', 'NegReg', (129, 136))
10163	32169072	To further examine whether raft-phospho-PHBY259 is required for CSC tumor formation in vivo, SKOV3GL-G4 sphere cells were transfected with pD-PHBY259F-HA or empty vector and then subcutaneously injected into the right or left flank of nude mice.	('CSC tumor', 'Disease', 'MESH:D009369', (64, 73))	('nude mice', 'Species', '10090', (235, 244))	('CSC tumor', 'Disease', (64, 73))	('pD-PHBY259F-HA', 'Var', (139, 153))	('PHBY259', 'Chemical', '-', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Y259F', 'Mutation', 'p.Y259F', (145, 150))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('PHBY259', 'Chemical', '-', (40, 47))
10169	32169072	After 31 days, the tumor volume and tumor weight formed in the pD-PHBY259F-HA combination with carboplatin group were significantly reduced compared with those in the empty vector control group and pD-PHBY259F-HA group.	('Y259F', 'Mutation', 'p.Y259F', (204, 209))	('pD-PHBY259F-HA', 'Var', (63, 77))	('carboplatin', 'Chemical', 'MESH:D016190', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('PHBY259', 'Chemical', '-', (66, 73))	('reduced', 'NegReg', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (19, 24))	('Y259F', 'Mutation', 'p.Y259F', (69, 74))	('PHBY259', 'Chemical', '-', (201, 208))	('tumor', 'Disease', (36, 41))
10170	32169072	Taken together, these results indicate that the c-Kit-mediated increase in phospho-PHBY259 plays an important role in the stemness, tumorigenicity and drug resistance of ovarian cancer in vitro and in vivo.	('ovarian cancer', 'Disease', (170, 184))	('increase', 'PosReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('drug resistance', 'CPA', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('phospho-PHBY259', 'Var', (75, 90))	('stemness', 'CPA', (122, 130))	('drug resistance', 'Phenotype', 'HP:0020174', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('drug resistance', 'biological_process', 'GO:0042493', ('151', '166'))	('PHBY259', 'Chemical', '-', (83, 90))	('tumor', 'Disease', (132, 137))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('ovarian cancer', 'Disease', 'MESH:D010051', (170, 184))	('drug resistance', 'biological_process', 'GO:0009315', ('151', '166'))
10175	32169072	Of note, since c-Kit is a tyrosine kinase, it can phosphorylate not only tyrosine 259 on PHB but also other tyrosine residues, such as tyrosine 114 and 249.	('tyrosine', 'Chemical', 'MESH:D014443', (108, 116))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('tyrosine', 'Chemical', 'MESH:D014443', (26, 34))	('tyrosine', 'Chemical', 'MESH:D014443', (135, 143))	('tyrosine 114', 'Var', (135, 147))	('tyrosine 259', 'Var', (73, 85))	('phosphorylate', 'MPA', (50, 63))	('c-Kit', 'Gene', (15, 20))
10180	32169072	5, we clearly demonstrated that c-Kit upregulates phospho-PHBY259 in the lipid raft domain to interact with the membrane-tethered Notch3 fragment and enhance the Notch3:PBX1 signaling pathway in ovarian cancer cells.	('c-Kit', 'Gene', (32, 37))	('PHBY259', 'Chemical', '-', (58, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (195, 209))	('ovarian cancer', 'Disease', 'MESH:D010051', (195, 209))	('interact', 'Interaction', (94, 102))	('phospho-PHBY259', 'Var', (50, 65))	('upregulates', 'PosReg', (38, 49))	('PBX1', 'Gene', '5087', (169, 173))	('signaling pathway', 'biological_process', 'GO:0007165', ('174', '191'))	('membrane', 'cellular_component', 'GO:0016020', ('112', '120'))	('lipid', 'Chemical', 'MESH:D008055', (73, 78))	('ovarian cancer', 'Disease', (195, 209))	('lipid raft', 'cellular_component', 'GO:0045121', ('73', '83'))	('enhance', 'PosReg', (150, 157))	('PBX1', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
10182	32169072	In this study, we found that PHB was associated with c-Kit and Notch3 in the lipid raft domain.	('Notch3', 'Var', (63, 69))	('associated', 'Reg', (37, 47))	('lipid raft', 'cellular_component', 'GO:0045121', ('77', '87'))	('c-Kit', 'Protein', (53, 58))	('lipid', 'Chemical', 'MESH:D008055', (77, 82))	('PHB', 'Gene', (29, 32))
10192	32169072	Here, we found that phospho-PHBY259 in the membrane raft domain acted as an adaptor molecule to initiate and transmit stemness and drug resistance signals in ovarian cancer cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('drug resistance', 'biological_process', 'GO:0009315', ('131', '146'))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('PHBY259', 'Chemical', '-', (28, 35))	('drug resistance', 'Phenotype', 'HP:0020174', (131, 146))	('drug resistance', 'biological_process', 'GO:0042493', ('131', '146'))	('ovarian cancer', 'Disease', (158, 172))	('phospho-PHBY259', 'Var', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('initiate', 'PosReg', (96, 104))	('membrane raft', 'cellular_component', 'GO:0045121', ('43', '56'))
10246	31823088	The risk of serous PPC increases in patients with hereditary breast and ovarian cancer syndrome or BRCA1 or BRCA2 mutations.	('BRCA2', 'Gene', (108, 113))	('patients', 'Species', '9606', (36, 44))	('BRCA1', 'Gene', (99, 104))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('BRCA2', 'Gene', '675', (108, 113))	('serous PPC increases', 'Disease', (12, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('serous PPC increases', 'Disease', 'MESH:D018284', (12, 32))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (50, 95))	('BRCA1', 'Gene', '672', (99, 104))	('PPC', 'Phenotype', 'HP:0030406', (19, 22))
10249	31823088	Besides BRCA 1/2 mutations, these high-grade serous carcinomas arise from STICs with subsequent inactivating mutations in TP53.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('TP53', 'Gene', (122, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('inactivating mutations', 'Var', (96, 118))	('serous carcinomas', 'Disease', (45, 62))	('arise', 'Reg', (63, 68))	('BRCA 1/2', 'Gene', '672;675', (8, 16))	('serous carcinomas', 'Disease', 'MESH:D018297', (45, 62))	('TP53', 'Gene', '7157', (122, 126))	('mutations', 'Var', (17, 26))	('BRCA 1/2', 'Gene', (8, 16))
10261	27887627	Disregulation of Eph/ephrin signaling has been implicated in oncogenesis and tumor progression.	('oncogenesis', 'CPA', (61, 72))	('Disregulation', 'Var', (0, 13))	('ephrin', 'molecular_function', 'GO:0046875', ('21', '27'))	('Eph', 'Gene', (17, 20))	('ephrin', 'molecular_function', 'GO:0005106', ('21', '27'))	('implicated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('ephrin', 'Gene', (21, 27))	('oncogenesis', 'biological_process', 'GO:0007048', ('61', '72'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('ephrin', 'Gene', '2041', (21, 27))	('tumor', 'Disease', (77, 82))	('Eph', 'Gene', '2041', (17, 20))
10312	27887627	Using the follow-up data of the 53 patients in conjunction with the results from the EphA5 IHC staining experiments, we showed that patients with high expression had a significantly favorable overall survival (OS) compared to patients with negative or weak expression (P = 0.004, Fig.	('patients', 'Species', '9606', (226, 234))	('overall survival', 'MPA', (192, 208))	('patients', 'Species', '9606', (35, 43))	('favorable', 'PosReg', (182, 191))	('patients', 'Species', '9606', (132, 140))	('high expression', 'Var', (146, 161))
10323	27887627	Identification of hypermethylated EphA5 DNA in ovarian serous carcinoma will improve our understanding of the mechanisms leading to the downregulation of EphA5 expression in ovarian tumorigenesis and can serve as valuable diagnostic marker.	('expression', 'MPA', (160, 170))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (47, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('tumor', 'Disease', (182, 187))	('downregulation', 'NegReg', (136, 150))	('EphA5', 'Gene', (154, 159))	('ovarian serous carcinoma', 'Disease', (47, 71))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('EphA5', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('hypermethylated', 'Var', (18, 33))
10396	28139510	The tumor suppressor PHLPP, located at 18q21.33, can directly dephosphorylate ser473 in the hydrophobic group of Akt, thus negatively regulating Akt and its downstream targets.	('tumor', 'Disease', (4, 9))	('ser473', 'Chemical', '-', (78, 84))	('Akt', 'Gene', (145, 148))	('regulating', 'Reg', (134, 144))	('ser473', 'Var', (78, 84))	('Akt', 'Gene', '207', (113, 116))	('ser', 'cellular_component', 'GO:0005790', ('78', '81'))	('Akt', 'Gene', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('Akt', 'Gene', '207', (145, 148))	('negatively', 'NegReg', (123, 133))	('PHLPP', 'Gene', '23239', (21, 26))	('PHLPP', 'Gene', (21, 26))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))
10400	28139510	The PHLPP-positive expression rate was decreased gradually from normal ovarian tissue to benign tumors to borderline tumors to low-grade adenocarcinomas, indicating that loss of PHLPP expression may be associated with the initiation of ovarian serous adenocarcinoma development, whereas no significant difference was observed between high-grade and low-grade tumors.	('PHLPP', 'Gene', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('tumors', 'Disease', 'MESH:D009369', (359, 365))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('initiation of ovarian serous adenocarcinoma', 'Disease', (222, 265))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('expression', 'MPA', (19, 29))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('decreased', 'NegReg', (39, 48))	('adenocarcinomas', 'Disease', 'MESH:D000230', (137, 152))	('adenocarcinomas', 'Disease', (137, 152))	('initiation of ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (222, 265))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('tumors', 'Phenotype', 'HP:0002664', (359, 365))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('loss', 'Var', (170, 174))	('benign tumors to borderline tumors', 'Disease', (89, 123))	('PHLPP', 'Gene', '23239', (4, 9))	('PHLPP', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('associated', 'Reg', (202, 212))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (359, 365))	('PHLPP', 'Gene', '23239', (178, 183))	('benign tumors to borderline tumors', 'Disease', 'MESH:D009369', (89, 123))
10417	28139510	Too strong or too weak homologous recombination will result in genome instability and DNA damage, and the consequent gene loss, loss of heterozygosity, and/or genetic translocation are important causes of tumorigenesis and tumor progression.	('gene', 'MPA', (117, 121))	('homologous recombination', 'biological_process', 'GO:0035825', ('23', '47'))	('genetic', 'CPA', (159, 166))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('causes', 'Reg', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('result in', 'Reg', (53, 62))	('genome instability', 'MPA', (63, 81))	('homologous recombination', 'Var', (23, 47))	('loss of heterozygosity', 'Var', (128, 150))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('loss', 'NegReg', (122, 126))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('DNA damage', 'MPA', (86, 96))
10423	28139510	Particularly, the positive rate of low-grade tumors was significantly higher than that in benign tumors and normal oviducts.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('low-grade', 'Var', (35, 44))	('benign tumors', 'Disease', (90, 103))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('higher', 'PosReg', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('benign tumors', 'Disease', 'MESH:D009369', (90, 103))
10428	28139510	In other words, we found that high-grade tumor patients with high expression of RAD51 had a lower survival rate and poor prognosis, indicating that RAD51 may be a prognostic factor in high-grade ovarian serous adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('high expression', 'Var', (61, 76))	('tumor', 'Disease', (41, 46))	('RAD51', 'Gene', (148, 153))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (195, 224))	('patients', 'Species', '9606', (47, 55))	('RAD51', 'Gene', (80, 85))	('RAD51', 'Gene', '5888', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('RAD51', 'Gene', '5888', (80, 85))	('ovarian serous adenocarcinoma', 'Disease', (195, 224))	('RAD', 'biological_process', 'GO:1990116', ('148', '151'))	('RAD', 'biological_process', 'GO:1990116', ('80', '83'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('lower', 'NegReg', (92, 97))	('survival rate', 'CPA', (98, 111))
10526	20015364	In contrast, nullipotent 2102Ep EC cells can avoid differentiation during tumourigenesis, generating pure embryonal carcinomas, tumours consisting almost entirely of undifferentiated stem cells.	('EC', 'Phenotype', 'HP:0002898', (32, 34))	('tumours', 'Disease', (128, 135))	('embryonal carcinomas', 'Phenotype', 'HP:0002898', (106, 126))	('pure', 'molecular_function', 'GO:0034023', ('101', '105'))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('embryonal carcinomas', 'Disease', (106, 126))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (106, 125))	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('nullipotent', 'Var', (13, 24))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', (128, 134))	('embryonal carcinomas', 'Disease', 'MESH:D018236', (106, 126))	('2102Ep EC', 'CellLine', 'CVCL:C522', (25, 34))
10538	20015364	Aberrant expression of cancer-specific 'onco-miRs' is associated with the targeting of oncogenes and tumour suppressors in several different malignancies.	('Aberrant', 'Var', (0, 8))	('tumour', 'Disease', (101, 107))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('malignancies', 'Disease', 'MESH:D009369', (141, 153))	('expression', 'MPA', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('malignancies', 'Disease', (141, 153))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
10544	20015364	While the malignancy-associated miR-17/92 cluster is prominent in both undifferentiated cell types, 2102Ep-specificity was associated with clustering to malignancy-associated chromosomes 19 and 14.	('miR-17/92', 'Gene', '407975;406952;407047', (32, 41))	('miR-17/92', 'Gene', (32, 41))	('malignancy', 'Disease', 'MESH:D009369', (10, 20))	('malignancy', 'Disease', (10, 20))	('malignancy', 'Disease', 'MESH:D009369', (153, 163))	('malignancy', 'Disease', (153, 163))	('2102Ep-specificity', 'Var', (100, 118))
10563	20015364	4 (NTera2) and 3 (2102Ep) of these miRNAs are members of the miR-17/92 family (miRs-17-5p, -19a, -19b, -106b and -25), a cluster associated with many malignancies.	('miRs-17-5p', 'Var', (79, 89))	('miR-17/92', 'Gene', (61, 70))	('malignancies', 'Disease', (150, 162))	('NTera2', 'CellLine', 'CVCL:0034', (3, 9))	('miR-17/92', 'Gene', '407975;406952;407047', (61, 70))	('malignancies', 'Disease', 'MESH:D009369', (150, 162))
10567	20015364	Additionally, 7 of these miRNAs are members of the miR-17/92 cluster (miRs-17-5p, -17-3p, 18a*, -18b, -92, -106a and-363) and were up to 6,000 fold higher expressed in undifferentiated 2102Ep cells (Tables 1, 2).	('miRs-17-5p', 'Var', (70, 80))	('miR-17/92', 'Gene', '407975;406952;407047', (51, 60))	('miR-17/92', 'Gene', (51, 60))	('higher', 'PosReg', (148, 154))
10592	20015364	4 members of the miR-17/92 family are downregulated (miRs-17-3p, -18a*, -20a and -92) but only 1 upregulated (miR-18a) in OSC samples.	('OSC', 'Disease', (122, 125))	('miR-18a', 'Gene', (110, 117))	('miRs-17-3p', 'Var', (53, 63))	('miR-17/92', 'Gene', '407975;406952;407047', (17, 26))	('downregulated', 'NegReg', (38, 51))	('miR-17/92', 'Gene', (17, 26))	('OSC', 'molecular_function', 'GO:0000250', ('122', '125'))	('miR-18a', 'Gene', '406953', (110, 117))
10600	20015364	All but 2 (miRs-202* and -216) top downregulated tumour-specific miRNAs were detected in 2102Ep cells.	('miRs-202* and -216', 'Var', (11, 29))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', (49, 55))
10624	20015364	For example, differentiation regulators are targeted by miRs-199a (Bmp2) and -206 (MyoD).	('miRs-199a', 'Var', (56, 65))	('Bmp2', 'Gene', '650', (67, 71))	('MyoD', 'Gene', '4654', (83, 87))	('MyoD', 'Gene', (83, 87))	('targeted', 'Reg', (44, 52))	('Bmp2', 'Gene', (67, 71))
10631	20015364	In contrast, 2102Ep cells generate a malignant tumour in vivo that is almost completely EC cells, while melanoma contains a high proportion of stem cells.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('2102Ep', 'Var', (13, 19))	('EC', 'Phenotype', 'HP:0002898', (88, 90))	('malignant tumour', 'Disease', 'MESH:D009369', (37, 53))	('malignant tumour', 'Disease', (37, 53))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
10704	28507579	The proliferative activity of neoplasms can be estimated by many methods; for example, argyrophilic nucleolar organizer regions (AgNORs) is one of them.	('neoplasms', 'Disease', (30, 39))	('neoplasm', 'Phenotype', 'HP:0002664', (30, 38))	('neoplasms', 'Phenotype', 'HP:0002664', (30, 39))	('argyrophilic', 'Var', (87, 99))	('neoplasms', 'Disease', 'MESH:D009369', (30, 39))
10756	19798417	MicroRNA Profiling of BRCA1/2 Mutation-Carrying and Non-Mutation-Carrying High-Grade Serous Carcinomas of Ovary MicroRNAs (miRNA) are 20~25 nucleotide non-coding RNAs that inhibit the translation of targeted mRNA, and they have been implicated in the development of human malignancies.	('translation', 'MPA', (184, 195))	('miR', 'Gene', '220972', (123, 126))	('translation', 'biological_process', 'GO:0006412', ('184', '195'))	('miR', 'Gene', (123, 126))	('Carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('Serous Carcinomas', 'Disease', 'MESH:D018284', (85, 102))	('BRCA1', 'Gene', '672', (22, 27))	('Carcinomas of Ovary', 'Phenotype', 'HP:0100615', (92, 111))	('Serous Carcinomas', 'Disease', (85, 102))	('inhibit', 'NegReg', (172, 179))	('implicated', 'Reg', (233, 243))	('Mutation-Carrying', 'Var', (30, 47))	('BRCA1', 'Gene', (22, 27))	('Serous Carcinomas of Ovary', 'Phenotype', 'HP:0012887', (85, 111))	('human', 'Species', '9606', (266, 271))
10759	19798417	Global miRNA expression profiling was performed on a series of 33 high grade serous carcinomas, characterized with respect to BRCA1/2 status (mutation, epigenetic silencing with loss of expression or normal), and with clinical follow-up, together with 2 low grade serous carcinomas, 2 serous borderline tumors, and 3 normal fallopian tube samples, using miRNA microarrays (328 human miRNA).	('BRCA1/2', 'Gene', '672;675', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('human', 'Species', '9606', (377, 382))	('miR', 'Gene', (354, 357))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('carcinomas', 'Phenotype', 'HP:0030731', (271, 281))	('serous carcinomas', 'Disease', 'MESH:D018284', (264, 281))	('serous borderline tumors', 'Disease', 'MESH:D012569', (285, 309))	('miR', 'Gene', '220972', (383, 386))	('loss', 'NegReg', (178, 182))	('serous carcinomas', 'Disease', (77, 94))	('miR', 'Gene', '220972', (7, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('mutation', 'Var', (142, 150))	('serous borderline tumors', 'Disease', (285, 309))	('BRCA1/2', 'Gene', (126, 133))	('miR', 'Gene', (383, 386))	('miR', 'Gene', (7, 10))	('serous carcinomas', 'Disease', (264, 281))	('epigenetic silencing', 'Var', (152, 172))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('miR', 'Gene', '220972', (354, 357))	('serous carcinomas', 'Disease', 'MESH:D018284', (77, 94))
10765	19798417	High grade serous ovarian carcinomas with and without BRCA1/2 abnormalities demonstrate very similar miRNA expression profiles.	('rat', 'Species', '10116', (83, 86))	('abnormalities', 'Var', (62, 75))	('serous ovarian carcinomas', 'Disease', (11, 36))	('BRCA1/2', 'Gene', '672;675', (54, 61))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (11, 36))	('BRCA1/2', 'Gene', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (18, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (11, 36))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (18, 35))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
10769	19798417	Women with germ-line BRCA1 or BRCA2 mutation are at increased risk of developing ovarian serous carcinoma while a subset of non-familial ovarian serous carcinomas also demonstrate loss of BRCA1 through either somatic mutations or promoter methylation with transcriptional silencing.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('BRCA1', 'Gene', '672', (21, 26))	('Women', 'Species', '9606', (0, 5))	('BRCA1', 'Gene', (188, 193))	('loss', 'NegReg', (180, 184))	('BRCA1', 'Gene', (21, 26))	('BRCA2', 'Gene', '675', (30, 35))	('rat', 'Species', '10116', (175, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('ovarian serous carcinoma', 'Disease', (81, 105))	('methylation', 'biological_process', 'GO:0032259', ('239', '250'))	('BRCA2', 'Gene', (30, 35))	('non-familial ovarian serous carcinomas', 'Disease', 'MESH:D010051', (124, 162))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (81, 105))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (137, 161))	('non-familial ovarian serous carcinomas', 'Disease', (124, 162))	('promoter methylation', 'Var', (230, 250))	('BRCA1', 'Gene', '672', (188, 193))	('mutation', 'Var', (36, 44))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (137, 162))
10770	19798417	More than half of high grade serous carcinomas overall possess some abnormality of BRCA1 or BRCA2.	('abnormality', 'Var', (68, 79))	('BRCA1', 'Gene', '672', (83, 88))	('BRCA2', 'Gene', (92, 97))	('BRCA1', 'Gene', (83, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('BRCA2', 'Gene', '675', (92, 97))	('serous carcinomas', 'Disease', 'MESH:D018284', (29, 46))	('serous carcinomas', 'Disease', (29, 46))
10771	19798417	The majority of high grade serous carcinomas also show mutation and/or loss of functional p53.	('p53', 'Gene', (90, 93))	('p53', 'Gene', '7157', (90, 93))	('serous carcinomas', 'Disease', 'MESH:D018284', (27, 44))	('serous carcinomas', 'Disease', (27, 44))	('loss', 'NegReg', (71, 75))	('mutation', 'Var', (55, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))
10777	19798417	There is also emerging evidence to suggest that quantitative and qualitative (mutational) changes in miRNA and their target binding sites can promote the development and progression of tumors.	('development', 'CPA', (154, 165))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('binding', 'Interaction', (124, 131))	('promote', 'PosReg', (142, 149))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('changes', 'Var', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
10781	19798417	Firstly, it is unclear whether high grade serous carcinomas with BRCA1/2 mutation differ in their miRNA expression patterns from non-mutation carrying cases; it is plausible that etiologically relevant differences in miRNA expression may be present.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('serous carcinomas', 'Disease', 'MESH:D018284', (42, 59))	('BRCA1/2', 'Gene', '672;675', (65, 72))	('serous carcinomas', 'Disease', (42, 59))	('miR', 'Gene', '220972', (217, 220))	('miR', 'Gene', (217, 220))	('mutation', 'Var', (73, 81))	('BRCA1/2', 'Gene', (65, 72))
10790	19798417	Among the 33 high grade serous carcinomas, 9 cases carry mutations in BRCA1 (8 germline and 1 somatic), 3 have mutations in BRCA2 (2 germline and 1 somatic), 10 show BRCA1 epigenetic loss (promoter methylation and decreased expression), while 11 cases show no demonstrable BRCA1 or BRCA2 loss (no mutation in BRCA1/BRCA2 and no promoter methylation with decreased BRCA1 mRNA or protein).	('BRCA2', 'Gene', '675', (315, 320))	('BRCA2', 'Gene', '675', (282, 287))	('protein', 'cellular_component', 'GO:0003675', ('378', '385'))	('serous carcinomas', 'Disease', (24, 41))	('BRCA2', 'Gene', '675', (124, 129))	('mutations', 'Var', (57, 66))	('BRCA1', 'Gene', '672', (273, 278))	('promoter methylation', 'MPA', (328, 348))	('mutations', 'Var', (111, 120))	('BRCA1', 'Gene', (273, 278))	('expression', 'MPA', (224, 234))	('decreased', 'NegReg', (214, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('BRCA1', 'Gene', '672', (309, 314))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('BRCA1', 'Gene', (309, 314))	('BRCA1', 'Gene', '672', (166, 171))	('serous carcinomas', 'Disease', 'MESH:D018284', (24, 41))	('methylation', 'biological_process', 'GO:0032259', ('337', '348'))	('BRCA1', 'Gene', (166, 171))	('BRCA2', 'Gene', (315, 320))	('BRCA2', 'Gene', (282, 287))	('BRCA1', 'Gene', '672', (364, 369))	('BRCA2', 'Gene', (124, 129))	('BRCA1', 'Gene', '672', (70, 75))	('BRCA1', 'Gene', (364, 369))	('methylation', 'biological_process', 'GO:0032259', ('198', '209'))	('BRCA1', 'Gene', (70, 75))	('decreased', 'NegReg', (354, 363))	('epigenetic', 'Var', (172, 182))
10803	19798417	Significance analysis of microarrays (SAM) was performed to identify differences in miRNA expression between groups of high grade serous carcinomas with mutations in BRCA1, with mutations in BRCA2, with BRCA1 epigenetic loss and with no demonstrable BRCA1 or BRCA2 loss.	('miR', 'Gene', '220972', (84, 87))	('mutations', 'Var', (153, 162))	('BRCA1', 'Gene', (203, 208))	('BRCA1', 'Gene', '672', (250, 255))	('epigenetic', 'Var', (209, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('BRCA1', 'Gene', (250, 255))	('serous carcinomas', 'Disease', 'MESH:D018284', (130, 147))	('miR', 'Gene', (84, 87))	('BRCA2', 'Gene', (191, 196))	('BRCA2', 'Gene', (259, 264))	('BRCA1', 'Gene', '672', (166, 171))	('BRCA1', 'Gene', (166, 171))	('BRCA2', 'Gene', '675', (191, 196))	('differences', 'Reg', (69, 80))	('serous carcinomas', 'Disease', (130, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('BRCA2', 'Gene', '675', (259, 264))	('mutations', 'Var', (178, 187))	('BRCA1', 'Gene', '672', (203, 208))
10809	19798417	The fimbriated end of the fallopian tube is the site where primary tubal carcinoma occurs in BRCA mutation carriers.	('carriers', 'Reg', (107, 115))	('mutation', 'Var', (98, 106))	('BRCA', 'Gene', '672', (93, 97))	('BRCA', 'Gene', (93, 97))	('occurs', 'Reg', (83, 89))	('tubal carcinoma', 'Disease', (67, 82))	('tubal carcinoma', 'Disease', 'MESH:D011274', (67, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
10818	19798417	Similarly, among high grade serous carcinomas, the expression of miR-29a and miR-29b were also significantly higher in group with BRCA1/2 abnormalities compared to group lacking demonstrable BRCA1/2 abnormalities.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('miR-29b', 'Gene', (77, 84))	('abnormalities', 'Var', (138, 151))	('miR-29a', 'Gene', (65, 72))	('miR-29a', 'Gene', '407021', (65, 72))	('higher', 'PosReg', (109, 115))	('BRCA1/2', 'Gene', (191, 198))	('serous carcinomas', 'Disease', 'MESH:D018284', (28, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('serous carcinomas', 'Disease', (28, 45))	('expression', 'MPA', (51, 61))	('BRCA1/2', 'Gene', (130, 137))	('miR-29b', 'Gene', '407024', (77, 84))	('BRCA1/2', 'Gene', '672;675', (191, 198))	('BRCA1/2', 'Gene', '672;675', (130, 137))
10829	19798417	17 of the 20 cases of high grade serous carcinomas demonstrated p53 mutation with 11 missense mutation, 3 frame-shift mutation, 2 in frame deletion and one intronic deletion (Table S5).	('mutation', 'Var', (68, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('frame-shift mutation', 'Var', (106, 126))	('rat', 'Species', '10116', (58, 61))	('serous carcinomas', 'Disease', 'MESH:D018284', (33, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('p53', 'Gene', (64, 67))	('serous carcinomas', 'Disease', (33, 50))	('missense mutation', 'Var', (85, 102))	('p53', 'Gene', '7157', (64, 67))
10832	19798417	During oncogenesis, dysregulated or dysfunctional miRNA can result in increased translation of oncoprotein(s) and/or decreased translation of tumor suppressor protein(s).	('dysregulated', 'Var', (20, 32))	('miR', 'Gene', '220972', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('miR', 'Gene', (50, 53))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('142', '158'))	('oncogenesis', 'biological_process', 'GO:0007048', ('7', '18'))	('increased', 'PosReg', (70, 79))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('tumor', 'Disease', (142, 147))	('decreased', 'NegReg', (117, 126))	('translation', 'MPA', (127, 138))	('translation', 'biological_process', 'GO:0006412', ('80', '91'))	('dysfunctional', 'Disease', 'MESH:D006331', (36, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('142', '158'))	('dysfunctional', 'Disease', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('translation', 'biological_process', 'GO:0006412', ('127', '138'))	('translation', 'MPA', (80, 91))
10837	19798417	BRCA1 or BRCA2 abnormalities are present in most high grade serous carcinomas and lead to chromosomal instability through loss of the ability to repair double strand breaks by homologous recombination.	('serous carcinomas', 'Disease', (60, 77))	('ability', 'MPA', (134, 141))	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', (9, 14))	('lead to', 'Reg', (82, 89))	('abnormalities', 'Var', (15, 28))	('BRCA2', 'Gene', '675', (9, 14))	('chromosomal instability', 'Phenotype', 'HP:0040012', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('homologous recombination', 'biological_process', 'GO:0035825', ('176', '200'))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('loss', 'NegReg', (122, 126))	('BRCA1', 'Gene', '672', (0, 5))	('serous carcinomas', 'Disease', 'MESH:D018284', (60, 77))	('chromosomal instability', 'MPA', (90, 113))
10839	19798417	Notably, high grade serous carcinomas carrying BRCA1 mutation were previously reported by us to possess lower PTEN mRNA levels, and PTEN is a among the top 20 predicted targets of miR-29a.	('miR-29a', 'Gene', '407021', (180, 187))	('PTEN', 'Gene', '5728', (110, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('BRCA1', 'Gene', (47, 52))	('PTEN', 'Gene', (132, 136))	('mutation', 'Var', (53, 61))	('serous carcinomas', 'Disease', 'MESH:D018284', (20, 37))	('PTEN', 'Gene', '5728', (132, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('serous carcinomas', 'Disease', (20, 37))	('lower', 'NegReg', (104, 109))	('miR-29a', 'Gene', (180, 187))	('BRCA1', 'Gene', '672', (47, 52))	('PTEN', 'Gene', (110, 114))
10841	19798417	It is important to note that only a small number of BRCA2 mutation-carrying tumors was included in this series and our analysis will likely not reveal subtle differences in this group compared to other groups.	('BRCA2', 'Gene', (52, 57))	('mutation-carrying', 'Var', (58, 75))	('BRCA2', 'Gene', '675', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
10842	19798417	Overall, very few differences were observed in the comparisons between high grade serous carcinomas possessing mutation in BRCA1, mutation in BRCA2, epigenetic silencing of BRCA1, and no demonstrable loss in BRCA1.	('BRCA1', 'Gene', '672', (123, 128))	('BRCA2', 'Gene', (142, 147))	('BRCA1', 'Gene', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('serous carcinomas', 'Disease', 'MESH:D018284', (82, 99))	('mutation', 'Var', (130, 138))	('BRCA1', 'Gene', (123, 128))	('BRCA2', 'Gene', '675', (142, 147))	('BRCA1', 'Gene', '672', (173, 178))	('BRCA1', 'Gene', '672', (208, 213))	('epigenetic silencing', 'Var', (149, 169))	('mutation', 'Var', (111, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('BRCA1', 'Gene', (208, 213))	('serous carcinomas', 'Disease', (82, 99))
10848	19798417	In patients with familial BRCA1/2 mutation, intraepithelial carcinoma at the tubal fimbriae represents the most common earliest evidence of neoplasm in prophylactic bilateral salpingooophrectomy specimens, whereas analogous precursor lesion on ovarian surface has not been consistently demonstrated despite careful examination.	('intraepithelial carcinoma', 'Disease', (44, 69))	('neoplasm', 'Disease', 'MESH:D009369', (140, 148))	('mutation', 'Var', (34, 42))	('fimbriae', 'cellular_component', 'GO:0009289', ('83', '91'))	('BRCA1/2', 'Gene', (26, 33))	('patients', 'Species', '9606', (3, 11))	('intraepithelial carcinoma', 'Disease', 'MESH:D002278', (44, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('BRCA1/2', 'Gene', '672;675', (26, 33))	('neoplasm', 'Disease', (140, 148))	('rat', 'Species', '10116', (293, 296))	('neoplasm', 'Phenotype', 'HP:0002664', (140, 148))
10869	19798417	Mutation of p53 is common in high grade ovarian serous carcinomas, occurring in about 80% of cases based on the literature and in the current series (85%), while low grade ovarian serous carcinomas and serous borderline tumors typically do not possess p53 mutation.	('ovarian serous carcinomas', 'Disease', (40, 65))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (40, 65))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('p53', 'Gene', '7157', (252, 255))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (172, 197))	('ovarian serous carcinomas and serous borderline tumors', 'Disease', 'MESH:D018284', (172, 226))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (252, 255))	('rat', 'Species', '10116', (116, 119))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (40, 65))	('ovarian serous carcinomas', 'Disease', (172, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('Mutation', 'Var', (0, 8))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('p53', 'Gene', (12, 15))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (172, 197))
10870	19798417	However, the lack of significant association between miR-34c downregulation and p53 mutation in our current series indicate that additional influences are likely important in regulating miR-34c expression in high grade serous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (226, 236))	('miR-34c', 'Gene', '407042', (53, 60))	('downregulation', 'NegReg', (61, 75))	('miR-34c', 'Gene', (186, 193))	('miR-34c', 'Gene', (53, 60))	('serous carcinomas', 'Disease', 'MESH:D018284', (219, 236))	('miR-34c', 'Gene', '407042', (186, 193))	('p53', 'Gene', (80, 83))	('serous carcinomas', 'Disease', (219, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('p53', 'Gene', '7157', (80, 83))	('mutation', 'Var', (84, 92))
10871	19798417	With regard to the prognostic significance of miR-34c, analysis based on the microarray data demonstrated significant association between low-level miR-34c expression and decreased disease-specific survival, while analysis based on qRT-PCR data showed a similar trend but did not reach statistical significance with a p-value of 0.06.	('miR-34c', 'Gene', (148, 155))	('decreased', 'NegReg', (171, 180))	('miR-34c', 'Gene', '407042', (46, 53))	('disease-specific survival', 'CPA', (181, 206))	('low-level', 'Var', (138, 147))	('miR-34c', 'Gene', (46, 53))	('expression', 'MPA', (156, 166))	('miR-34c', 'Gene', '407042', (148, 155))	('rat', 'Species', '10116', (100, 103))
10900	19798417	All high grade serous carcinoma samples were screened for p53 mutation with exons 5 to 8 analyzed by direct sequencing in both sense and antisense directions using the BigDye Terminator Cycle Sequencing 3.1 Kit (Applied Biosystems).	('serous carcinoma', 'Disease', (15, 31))	('serous carcinoma', 'Disease', 'MESH:D018284', (15, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('mutation', 'Var', (62, 70))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
10904	31993547	Nonetheless, any alteration in their expression level has been reported to be directly associated with the incidence and aggressiveness of several diseases.	('alteration', 'Var', (17, 27))	('associated', 'Reg', (87, 97))	('aggressiveness of several diseases', 'Disease', (121, 155))	('expression level', 'MPA', (37, 53))	('aggressiveness of several diseases', 'Disease', 'MESH:D001523', (121, 155))	('aggressiveness', 'Phenotype', 'HP:0000718', (121, 135))
10921	31993547	Secondly, the regulatory ncRNAs that can regulate the expression pattern of other coding transcripts includes long non-coding RNAs (lncRNAs) >=200 nucleotides and short non-coding RNAs (sncRNAs) < 200 nucleotides as shown in Table 1.	('expression', 'MPA', (54, 64))	('ncRNA', 'Gene', (187, 192))	('ncRNA', 'Gene', (133, 138))	('ncRNA', 'Gene', '220202', (25, 30))	('ncRNA', 'Gene', '220202', (187, 192))	('ncRNA', 'Gene', '220202', (133, 138))	('>=200 nucleotides', 'Var', (141, 158))	('ncRNA', 'Gene', (25, 30))
10922	31993547	SncRNAs are divided into microRNAs (miRNAs), small interfering RNAs (siRNAs) and piwi-associated RNAs (piRNAs).	('ncRNA', 'Gene', '220202', (1, 6))	('small interfering', 'Var', (45, 62))	('miR', 'Gene', (36, 39))	('miR', 'Gene', '220972', (36, 39))	('ncRNA', 'Gene', (1, 6))
10923	31993547	However, antisense RNAs and enhancer RNAs (eRNAs) are intermediate-sized ncRNA molecules lying at the bay between both classes of lncRNAs and sncRNAs.	('antisense', 'Var', (9, 18))	('ncRNA', 'Gene', '220202', (131, 136))	('ncRNA', 'Gene', '220202', (73, 78))	('enhancer', 'PosReg', (28, 36))	('ncRNA', 'Gene', '220202', (143, 148))	('ncRNA', 'Gene', (143, 148))	('ncRNA', 'Gene', (131, 136))	('ncRNA', 'Gene', (73, 78))
10949	31993547	Drosha/DGCR8-independent pathway includes splicing of mRNA introns and their conversion into mirtrons transcripts.	('DGCR8', 'Gene', '54487', (7, 12))	('mRNA introns', 'MPA', (54, 66))	('mirtrons transcripts', 'MPA', (93, 113))	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('Drosha', 'Gene', '29102', (0, 6))	('conversion', 'MPA', (77, 87))	('Drosha', 'Gene', (0, 6))	('DGCR8', 'Gene', (7, 12))	('splicing', 'Var', (42, 50))
11013	31993547	Collectively, exosomal miR-486-5p is believed to act as a circulating marker for high-risk LARC.	('LARC', 'Disease', (91, 95))	('exosomal', 'Var', (14, 22))	('miR-486', 'Gene', '619554', (23, 30))	('miR-486', 'Gene', (23, 30))
11030	31993547	Our research group has found that miR-486-5p was down-regulated in HCC liver tissues and cell lines (Huh-7 cells), where its ectopic expression was found to block one of the most aggressive deregulated oncogenic signaling pathway in HCC patients.	('ectopic expression', 'Var', (125, 143))	('HCC', 'Disease', (67, 70))	('CC', 'Phenotype', 'HP:0002664', (68, 70))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('signaling pathway', 'biological_process', 'GO:0007165', ('212', '229'))	('down-regulated', 'NegReg', (49, 63))	('HCC', 'Disease', 'MESH:D006528', (233, 236))	('CC', 'Phenotype', 'HP:0002664', (234, 236))	('Huh-7', 'CellLine', 'CVCL:0336', (101, 106))	('HCC', 'Disease', (233, 236))	('miR-486', 'Gene', (34, 41))	('deregulated oncogenic signaling pathway', 'Pathway', (190, 229))	('HCC', 'Phenotype', 'HP:0001402', (233, 236))	('patients', 'Species', '9606', (237, 245))	('HCC', 'Disease', 'MESH:D006528', (67, 70))	('miR-486', 'Gene', '619554', (34, 41))	('block', 'NegReg', (157, 162))
11056	31993547	It has been found that the hyper-activation of estrogen receptor alpha (ERalpha) causes changes on the genetic and epigenetic levels in ovarian cancer cells.	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('hyper-activation', 'Var', (27, 43))	('changes', 'Reg', (88, 95))	('ERalpha', 'Gene', '2099', (72, 79))	('ERalpha', 'Gene', (72, 79))	('ovarian cancer', 'Disease', (136, 150))	('estrogen receptor alpha', 'Gene', (47, 70))	('estrogen receptor alpha', 'Gene', '2099', (47, 70))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
11059	31993547	Impairment of the expression of ERalpha-mediated OLFM4 facilitates malignant development of ovarian serous adenocarcinoma.	('OLFM4', 'Gene', '10562', (49, 54))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (92, 121))	('OLFM4', 'Gene', (49, 54))	('ovarian serous adenocarcinoma', 'Disease', (92, 121))	('facilitates', 'PosReg', (55, 66))	('men', 'Species', '9606', (84, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('expression', 'MPA', (18, 28))	('ERalpha', 'Gene', (32, 39))	('malignant development', 'CPA', (67, 88))	('Impairment', 'Var', (0, 10))	('ERalpha', 'Gene', '2099', (32, 39))	('men', 'Species', '9606', (6, 9))
11066	31993547	Thus miR-486-5p ectopic-expression leads to an increase in the apoptosis of leukemia cells by targeting FOXO1.	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('miR-486', 'Gene', (5, 12))	('miR-486', 'Gene', '619554', (5, 12))	('FOXO1', 'Gene', (104, 109))	('ectopic-expression', 'Var', (16, 34))	('leukemia', 'Disease', (76, 84))	('apoptosis', 'CPA', (63, 72))	('increase', 'PosReg', (47, 55))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('targeting', 'Reg', (94, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('FOXO1', 'Gene', '2308', (104, 109))
11080	31993547	As it was mentioned above that ANK1 irregular epigenetic modifications could lead to suppression of miR-486-5p in NSCLC.	('ANK1', 'Gene', (31, 35))	('men', 'Species', '9606', (10, 13))	('miR-486', 'Gene', '619554', (100, 107))	('ANK1', 'Gene', '286', (31, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('suppression', 'NegReg', (85, 96))	('miR-486', 'Gene', (100, 107))	('epigenetic modifications', 'Var', (46, 70))
11081	31993547	Accordingly, hyper-methylation of ANK1 promoter by DNMT3B which is found in arecoline (a major component of betel quid chewing) leads to a reduction of ANK1 and miR-486-3p expression subsequently leading to DDR1 expression.	('DNMT3B', 'Gene', (51, 57))	('DNMT3B', 'Gene', '1789', (51, 57))	('DDR1', 'Gene', '780', (207, 211))	('reduction', 'NegReg', (139, 148))	('DDR1', 'Gene', (207, 211))	('ANK1', 'Gene', '286', (152, 156))	('expression', 'MPA', (212, 222))	('ANK1', 'Gene', (152, 156))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('miR-486', 'Gene', (161, 168))	('arecoline', 'Chemical', 'MESH:D001115', (76, 85))	('hyper-methylation', 'Var', (13, 30))	('leading to', 'Reg', (196, 206))	('ANK1', 'Gene', '286', (34, 38))	('chewing', 'biological_process', 'GO:0071626', ('119', '126'))	('miR-486', 'Gene', '619554', (161, 168))	('ANK1', 'Gene', (34, 38))
11092	31993547	Eventually, cell growth and metastasis were inhibited by miR-486-3p ectopic-expression.	('miR-486', 'Gene', (57, 64))	('inhibited', 'NegReg', (44, 53))	('miR-486', 'Gene', '619554', (57, 64))	('cell growth', 'biological_process', 'GO:0016049', ('12', '23'))	('ectopic-expression', 'Var', (68, 86))
11120	31993547	CF is a genetic disease caused by mutations in the gene of cystic fibrosis conductance regulator (CFTR).	('cystic fibrosis conductance regulator', 'Gene', '1080', (59, 96))	('CFTR', 'Gene', (98, 102))	('cystic fibrosis conductance regulator', 'Gene', (59, 96))	('CF', 'Disease', 'MESH:D003550', (98, 100))	('genetic disease', 'Disease', 'MESH:D030342', (8, 23))	('CF', 'Disease', 'MESH:D003550', (0, 2))	('genetic disease', 'Disease', (8, 23))	('caused by', 'Reg', (24, 33))	('CFTR', 'Gene', '1080', (98, 102))	('mutations', 'Var', (34, 43))
11159	31993547	Collectively, those few studies highlight a clear research gap in connecting the lines between different classes of ncRNAs and the assembly of the ceRNAs circuits that when dys-regulated lead to several malignant and non-malignant phenotypes.	('malignant', 'CPA', (203, 212))	('dys-regulated', 'Var', (173, 186))	('ncRNA', 'Gene', (116, 121))	('ncRNA', 'Gene', '220202', (116, 121))	('lead to', 'Reg', (187, 194))
11217	29456732	The risk score formula for this model was (-0.53179 x expression value of MANF) + (0.324759 x expression value of DOCK11).	('DOCK11', 'Gene', '139818', (114, 120))	('DOCK11', 'Gene', (114, 120))	('-0.53179', 'Var', (43, 51))	('0.324759', 'Var', (83, 91))
11231	29456732	Notably, prior studies have indicated that MANF is important for protein homeostasis in the endoplasmic reticulum, as the knockdown of MANF in cultured cells and the knockout of MANF in mice and Drosophila resulted in the activation of the unfolded protein response, a signaling pathway induced by endoplasmic reticulum stress.	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('signaling pathway', 'biological_process', 'GO:0007165', ('269', '286'))	('unfolded protein response', 'Pathway', (240, 265))	('MANF', 'Gene', (178, 182))	('activation', 'PosReg', (222, 232))	('knockdown', 'Var', (122, 131))	('endoplasmic reticulum stress', 'Disease', 'MESH:D004194', (298, 326))	('MANF', 'Gene', (135, 139))	('Drosophila', 'Species', '7227', (195, 205))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('92', '113'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('298', '319'))	('endoplasmic reticulum stress', 'Disease', (298, 326))	('mice', 'Species', '10090', (186, 190))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('homeostasis', 'biological_process', 'GO:0042592', ('73', '84'))	('knockout', 'Var', (166, 174))
11272	27807494	The immunohistochemical studies gave positive reactions for cytokeratin (AE1/AE3) and cytokeratin 7 in the carcinomatous component (Figure 2(b)), whereas only a rare focal reaction was observed in the sarcomatous part.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('AE3', 'Gene', '6508', (77, 80))	('cytokeratin', 'Protein', (60, 71))	('AE1', 'Gene', '6521', (73, 76))	('sarcomatous part', 'Disease', 'MESH:D018316', (201, 217))	('AE1', 'Gene', (73, 76))	('sarcomatous part', 'Disease', (201, 217))	('sarcomatous part', 'Phenotype', 'HP:0100242', (201, 217))	('AE3', 'Gene', (77, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('cytokeratin 7', 'Var', (86, 99))	('carcinomatous', 'Disease', (107, 120))
11339	18842102	It is well established that tumors develop and progress as the result of accumulated molecular genetic or genomic changes such as point mutation, gene amplification, deletion, and translocation.	('deletion', 'Var', (166, 174))	('progress', 'CPA', (47, 55))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('translocation', 'Var', (180, 193))	('gene amplification', 'Var', (146, 164))	('point mutation', 'Var', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
11340	18842102	Analysis of these alterations has historically led to the identification of new cancer-associated genes including oncogenes, tumor suppressor genes and genes involved in DNA damage repair.	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('alterations', 'Var', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('125', '141'))	('tumor', 'Disease', (125, 130))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('125', '141'))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
11360	18842102	For example, TP53 is mutated in 50% or more high-grade serous carcinomas, and activating mutations of KRAS or BRAF are present in over half of low-grade serous carcinomas and SBTs.	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('TP53', 'Gene', (13, 17))	('activating', 'PosReg', (78, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('TP53', 'Gene', '7157', (13, 17))	('serous carcinomas', 'Disease', 'MESH:D018284', (55, 72))	('serous carcinomas', 'Disease', (55, 72))	('BRAF', 'Gene', '673', (110, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('serous carcinomas', 'Disease', 'MESH:D018284', (153, 170))	('KRAS', 'Gene', (102, 106))	('mutated', 'Var', (21, 28))	('BRAF', 'Gene', (110, 114))	('serous carcinomas', 'Disease', (153, 170))	('KRAS', 'Gene', '3845', (102, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
11361	18842102	Mutations in several other tumor suppressor genes and oncogenes such as BRCA1/2, PTEN, and PIK3CA have also been reported in ovarian serous carcinomas, but their mutation frequency is generally low (< 10%).	('PIK3CA', 'Gene', (91, 97))	('BRCA1/2', 'Gene', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('tumor', 'Disease', (27, 32))	('BRCA1/2', 'Gene', '672;675', (72, 79))	('PIK3CA', 'Gene', '5290', (91, 97))	('ovarian serous carcinomas', 'Disease', (125, 150))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (125, 150))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (81, 85))	('PTEN', 'Gene', '5728', (81, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (125, 150))	('reported', 'Reg', (113, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))
11362	18842102	Although early studies identified rather frequent HER2/neu (ERBB2) amplification/copy number gains in ovarian serous carcinomas, a recent analysis using comprehensive genome-wide digital karyotyping technologies failed to identify high levels of ERBB2 gene amplification in 33 high-grade or 10 low-grade serous carcinomas.	('amplification/copy number', 'Var', (67, 92))	('ERBB2', 'Gene', '2064', (60, 65))	('HER2/neu', 'Gene', '2064', (50, 58))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (102, 127))	('amplification/copy', 'Var', (67, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('carcinomas', 'Phenotype', 'HP:0030731', (311, 321))	('serous carcinomas', 'Disease', 'MESH:D018284', (304, 321))	('gains', 'PosReg', (93, 98))	('ERBB2', 'Gene', (246, 251))	('ovarian serous carcinomas', 'Disease', (102, 127))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (102, 127))	('ERBB2', 'Gene', '2064', (246, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('HER2/neu', 'Gene', (50, 58))	('serous carcinomas', 'Disease', (304, 321))	('ERBB2', 'Gene', (60, 65))	('high-grade', 'Disease', (277, 287))	('serous carcinomas', 'Disease', 'MESH:D018284', (110, 127))
11363	18842102	Therefore, in the following discussion we will focus mainly on mutations in TP53, KRAS and BRAF in serous carcinomas.	('mutations', 'Var', (63, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('serous carcinomas', 'Disease', 'MESH:D018284', (99, 116))	('serous carcinomas', 'Disease', (99, 116))	('BRAF', 'Gene', '673', (91, 95))	('TP53', 'Gene', '7157', (76, 80))	('BRAF', 'Gene', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('TP53', 'Gene', (76, 80))	('KRAS', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (82, 86))
11364	18842102	In contrast to low-grade serous carcinoma where mutations in TP53 are rare, approximately 50% or more of advanced stage, presumably high-grade, serous carcinomas have mutant TP53.	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('TP53', 'Gene', (174, 178))	('serous carcinoma', 'Disease', 'MESH:D018284', (144, 160))	('serous carcinomas', 'Disease', 'MESH:D018284', (144, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('serous carcinomas', 'Disease', (144, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('serous carcinoma', 'Disease', (25, 41))	('mutant', 'Var', (167, 173))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (174, 178))	('serous carcinoma', 'Disease', 'MESH:D018284', (25, 41))
11365	18842102	The TP53 mutation frequency was found to be even higher (~80%) in high-grade serous carcinoma when purified tumor samples were used for sequence analysis.	('mutation', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('TP53', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Disease', (108, 113))	('serous carcinoma', 'Disease', (77, 93))	('serous carcinoma', 'Disease', 'MESH:D018284', (77, 93))	('TP53', 'Gene', '7157', (4, 8))	('higher', 'Reg', (49, 55))
11366	18842102	In their study of early (stage I) serous carcinomas Leitao and colleagues identified overexpression of p53 and mutation of TP53 in well over half of the cases, suggesting that TP53 mutation is an early event in the development of high-grade serous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('serous carcinomas', 'Disease', 'MESH:D018284', (34, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (248, 258))	('serous carcinomas Leitao', 'Disease', (34, 58))	('TP53', 'Gene', '7157', (176, 180))	('serous carcinomas Leitao', 'Disease', 'MESH:D018284', (34, 58))	('overexpression', 'PosReg', (85, 99))	('serous carcinomas', 'Disease', 'MESH:D018284', (241, 258))	('TP53', 'Gene', (176, 180))	('serous carcinomas', 'Disease', (241, 258))	('TP53', 'Gene', '7157', (123, 127))	('mutation', 'Var', (111, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('TP53', 'Gene', (123, 127))
11367	18842102	On a related note, a small series of intraepithelial serous carcinomas in the fallopian tube with co-existing ovarian serous carcinomas were recently found to share identical TP53 mutations, suggesting a common origin of tumors in the two sites and providing further evidence of a role for TP53 mutations early in serous carcinoma pathogenesis.	('serous carcinoma', 'Disease', (314, 330))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('serous carcinoma', 'Disease', 'MESH:D018284', (53, 69))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('TP53', 'Gene', (290, 294))	('intraepithelial serous carcinomas', 'Disease', (37, 70))	('TP53', 'Gene', '7157', (175, 179))	('pathogenesis', 'biological_process', 'GO:0009405', ('331', '343'))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (110, 135))	('serous carcinoma', 'Disease', 'MESH:D018284', (314, 330))	('tumors', 'Disease', (221, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('mutations', 'Var', (180, 189))	('ovarian serous carcinomas', 'Disease', (110, 135))	('TP53', 'Gene', '7157', (290, 294))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (110, 135))	('TP53', 'Gene', (175, 179))	('serous carcinoma', 'Disease', 'MESH:D018284', (118, 134))	('intraepithelial serous carcinomas', 'Disease', 'MESH:D002278', (37, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (321, 330))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))
11368	18842102	Activating mutations in KRAS and one of its downstream effectors, BRAF, have been identified in a variety of human cancers and mutations of either KRAS or BRAF lead to constitutive activation of MAPK signaling (Figure 2).	('MAPK', 'molecular_function', 'GO:0004707', ('195', '199'))	('BRAF', 'Gene', (155, 159))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('human', 'Species', '9606', (109, 114))	('KRAS', 'Gene', '3845', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('MAPK signaling', 'biological_process', 'GO:0000165', ('195', '209'))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MAPK signaling', 'MPA', (195, 209))	('activation', 'PosReg', (181, 191))	('BRAF', 'Gene', '673', (66, 70))	('mutations', 'Var', (127, 136))	('KRAS', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (155, 159))	('BRAF', 'Gene', (66, 70))	('KRAS', 'Gene', '3845', (147, 151))	('KRAS', 'Gene', (24, 28))
11370	18842102	Frequent KRAS mutations in SBT were first reported by Mok et al.. Several subsequent studies verified the original finding and further demonstrated that mutations in KRAS and BRAF characterize both SBTs and low-grade serous carcinomas.	('Mok', 'Gene', '5891', (54, 57))	('Mok', 'Gene', (54, 57))	('SBTs', 'Disease', (198, 202))	('KRAS', 'Gene', (9, 13))	('mutations', 'Var', (153, 162))	('serous carcinomas', 'Disease', 'MESH:D018284', (217, 234))	('KRAS', 'Gene', (166, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('serous carcinomas', 'Disease', (217, 234))	('BRAF', 'Gene', (175, 179))	('KRAS', 'Gene', '3845', (166, 170))	('BRAF', 'Gene', '673', (175, 179))	('KRAS', 'Gene', '3845', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('characterize', 'Reg', (180, 192))
11372	18842102	Mutations in KRAS and BRAF are mutually exclusive insofar as tumors with mutant KRAS do not have mutant BRAF and vice versa.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('KRAS', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (22, 26))	('BRAF', 'Gene', (22, 26))	('mutant', 'Var', (73, 79))	('KRAS', 'Gene', '3845', (80, 84))	('BRAF', 'Gene', '673', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('KRAS', 'Gene', (13, 17))	('BRAF', 'Gene', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('KRAS', 'Gene', '3845', (13, 17))
11374	18842102	In contrast, KRAS and BRAF mutations are very uncommon in high-grade serous carcinomas.	('mutations', 'Var', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('BRAF', 'Gene', '673', (22, 26))	('serous carcinomas', 'Disease', 'MESH:D018284', (69, 86))	('serous carcinomas', 'Disease', (69, 86))	('BRAF', 'Gene', (22, 26))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
11375	18842102	These data provide compelling evidence indicating that KRAS and BRAF mutations are largely confined to low-grade serous carcinomas and SBTs and suggest that SBTs are likely precursors of low-grade serous carcinomas, but not the more common high-grade serous carcinomas.	('KRAS', 'Gene', (55, 59))	('serous carcinomas', 'Disease', (197, 214))	('serous carcinomas', 'Disease', (113, 130))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', '673', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('BRAF', 'Gene', (64, 68))	('serous carcinomas', 'Disease', 'MESH:D018284', (251, 268))	('KRAS', 'Gene', '3845', (55, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('serous carcinomas', 'Disease', (251, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (258, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('serous carcinomas', 'Disease', 'MESH:D018284', (113, 130))	('serous carcinomas', 'Disease', 'MESH:D018284', (197, 214))
11376	18842102	KRAS and BRAF mutations are lacking in isolated serous cystadenomas, putative precursors of SBTs.	('KRAS', 'Gene', '3845', (0, 4))	('serous cystadenomas', 'Phenotype', 'HP:0012887', (48, 67))	('serous cystadenoma', 'Phenotype', 'HP:0012887', (48, 66))	('BRAF', 'Gene', (9, 13))	('isolated serous cystadenomas', 'Disease', 'MESH:D018293', (39, 67))	('isolated serous cystadenomas', 'Disease', (39, 67))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
11377	18842102	However, identical KRAS or BRAF mutations were detected the SBTs and adjacent cystadenoma epithelium in serous cystadenomas associated with small SBTs.	('serous cystadenoma', 'Phenotype', 'HP:0012887', (104, 122))	('KRAS', 'Gene', (19, 23))	('cystadenoma epithelium in serous cystadenomas', 'Disease', (78, 123))	('BRAF', 'Gene', '673', (27, 31))	('associated', 'Reg', (124, 134))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', '3845', (19, 23))	('cystadenoma epithelium in serous cystadenomas', 'Disease', 'MESH:D018293', (78, 123))	('BRAF', 'Gene', (27, 31))	('serous cystadenomas', 'Phenotype', 'HP:0012887', (104, 123))
11378	18842102	Collectively, these findings suggest mutations of KRAS and BRAF are early events associated with serous tumor initiation and that a small subset of serous cystadenomas which acquire KRAS or BRAF mutations may progress to SBT.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('serous cystadenoma', 'Phenotype', 'HP:0012887', (148, 166))	('KRAS', 'Gene', '3845', (50, 54))	('BRAF', 'Gene', '673', (190, 194))	('BRAF', 'Gene', (190, 194))	('KRAS', 'Gene', (50, 54))	('serous tumor initiation', 'Disease', 'MESH:D018284', (97, 120))	('serous cystadenomas', 'Phenotype', 'HP:0012887', (148, 167))	('progress', 'PosReg', (209, 217))	('SBT', 'Disease', (221, 224))	('mutations', 'Var', (37, 46))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('mutations', 'Var', (195, 204))	('serous tumor initiation', 'Disease', (97, 120))	('KRAS', 'Gene', '3845', (182, 186))	('serous cystadenomas', 'Disease', (148, 167))	('associated', 'Reg', (81, 91))	('serous cystadenomas', 'Disease', 'MESH:D018293', (148, 167))	('KRAS', 'Gene', (182, 186))
11381	18842102	who applied serial analysis of gene expression (SAGE) to identify genes regulated by activated MAPK in low-grade serous carcinoma cells with mutant BRAF.	('MAPK', 'Gene', (95, 99))	('mutant', 'Var', (141, 147))	('serous carcinoma', 'Disease', (113, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('serous carcinoma', 'Disease', 'MESH:D018284', (113, 129))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))	('BRAF', 'Gene', '673', (148, 152))	('activated MAPK', 'Gene', (85, 99))	('BRAF', 'Gene', (148, 152))
11386	18842102	Although activating mutations of KRAS and BRAF are required to maintain cellular proliferation and survival, in non-transformed normal cells such mutations may induce cell cycle arrest and cellular senescence, a phenomenon known as "oncogene-induced senescence".	('BRAF', 'Gene', '673', (42, 46))	('cellular senescence', 'biological_process', 'GO:0090398', ('189', '208'))	('mutations', 'Var', (146, 155))	('arrest', 'Disease', (178, 184))	('KRAS', 'Gene', (33, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (167, 184))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('167', '184'))	('KRAS', 'Gene', '3845', (33, 37))	('cellular senescence', 'CPA', (189, 208))	('induce', 'Reg', (160, 166))	('BRAF', 'Gene', (42, 46))	('arrest', 'Disease', 'MESH:D006323', (178, 184))
11395	18842102	For example, deregulation of the PI3K/Pten signaling pathway, for example through amplification of PIK3CA which encodes the catalytic subunit of PI3K, has been shown to play a causal role in invasion, metastasis and chemoresistance in ovarian cancer.	('invasion', 'CPA', (191, 199))	('ovarian cancer', 'Phenotype', 'HP:0100615', (235, 249))	('PI3K/Pten', 'Gene', '5290;5728', (33, 42))	('ovarian cancer', 'Disease', 'MESH:D010051', (235, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('metastasis', 'CPA', (201, 211))	('PI3K/Pten', 'Gene', (33, 42))	('PIK3CA', 'Gene', '5290', (99, 105))	('amplification', 'Var', (82, 95))	('causal', 'Reg', (176, 182))	('ovarian cancer', 'Disease', (235, 249))	('signaling pathway', 'biological_process', 'GO:0007165', ('43', '60'))	('PI3K', 'molecular_function', 'GO:0016303', ('145', '149'))	('chemoresistance', 'CPA', (216, 231))	('deregulation', 'Var', (13, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('PIK3CA', 'Gene', (99, 105))
11396	18842102	CCNE1 gene amplification and overexpression contributes to oncogenesis and genetic instability, particularly in the presence of mutant p53, which is present in most high-grade serous carcinomas.	('overexpression', 'PosReg', (29, 43))	('CCNE1', 'Gene', '898', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('CCNE1', 'Gene', (0, 5))	('oncogenesis', 'CPA', (59, 70))	('genetic instability', 'CPA', (75, 94))	('p53', 'Gene', (135, 138))	('mutant', 'Var', (128, 134))	('serous carcinomas', 'Disease', 'MESH:D018284', (176, 193))	('oncogenesis', 'biological_process', 'GO:0007048', ('59', '70'))	('serous carcinomas', 'Disease', (176, 193))	('contributes', 'Reg', (44, 55))
11397	18842102	Moreover, expression of low molecular weight cyclin E is associated with worse clinical outcome in ovarian cancer patients.	('ovarian cancer', 'Phenotype', 'HP:0100615', (99, 113))	('ovarian cancer', 'Disease', 'MESH:D010051', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ovarian cancer', 'Disease', (99, 113))	('cyclin', 'molecular_function', 'GO:0016538', ('45', '51'))	('low molecular', 'Var', (24, 37))	('patients', 'Species', '9606', (114, 122))	('expression', 'Var', (10, 20))
11401	18842102	Patients with 11q13.5 amplification or Rsf-1 over-expression had a significantly shorter overall survival than those without.	('11q13.5 amplification', 'Var', (14, 35))	('over-expression', 'PosReg', (45, 60))	('amplification', 'Var', (22, 35))	('Patients', 'Species', '9606', (0, 8))	('Rsf-1', 'Gene', (39, 44))	('overall survival', 'MPA', (89, 105))	('Rsf-1', 'Gene', '51773', (39, 44))	('shorter', 'NegReg', (81, 88))
11404	18842102	Inactivation of Notch3 by either gamma-secretase inhibitors or Notch3-specific siRNAs suppressed cell proliferation and induced apoptosis in cell lines that overexpressed Notch3 but not in those with minimal Notch3 expression.	('Notch3', 'Gene', '4854', (171, 177))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('Notch3', 'Gene', (171, 177))	('Notch3', 'Gene', (16, 22))	('Notch3', 'Gene', '4854', (208, 214))	('induced', 'Reg', (120, 127))	('Notch3', 'Gene', '4854', (63, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('Notch3', 'Gene', (63, 69))	('suppressed', 'NegReg', (86, 96))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('Notch3', 'Gene', '4854', (16, 22))	('cell proliferation', 'CPA', (97, 115))	('Inactivation', 'Var', (0, 12))	('Notch3', 'Gene', (208, 214))	('overexpressed', 'Var', (157, 170))	('apoptosis', 'CPA', (128, 137))
11405	18842102	These results indicate that Notch3 is required for proliferation and survival of Notch3-amplified tumors and suggest inactivation of Notch3 as a potential therapeutic approach for a subset ovarian high-grade serous carcinomas.	('Notch3', 'Gene', '4854', (81, 87))	('tumors', 'Disease', (98, 104))	('Notch3', 'Gene', (81, 87))	('Notch3', 'Gene', '4854', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('Notch3', 'Gene', '4854', (28, 34))	('Notch3', 'Gene', (133, 139))	('Notch3', 'Gene', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('inactivation', 'Var', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('carcinomas', 'Phenotype', 'HP:0030731', (215, 225))	('serous carcinomas', 'Disease', 'MESH:D018284', (208, 225))	('serous carcinomas', 'Disease', (208, 225))	('ovarian high', 'Phenotype', 'HP:0008209', (189, 201))
11407	18842102	However, a few sub-chromosomal regions show frequent deletion in low-grade serous carcinomas.	('serous carcinomas', 'Disease', (75, 92))	('deletion', 'Var', (53, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('serous carcinomas', 'Disease', 'MESH:D018284', (75, 92))
11408	18842102	Kuo and colleagues applied high resolution SNP arrays on purified tumor cells from low-grade serous carcinomas and SBTs, and found that heterozygous chromosome 1p losses characterized many low-grade serous carcinomas but rarely SBTs, suggesting that inactivation of potential tumor suppressor genes in this region may propel progression from SBT to low-grade serous carcinoma (I-M Shih laboratory, unpublished studies).	('losses', 'NegReg', (163, 169))	('serous carcinoma', 'Disease', 'MESH:D018284', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('serous carcinomas', 'Disease', (199, 216))	('propel', 'Reg', (318, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (366, 375))	('inactivation', 'Var', (250, 262))	('chromosome', 'cellular_component', 'GO:0005694', ('149', '159'))	('serous carcinoma', 'Disease', (359, 375))	('tumor', 'Disease', (66, 71))	('serous carcinomas', 'Disease', (93, 110))	('SBT', 'Disease', (342, 345))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('serous carcinomas', 'Disease', 'MESH:D018284', (199, 216))	('serous carcinoma', 'Disease', 'MESH:D018284', (359, 375))	('tumor', 'Disease', (276, 281))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('276', '292'))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('serous carcinoma', 'Disease', 'MESH:D018284', (199, 215))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('serous carcinomas', 'Disease', 'MESH:D018284', (93, 110))	('tumor suppressor', 'biological_process', 'GO:0051726', ('276', '292'))
11412	18842102	Further studies are required to determine possible roles for CHD5 or miR-34 inactivation in the pathogenesis of low-grade ovarian serous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('miR-34', 'Gene', (69, 75))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (122, 147))	('low-grade ovarian serous carcinomas', 'Disease', 'MESH:D008228', (112, 147))	('low-grade ovarian serous carcinomas', 'Disease', (112, 147))	('miR-34', 'Gene', '407040', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('CHD5', 'Gene', (61, 65))	('inactivation', 'Var', (76, 88))	('CHD5', 'Gene', '26038', (61, 65))	('pathogenesis', 'biological_process', 'GO:0009405', ('96', '108'))
11426	18842102	p21 may contribute to negative cell cycle regulation in response to a variety of environmental cues or to oncogenic stress, since most SBTs and low-grade serous carcinomas have activating mutations of KRAS, BRAF or ERBB2.	('BRAF', 'Gene', (207, 211))	('serous carcinomas', 'Disease', 'MESH:D018284', (154, 171))	('ERBB2', 'Gene', '2064', (215, 220))	('BRAF', 'Gene', '673', (207, 211))	('SBTs', 'Disease', (135, 139))	('p21', 'Gene', (0, 3))	('serous carcinomas', 'Disease', (154, 171))	('ERBB2', 'Gene', (215, 220))	('KRAS', 'Gene', (201, 205))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('31', '52'))	('KRAS', 'Gene', '3845', (201, 205))	('cell', 'MPA', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('mutations', 'Var', (188, 197))	('p21', 'Gene', '1026', (0, 3))	('activating', 'PosReg', (177, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))
11429	18842102	Although somatic mutations of BRCA1 and BRCA2 are known to be rather uncommon in sporadic ovarian carcinomas, accumulated studies suggest these genes may be inactivated, particularly in serous carcinomas, through mechanisms other than mutation.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (90, 107))	('BRCA1', 'Gene', (30, 35))	('sporadic ovarian carcinomas', 'Disease', (81, 108))	('inactivated', 'NegReg', (157, 168))	('sporadic ovarian carcinomas', 'Disease', 'MESH:D010051', (81, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('BRCA2', 'Gene', (40, 45))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (90, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('serous carcinomas', 'Disease', 'MESH:D018284', (186, 203))	('BRCA1', 'Gene', '672', (30, 35))	('serous carcinomas', 'Disease', (186, 203))	('mutations', 'Var', (17, 26))	('BRCA2', 'Gene', '675', (40, 45))
11431	18842102	Hypermethylation of the BRCA1 promoter accompanied by loss of Brca1 protein expression has been observed in 15-31% of sporadic ovarian carcinomas.	('BRCA1', 'Gene', '672', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (127, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('Hypermethylation', 'Var', (0, 16))	('Brca1', 'Gene', (62, 67))	('BRCA1', 'Gene', (24, 29))	('loss', 'NegReg', (54, 58))	('expression', 'MPA', (76, 86))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('Brca1', 'Gene', '672', (62, 67))	('sporadic ovarian carcinomas', 'Disease', 'MESH:D010051', (118, 145))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (127, 144))	('protein', 'Protein', (68, 75))	('sporadic ovarian carcinomas', 'Disease', (118, 145))
11432	18842102	Moreover, high-grade serous carcinomas with genetic vs. epigenetic inactivation of BRCA1 have recently been shown to have distinct molecular abnormalities involving the PI3K/Pten signaling pathway.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('PI3K/Pten', 'Gene', '5290;5728', (169, 178))	('BRCA1', 'Gene', '672', (83, 88))	('molecular abnormalities', 'Disease', (131, 154))	('PI3K/Pten', 'Gene', (169, 178))	('serous carcinomas', 'Disease', 'MESH:D018284', (21, 38))	('signaling pathway', 'biological_process', 'GO:0007165', ('179', '196'))	('serous carcinomas', 'Disease', (21, 38))	('BRCA1', 'Gene', (83, 88))	('molecular abnormalities', 'Disease', 'MESH:C567116', (131, 154))	('epigenetic inactivation', 'Var', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('genetic vs.', 'Var', (44, 55))	('PI3K', 'molecular_function', 'GO:0016303', ('169', '173'))
11433	18842102	Specifically, tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gains of PIK3CA.	('PIK3CA', 'Gene', (150, 156))	('gains', 'PosReg', (141, 146))	('PTEN', 'Gene', (66, 70))	('BRCA1', 'Gene', (26, 31))	('BRCA1', 'Gene', (119, 124))	('PTEN', 'Gene', '5728', (66, 70))	('PIK3CA', 'Gene', '5290', (150, 156))	('decreased', 'NegReg', (56, 65))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (32, 41))	('BRCA1', 'Gene', '672', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BRCA1', 'Gene', '672', (119, 124))
11441	18842102	Indeed, mutations in several of the same tumor suppressor genes, oncogenes, and genes involved in DNA repair have been observed in both endometrial and ovarian endometrioid carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('DNA repair', 'biological_process', 'GO:0006281', ('98', '108'))	('tumor', 'Disease', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('mutations', 'Var', (8, 17))	('observed', 'Reg', (119, 127))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('endometrial and ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (136, 183))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (160, 182))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (160, 183))
11445	18842102	beta-catenin-mediated signaling is deregulated in 16-38% of human ovarian endometrioid carcinomas, usually on the basis of activating mutations of CTNNB1, the gene that encodes beta-catenin, and rarely because of inactivating mutations in genes encoding negative regulators of beta-catenin such as APC, AXIN1, or AXIN2.	('AXIN1', 'Gene', (303, 308))	('AXIN2', 'Gene', '8313', (313, 318))	('beta-catenin', 'Gene', (177, 189))	('beta-catenin', 'Gene', (0, 12))	('beta-catenin', 'Gene', '1499', (177, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('deregulated', 'Reg', (35, 46))	('beta-catenin', 'Gene', '1499', (0, 12))	('CTNNB1', 'Gene', (147, 153))	('mutations', 'Var', (134, 143))	('beta-catenin', 'Gene', (277, 289))	('beta-catenin', 'Gene', '1499', (277, 289))	('APC', 'Disease', 'MESH:D011125', (298, 301))	('AXIN2', 'Gene', (313, 318))	('APC', 'Disease', (298, 301))	('AXIN1', 'Gene', '8312', (303, 308))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('ovarian endometrioid carcinomas', 'Disease', (66, 97))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (74, 97))	('activating', 'PosReg', (123, 133))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (66, 97))	('APC', 'cellular_component', 'GO:0005680', ('298', '301'))	('human', 'Species', '9606', (60, 65))	('CTNNB1', 'Gene', '1499', (147, 153))
11446	18842102	Notably, CTNNB1 mutations are very uncommon in the other major types of ovarian carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('ovarian carcinoma', 'Disease', (72, 89))	('CTNNB1', 'Gene', '1499', (9, 15))	('mutations', 'Var', (16, 25))	('CTNNB1', 'Gene', (9, 15))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (72, 89))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (72, 89))
11447	18842102	Several studies have noted the association of CTNNB1 mutation with squamous differentiation, low tumor grade, and favorable outcome  Inactivating mutations of the tumor suppressor gene PTEN have been reported in 14-21% of ovarian endometrioid carcinomas, and like CTNNB1, PTEN mutations are rare in the other major types of ovarian carcinomas.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (324, 341))	('mutation', 'Var', (53, 61))	('ovarian endometrioid carcinomas', 'Disease', (222, 253))	('Inactivating', 'NegReg', (133, 145))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (230, 253))	('association', 'Interaction', (31, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('163', '179'))	('tumor', 'Disease', (163, 168))	('CTNNB1', 'Gene', '1499', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (222, 253))	('tumor', 'Disease', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('reported', 'Reg', (200, 208))	('squamous', 'Disease', (67, 75))	('PTEN', 'Gene', (185, 189))	('PTEN', 'Gene', (272, 276))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('low tumor', 'Disease', 'MESH:D009800', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CTNNB1', 'Gene', '1499', (46, 52))	('CTNNB1', 'Gene', (264, 270))	('carcinomas', 'Phenotype', 'HP:0030731', (332, 342))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (324, 342))	('PTEN', 'Gene', '5728', (185, 189))	('PTEN', 'Gene', '5728', (272, 276))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('low tumor', 'Disease', (93, 102))	('ovarian carcinomas', 'Disease', (324, 342))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (324, 342))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('163', '179'))	('carcinomas', 'Phenotype', 'HP:0030731', (243, 253))	('CTNNB1', 'Gene', (46, 52))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (230, 252))
11448	18842102	Inactivation of Pten, the lipid phosphatase that converts PIP3 to PIP2, is one mechanism by which activation of phosphotidylinositol 3-kinase (PI3K) signaling occurs in human tumors (Figure 4).	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('PI3K) signaling', 'biological_process', 'GO:0014065', ('143', '158'))	('phosphotidylinositol 3-kinase', 'Gene', '5290', (112, 141))	('activation', 'PosReg', (98, 108))	('phosphatase', 'molecular_function', 'GO:0016791', ('32', '43'))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('Pten', 'Gene', (16, 20))	('human', 'Species', '9606', (169, 174))	('phosphotidylinositol 3-kinase', 'Gene', (112, 141))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('Inactivation', 'Var', (0, 12))
11449	18842102	An alternative mechanism by which PI3K/Pten signaling is activated in endometrioid adenocarcinomas is through activating mutations of PIK3CA, which encodes the p110 catalytic subunit of PI3K.	('PIK3CA', 'Gene', (134, 140))	('mutations', 'Var', (121, 130))	('activated', 'PosReg', (57, 66))	('PIK3CA', 'Gene', '5290', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('PI3K/Pten', 'Gene', '5290;5728', (34, 43))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('activating', 'PosReg', (110, 120))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (70, 98))	('PI3K/Pten', 'Gene', (34, 43))	('endometrioid adenocarcinomas', 'Disease', (70, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))
11450	18842102	Most reported PIK3CA mutations are clustered in exons 9 and 20, and PIK3CA mutations in these exons have been identified in 20% of ovarian endometrioid and clear cell carcinomas but in only 2% of ovarian serous carcinomas.	('clear cell carcinomas', 'Disease', (156, 177))	('mutations', 'Var', (21, 30))	('PIK3CA', 'Gene', (68, 74))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (196, 221))	('identified', 'Reg', (110, 120))	('ovarian endometrioid', 'Disease', 'MESH:D016889', (131, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('PIK3CA', 'Gene', '5290', (68, 74))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (196, 221))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (156, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('mutations', 'Var', (75, 84))	('PIK3CA', 'Gene', (14, 20))	('ovarian endometrioid', 'Disease', (131, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('PIK3CA', 'Gene', '5290', (14, 20))	('ovarian serous carcinomas', 'Disease', (196, 221))
11451	18842102	Interestingly, Oda and colleagues reported a high frequency of concomitant PIK3CA and PTEN mutations in uterine endometrioid adenocarcinomas, and functional studies suggested that mutation of both genes may have an additive effect on PI3K pathway activation.	('PIK3CA', 'Gene', (75, 81))	('PTEN', 'Gene', (86, 90))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (112, 140))	('PIK3CA', 'Gene', '5290', (75, 81))	('PTEN', 'Gene', '5728', (86, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('234', '238'))	('mutations', 'Var', (91, 100))	('endometrioid adenocarcinomas', 'Disease', (112, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('activation', 'PosReg', (247, 257))	('PI3K pathway', 'Pathway', (234, 246))	('mutation', 'Var', (180, 188))
11452	18842102	PIK3CA and PTEN mutations also co-occur in a subset of ovarian endometrioid carcinomas and in both the ovary and the endometrium, PIK3CA mutations are associated with adverse prognostic indicators.	('PIK3CA', 'Gene', (130, 136))	('PTEN', 'Gene', (11, 15))	('PTEN', 'Gene', '5728', (11, 15))	('PIK3CA', 'Gene', '5290', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (63, 85))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (137, 146))	('PIK3CA', 'Gene', '5290', (0, 6))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (63, 86))	('ovarian endometrioid carcinomas', 'Disease', (55, 86))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (55, 86))
11453	18842102	In a recent mutational analysis of 72 primary ovarian endometrioid carcinomas, Wu and colleagues found that mutational defects in canonical Wnt signaling were significantly associated with mutations predicted to deregulate PI3K/Pten signaling.	('signaling', 'biological_process', 'GO:0023052', ('233', '242'))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (54, 76))	('ovarian endometrioid carcinomas', 'Disease', (46, 77))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (46, 77))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('defects', 'NegReg', (119, 126))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (54, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('associated', 'Reg', (173, 183))	('canonical Wnt signaling', 'Pathway', (130, 153))	('PI3K/Pten', 'Gene', '5290;5728', (223, 232))	('PI3K', 'molecular_function', 'GO:0016303', ('223', '227'))	('mutations', 'Var', (189, 198))	('PI3K/Pten', 'Gene', (223, 232))
11454	18842102	Tumors with these mutations tended to be low-grade and low-stage.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('low-grade', 'CPA', (41, 50))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('low-stage', 'CPA', (55, 64))	('mutations', 'Var', (18, 27))
11459	18842102	In contrast, TP53 mutations are common in both uterine and ovarian endometrioid carcinomas.	('TP53', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('uterine', 'Disease', (47, 54))	('common', 'Reg', (32, 38))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (67, 89))	('ovarian endometrioid carcinomas', 'Disease', (59, 90))	('TP53', 'Gene', '7157', (13, 17))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (67, 90))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (59, 90))	('mutations', 'Var', (18, 27))
11460	18842102	TP53 mutations have been reported in upwards of 60% of endometrioid carcinomas arising in the ovary overall, and in a greater percentage of high-grade tumors.	('TP53', 'Gene', '7157', (0, 4))	('reported', 'Reg', (25, 33))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('endometrioid carcinomas', 'Disease', (55, 78))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (5, 14))	('carcinomas arising in the ovary', 'Phenotype', 'HP:0100615', (68, 99))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (55, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (55, 78))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (55, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
11461	18842102	In the aforementioned series of 72 endometrioid carcinomas, Wu and colleagues documented TP53 mutations in 32 tumors; five additional tumors showed diffuse and strong nuclear accumulation of p53 protein, presumably because of missense mutations outside of the exons sequenced.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('TP53', 'Gene', '7157', (89, 93))	('tumors', 'Disease', (134, 140))	('additional tumors', 'Disease', 'MESH:D009369', (123, 140))	('endometrioid carcinomas', 'Disease', (35, 58))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('additional tumors', 'Disease', (123, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('missense mutations', 'Var', (226, 244))	('mutations', 'Var', (94, 103))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (35, 58))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('p53 protein', 'Protein', (191, 202))	('nuclear accumulation', 'MPA', (167, 187))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('protein', 'Protein', (195, 202))	('TP53', 'Gene', (89, 93))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (35, 57))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (35, 58))
11462	18842102	TP53 mutations were significantly associated with high tumor grade and were uncommon in tumors with documented Wnt/beta-cat and/or PI3K/Pten signaling defects.	('associated', 'Reg', (34, 44))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PI3K/Pten', 'Gene', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('mutations', 'Var', (5, 14))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('cat', 'molecular_function', 'GO:0004096', ('120', '123'))	('high tumor', 'Disease', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('high tumor', 'Disease', 'MESH:D009369', (50, 60))	('PI3K/Pten', 'Gene', '5290;5728', (131, 140))
11464	18842102	Low-grade (FIGO grade 1) tumors are characterized by mutations that deregulate the canonical Wnt/beta-cat and PI3K/Pten signaling pathways and typically lack TP53 mutations.	('PI3K/Pten', 'Gene', '5290;5728', (110, 119))	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PI3K/Pten', 'Gene', (110, 119))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('deregulate', 'PosReg', (68, 78))	('mutations', 'Var', (53, 62))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('cat', 'molecular_function', 'GO:0004096', ('102', '105'))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))
11465	18842102	High-grade (FIGO grade 2 and 3) tumors often harbor mutations of TP53 and lack Wnt/beta-cat or PI3K/Pten signaling pathway defects.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('PI3K/Pten', 'Gene', (95, 104))	('cat', 'molecular_function', 'GO:0004096', ('88', '91'))	('harbor', 'Reg', (45, 51))	('signaling pathway', 'biological_process', 'GO:0007165', ('105', '122'))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('PI3K/Pten', 'Gene', '5290;5728', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('lack', 'NegReg', (74, 78))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
11474	18842102	When the mutational status of the above genes was taken into account, it was noted that endometrioid tumors with gene expression profiles similar to serous carcinomas were usually high-grade and harbored TP53 mutations, while the endometrioid tumors with expression patterns distinct from the serous carcinomas tended to be low-grade and harbor mutations of CTNNB1, PTEN, and/or PIK3CA.	('endometrioid tumors', 'Disease', (88, 107))	('endometrioid tumors', 'Disease', (230, 249))	('gene expression', 'biological_process', 'GO:0010467', ('113', '128'))	('TP53', 'Gene', (204, 208))	('CTNNB1', 'Gene', '1499', (358, 364))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('serous carcinomas', 'Disease', (149, 166))	('PIK3CA', 'Gene', '5290', (379, 385))	('serous carcinomas', 'Disease', (293, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (300, 310))	('TP53', 'Gene', '7157', (204, 208))	('PTEN', 'Gene', (366, 370))	('CTNNB1', 'Gene', (358, 364))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('mutations', 'Var', (345, 354))	('endometrioid tumors', 'Disease', 'MESH:D016889', (88, 107))	('serous carcinomas', 'Disease', 'MESH:D018284', (293, 310))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('mutations', 'Var', (209, 218))	('PIK3CA', 'Gene', (379, 385))	('serous carcinomas', 'Disease', 'MESH:D018284', (149, 166))	('endometrioid tumors', 'Disease', 'MESH:D016889', (230, 249))	('PTEN', 'Gene', '5728', (366, 370))
11476	18842102	Shared genetic alterations such as TP53 mutation may be responsible for similarities in global gene expression pattern between high-grade endometrioid carcinomas and typical (high-grade) serous carcinomas.	('mutation', 'Var', (40, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (138, 160))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (138, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('TP53', 'Gene', '7157', (35, 39))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('TP53', 'Gene', (35, 39))	('endometrioid carcinomas', 'Disease', (138, 161))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (138, 161))	('serous carcinomas', 'Disease', 'MESH:D018284', (187, 204))	('serous carcinomas', 'Disease', (187, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
11485	18842102	Mutations in KRAS, BRAF, and TP53 are present in some clear cell carcinomas but their frequency is generally low.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('clear cell carcinomas', 'Disease', (54, 75))	('BRAF', 'Gene', '673', (19, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('BRAF', 'Gene', (19, 23))	('present', 'Reg', (38, 45))	('TP53', 'Gene', '7157', (29, 33))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (29, 33))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (54, 75))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
11486	18842102	For example, TP53 mutation and BRAF mutation were found in 8.3% and 6.3% of clear cell carcinomas, respectively.	('TP53', 'Gene', (13, 17))	('clear cell carcinomas', 'Disease', (76, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('found', 'Reg', (50, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (76, 97))	('mutation', 'Var', (18, 26))	('BRAF', 'Gene', '673', (31, 35))	('TP53', 'Gene', '7157', (13, 17))	('mutation', 'Var', (36, 44))	('BRAF', 'Gene', (31, 35))
11487	18842102	Mutations predicted to deregulate PI3K/Pten signaling are more common in clear cell carcinomas, with PIK3CA mutations reported in 20-25% and PTEN mutations in 8% of tumors in a few small series.	('PTEN', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('PI3K/Pten', 'Gene', (34, 43))	('clear cell carcinomas', 'Disease', (73, 94))	('PIK3CA', 'Gene', (101, 107))	('PTEN', 'Gene', '5728', (141, 145))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (73, 94))	('Mutations', 'Var', (0, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('tumors', 'Disease', (165, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('PI3K/Pten', 'Gene', '5290;5728', (34, 43))	('PIK3CA', 'Gene', '5290', (101, 107))	('mutations', 'Var', (146, 155))	('mutations', 'Var', (108, 117))	('tumors', 'Disease', 'MESH:D009369', (165, 171))
11492	18842102	The findings suggest that inactivation of the PTEN tumor suppressor gene, when it occurs, is a relatively early event in the development of ovarian clear cell carcinoma.	('inactivation', 'Var', (26, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PTEN', 'Gene', (46, 50))	('tumor', 'Disease', (51, 56))	('PTEN', 'Gene', '5728', (46, 50))	('ovarian clear cell carcinoma', 'Disease', (140, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('51', '67'))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (140, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('51', '67'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
11493	18842102	Although studies to date are rather limited, the clear cell carcinomas do not appear to share many other changes with endometrioid carcinomas, as canonical Wnt signaling pathway defects and microsatellite instability have not been observed with significant frequency in the clear cell tumors.	('canonical Wnt signaling pathway', 'biological_process', 'GO:0060070', ('146', '177'))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('microsatellite', 'Var', (190, 204))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (49, 70))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (118, 141))	('endometrioid carcinomas', 'Disease', (118, 141))	('defects', 'NegReg', (178, 185))	('canonical Wnt signaling pathway', 'Pathway', (146, 177))	('clear cell tumors', 'Disease', 'MESH:D008649', (274, 291))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (118, 140))	('clear cell tumors', 'Disease', (274, 291))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('clear cell carcinomas', 'Disease', (49, 70))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (118, 141))
11494	18842102	In primary ovarian mucinous carcinomas, KRAS mutation is a very common molecular alteration - occurring in upwards of 75% of ovarian mucinous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (19, 37))	('ovarian mucinous carcinomas', 'Disease', 'MESH:D002288', (125, 152))	('ovarian mucinous carcinomas', 'Phenotype', 'HP:0031494', (125, 152))	('primary ovarian mucinous carcinomas', 'Disease', 'MESH:D002288', (3, 38))	('KRAS', 'Gene', (40, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('ovarian mucinous carcinomas', 'Disease', (125, 152))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (133, 151))	('mutation', 'Var', (45, 53))	('KRAS', 'Gene', '3845', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('ovarian mucinous carcinomas', 'Phenotype', 'HP:0031494', (11, 38))	('primary ovarian mucinous carcinomas', 'Disease', (3, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('ovarian mucinous carcinomas', 'Disease', 'MESH:D002288', (11, 38))
11496	18842102	Interestingly, identical KRAS mutations have been detected in mucinous carcinomas and adjacent mucinous cystadenoma and borderline tumor, a molecular finding supporting this morphological continuum of tumor progression in ovarian mucinous neoplasms.	('tumor', 'Disease', (131, 136))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (230, 248))	('KRAS', 'Gene', '3845', (25, 29))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (62, 81))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('ovarian mucinous neoplasms', 'Disease', 'MESH:D010051', (222, 248))	('detected', 'Reg', (50, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('mucinous cystadenoma', 'Disease', 'MESH:D018291', (95, 115))	('tumor', 'Disease', (201, 206))	('KRAS', 'Gene', (25, 29))	('ovarian mucinous neoplasms', 'Phenotype', 'HP:0031494', (222, 248))	('neoplasms', 'Phenotype', 'HP:0002664', (239, 248))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('borderline tumor', 'Disease', (120, 136))	('borderline tumor', 'Disease', 'MESH:D012569', (120, 136))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (62, 80))	('mucinous cystadenoma', 'Disease', (95, 115))	('mutations', 'Var', (30, 39))	('ovarian mucinous neoplasms', 'Disease', (222, 248))	('neoplasm', 'Phenotype', 'HP:0002664', (239, 247))	('mucinous carcinomas', 'Disease', (62, 81))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))
11500	18842102	The discordant findings between the two studies suggest that clear cell carcinomas may be quite heterogeneous and analysis of large numbers of tumor samples using more advanced technologies with higher resolution may be needed to reliably identify common alterations of DNA copy number in clear cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (300, 310))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('tumor', 'Disease', (143, 148))	('clear cell carcinomas', 'Disease', (289, 310))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('clear cell carcinomas', 'Disease', (61, 82))	('DNA', 'cellular_component', 'GO:0005574', ('270', '273'))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (289, 310))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('DNA', 'Gene', (270, 273))	('alterations', 'Var', (255, 266))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (61, 82))
11502	18842102	The results demonstrate that on a genome-wide scale, the extent and level of DNA copy number gains and losses are less pronounced in clear cell carcinoma than in high-grade serous carcinomas.	('gains', 'PosReg', (93, 98))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 153))	('clear cell carcinoma', 'Disease', (133, 153))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('copy number', 'Var', (81, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('DNA', 'Gene', (77, 80))	('serous carcinomas', 'Disease', 'MESH:D018284', (173, 190))	('losses', 'NegReg', (103, 109))	('serous carcinomas', 'Disease', (173, 190))
11503	18842102	The most common changes in clear cell carcinomas include amplifications of regions on chromosomes 8q and 20q, and deletions on chromosome 9q; however, these events are not unique to clear cell carcinoma as they are also observed in high-grade serous carcinomas.	('clear cell carcinoma', 'Disease', (182, 202))	('serous carcinomas', 'Disease', (243, 260))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (27, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (27, 48))	('amplifications', 'MPA', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('chromosome', 'cellular_component', 'GO:0005694', ('127', '137'))	('carcinomas', 'Phenotype', 'HP:0030731', (250, 260))	('serous carcinomas', 'Disease', 'MESH:D018284', (243, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('deletions', 'Var', (114, 123))	('clear cell carcinomas', 'Disease', (27, 48))
11537	18842102	However, as described above, KRAS mutations in human ovarian endometrioid carcinomas are rather uncommon, and data supporting cooperation between mutant KRAS and PTEN loss in human tumors are lacking.	('KRAS', 'Gene', (29, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('human', 'Species', '9606', (175, 180))	('ovarian endometrioid carcinomas', 'Disease', (53, 84))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('PTEN loss', 'Disease', (162, 171))	('KRAS', 'Gene', '3845', (153, 157))	('human', 'Species', '9606', (47, 52))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (53, 84))	('tumors', 'Disease', (181, 187))	('KRAS', 'Gene', (153, 157))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('KRAS', 'Gene', '3845', (29, 33))	('mutations', 'Var', (34, 43))	('PTEN loss', 'Disease', 'MESH:D006223', (162, 171))
11543	18842102	As described above, mice with conditional deregulation of canonical Wnt and PI3K/Pten signaling due to Apc and Pten inactivation, respectively, consistently develop endometrioid-like carcinomas.	('Apc', 'cellular_component', 'GO:0005680', ('103', '106'))	('Apc', 'Gene', (103, 106))	('inactivation', 'Var', (116, 128))	('PI3K/Pten', 'Gene', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('develop', 'Reg', (157, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('mice', 'Species', '10090', (20, 24))	('carcinomas', 'Disease', 'MESH:D002277', (183, 193))	('deregulation', 'NegReg', (42, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('carcinomas', 'Disease', (183, 193))	('Pten', 'Gene', (111, 115))	('PI3K/Pten', 'Gene', '5290;5728', (76, 85))
11547	18842102	Intrabursal injection of AdCre was used to induce small tumors in the ovaries of Apcflox/flox;Ptenflox/flox mice, and then animals were treated for one month with rapamycin.	('ovaries', 'Disease', 'MESH:D010051', (70, 77))	('tumors in the ovaries', 'Phenotype', 'HP:0100615', (56, 77))	('rapamycin', 'Chemical', 'MESH:D020123', (163, 172))	('flox', 'Chemical', '-', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('flox', 'Chemical', '-', (103, 107))	('Ptenflox/flox', 'Var', (94, 107))	('mice', 'Species', '10090', (108, 112))	('ovaries', 'Disease', (70, 77))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('small tumors', 'Disease', 'MESH:D058405', (50, 62))	('Apcflox/flox', 'Var', (81, 93))	('flox', 'Chemical', '-', (84, 88))	('induce', 'PosReg', (43, 49))	('small tumors', 'Disease', (50, 62))	('Ptenflox', 'Chemical', '-', (94, 102))	('flox', 'Chemical', '-', (98, 102))
11570	18842102	Type I tumors often harbor somatic mutations of genes encoding protein kinases including KRAS, BRAF, PIK3CA and ERRB2, and other signaling molecules including CTNNB1 and PTEN.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('PIK3CA', 'Gene', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('PTEN', 'Gene', (170, 174))	('CTNNB1', 'Gene', '1499', (159, 165))	('BRAF', 'Gene', '673', (95, 99))	('ERRB2', 'Gene', (112, 117))	('BRAF', 'Gene', (95, 99))	('harbor', 'Reg', (20, 26))	('KRAS', 'Gene', '3845', (89, 93))	('PTEN', 'Gene', '5728', (170, 174))	('Type I tumors', 'Disease', (0, 13))	('CTNNB1', 'Gene', (159, 165))	('KRAS', 'Gene', (89, 93))	('PIK3CA', 'Gene', '5290', (101, 107))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('mutations', 'Var', (35, 44))
11571	18842102	In contrast, Type II tumors generally lack these mutations but are characterized by a high frequency of TP53 mutations which are rare in Type I tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Type I tumors', 'Disease', (137, 150))	('Type I tumors', 'Disease', 'MESH:D005776', (137, 150))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Type II tumors', 'Disease', (13, 27))	('Type II tumors', 'Disease', 'MESH:D009369', (13, 27))
11591	18842102	Because mutations of TP53 are currently the most common molecular genetic change in Type II tumors, it is possible that tumor DNA containing mutant TP53 DNA or polypeptides released from these tumors can be detected in body fluids.	('TP53', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', (92, 97))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('Type II tumors', 'Disease', 'MESH:D009369', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (193, 198))	('tumors', 'Disease', (92, 98))	('tumor', 'Disease', (120, 125))	('TP53', 'Gene', '7157', (21, 25))	('mutant', 'Var', (141, 147))	('TP53', 'Gene', '7157', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('Type II tumors', 'Disease', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (193, 199))
11592	18842102	Accordingly, tests that detect mutant TP53 or autoantibodies that react to mutant p53 protein in the blood could prove to be very useful for detecting small volume disease in high-risk patients.	('protein', 'Protein', (86, 93))	('TP53', 'Gene', (38, 42))	('small volume disease', 'Disease', (151, 171))	('mutant', 'Var', (75, 81))	('p53', 'Gene', (82, 85))	('patients', 'Species', '9606', (185, 193))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('TP53', 'Gene', '7157', (38, 42))
11595	18842102	This notion is supported by studies of Pohl et al., who demonstrated that treatment of ovarian serous carcinoma cells harboring KRAS or BRAF mutations with a MEK inhibitor, CI-1040, resulted in significant growth inhibition in vitro as compared to tumor cells with wild-type KRAS and BRAF.	('MEK', 'Gene', (158, 161))	('CI-1040', 'Chemical', 'MESH:C120227', (173, 180))	('BRAF', 'Gene', '673', (136, 140))	('BRAF', 'Gene', (136, 140))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (87, 111))	('growth inhibition', 'CPA', (206, 223))	('tumor', 'Disease', (248, 253))	('BRAF', 'Gene', '673', (284, 288))	('BRAF', 'Gene', (284, 288))	('KRAS', 'Gene', '3845', (128, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('KRAS', 'Gene', (128, 132))	('mutations', 'Var', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('MEK', 'Gene', '5609', (158, 161))	('KRAS', 'Gene', '3845', (275, 279))	('KRAS', 'Gene', (275, 279))	('ovarian serous carcinoma', 'Disease', (87, 111))
11596	18842102	Since low-grade serous carcinoma and its presumptive precursor SBT have a high frequency of mutations in KRAS and BRAF, future clinical trials should help to determine if MEK inhibitors can prolong disease-free interval and overall survival in patients with advanced stage low-grade serous carcinomas.	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('serous carcinoma', 'Disease', 'MESH:D018284', (283, 299))	('KRAS', 'Gene', '3845', (105, 109))	('patients', 'Species', '9606', (244, 252))	('MEK', 'Gene', '5609', (171, 174))	('serous carcinoma', 'Disease', (16, 32))	('KRAS', 'Gene', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('serous carcinomas', 'Disease', (283, 300))	('MEK', 'Gene', (171, 174))	('prolong', 'PosReg', (190, 197))	('mutations', 'Var', (92, 101))	('serous carcinoma', 'Disease', 'MESH:D018284', (16, 32))	('disease-free interval', 'CPA', (198, 219))	('overall survival', 'CPA', (224, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('carcinomas', 'Phenotype', 'HP:0030731', (290, 300))	('serous carcinomas', 'Disease', 'MESH:D018284', (283, 300))
11597	18842102	Similarly, the observation that growth of murine ovarian carcinomas with PI3K/Pten signaling pathway defects is profoundly inhibited by drugs that target this pathway provides further support for testing such agents in women with disseminated low grade (Type I) endometrioid carcinomas.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (262, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (262, 285))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('PI3K/Pten', 'Gene', (73, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('inhibited', 'NegReg', (123, 132))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (262, 285))	('growth', 'CPA', (32, 38))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (49, 66))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (49, 67))	('ovarian carcinomas', 'Disease', (49, 67))	('murine', 'Species', '10090', (42, 48))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (49, 67))	('PI3K/Pten', 'Gene', '5290;5728', (73, 82))	('women', 'Species', '9606', (219, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (275, 285))	('defects', 'Var', (101, 108))	('endometrioid carcinomas', 'Disease', (262, 285))	('signaling pathway', 'biological_process', 'GO:0007165', ('83', '100'))
11607	18842102	Serous carcinomas comprise the majority of ovarian carcinomas, and most serous carcinomas are high grade and harbor TP53 mutations (Type II).	('TP53', 'Gene', (116, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (7, 17))	('mutations', 'Var', (121, 130))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (43, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('harbor', 'Reg', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (43, 60))	('Serous carcinomas', 'Disease', 'MESH:D018284', (0, 17))	('serous carcinomas', 'Disease', 'MESH:D018284', (72, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('serous carcinomas', 'Disease', (72, 89))	('ovarian carcinomas', 'Disease', (43, 61))	('TP53', 'Gene', '7157', (116, 120))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (43, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('Serous carcinomas', 'Disease', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
11610	18842102	The high level of chromosomal instability and relative paucity of known "hallmark" sequence mutations (other than TP53) that characterize the majority of ovarian carcinomas present a tremendous challenge with respect to developing effective screening programs or novel therapeutic strategies that target specific molecular defects in a given patient's tumor.	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (154, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('patient', 'Species', '9606', (342, 349))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('TP53', 'Gene', '7157', (114, 118))	('mutations', 'Var', (92, 101))	('high level of chromosomal instability', 'Phenotype', 'HP:0040012', (4, 41))	('chromosomal instability', 'Phenotype', 'HP:0040012', (18, 41))	('tumor', 'Disease', (352, 357))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (154, 172))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (154, 171))	('TP53', 'Gene', (114, 118))	('ovarian carcinomas', 'Disease', (154, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
11616	18842102	aCGH array comparative genomic hybridization AdCre adenovirus expressing Cre recombinase FIGO International Federation of Gynecology and Obstetrics FISH fluorescence in situ hybridization GEM genetically engineered mouse MOSE murine ovarian surface epithelium OSE ovarian surface epithelium SBT serous borderline tumor, also known as serous tumor of low malignant potential or atypical proliferative serous tumor SNP single nucleotide polymorphism Mullerian system includes organs derived from the Mullerian ducts during embryogenesis (fallopian tubes, uterus, and vagina) Endometriosis endometrial tissue outside of the endometrium and myometrium Chromosomal instability increased tendency to acquire chromosomal aberrations when chromosome replication, repair, or segregation are dysfunctional Microsatellite instability increased tendency to acquire alterations in the number of microsatellite repeats (short, repeated DNA sequences) when DNA mismatch repair is dysfunctional Conditional (floxed) alleles alleles with strategically located loxP recognition sequences allowing deletion of DNA between flanking loxP (flox) sites when Cre recombinase is expressed DNA copy number change somatic increase or decrease of tumor DNA dosage in defined regions of chromosomes compared to normal DNA in the same regions	('embryogenesis', 'biological_process', 'GO:0009793', ('521', '534'))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('tumor', 'Disease', (313, 318))	('serous borderline tumor', 'Disease', 'MESH:D012569', (295, 318))	('dysfunctional', 'Disease', (965, 978))	('tumor', 'Disease', 'MESH:D009369', (1219, 1224))	('DNA', 'cellular_component', 'GO:0005574', ('922', '925'))	('embryogenesis', 'biological_process', 'GO:0009792', ('521', '534'))	('deletion', 'Var', (1079, 1087))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('mouse', 'Species', '10090', (215, 220))	('flox', 'Chemical', '-', (1118, 1122))	('Endometriosis', 'Disease', 'MESH:D004715', (573, 586))	('DNA', 'Gene', (1091, 1094))	('serous tumor', 'Disease', (400, 412))	('fallopian tubes', 'Disease', 'MESH:D005184', (536, 551))	('mismatch repair', 'biological_process', 'GO:0006298', ('946', '961'))	('DNA', 'cellular_component', 'GO:0005574', ('1164', '1167'))	('DNA', 'cellular_component', 'GO:0005574', ('1225', '1228'))	('DNA', 'cellular_component', 'GO:0005574', ('1289', '1292'))	('serous tumor', 'Disease', (334, 346))	('serous tumor', 'Disease', 'MESH:D018284', (400, 412))	('tumor', 'Disease', (407, 412))	('tumor', 'Phenotype', 'HP:0002664', (1219, 1224))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('dysfunctional', 'Disease', 'MESH:D006331', (782, 795))	('Microsatellite instability', 'Disease', 'MESH:D053842', (796, 822))	('OSE', 'Chemical', '-', (260, 263))	('OSE', 'Chemical', '-', (222, 225))	('dysfunctional', 'Disease', 'MESH:D006331', (965, 978))	('tumor', 'Disease', 'MESH:D009369', (407, 412))	('increase', 'PosReg', (1195, 1203))	('serous tumor', 'Disease', 'MESH:D018284', (334, 346))	('tumor', 'Disease', (341, 346))	('flox', 'Chemical', '-', (992, 996))	('Chromosomal instability increased', 'Phenotype', 'HP:0040012', (648, 681))	('DNA', 'cellular_component', 'GO:0005574', ('942', '945'))	('embryogenesis', 'biological_process', 'GO:0009790', ('521', '534'))	('serous borderline tumor', 'Disease', (295, 318))	('decrease', 'NegReg', (1207, 1215))	('murine', 'Species', '10090', (226, 232))	('Endometriosis', 'Phenotype', 'HP:0030127', (573, 586))	('chromosome', 'cellular_component', 'GO:0005694', ('731', '741'))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('DNA', 'cellular_component', 'GO:0005574', ('1091', '1094'))	('Microsatellite instability', 'Disease', (796, 822))	('fallopian tubes', 'Disease', (536, 551))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (648, 671))	('Endometriosis', 'Disease', (573, 586))	('tumor', 'Disease', (1219, 1224))	('dysfunctional', 'Disease', (782, 795))
11625	23388101	The frequency of KRAS mutation was significantly higher in low-grade as compared to high-grade group (P = 0.006).	('low-grade', 'Var', (59, 68))	('mutation', 'Var', (22, 30))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))	('higher', 'PosReg', (49, 55))
11626	23388101	None of the samples had BRAF mutation.	('mutation', 'Var', (29, 37))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))
11630	23388101	Mutational analysis for KRAS and BRAF discloses some possible interactions between different tumorigenic pathways of low- and high-grade carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('carcinomas', 'Disease', (137, 147))	('carcinomas', 'Disease', 'MESH:D002277', (137, 147))	('BRAF', 'Gene', '673', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('KRAS', 'Gene', '3845', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Mutational', 'Var', (0, 10))	('BRAF', 'Gene', (33, 37))	('tumor', 'Disease', (93, 98))	('interactions', 'Reg', (62, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('KRAS', 'Gene', (24, 28))
11631	23388101	Immunohistochemical staining for MAPK was not sufficiently sensitive, nor specific, to precisely predict the KRAS mutation.	('mutation', 'Var', (114, 122))	('KRAS', 'Gene', '3845', (109, 113))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('KRAS', 'Gene', (109, 113))
11632	23388101	However, it appears to be quite reliable in ruling out a KRAS mutation if the staining is negative.	('KRAS', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('KRAS', 'Gene', '3845', (57, 61))
11642	23388101	Die Haufigkeit der KRAS Mutation war bedeutend hoher in "low-grade" im Verglich zu der "high-grade" Gruppe (P = 0.006).	('Mutation', 'Var', (24, 32))	('KRAS', 'Gene', '3845', (19, 23))	('KRAS', 'Gene', (19, 23))
11643	23388101	Keiner der Stichproben hate BRAF Mutation.	('BRAF', 'Gene', (28, 32))	('Stichproben', 'Chemical', '-', (11, 22))	('BRAF', 'Gene', '673', (28, 32))	('Mutation', 'Var', (33, 41))
11645	23388101	Sieben der "high-grade" Stichproben (11.7%) waren KRAS Mutation und p53 Expression positive.	('KRAS', 'Gene', (50, 54))	('Stichproben', 'Chemical', '-', (24, 35))	('Expression', 'MPA', (72, 82))	('Mutation', 'Var', (55, 63))	('KRAS', 'Gene', '3845', (50, 54))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))
11648	23388101	Die Immunohistochemische Expression fur MAPK war nicht empfindlich oder spezifisch genug um den KRAS mutations Status des Tumor genau vorauszusagen.	('Tumor', 'Phenotype', 'HP:0002664', (122, 127))	('KRAS', 'Gene', '3845', (96, 100))	('mutations', 'Var', (101, 110))	('fur', 'Chemical', '-', (36, 39))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('KRAS', 'Gene', (96, 100))
11660	23388101	More than 75% of high-grade carcinomas harbor TP53 mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('carcinomas', 'Disease', (28, 38))	('carcinomas', 'Disease', 'MESH:D002277', (28, 38))	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))
11662	23388101	The loss of wild type p53 as a transcriptional suppressor may lead to unregulated or inappropriate expression of topoisomerase II alpha (topoII alpha), resulting in increased cell proliferation.	('expression', 'MPA', (99, 109))	('cell proliferation', 'CPA', (175, 193))	('p53', 'Gene', (22, 25))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('113', '129'))	('p53', 'Gene', '7157', (22, 25))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('increased', 'PosReg', (165, 174))	('loss', 'Var', (4, 8))
11710	23388101	KRAS mutation was found in 54.5% of low-grade and 13.8% of high-grade OSCs.	('KRAS', 'Gene', '3845', (0, 4))	('OSCs', 'Phenotype', 'HP:0012887', (70, 74))	('low-grade', 'Disease', (36, 45))	('OSC', 'Gene', (70, 73))	('found', 'Reg', (18, 23))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('OSC', 'Gene', '4047', (70, 73))
11711	23388101	The frequency of KRAS mutation was significantly higher in low-grade as compared to high-grade group (chi2 = 7.4, P = 0.006).	('KRAS', 'Gene', '3845', (17, 21))	('higher', 'PosReg', (49, 55))	('mutation', 'Var', (22, 30))	('KRAS', 'Gene', (17, 21))
11714	23388101	As shown in Table 3, the relationship between immunoreactivity and KRAS status is not statistically strong enough to use immunoreactivity to reliably detect KRAS mutation.	('KRAS', 'Gene', '3845', (157, 161))	('mutation', 'Var', (162, 170))	('KRAS', 'Gene', (67, 71))	('KRAS', 'Gene', (157, 161))	('KRAS', 'Gene', '3845', (67, 71))
11717	23388101	Therefore, MAPK immunopositivity has only limited value in predicting KRAS mutations, with a sensitivity of 0.43, a specificity of 0.78, a positive predictive value of 0.32, and a negative predictive value of 0.85.	('KRAS', 'Gene', (70, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('11', '15'))	('mutations', 'Var', (75, 84))	('KRAS', 'Gene', '3845', (70, 74))
11718	23388101	Currently, low-grade and high-grade serous carcinomas are thought to represent two distinct pathways of ovarian carcinogenesis, rather than opposite ends of severity along a single trajectory of tumor progression.	('serous carcinomas', 'Disease', (36, 53))	('tumor', 'Disease', (195, 200))	('low-grade', 'Var', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('ovarian carcinogenesis', 'Disease', 'MESH:D063646', (104, 126))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('ovarian carcinogenesis', 'Disease', (104, 126))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('serous carcinomas', 'Disease', 'MESH:D018284', (36, 53))
11726	23388101	Reports point towards a high frequency of KRAS and BRAF mutations in low-grade OSCs, making this pathway an attractive therapeutic target by interfering with its downstream effectors.	('KRAS', 'Gene', (42, 46))	('mutations', 'Var', (56, 65))	('KRAS', 'Gene', '3845', (42, 46))	('OSCs', 'Phenotype', 'HP:0012887', (79, 83))	('interfering', 'NegReg', (141, 152))	('OSC', 'Gene', (79, 82))	('OSC', 'Gene', '4047', (79, 82))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (51, 55))
11727	23388101	The preliminary promising results of a phase II clinical trial evaluating AZD6244 (selumetenib), an inhibitor of MEK-1/2, have been reported.	('MEK', 'Gene', '5609', (113, 116))	('MEK-1', 'molecular_function', 'GO:0004708', ('113', '118'))	('clinical', 'Species', '191496', (48, 56))	('AZD6244', 'Var', (74, 81))	('AZD6244', 'Chemical', 'MESH:C517975', (74, 81))	('selumetenib', 'Chemical', '-', (83, 94))	('MEK', 'Gene', (113, 116))
11728	23388101	We report our findings of the immunohistochemical expression of p53, MAPK, topoII alpha and Ki67, and molecular analysis for KRAS and BRAF mutations in the OSCs.	('OSC', 'Gene', '4047', (156, 159))	('KRAS', 'Gene', (125, 129))	('mutations', 'Var', (139, 148))	('BRAF', 'Gene', '673', (134, 138))	('KRAS', 'Gene', '3845', (125, 129))	('MAPK', 'Gene', (69, 73))	('OSCs', 'Phenotype', 'HP:0012887', (156, 160))	('BRAF', 'Gene', (134, 138))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('OSC', 'Gene', (156, 159))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
11742	23388101	Mutations (including KRAS and BRAF) or overexpression of upstream components in signal transduction cascades, lead to constitutive activation of MAPK pathway.	('overexpression', 'PosReg', (39, 53))	('activation', 'PosReg', (131, 141))	('KRAS', 'Gene', '3845', (21, 25))	('MAPK', 'molecular_function', 'GO:0004707', ('145', '149'))	('MAPK pathway', 'Pathway', (145, 157))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('Mutations', 'Var', (0, 9))	('signal transduction', 'biological_process', 'GO:0007165', ('80', '99'))	('KRAS', 'Gene', (21, 25))
11743	23388101	Because of the frequent KRAS or BRAF mutations in serous tumors that follow type I pathway, we examined whether there would be a differential immunoexpression of activated MAPK in our low- and high-grade group.	('serous tumors', 'Disease', 'MESH:D018284', (50, 63))	('BRAF', 'Gene', '673', (32, 36))	('KRAS', 'Gene', '3845', (24, 28))	('MAPK', 'molecular_function', 'GO:0004707', ('172', '176'))	('BRAF', 'Gene', (32, 36))	('serous tumors', 'Disease', (50, 63))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('KRAS', 'Gene', (24, 28))
11746	23388101	Although the literature on MAPK immunoexpression in serous ovarian tumors is quite limited, our results support findings reported by Hsu et al.. We compared the findings of KRAS mutational analysis with active MAPK immunoreactivity.	('serous ovarian tumors', 'Disease', (52, 73))	('KRAS', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('MAPK', 'molecular_function', 'GO:0004707', ('210', '214'))	('KRAS', 'Gene', '3845', (173, 177))	('serous ovarian tumors', 'Phenotype', 'HP:0012887', (52, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutational', 'Var', (178, 188))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (52, 73))	('ovarian tumors', 'Phenotype', 'HP:0100615', (59, 73))
11747	23388101	In this study, frequency of KRAS mutation was significantly higher in low-grade as compared to the high-grade group.	('KRAS', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('KRAS', 'Gene', '3845', (28, 32))	('higher', 'PosReg', (60, 66))	('low-grade', 'Var', (70, 79))
11748	23388101	Interestingly, none of our OSC samples had BRAF mutation.	('BRAF', 'Gene', '673', (43, 47))	('OSC', 'Gene', (27, 30))	('BRAF', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))	('OSC', 'Gene', '4047', (27, 30))	('OSC', 'molecular_function', 'GO:0000250', ('27', '30'))
11749	23388101	Similar findings were reported by Wong et al., who detected BRAF mutation in only 2%, and KRAS mutation in 19% of low-grade OSCs.	('OSCs', 'Phenotype', 'HP:0012887', (124, 128))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('OSC', 'Gene', (124, 127))	('mutation', 'Var', (65, 73))	('OSC', 'Gene', '4047', (124, 127))
11754	23388101	According to our results, unlike the ones of Hsu et al., MAPK immunostaining was not sufficiently sensitive, nor specific, to precisely predict the KRAS mutational status of the tumor.	('KRAS', 'Gene', (148, 152))	('tumor', 'Disease', (178, 183))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('mutational', 'Var', (153, 163))	('KRAS', 'Gene', '3845', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
11755	23388101	However, MAPK immunostaining appears to be quite reliable in ruling out a KRAS mutation if the staining is negative.	('KRAS', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))	('MAPK', 'molecular_function', 'GO:0004707', ('9', '13'))	('KRAS', 'Gene', '3845', (74, 78))
11768	23388101	Also, mutational analysis for KRAS and BRAF discloses some possible interactions between type I and type II pathway and could be useful in detection of small proportion of high-grade carcinomas arising through type I pathway, with possible diverse clinical behavior and specific therapy requirements.	('interactions', 'Interaction', (68, 80))	('BRAF', 'Gene', '673', (39, 43))	('clinical', 'Species', '191496', (248, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('mutational analysis', 'Var', (6, 25))	('BRAF', 'Gene', (39, 43))	('carcinomas', 'Disease', 'MESH:D002277', (183, 193))	('type I', 'Pathway', (89, 95))	('carcinomas', 'Disease', (183, 193))	('type II pathway', 'Pathway', (100, 115))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (30, 34))
11786	23565736	Lastly, knockdown of CD44v6 decreases the adhesion and migration but not invasion capacities of SKOV3 cells.	('decreases', 'NegReg', (28, 37))	('CD44v6', 'Gene', (21, 27))	('knockdown', 'Var', (8, 17))	('rat', 'Species', '10116', (58, 61))	('SKOV3', 'CellLine', 'CVCL:0532', (96, 101))
11797	23565736	Alternative splicing of exons 6-15 (variant exons 1-10) gives rise to numerous variant forms of CD44 (CD44v), in which an additional segment encoded by one or more of the variant exons is inserted in the extracellular domain of CD44s, which is encoded by exons 1-5 and exons 16-20 .	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('CD44', 'Gene', (228, 232))	('CD44', 'Gene', '960', (102, 106))	('CD44', 'Gene', '960', (96, 100))	('variant', 'Var', (171, 178))	('CD44', 'Gene', '960', (228, 232))	('CD44', 'Gene', (102, 106))	('extracellular', 'cellular_component', 'GO:0005576', ('204', '217'))	('CD44', 'Gene', (96, 100))	('variant', 'Var', (79, 86))
11801	23565736	However, aberrant expression of CD44v has been implicated in the initiation, progression and recurrence of various human cancers .	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CD44v', 'Gene', (32, 37))	('implicated', 'Reg', (47, 57))	('human', 'Species', '9606', (115, 120))	('aberrant expression', 'Var', (9, 28))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
11803	23565736	Among numerous CD44v, CD44v6 was initially shown to be able to promote the metastatic potential of a rat pancreatic adenocarcinoma cell line in animal models .	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (105, 130))	('rat', 'Species', '10116', (101, 104))	('CD44v6', 'Var', (22, 28))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (105, 130))	('promote', 'PosReg', (63, 70))	('pancreatic adenocarcinoma', 'Disease', (105, 130))
11805	23565736	Specifically, CD44v6 has been shown to promote ovarian cancer metastasis by mediating ovarian tumor cell attachment to the peritoneum .	('mediating', 'Reg', (76, 85))	('CD44v6', 'Var', (14, 20))	('promote', 'PosReg', (39, 46))	('ovarian tumor', 'Disease', 'MESH:D010051', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ovarian cancer metastasis', 'Disease', 'MESH:D009362', (47, 72))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('ovarian tumor', 'Disease', (86, 99))	('ovarian cancer metastasis', 'Disease', (47, 72))	('ovarian tumor', 'Phenotype', 'HP:0100615', (86, 99))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
11866	23565736	To explore this possibility, we extended our study to knock down CD44v6 expression in SKOV3 cells, a human serous ovarian cancer cell line, and assess the impact of knockdown of CD44v6 on the adhesion, invasion and migration capacities of SKOV3 cells.	('serous ovarian cancer', 'Disease', (107, 128))	('SKOV3', 'CellLine', 'CVCL:0532', (239, 244))	('knock', 'Var', (54, 59))	('CD44v6', 'Gene', (65, 71))	('human', 'Species', '9606', (101, 106))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (107, 128))	('rat', 'Species', '10116', (218, 221))	('invasion', 'CPA', (202, 210))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('CD44v6', 'Var', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SKOV3', 'CellLine', 'CVCL:0532', (86, 91))	('adhesion', 'CPA', (192, 200))	('migration capacities', 'CPA', (215, 235))
11869	23565736	The data indicate that SKOV3 cells with CD44v6 knockdown showed a decreased cell adhesion (Figure  5A) and migration (Figure  5C) compared with the cells transfected with siRNA-NC control groups.	('rat', 'Species', '10116', (110, 113))	('migration', 'CPA', (107, 116))	('SKOV3', 'CellLine', 'CVCL:0532', (23, 28))	('decreased', 'NegReg', (66, 75))	('cell adhesion', 'CPA', (76, 89))	('cell adhesion', 'biological_process', 'GO:0007155', ('76', '89'))	('knockdown', 'Var', (47, 56))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (66, 89))	('CD44v6', 'Gene', (40, 46))
11870	23565736	However, we found that knockdown of CD44v6 in SKOV3 cells did not affect the invasion capacity of this human serous ovarian cancer cell line (Figure  5B).	('serous ovarian cancer', 'Disease', 'MESH:D010051', (109, 130))	('human', 'Species', '9606', (103, 108))	('knockdown', 'Var', (23, 32))	('serous ovarian cancer', 'Disease', (109, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CD44v6', 'Gene', (36, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('SKOV3', 'CellLine', 'CVCL:0532', (46, 51))
11871	23565736	Taken together, these findings suggest that CD44v6 may play a role in ovarian cancer metastasis by mediating tumor cell adhesion and migration.	('ovarian cancer metastasis', 'Disease', (70, 95))	('cell adhesion', 'biological_process', 'GO:0007155', ('115', '128'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('mediating', 'Reg', (99, 108))	('CD44v6', 'Var', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('rat', 'Species', '10116', (136, 139))	('ovarian cancer metastasis', 'Disease', 'MESH:D009362', (70, 95))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (109, 114))
11872	23565736	Recently, numerous studies have focused on investigating the expression of CD44v6 in malignancy to address the association of CD44v6 with tumor progression, metastasis and recurrence.	('malignancy', 'Disease', (85, 95))	('tumor', 'Disease', (138, 143))	('malignancy', 'Disease', 'MESH:D009369', (85, 95))	('CD44v6', 'Var', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('metastasis', 'CPA', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
11873	23565736	So far, CD44v6 has been shown to be a useful prognostic factor for a variety of cancers including those of the stomach , head and neck , prostate , and lung .	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('CD44v6', 'Var', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('stomach', 'Disease', (111, 118))	('prostate', 'Disease', (137, 145))	('cancers', 'Disease', (80, 87))	('lung', 'Disease', (152, 156))	('neck', 'cellular_component', 'GO:0044326', ('130', '134'))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
11874	23565736	As expected, a number of groups have also investigated the expression of CD44v6 in ovarian cancer to examine the potential correlation of this CD44 variant with ovarian cancer development and progression.	('variant', 'Var', (148, 155))	('CD44', 'Gene', '960', (143, 147))	('investigated', 'Reg', (42, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('ovarian cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('CD44', 'Gene', (143, 147))	('ovarian cancer', 'Disease', 'MESH:D010051', (161, 175))	('CD44', 'Gene', '960', (73, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ovarian cancer', 'Disease', (161, 175))	('CD44', 'Gene', (73, 77))
11875	23565736	While several studies demonstrated that soluble CD44v6 is not associated with the development and metastasis of ovarian cancer , other investigations showed that CD44v6 is correlated with tumor progression and metastasis .	('tumor', 'Disease', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('metastasis', 'CPA', (210, 220))	('CD44v6', 'Var', (162, 168))	('correlated with', 'Reg', (172, 187))	('rat', 'Species', '10116', (29, 32))	('soluble', 'cellular_component', 'GO:0005625', ('40', '47'))	('metastasis of ovarian cancer', 'Disease', (98, 126))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (98, 126))
11882	23565736	Our data indicate that CD44v6 expression is associated with ovarian serous cancer recurrence (Figure  1), which is consistent with the finding of a previous study in which CD44v6 expression was assessed by IHC .	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (60, 81))	('CD44v6 expression', 'Var', (23, 40))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (60, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ovarian serous cancer', 'Disease', (60, 81))	('associated with', 'Reg', (44, 59))
11884	23565736	Interestingly, we found that CD44v6 expression is correlated with the abdominal cavity metastasis of epithelial ovarian cancer (Figure  2).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('CD44v6', 'Var', (29, 35))	('abdominal cavity', 'Disease', (70, 86))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (101, 126))	('correlated', 'Reg', (50, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('metastasis of epithelial ovarian cancer', 'Disease', 'MESH:D009362', (87, 126))	('metastasis of epithelial ovarian cancer', 'Disease', (87, 126))
11896	23565736	Our results indicate that CD44v6 expression is only up-regulated in tumor tissues from the recurrent disease and abdominal cavity metastasis site, suggesting that CD44v6 may be an adhesion molecule during the process of ovarian cancer cell adhesion and metastasis.	('tumor', 'Disease', (68, 73))	('cell adhesion', 'biological_process', 'GO:0007155', ('235', '248'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (220, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('ovarian cancer', 'Disease', 'MESH:D010051', (220, 234))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CD44v6', 'Gene', (26, 32))	('ovarian cancer', 'Disease', (220, 234))	('CD44v6', 'Var', (163, 169))
11897	23565736	Moreover, SKOV3 cell adhesion and migration were decreased after knocking down CD44v6 expression by siRNA, indicating that CD44v6 may play a role in mediating tumor cell adhesion and migration during the metastasis process.	('knocking down', 'Var', (65, 78))	('rat', 'Species', '10116', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('CD44v6', 'Gene', (79, 85))	('rat', 'Species', '10116', (37, 40))	('decreased', 'NegReg', (49, 58))	('tumor', 'Disease', (159, 164))	('expression', 'MPA', (86, 96))	('cell adhesion', 'biological_process', 'GO:0007155', ('165', '178'))	('play', 'Reg', (134, 138))	('SKOV3', 'CellLine', 'CVCL:0532', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cell adhesion', 'biological_process', 'GO:0007155', ('16', '29'))
11907	21240255	Based on fluorescence in situ hybridization, we found that 35 (20%) of 175 high-grade serous carcinomas had an increased DNA copy number at the NACC1 locus, and those amplified cases were associated with early disease recurrence within 6 months (p= 0.013).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('increased', 'PosReg', (111, 120))	('NACC1', 'Gene', (144, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('serous carcinomas', 'Disease', 'MESH:D018284', (86, 103))	('serous carcinomas', 'Disease', (86, 103))	('DNA copy number', 'Var', (121, 136))	('NACC1', 'Gene', '112939', (144, 149))
11908	21240255	A significantly high level of NAC1 protein expression based on immunohistochemistry was detected in amplified tumors as compared to non-amplified tumors (p< 0.005).	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('protein', 'Protein', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('amplified', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('tumors', 'Disease', (146, 152))	('NAC', 'cellular_component', 'GO:0005854', ('30', '33'))	('expression', 'MPA', (43, 53))	('NAC1', 'Gene', (30, 34))
11909	21240255	In summary, our data suggest that amplification at the ch19p13.2 NACC1 locus, leading to NAC1 overexpression, is one of the molecular genetic alterations associated with early tumor recurrence in ovarian cancer.	('overexpression', 'PosReg', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('tumor', 'Disease', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('NACC1', 'Gene', (65, 70))	('ovarian cancer', 'Disease', 'MESH:D010051', (196, 210))	('NAC', 'cellular_component', 'GO:0005854', ('89', '92'))	('NACC1', 'Gene', '112939', (65, 70))	('ovarian cancer', 'Disease', (196, 210))	('amplification', 'Var', (34, 47))	('NAC1', 'Gene', (89, 93))	('associated', 'Reg', (154, 164))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
11915	21240255	The results from these reports indicate that high-grade serous carcinomas are characterized by higher levels of sub-chromosomal gains and losses than clear cell carcinoma, low-grade serous carcinomas, and their precursor lesions, serous borderline tumors.	('serous carcinomas', 'Disease', (56, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('losses', 'NegReg', (138, 144))	('carcinoma', 'Disease', (63, 72))	('serous carcinomas', 'Disease', (182, 199))	('serous borderline tumors', 'Disease', 'MESH:D012569', (230, 254))	('carcinoma', 'Disease', 'MESH:D002277', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('sub-chromosomal gains', 'Var', (112, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('carcinoma', 'Disease', (189, 198))	('serous carcinomas', 'Disease', 'MESH:D018284', (56, 73))	('serous borderline tumors', 'Disease', (230, 254))	('carcinoma', 'Disease', 'MESH:D002277', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('serous carcinomas', 'Disease', 'MESH:D018284', (182, 199))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Disease', 'MESH:D002277', (189, 198))	('carcinoma', 'Disease', (161, 170))
11916	21240255	This finding suggests that chromosomal instability is more pronounced in high-grade serous carcinomas than other types of ovarian cancer.	('chromosomal instability', 'Var', (27, 50))	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('chromosomal instability', 'Phenotype', 'HP:0040012', (27, 50))	('ovarian cancer', 'Disease', (122, 136))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('serous carcinomas', 'Disease', 'MESH:D018284', (84, 101))	('serous carcinomas', 'Disease', (84, 101))
11918	21240255	As a result, in addition to several previously known amplified chromosomal regions containing CCNE1, AKT2, and PIK3CA loci, we identified several new amplified loci including chromosome (ch)11q13.5 harboring Rsf-1 (HBXAP), chr19p13.12 harboring NOTCH3, and regions at chr12p13, chr8q24 and chr19p13.2.	('chr19p13.12', 'Var', (223, 234))	('AKT2', 'Gene', (101, 105))	('Rsf-1', 'Gene', '51773', (208, 213))	('HBXAP', 'Gene', (215, 220))	('CCNE1', 'Gene', '898', (94, 99))	('NOTCH3', 'Gene', '4854', (245, 251))	('HBXAP', 'Gene', '51773', (215, 220))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('AKT2', 'Gene', '208', (101, 105))	('PIK3CA', 'Gene', (111, 117))	('Rsf-1', 'Gene', (208, 213))	('chr12p13', 'Var', (268, 276))	('chr8q24', 'Var', (278, 285))	('CCNE1', 'Gene', (94, 99))	('PIK3CA', 'Gene', '5290', (111, 117))	('chr19p13.2', 'Var', (290, 300))	('NOTCH3', 'Gene', (245, 251))
11926	21240255	Copy number variations of the ch9p13.2 amplicon in 343 ovarian tumor samples and paired normal samples were characterized using the Affymetrix SNP6.0 array by the Broad Institute (Boston).	('ovarian tumor', 'Phenotype', 'HP:0100615', (55, 68))	('ovarian tumor', 'Disease', 'MESH:D010051', (55, 68))	('Copy number variations', 'Var', (0, 22))	('ch9p13.2', 'Gene', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ovarian tumor', 'Disease', (55, 68))
11940	21240255	Based on this preliminary finding, we decided to determine the frequency of increased copy number at this region in a large set of high-grade serous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('serous carcinomas', 'Disease', 'MESH:D018284', (142, 159))	('serous carcinomas', 'Disease', (142, 159))	('copy number', 'Var', (86, 97))
11950	21240255	In this study, we further determined if amplification of the NACC1 locus was related to early disease recurrence in high-grade ovarian serous carcinomas.	('ovarian serous carcinomas', 'Disease', (127, 152))	('NACC1', 'Gene', (61, 66))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (127, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('NACC1', 'Gene', '112939', (61, 66))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (127, 152))	('amplification', 'Var', (40, 53))	('related to', 'Reg', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
11955	21240255	We observed that amplified tumors exhibited a significantly higher level of NAC1 expression than those without amplification (p< 0.005, Fisher's exact test).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('higher', 'PosReg', (60, 66))	('NAC1', 'Protein', (76, 80))	('NAC', 'cellular_component', 'GO:0005854', ('76', '79'))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('amplified', 'Var', (17, 26))	('expression', 'MPA', (81, 91))
11956	21240255	As shown in Table 2, the percentage of tumors with an immunostaining score of 3+ was 63%, 26%, and 13% in specimens showing high amplification, low level gain, and no amplification at the NACC1 locus, respectively.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('low level gain', 'Var', (144, 158))	('high amplification', 'Var', (124, 142))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('NACC1', 'Gene', (188, 193))	('NACC1', 'Gene', '112939', (188, 193))	('tumors', 'Disease', (39, 45))
11958	21240255	Next, we asked whether NACC1 amplification was associated with amplification of other chromosomal loci, including CCNE1, RSF1, NOTCH3, AKT2, and PIK3CA, which were frequently amplified in high-grade serous carcinoma.	('serous carcinoma', 'Disease', 'MESH:D018284', (199, 215))	('NACC1', 'Gene', (23, 28))	('PIK3CA', 'Gene', '5290', (145, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('amplification', 'Var', (29, 42))	('NOTCH3', 'Gene', (127, 133))	('AKT2', 'Gene', (135, 139))	('amplification', 'MPA', (63, 76))	('NACC1', 'Gene', '112939', (23, 28))	('RSF1', 'Gene', '51773', (121, 125))	('RSF1', 'Gene', (121, 125))	('AKT2', 'Gene', '208', (135, 139))	('PIK3CA', 'Gene', (145, 151))	('NOTCH3', 'Gene', '4854', (127, 133))	('serous carcinoma', 'Disease', (199, 215))	('CCNE1', 'Gene', (114, 119))	('associated', 'Reg', (47, 57))	('CCNE1', 'Gene', '898', (114, 119))
11965	21240255	The significant co-amplification event of ch19p13.2 and the NOTCH3 locus (ch19p13.12) suggests such a possibility given the proximal location of both loci.	('NOTCH3', 'Gene', (60, 66))	('NOTCH3', 'Gene', '4854', (60, 66))	('co-amplification', 'MPA', (16, 32))	('ch19p13.2', 'Gene', (42, 51))	('ch19p13.12', 'Var', (74, 84))
11973	21240255	This finding suggests that NACC1 is one of the genes that contribute to tumor progression in ovarian cancer in which ch19p13.2 amplification is found.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ovarian cancer', 'Disease', (93, 107))	('ch19p13.2', 'Var', (117, 126))	('tumor', 'Disease', (72, 77))	('NACC1', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('NACC1', 'Gene', '112939', (27, 32))
11980	21240255	Induced expression of a NAC1 deletion mutant (N130) containing exclusively the BTB domain attenuates the tumor-promoting functions of NAC1.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('attenuates', 'NegReg', (90, 100))	('NAC', 'cellular_component', 'GO:0005854', ('134', '137'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('BTB', 'Chemical', '-', (79, 82))	('NAC', 'cellular_component', 'GO:0005854', ('24', '27'))	('N130', 'Var', (46, 50))	('tumor', 'Disease', (105, 110))	('BTB domain', 'molecular_function', 'GO:0031208', ('79', '89'))	('NAC1', 'Gene', (24, 28))
11982	21240255	More recently, we observed that enforced expression of NAC1 conferred drug resistance, and NAC1 knockdown by shRNA sensitized paclitaxel cytotoxicity in ovarian cancer cells in vitro.	('knockdown', 'Var', (96, 105))	('NAC', 'cellular_component', 'GO:0005854', ('91', '94'))	('sensitized', 'PosReg', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('drug resistance', 'biological_process', 'GO:0042493', ('70', '85'))	('cytotoxicity', 'Disease', (137, 149))	('ovarian cancer', 'Disease', (153, 167))	('drug resistance', 'Phenotype', 'HP:0020174', (70, 85))	('NAC', 'cellular_component', 'GO:0005854', ('55', '58'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (153, 167))	('drug resistance', 'biological_process', 'GO:0009315', ('70', '85'))	('conferred', 'Reg', (60, 69))	('cytotoxicity', 'Disease', 'MESH:D064420', (137, 149))	('drug resistance', 'MPA', (70, 85))	('NAC1', 'Gene', (91, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (126, 136))	('ovarian cancer', 'Disease', 'MESH:D010051', (153, 167))	('NAC1', 'Gene', (55, 59))
11987	21240255	Our previous studies showed amplification of the NOTCH3 locus in 32% of ovarian high-grade serous carcinomas, and Notch3 overexpression is related to the recurrence of ovarian cancer and confers drug resistance.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('ovarian high', 'Phenotype', 'HP:0008209', (72, 84))	('serous carcinomas', 'Disease', 'MESH:D018284', (91, 108))	('drug resistance', 'biological_process', 'GO:0009315', ('195', '210'))	('amplification', 'Var', (28, 41))	('drug resistance', 'Phenotype', 'HP:0020174', (195, 210))	('drug resistance', 'biological_process', 'GO:0042493', ('195', '210'))	('ovarian cancer', 'Disease', 'MESH:D010051', (168, 182))	('related to', 'Reg', (139, 149))	('overexpression', 'PosReg', (121, 135))	('Notch3', 'Gene', '4854', (114, 120))	('Notch3', 'Gene', (114, 120))	('ovarian cancer', 'Disease', (168, 182))	('NOTCH3', 'Gene', '4854', (49, 55))	('serous carcinomas', 'Disease', (91, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (168, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('NOTCH3', 'Gene', (49, 55))
11988	21240255	Ovarian cancer cells which had amplified and overexpressed Notch3 were dependent on Notch3 signaling for cellular survival and growth.	('dependent', 'Reg', (71, 80))	('amplified', 'Var', (31, 40))	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('overexpressed', 'PosReg', (45, 58))	('Notch3', 'Gene', '4854', (59, 65))	('Notch3', 'Gene', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('Notch3', 'Gene', '4854', (84, 90))	('Ovarian cancer', 'Disease', (0, 14))	('Notch3', 'Gene', (84, 90))
11990	21240255	Interestingly, we have recently demonstrated that inactivation of the Notch3 pathway led to inhibition of NAC1 expression, indicating that Notch3 signaling may regulate the expression of NAC1.	('regulate', 'Reg', (160, 168))	('NAC', 'cellular_component', 'GO:0005854', ('187', '190'))	('NAC1', 'Gene', (187, 191))	('inhibition', 'NegReg', (92, 102))	('Notch3', 'Gene', '4854', (70, 76))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('expression', 'MPA', (111, 121))	('Notch3', 'Gene', (70, 76))	('NAC1', 'Gene', (106, 110))	('Notch3', 'Gene', '4854', (139, 145))	('Notch3', 'Gene', (139, 145))	('expression', 'MPA', (173, 183))	('inactivation', 'Var', (50, 62))	('NAC', 'cellular_component', 'GO:0005854', ('106', '109'))
11991	21240255	In summary, based on analysis of the TCGA ovarian cancer dataset and our FISH result, we were able to demonstrate that amplification at the NACC1 locus was one of the frequent molecular genetic alterations in ovarian high-grade serous carcinomas.	('serous carcinomas', 'Disease', (228, 245))	('ovarian cancer', 'Phenotype', 'HP:0100615', (42, 56))	('ovarian high', 'Phenotype', 'HP:0008209', (209, 221))	('NACC1', 'Gene', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('ovarian cancer', 'Disease', 'MESH:D010051', (42, 56))	('ovarian cancer', 'Disease', (42, 56))	('amplification', 'Var', (119, 132))	('serous carcinomas', 'Disease', 'MESH:D018284', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('NACC1', 'Gene', '112939', (140, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (235, 245))
11992	21240255	NAC1 overexpression may be, in part, attributed to the increase in DNA copy number, explaining why amplification at the NACC1 locus is related to early tumor recurrence in ovarian cancer.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('related to', 'Reg', (135, 145))	('NACC1', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('ovarian cancer', 'Phenotype', 'HP:0100615', (172, 186))	('tumor', 'Disease', (152, 157))	('ovarian cancer', 'Disease', 'MESH:D010051', (172, 186))	('amplification', 'Var', (99, 112))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('NACC1', 'Gene', '112939', (120, 125))	('ovarian cancer', 'Disease', (172, 186))	('NAC', 'cellular_component', 'GO:0005854', ('0', '3'))
11993	21240255	Future studies should aim at fine mapping the ch19p13.2 amplified region and assessing the potential of other genes at the ch19p13.2 locus to contribute to the aggressive behavior of ovarian serous carcinomas that harbor this amplification.	('aggressive behavior of ovarian serous carcinomas', 'Disease', 'MESH:D001523', (160, 208))	('aggressive behavior', 'Phenotype', 'HP:0000718', (160, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('aggressive behavior', 'biological_process', 'GO:0002118', ('160', '179'))	('amplification', 'Var', (226, 239))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (183, 208))	('aggressive behavior of ovarian serous carcinomas', 'Disease', (160, 208))	('contribute', 'Reg', (142, 152))
12119	23788864	analyzed WT-1 immunoreactivity in 119 patients with ovarian serous cancer and showed that WT-1 positivity is positively correlated with high grade, advanced stage and higher Ki-67 labeling index, higher bcl-2 expression and poorer outcome in a study.	('higher', 'PosReg', (167, 173))	('expression', 'MPA', (209, 219))	('WT-1', 'Gene', '7490', (9, 13))	('WT-1', 'Gene', '7490', (90, 94))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (52, 73))	('patients', 'Species', '9606', (38, 46))	('high grade', 'CPA', (136, 146))	('bcl-2', 'Gene', (203, 208))	('ovarian serous cancer', 'Disease', (52, 73))	('bcl-2', 'molecular_function', 'GO:0015283', ('203', '208'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('higher', 'PosReg', (196, 202))	('WT-1', 'Gene', (90, 94))	('Ki-67 labeling index', 'MPA', (174, 194))	('bcl-2', 'Gene', '596', (203, 208))	('WT-1', 'Gene', (9, 13))	('positivity', 'Var', (95, 105))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (52, 73))
12146	31474227	The IHC results showed that ANXA8 expression was higher in the malignant tumor group than in the borderline and benign tumor groups and normal ovary group, and high ANXA8 expression was an independent risk factor for survival and prognosis of ovarian cancer patients (P = 0.013).	('high', 'Var', (160, 164))	('expression', 'MPA', (34, 44))	('malignant tumor', 'Disease', (63, 78))	('ANXA8', 'Gene', (28, 33))	('ovarian cancer', 'Disease', 'MESH:D010051', (243, 257))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('benign tumor', 'Disease', (112, 124))	('malignant tumor', 'Disease', 'MESH:D018198', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ANXA8', 'Gene', '653145', (165, 170))	('ovarian cancer', 'Disease', (243, 257))	('patients', 'Species', '9606', (258, 266))	('ovarian cancer', 'Phenotype', 'HP:0100615', (243, 257))	('ANXA8', 'Gene', '653145', (28, 33))	('expression', 'MPA', (171, 181))	('ANXA8', 'Gene', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('benign tumor', 'Disease', 'MESH:D009369', (112, 124))	('higher', 'PosReg', (49, 55))
12148	31474227	ANXA8 was significantly highly expressed in ovarian cancer, and high ANXA8 expression was significantly correlated with poor prognosis.	('ANXA8', 'Gene', (0, 5))	('ANXA8', 'Gene', '653145', (0, 5))	('high', 'Var', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))	('ANXA8', 'Gene', (69, 74))	('ANXA8', 'Gene', '653145', (69, 74))	('highly', 'PosReg', (24, 30))	('ovarian cancer', 'Disease', (44, 58))	('expression', 'MPA', (75, 85))
12230	31474227	We found varying degrees of genetic variation among the 12 Annexin family members, among which ANXA13 displayed the highest incidence rate (34.65% in TCGA) of genetic variations (the incidence rates of amplification, deep deletion, and mutation were 34.13%, 0.34%, and 0.17%, respectively), followed by ANXA9 whose incidence rate of amplification was 12.01% (in TCGA).	('mutation', 'Var', (236, 244))	('ANXA9', 'Gene', '8416', (303, 308))	('ANXA9', 'Gene', (303, 308))	('ANXA13', 'Gene', (95, 101))	('amplification', 'MPA', (202, 215))	('ANXA13', 'Gene', '312', (95, 101))	('deep deletion', 'Var', (217, 230))	('variations', 'Var', (167, 177))
12231	31474227	Most genetic variations in Annexins were amplifications, although ANXA3 (whose incidence rates of deep deletion and amplification were 1.20% and 0.69%, respectively), ANXA5 (whose incidence rates of deep deletion, amplification, and mutation were 1.03%, 0.86%, and 0.17%, respectively), and ANXA10 (whose incidence rates of deep deletion and amplification were 1.89% and 0.86%, respectively) had higher probabilities of deletion events.	('variations', 'Var', (13, 23))	('ANXA10', 'Gene', '11199', (291, 297))	('ANXA3', 'Gene', (66, 71))	('ANXA3', 'Gene', '306', (66, 71))	('mutation', 'Var', (233, 241))	('Annexins', 'Protein', (27, 35))	('ANXA10', 'Gene', (291, 297))	('ANXA5', 'Gene', '308', (167, 172))	('ANXA5', 'Gene', (167, 172))
12232	31474227	Amplifications, deep deletions, and mutations were found in ANXA1, ANXA2, ANXA3, ANXA5, ANXA6, ANXA7, ANXA10, and ANXA13.	('ANXA7', 'Gene', (95, 100))	('ANXA1', 'Gene', '301', (102, 107))	('ANXA1', 'Gene', (60, 65))	('ANXA10', 'Gene', '11199', (102, 108))	('ANXA5', 'Gene', '308', (81, 86))	('ANXA1', 'Gene', (114, 119))	('ANXA6', 'Gene', '309', (88, 93))	('ANXA2', 'Gene', (67, 72))	('ANXA1', 'Gene', '301', (60, 65))	('deep deletions', 'Var', (16, 30))	('ANXA7', 'Gene', '310', (95, 100))	('ANXA1', 'Gene', '301', (114, 119))	('ANXA1', 'Gene', (102, 107))	('ANXA3', 'Gene', '306', (74, 79))	('ANXA10', 'Gene', (102, 108))	('ANXA5', 'Gene', (81, 86))	('ANXA13', 'Gene', (114, 120))	('mutations', 'Var', (36, 45))	('ANXA2', 'Gene', '302', (67, 72))	('ANXA13', 'Gene', '312', (114, 120))	('ANXA3', 'Gene', (74, 79))	('ANXA6', 'Gene', (88, 93))
12257	31474227	7i) mRNAs was significantly correlated with poor PFS in patients with ovarian serous tumors, whereas ANXA7 (Fig.	('patients', 'Species', '9606', (56, 64))	('ovarian serous tumors', 'Disease', 'MESH:D010051', (70, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PFS', 'MPA', (49, 52))	('ovarian serous tumors', 'Disease', (70, 91))	('ANXA7', 'Gene', (101, 106))	('ovarian serous tumors', 'Phenotype', 'HP:0012887', (70, 91))	('mRNAs', 'Var', (4, 9))	('ANXA7', 'Gene', '310', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
12259	31474227	ANXA8, which showed the greatest prognostic significance for OS and PFS in patients with ovarian serous tumors, was selected to study correlations between its mRNA expression level and PFS during different degrees of differentiation, FIGO stages, and TP53 mutations (Fig.	('ANXA8', 'Gene', (0, 5))	('ovarian serous tumors', 'Disease', (89, 110))	('ANXA8', 'Gene', '653145', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TP53', 'Gene', (251, 255))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian serous tumors', 'Phenotype', 'HP:0012887', (89, 110))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (256, 265))	('OS', 'Chemical', '-', (61, 63))	('ovarian serous tumors', 'Disease', 'MESH:D010051', (89, 110))	('TP53', 'Gene', '7157', (251, 255))
12262	31474227	A significant correlation was observed between of ANXA8 mRNA upregulation and poor PFS in patients with TP53 mutations, when compared to patients with wild-type TP53 (Fig.	('TP53', 'Gene', (161, 165))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('patients', 'Species', '9606', (137, 145))	('upregulation', 'PosReg', (61, 73))	('mutations', 'Var', (109, 118))	('PFS', 'CPA', (83, 86))	('ANXA8', 'Gene', (50, 55))	('TP53', 'Gene', '7157', (161, 165))	('patients', 'Species', '9606', (90, 98))	('ANXA8', 'Gene', '653145', (50, 55))
12263	31474227	Therefore, ANXA8 can better reflect the prognosis in patients with ovarian serous tumors, and its correlation with prognosis was even more pronounced in patients with poor differentiation, advanced FIGO stages, and TP53 mutations.	('ovarian serous tumors', 'Phenotype', 'HP:0012887', (67, 88))	('ANXA8', 'Gene', (11, 16))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (153, 161))	('ANXA8', 'Gene', '653145', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (215, 219))	('ovarian serous tumors', 'Disease', 'MESH:D010051', (67, 88))	('FIGO stages', 'Disease', (198, 209))	('poor differentiation', 'CPA', (167, 187))	('ovarian serous tumors', 'Disease', (67, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TP53', 'Gene', (215, 219))	('mutations', 'Var', (220, 229))
12275	31474227	Among signaling pathways showing the greatest correlation for genes co-expressed with ANXA8, hsa04151 (PI3K-Akt signaling pathway), hsa05205 (proteoglycans in cancer), hsa05200 (pathways in cancer), hsa04510 (focal adhesion), hsa04512 (ECM-receptor interaction), and hsa04020 (calcium signaling pathway) were correlated with the tumorigenesis and progression of tumors (Fig.	('hsa04020', 'Var', (267, 275))	('calcium signaling', 'biological_process', 'GO:0019722', ('277', '294'))	('tumor', 'Disease', (362, 367))	('tumor', 'Disease', (329, 334))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (190, 196))	('Akt signaling', 'biological_process', 'GO:0043491', ('108', '121'))	('Akt', 'Gene', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ANXA8', 'Gene', '653145', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('signaling pathway', 'biological_process', 'GO:0007165', ('112', '129'))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (362, 368))	('correlated', 'Reg', (309, 319))	('Akt', 'Gene', '207', (108, 111))	('hsa04512', 'Var', (226, 234))	('focal adhesion', 'cellular_component', 'GO:0005925', ('209', '223'))	('hsa05200', 'Var', (168, 176))	('signaling', 'biological_process', 'GO:0023052', ('6', '15'))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumors', 'Disease', (362, 368))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('PI3K', 'molecular_function', 'GO:0016303', ('103', '107'))	('hsa04151', 'Var', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('signaling pathway', 'biological_process', 'GO:0007165', ('285', '302'))	('ANXA8', 'Gene', (86, 91))	('calcium', 'Chemical', 'MESH:D002118', (277, 284))	('hsa04510', 'Var', (199, 207))	('tumors', 'Disease', 'MESH:D009369', (362, 368))	('hsa05205', 'Var', (132, 140))
12276	31474227	The functional analysis results showed that the following biological processes were enriched for the genes co-expressed with ANXA8: GO:0048870 (cell motility), GO:0022610 (biological adhesion), GO:0016477 (cell migration), GO:0007155 (cell adhesion), GO:0006954 (inflammatory response), and GO:0001568 (blood vessel development), as shown in Fig.	('GO:0007155', 'Var', (223, 233))	('GO:0016477', 'Var', (194, 204))	('cell adhesion', 'biological_process', 'GO:0007155', ('235', '248'))	('GO:0048870', 'Var', (132, 142))	('cell migration', 'biological_process', 'GO:0016477', ('206', '220'))	('blood vessel development', 'biological_process', 'GO:0001568', ('303', '327'))	('ANXA8', 'Gene', (125, 130))	('inflammatory response', 'biological_process', 'GO:0006954', ('263', '284'))	('cell motility', 'biological_process', 'GO:0048870', ('144', '157'))	('ANXA8', 'Gene', '653145', (125, 130))	('biological adhesion', 'biological_process', 'GO:0022610', ('172', '191'))	('GO:0022610', 'Var', (160, 170))	('GO:0001568', 'Var', (291, 301))	('GO:0006954', 'Var', (251, 261))
12293	31474227	Analyses using Kaplan-Meier and log-rank tests revealed that patients in the high ANXA8-expression group had significantly lower 5-year survival rates than patients in the low ANXA8-expression group (P < 0.01; Fig.	('ANXA8', 'Gene', '653145', (82, 87))	('patients', 'Species', '9606', (156, 164))	('high', 'Var', (77, 81))	('lower', 'NegReg', (123, 128))	('patients', 'Species', '9606', (61, 69))	('ANXA8', 'Gene', (176, 181))	('ANXA8', 'Gene', '653145', (176, 181))	('5-year', 'CPA', (129, 135))	('ANXA8', 'Gene', (82, 87))
12296	31474227	Multivariate analysis indicated that the high ANXA8 expression (P = 0.013), late FIGO stages (P = 0.037), and poor differentiation (P = 0.049) were independent risk factors affecting the survival and prognosis of patients with epithelial ovarian cancer (Fig.	('epithelial ovarian cancer', 'Disease', (227, 252))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (227, 252))	('expression', 'MPA', (52, 62))	('ANXA8', 'Gene', (46, 51))	('high', 'Var', (41, 45))	('ANXA8', 'Gene', '653145', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('ovarian cancer', 'Phenotype', 'HP:0100615', (238, 252))	('patients', 'Species', '9606', (213, 221))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (227, 252))	('affecting', 'Reg', (173, 182))
12326	31474227	In addition, ANXA8 showed an even more significant correlation with prognosis in patients with poor differentiation, advanced FIGO stages, and TP53 mutations.	('TP53', 'Gene', (143, 147))	('mutations', 'Var', (148, 157))	('ANXA8', 'Gene', (13, 18))	('ANXA8', 'Gene', '653145', (13, 18))	('TP53', 'Gene', '7157', (143, 147))	('patients', 'Species', '9606', (81, 89))	('poor differentiation', 'CPA', (95, 115))	('FIGO stages', 'CPA', (126, 137))
12327	31474227	Hence, we speculate that ANXA8 is extremely important for evaluating the survival and prognosis in patients with ovarian cancer and may serve as an indicator for TP53 mutations in patients with ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('ovarian cancer', 'Disease', (194, 208))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('ANXA8', 'Gene', (25, 30))	('mutations', 'Var', (167, 176))	('patients', 'Species', '9606', (99, 107))	('ANXA8', 'Gene', '653145', (25, 30))	('ovarian cancer', 'Disease', (113, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (194, 208))	('patients', 'Species', '9606', (180, 188))	('ovarian cancer', 'Disease', 'MESH:D010051', (194, 208))
12330	31474227	EGF-mediated FOXO4 phosphorylation in cholangiocarcinoma leads to the transcriptional inhibition of ANXA8, FAK downregulation, and alteration of F-actin kinetics.	('EGF', 'molecular_function', 'GO:0005154', ('0', '3'))	('F-actin kinetics', 'MPA', (145, 161))	('ANXA8', 'Gene', (100, 105))	('FOXO4', 'Gene', (13, 18))	('FAK', 'Gene', (107, 110))	('inhibition', 'NegReg', (86, 96))	('transcriptional', 'MPA', (70, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('alteration', 'Reg', (131, 141))	('phosphorylation', 'Var', (19, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('FAK', 'Gene', '5747', (107, 110))	('FOXO4', 'Gene', '4303', (13, 18))	('ANXA8', 'Gene', '653145', (100, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('cholangiocarcinoma', 'Disease', (38, 56))	('F-actin', 'cellular_component', 'GO:0031941', ('145', '152'))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('downregulation', 'NegReg', (111, 125))	('FAK', 'molecular_function', 'GO:0004717', ('107', '110'))
12335	31474227	The epigenetic silencing of Th1-type chemokines is a novel mechanism of immune evasion in tumors, and selective epigenetic reprogramming can enhance the clinical efficacy of treatments against ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))	('clinical efficacy', 'CPA', (153, 170))	('ovarian cancer', 'Disease', 'MESH:D010051', (193, 207))	('immune evasion', 'biological_process', 'GO:0051842', ('72', '86'))	('epigenetic silencing', 'Var', (4, 24))	('Th1', 'Gene', (28, 31))	('ovarian cancer', 'Disease', (193, 207))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('epigenetic', 'Var', (112, 122))	('enhance', 'PosReg', (141, 148))	('clinical', 'Species', '191496', (153, 161))	('tumors', 'Disease', (90, 96))	('immune evasion', 'MPA', (72, 86))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Th1', 'Gene', '51497', (28, 31))	('immune evasion', 'biological_process', 'GO:0042783', ('72', '86'))
12338	31474227	In addition, osteopontin overexpression upregulates PD-L1 expression in hepatocellular carcinoma cells by activating the CSF1-CSF1R pathway in macrophages, and blockage of CSF1/CSF1R prevents TAM trafficking.	('CSF1', 'Gene', '1435', (177, 181))	('expression', 'MPA', (58, 68))	('activating', 'PosReg', (106, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('osteopontin', 'Gene', '6696', (13, 24))	('CSF1', 'Gene', (126, 130))	('TAM trafficking', 'CPA', (192, 207))	('osteopontin', 'Gene', (13, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('CSF1', 'molecular_function', 'GO:0005011', ('172', '176'))	('hepatocellular carcinoma', 'Disease', (72, 96))	('CSF1', 'Gene', '1435', (126, 130))	('CSF1', 'Gene', (172, 176))	('CSF1R', 'Gene', '1436', (177, 182))	('CSF1', 'molecular_function', 'GO:0005011', ('177', '181'))	('CSF1', 'molecular_function', 'GO:0005011', ('126', '130'))	('CSF1R', 'Gene', (177, 182))	('TAM', 'Chemical', '-', (192, 195))	('CSF1', 'Gene', '1435', (172, 176))	('PD-L1', 'Gene', (52, 57))	('prevents', 'NegReg', (183, 191))	('CSF1', 'Gene', (121, 125))	('overexpression upregulates', 'PosReg', (25, 51))	('CSF1R', 'Gene', '1436', (126, 131))	('CSF1', 'Gene', (177, 181))	('PD-L1', 'Gene', '29126', (52, 57))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('blockage', 'Var', (160, 168))	('CSF1R', 'Gene', (126, 131))	('CSF1', 'molecular_function', 'GO:0005011', ('121', '125'))	('CSF1', 'Gene', '1435', (121, 125))
12343	31474227	COX regression model analysis suggested that high ANXA8 expression was an independent risk factor affecting the survival and prognosis in patients with epithelial ovarian cancer.	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (152, 177))	('affecting', 'Reg', (98, 107))	('epithelial ovarian cancer', 'Disease', (152, 177))	('COX', 'Gene', (0, 3))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (152, 177))	('high', 'Var', (45, 49))	('expression', 'MPA', (56, 66))	('COX', 'Gene', '1351', (0, 3))	('ovarian cancer', 'Phenotype', 'HP:0100615', (163, 177))	('ANXA8', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('ANXA8', 'Gene', '653145', (50, 55))	('patients', 'Species', '9606', (138, 146))
12354	31474227	Copy number alterations are ubiquitous in cancer, and are associated with cancer outcomes such as recurrence and death.	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('death', 'Disease', 'MESH:D003643', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('death', 'Disease', (113, 118))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('recurrence', 'Disease', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
12355	31474227	The incidence rate of genetic variations in the ANXA13 gene was up to 34.65%, whereas the incidence rate of amplifications in the ANXA9 gene was up to 12.01%.	('ANXA9', 'Gene', '8416', (130, 135))	('ANXA13', 'Gene', '312', (48, 54))	('genetic variations', 'Var', (22, 40))	('ANXA9', 'Gene', (130, 135))	('ANXA13', 'Gene', (48, 54))
12356	31474227	Therefore, genetic variations in ANXA9 and ANXA13 genes may be correlated with ovarian cancer tumorigenesis and progression.	('correlated', 'Reg', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('ANXA9', 'Gene', (33, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('ANXA13', 'Gene', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', (94, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('ANXA13', 'Gene', '312', (43, 49))	('ovarian cancer', 'Disease', (79, 93))	('ANXA9', 'Gene', '8416', (33, 38))	('genetic variations', 'Var', (11, 29))
12358	31474227	Therefore, increased amplifications of Annexin family may be associated with poor prognosis in ovarian cancer.	('Annexin family', 'Protein', (39, 53))	('increased', 'PosReg', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ovarian cancer', 'Disease', 'MESH:D010051', (95, 109))	('amplifications', 'Var', (21, 35))	('ovarian cancer', 'Disease', (95, 109))	('associated', 'Reg', (61, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
12394	28674634	TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma-evidence supporting the clonal relationship of the two lesions.	('serous tubal intraepithelial carcinoma', 'Disease', (18, 56))	('serous carcinoma', 'Disease', 'MESH:D018284', (90, 106))	('TP53', 'Gene', '7157', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('TP53', 'Gene', (0, 4))	('serous tubal intraepithelial carcinoma', 'Disease', 'MESH:D002278', (18, 56))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('serous carcinoma', 'Disease', (90, 106))
12412	28674634	Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('mismatch repair', 'biological_process', 'GO:0006298', ('127', '142'))	('Ovarian endometrioid adenocarcinoma', 'Disease', (0, 35))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('tumor', 'Disease', (163, 168))	('Ovarian endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (0, 35))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (8, 35))	('defects', 'Var', (151, 158))
12417	28674634	Breast and ovarian cancer risks due to inherited mutations in brca1 andBRCA2.	('mutations', 'Var', (49, 58))	('brca1', 'Gene', '672', (62, 67))	('BRCA2', 'Gene', (71, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('Breast and ovarian cancer', 'Disease', 'MESH:D010051', (0, 25))	('BRCA2', 'Gene', '675', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('brca1', 'Gene', (62, 67))
12418	28674634	Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.	('peritoneal carcinoma', 'Disease', 'MESH:D010534', (65, 85))	('peritoneal carcinoma', 'Disease', (65, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('Mutations', 'Var', (0, 9))	('inherited ovarian', 'Disease', 'MESH:D010051', (26, 43))	('inherited ovarian', 'Disease', (26, 43))	('fallopian tube', 'Disease', (45, 59))
12419	28674634	Germline mutations in RAD51D confer susceptibility to ovarian cancer.	('Germline mutations', 'Var', (0, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (54, 68))	('RAD', 'biological_process', 'GO:1990116', ('22', '25'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('ovarian cancer', 'Disease', (54, 68))	('RAD51D', 'Gene', '5892', (22, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (54, 68))	('RAD51D', 'Gene', (22, 28))	('susceptibility', 'Reg', (36, 50))
12420	28674634	Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.	('familial breast cancer', 'Disease', 'MESH:D001943', (78, 100))	('mutations', 'Var', (26, 35))	('BRCA2', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('familial breast cancer', 'Disease', (78, 100))	('PALB2', 'Gene', (69, 74))	('BRCA2', 'Gene', '675', (43, 48))	('PALB2', 'Gene', '79728', (69, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
12422	28674634	Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('RAD', 'biological_process', 'GO:1990116', ('68', '71'))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (22, 47))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('human', 'Species', '9606', (80, 85))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('RAD51C', 'Gene', (68, 74))	('RAD51C', 'Gene', '5889', (68, 74))	('cancer', 'Disease', (86, 92))
12431	28674634	Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary.	('TP53', 'Gene', (20, 24))	('serous carcinoma of the ovary', 'Disease', 'MESH:D010051', (54, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('serous carcinoma of the ovary', 'Disease', (54, 83))	('TP53', 'Gene', '7157', (20, 24))	('mutations', 'Var', (7, 16))
12432	28674634	Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mutations', 'Var', (86, 95))	('p53', 'Gene', '7157', (41, 44))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (99, 116))	('p53', 'Gene', (41, 44))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (99, 116))	('ovarian carcinoma', 'Disease', (99, 116))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
12435	28674634	Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.	('invasive epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (73, 107))	('BRCA1', 'Gene', (20, 25))	('invasive epithelial ovarian cancer', 'Disease', (73, 107))	('mutations', 'Var', (36, 45))	('BRCA2', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('Association', 'Interaction', (0, 11))	('BRCA1', 'Gene', '672', (20, 25))	('women', 'Species', '9606', (62, 67))	('BRCA2', 'Gene', '675', (30, 35))
12436	28674634	BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (10, 15))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (60, 77))	('BRCA1', 'Gene', '672', (0, 5))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (60, 77))	('ovarian carcinoma', 'Disease', (60, 77))	('mutations', 'Var', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('BRCA2', 'Gene', (10, 15))
12438	28674634	Integrated analysis of germline and somatic variants in ovarian cancer.	('variants', 'Var', (44, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('ovarian cancer', 'Disease', 'MESH:D010051', (56, 70))	('ovarian cancer', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
12442	28674634	Germline and somatic mutations in homologous recombination genes predict Platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.	('predict', 'Reg', (65, 72))	('homologous recombination', 'biological_process', 'GO:0035825', ('34', '58'))	('peritoneal carcinomas', 'Disease', 'MESH:D010534', (136, 157))	('homologous recombination genes', 'Gene', (34, 64))	('Platinum', 'Disease', (73, 81))	('fallopian tube', 'Disease', (116, 130))	('ovarian', 'Disease', (107, 114))	('peritoneal carcinomas', 'Disease', (136, 157))	('ovarian', 'Disease', 'MESH:D010051', (107, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('survival', 'CPA', (95, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))	('mutations', 'Var', (21, 30))
12443	28674634	High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.	('ovarian cancer', 'Disease', 'MESH:D010051', (61, 75))	('BRCA', 'Gene', '672', (104, 108))	('patients', 'Species', '9606', (76, 84))	('BRCA', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ovarian cancer', 'Disease', (61, 75))	('platinum', 'Chemical', 'MESH:D010984', (35, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))	('mutation', 'Var', (109, 117))
12450	28674634	Germline mutation in brca1 or brca2 and ten-year survival for women diagnosed with epithelial ovarian cancer.	('brca1', 'Gene', '672', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('brca2', 'Gene', (30, 35))	('brca1', 'Gene', (21, 26))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (83, 108))	('Germline mutation', 'Var', (0, 17))	('epithelial ovarian cancer', 'Disease', (83, 108))	('women', 'Species', '9606', (62, 67))	('brca2', 'Gene', '675', (30, 35))
12452	28674634	BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study.	('BRCA1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('hypermethylation', 'Var', (22, 38))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (42, 59))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (42, 59))	('BRCA1', 'Gene', '672', (0, 5))	('ovarian carcinoma', 'Disease', (42, 59))
12453	28674634	BRCA1 promoter methylation predicts adverse ovarian cancer prognosis.	('methylation', 'Var', (15, 26))	('BRCA1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('adverse ovarian cancer', 'Disease', 'MESH:D010051', (36, 58))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('adverse ovarian cancer', 'Disease', (36, 58))	('BRCA1', 'Gene', '672', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))
12457	28674634	Synthetic lethality between ccne1 amplification and loss of BRCA1.	('BRCA1', 'Gene', (60, 65))	('loss', 'NegReg', (52, 56))	('ccne1', 'Gene', (28, 33))	('ccne1', 'Gene', '898', (28, 33))	('BRCA1', 'Gene', '672', (60, 65))	('amplification', 'Var', (34, 47))
12495	28674634	Systematic review and meta-analysis of ovarian cancers: estimation of Microsatellite-High frequency and characterization of mismatch repair deficient tumor histology.	('Microsatellite-High', 'Var', (70, 89))	('ovarian cancers', 'Phenotype', 'HP:0100615', (39, 54))	('ovarian cancers', 'Disease', (39, 54))	('deficient tumor', 'Disease', (140, 155))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('ovarian cancers', 'Disease', 'MESH:D010051', (39, 54))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mismatch repair', 'biological_process', 'GO:0006298', ('124', '139'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('deficient tumor', 'Disease', 'MESH:D009369', (140, 155))
12502	28674634	Distinct beta-Catenin and PIK3CA mutation profiles in endometriosis-associated ovarian endometrioid and clear cell carcinomas.	('clear cell carcinomas', 'Disease', (104, 125))	('mutation', 'Var', (33, 41))	('beta-Catenin', 'Gene', (9, 21))	('endometriosis', 'Phenotype', 'HP:0030127', (54, 67))	('beta-Catenin', 'Gene', '1499', (9, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('PIK3CA', 'Gene', '5290', (26, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('endometriosis-associated ovarian endometrioid', 'Disease', (54, 99))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (104, 125))	('endometriosis-associated ovarian endometrioid', 'Disease', 'MESH:D004715', (54, 99))	('PIK3CA', 'Gene', (26, 32))
12504	28674634	Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors.	('mucinous epithelial ovarian tumors', 'Disease', 'MESH:D000077216', (63, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('endometrioid', 'Disease', (32, 44))	('PTEN', 'Gene', (9, 13))	('PTEN', 'Gene', '5728', (9, 13))	('mutations', 'Var', (19, 28))	('mucinous epithelial ovarian tumors', 'Disease', (63, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ovarian tumors', 'Phenotype', 'HP:0100615', (83, 97))
12505	28674634	ARID1A mutations in Endometriosis-Associated ovarian carcinomas.	('Endometriosis-Associated ovarian carcinomas', 'Disease', (20, 63))	('mutations', 'Var', (7, 16))	('ARID1A', 'Gene', '8289', (0, 6))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (45, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('ARID1A', 'Gene', (0, 6))	('Endometriosis', 'Phenotype', 'HP:0030127', (20, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (45, 62))	('Endometriosis-Associated ovarian carcinomas', 'Disease', 'MESH:D004715', (20, 63))
12509	28674634	Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.	('ARID1A', 'Gene', '8289', (48, 54))	('mutations', 'Var', (9, 18))	('ovarian clear cell carcinoma', 'Disease', (58, 86))	('ARID1A', 'Gene', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('22', '42'))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (58, 86))	('chromatin', 'cellular_component', 'GO:0000785', ('22', '31'))
12511	28674634	3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: Possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('benign endometrial cyst to endometrioid carcinoma', 'Disease', (125, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('benign endometrial cyst of the ovary', 'Disease', (52, 88))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('benign endometrial cyst to endometrioid carcinoma', 'Disease', 'MESH:D016889', (125, 174))	('mutation', 'Var', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('clear cell carcinoma of the ovary', 'Disease', (179, 212))	('PTEN', 'Gene', (44, 48))	('clear cell carcinoma of the ovary', 'Disease', 'MESH:C538614', (179, 212))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (152, 174))	('tumor', 'Disease', (22, 27))	('PTEN', 'Gene', '5728', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))
12513	28674634	Mutation of the PIK3CA gene in ovarian and breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('PIK3CA', 'Gene', '5290', (16, 22))	('Mutation', 'Var', (0, 8))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (31, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('PIK3CA', 'Gene', (16, 22))
12522	28674634	Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma.	('mutations', 'Var', (27, 36))	('mucinous ovarian carcinoma', 'Disease', (40, 66))	('mucinous ovarian carcinoma', 'Disease', 'MESH:D002288', (40, 66))	('BRAF', 'Gene', '673', (17, 21))	('KRAS', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('KRAS', 'Gene', '3845', (8, 12))	('BRAF', 'Gene', (17, 21))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (49, 66))
12523	28674634	Patterns of p53 mutations separate ovarian serous borderline tumors and low-and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis -A mutational analysis with immunohistochemical correlation.	('ovarian carcinogenesis', 'Disease', (141, 163))	('mutations', 'Var', (16, 25))	('ovarian serous borderline tumors', 'Disease', 'MESH:D010051', (35, 67))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ovarian serous borderline tumors', 'Disease', (35, 67))	('ovarian carcinogenesis', 'Disease', 'MESH:D063646', (141, 163))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('carcinomas', 'Disease', (91, 101))	('carcinomas', 'Disease', 'MESH:D002277', (91, 101))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
12525	28674634	In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours.	('serous tumours', 'Disease', (80, 94))	('serous tumours', 'Disease', 'MESH:D018284', (80, 94))	('BRAF', 'Gene', '673', (22, 26))	('KRAS', 'Gene', (36, 40))	('BRAF', 'Gene', (22, 26))	('KRAS', 'Gene', '3845', (36, 40))	('ovarian neoplasms', 'Disease', (3, 20))	('ovarian neoplasms', 'Phenotype', 'HP:0100615', (3, 20))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian neoplasms', 'Disease', 'MESH:D010051', (3, 20))	('neoplasms', 'Phenotype', 'HP:0002664', (11, 20))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('mutations', 'Var', (42, 51))
12526	28674634	Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.	('low-grade ovarian serous carcinoma', 'Disease', 'MESH:D008228', (59, 93))	('low-grade ovarian serous carcinoma', 'Disease', (59, 93))	('BRAF', 'Gene', '673', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (22, 26))	('KRAS', 'Gene', '3845', (22, 26))
12528	28674634	BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas.	('low-grade ovarian serous carcinoma', 'Disease', (40, 74))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (50, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('low-grade ovarian serous carcinoma', 'Disease', 'MESH:D008228', (40, 74))	('BRAF', 'Gene', '673', (0, 4))	('ovarian serous carcinomas', 'Disease', (50, 75))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
12530	28674634	KRAS (but not BRAF) mutations in ovarian serous borderline tumour are associated with recurrent low-grade serous carcinoma.	('ovarian serous borderline tumour', 'Disease', (33, 65))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('associated with', 'Reg', (70, 85))	('ovarian serous borderline tumour', 'Disease', 'MESH:D010051', (33, 65))	('BRAF', 'Gene', '673', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('serous carcinoma', 'Disease', (106, 122))	('BRAF', 'Gene', (14, 18))	('serous carcinoma', 'Disease', 'MESH:D018284', (106, 122))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (20, 29))	('KRAS', 'Gene', '3845', (0, 4))
12547	32950970	Several common RNA modification forms have been documented including N6-methyladenosine (m6A), N1-methyladenosine (m1A) and 5-methylcytosine (m5C).	('5-methylcytosine', 'MPA', (124, 140))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (124, 140))	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (95, 113))	('RNA modification', 'biological_process', 'GO:0009451', ('15', '31'))	('RNA', 'cellular_component', 'GO:0005562', ('15', '18'))	('m6A', 'Gene', (89, 92))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (69, 87))	('N1-methyladenosine', 'Var', (95, 113))	('m1A', 'Chemical', '-', (115, 118))	('m6A', 'Gene', '56339', (89, 92))	('N6-methyladenosine', 'Var', (69, 87))
12555	32950970	The m6A modification regulates a variety of critical steps in the RNA life cycle starting from transcription to degradation (such as transcription, splicing, exportation, translation, and degradation) and can influence cell process (such as cell cycle progression, cell proliferation, cell apoptosis, cell migration and invasion and cell differentiation) and physiological function (such as neural development, embryonic development and adipogenesis, etc.)	('cell process', 'CPA', (219, 231))	('adipogenesis', 'biological_process', 'GO:0045444', ('437', '449'))	('degradation', 'biological_process', 'GO:0009056', ('188', '199'))	('regulates', 'Reg', (21, 30))	('cell proliferation', 'CPA', (265, 283))	('translation', 'MPA', (171, 182))	('exportation', 'MPA', (158, 169))	('degradation', 'MPA', (188, 199))	('RNA', 'cellular_component', 'GO:0005562', ('66', '69'))	('transcription', 'biological_process', 'GO:0006351', ('95', '108'))	('adipogenesis', 'biological_process', 'GO:0060612', ('437', '449'))	('cell process', 'cellular_component', 'GO:0042995', ('219', '231'))	('cell cycle', 'biological_process', 'GO:0007049', ('241', '251'))	('cell proliferation', 'biological_process', 'GO:0008283', ('265', '283'))	('neural development', 'CPA', (391, 409))	('embryonic development', 'CPA', (411, 432))	('invasion', 'CPA', (320, 328))	('modification', 'Var', (8, 20))	('cell migration', 'biological_process', 'GO:0016477', ('301', '315'))	('adipogenesis', 'CPA', (437, 449))	('m6A', 'Gene', '56339', (4, 7))	('cell cycle progression', 'CPA', (241, 263))	('splicing', 'biological_process', 'GO:0045292', ('148', '156'))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('cell migration', 'CPA', (301, 315))	('m6A', 'Gene', (4, 7))	('cell apoptosis', 'CPA', (285, 299))	('degradation', 'biological_process', 'GO:0009056', ('112', '123'))	('apoptosis', 'biological_process', 'GO:0097194', ('290', '299'))	('translation', 'biological_process', 'GO:0006412', ('171', '182'))	('apoptosis', 'biological_process', 'GO:0006915', ('290', '299'))	('influence', 'Reg', (209, 218))	('cell differentiation', 'biological_process', 'GO:0030154', ('333', '353'))	('splicing', 'MPA', (148, 156))
12561	32950970	Therefore, restraining the WNT signaling pathway in combination with PARPi represents a potential therapeutic strategy for OC.	('WNT signaling pathway', 'biological_process', 'GO:0016055', ('27', '48'))	('OC', 'Gene', '632', (123, 125))	('WNT signaling pathway', 'Pathway', (27, 48))	('OC', 'Phenotype', 'HP:0100615', (123, 125))	('restraining', 'Var', (11, 22))
12581	32950970	Moreover, we also found that the frequencies of genetic changes (mutation or copy number change) of these 18 m6A RNA methylation regulators were relatively high (the maximum was 27%) in OC tissue compared with normal (Supplementary Figure 2), which might explain the altered expression of these genes in OC.	('RNA methylation', 'biological_process', 'GO:0001510', ('113', '128'))	('genetic changes', 'Var', (48, 63))	('OC', 'Gene', '632', (304, 306))	('OC', 'Phenotype', 'HP:0100615', (304, 306))	('m6A', 'Gene', (109, 112))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('m6A', 'Gene', '56339', (109, 112))	('OC', 'Phenotype', 'HP:0100615', (186, 188))	('OC', 'Gene', '632', (186, 188))	('copy number change', 'Var', (77, 95))
12594	32950970	From Figure 4F, we can see that the number of deaths of patients with high-risk scores is slightly larger than that of patients with low-risk scores.	('patients', 'Species', '9606', (56, 64))	('high-risk', 'Var', (70, 79))	('patients', 'Species', '9606', (119, 127))	('deaths', 'Disease', 'MESH:D003643', (46, 52))	('deaths', 'Disease', (46, 52))
12619	32950970	We noticed that OC patients with high VIRMA expression had a shorter median OS than those with low expression (P < 0.05, Figure 6B).	('OC', 'Gene', '632', (16, 18))	('shorter', 'NegReg', (61, 68))	('patients', 'Species', '9606', (19, 27))	('OC', 'Phenotype', 'HP:0100615', (16, 18))	('high VIRMA expression', 'Var', (33, 54))	('median OS', 'MPA', (69, 78))
12685	25304388	In vitro experiments showed that 4-MU inhibited HRA cell proliferation in a dose-dependent manner, while it did not affect HRA cell invasion and migration.	('4-MU', 'Chemical', 'MESH:D006923', (33, 37))	('rat', 'Species', '10116', (148, 151))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('4-MU', 'Var', (33, 37))	('inhibited', 'NegReg', (38, 47))	('rat', 'Species', '10116', (64, 67))	('HRA cell proliferation', 'CPA', (48, 70))
12688	25304388	These results suggest that 4-MU exerts its antitumor effect on ovarian cancer through suppressing TP expression.	('TP', 'Gene', '1890', (98, 100))	('4-MU', 'Chemical', 'MESH:D006923', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('suppressing', 'NegReg', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('4-MU', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('ovarian cancer', 'Disease', (63, 77))
12709	25304388	Recent studies showed that 4-MU had an antitumor effect on prostate, breast, and hepatocellular carcinomas through the inhibition of HA synthesis.	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (81, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('hepatocellular carcinomas', 'Disease', (81, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('HA', 'Chemical', 'MESH:D006820', (133, 135))	('HA synthesis', 'MPA', (133, 145))	('synthesis', 'biological_process', 'GO:0009058', ('136', '145'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('breast', 'Disease', (69, 75))	('4-MU', 'Chemical', 'MESH:D006923', (27, 31))	('inhibition', 'NegReg', (119, 129))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (81, 106))	('4-MU', 'Var', (27, 31))	('tumor', 'Disease', (43, 48))	('prostate', 'Disease', (59, 67))
12712	25304388	This study was conducted to investigate the antitumor potential of 4-MU against human ovarian cancer cells and to elucidate its mechanism of action.	('ovarian cancer', 'Disease', (86, 100))	('4-MU', 'Chemical', 'MESH:D006923', (67, 71))	('tumor', 'Disease', (48, 53))	('4-MU', 'Var', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('human', 'Species', '9606', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
12751	25304388	The survival times were significantly longer in the 4-MU-treated group than in the control group (P < 0.05, Figure 1A).	('4-MU-treated', 'Var', (52, 64))	('survival times', 'CPA', (4, 18))	('4-MU', 'Chemical', 'MESH:D006923', (52, 56))	('longer', 'PosReg', (38, 44))
12759	25304388	Western blot analysis showed that 4-MU reduced TP protein level in a dose-dependent manner (Figure 3A).	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('4-MU', 'Chemical', 'MESH:D006923', (34, 38))	('TP', 'Gene', '1890', (47, 49))	('reduced', 'NegReg', (39, 46))	('4-MU', 'Var', (34, 38))
12763	25304388	4-MU also showed potential for reducing peritoneal dissemination of tumors as well as malignant ascites production.	('dissemination of tumors', 'Disease', 'MESH:D009103', (51, 74))	('malignant ascites', 'Disease', (86, 103))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('malignant ascites', 'Disease', 'MESH:D001201', (86, 103))	('reducing', 'NegReg', (31, 39))	('ascites', 'Phenotype', 'HP:0001541', (96, 103))	('4-MU', 'Chemical', 'MESH:D006923', (0, 4))	('dissemination of tumors', 'Disease', (51, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('4-MU', 'Var', (0, 4))
12767	25304388	In the in vitro experiments, 4-MU inhibited proliferation of HRA cells in a dose-dependent manner, supporting previous results obtained in other types of cancer cells.	('4-MU', 'Chemical', 'MESH:D006923', (29, 33))	('4-MU', 'Var', (29, 33))	('rat', 'Species', '10116', (51, 54))	('inhibited', 'NegReg', (34, 43))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('proliferation', 'CPA', (44, 57))
12784	25304388	reported that 4-MU might be an anti-cancer agent for HCC associated with advanced fibrosis because it induced apoptosis of hepatic stellate cells (HSCs), which play a key role in advancing liver fibrosis, and decreased the number of activated HSCs.	('advancing', 'PosReg', (179, 188))	('fibrosis', 'Disease', 'MESH:D005355', (82, 90))	('fibrosis', 'Disease', (82, 90))	('4-MU', 'Var', (14, 18))	('fibrosis', 'Disease', 'MESH:D005355', (195, 203))	('fibrosis', 'Disease', (195, 203))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('liver fibrosis', 'Phenotype', 'HP:0001395', (189, 203))	('cancer', 'Disease', (36, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('4-MU', 'Chemical', 'MESH:D006923', (14, 18))	('liver fibrosis', 'Disease', (189, 203))	('HCC', 'Phenotype', 'HP:0001402', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('apoptosis', 'CPA', (110, 119))	('liver fibrosis', 'Disease', 'MESH:D008103', (189, 203))	('decreased', 'NegReg', (209, 218))
12785	25304388	also reported that 4-MU inhibited cell proliferation and induced apoptosis in breast cancer cells together with inhibiting HA synthesis accompanied by downregulation of HAS2 mRNA levels in a dose-depending manner.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('cell proliferation', 'CPA', (34, 52))	('downregulation', 'NegReg', (151, 165))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('breast cancer', 'Disease', (78, 91))	('HAS2', 'Gene', (169, 173))	('rat', 'Species', '10116', (46, 49))	('induced', 'Reg', (57, 64))	('4-MU', 'Var', (19, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('inhibiting', 'NegReg', (112, 122))	('HA', 'Chemical', 'MESH:D006820', (123, 125))	('4-MU', 'Chemical', 'MESH:D006923', (19, 23))	('inhibited', 'NegReg', (24, 33))	('HA', 'Chemical', 'MESH:D006820', (169, 171))	('apoptosis', 'CPA', (65, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('HAS2', 'Gene', '3037', (169, 173))	('HA synthesis', 'MPA', (123, 135))	('synthesis', 'biological_process', 'GO:0009058', ('126', '135'))
12788	25304388	A recent study indicated that 4-MU inhibited angiogenesis in vitro and in vivo.	('angiogenesis', 'biological_process', 'GO:0001525', ('45', '57'))	('4-MU', 'Chemical', 'MESH:D006923', (30, 34))	('4-MU', 'Var', (30, 34))	('inhibited', 'NegReg', (35, 44))	('angiogenesis', 'CPA', (45, 57))
12799	25304388	Therefore, 4-MU might inactivate PI3K/Akt signaling by suppressing a ligand-receptor interaction different from the HA-CD44 interaction.	('4-MU', 'Var', (11, 15))	('CD44', 'Gene', '960', (119, 123))	('inactivate', 'NegReg', (22, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('ligand', 'molecular_function', 'GO:0005488', ('69', '75'))	('Akt signaling', 'biological_process', 'GO:0043491', ('38', '51'))	('CD44', 'Gene', (119, 123))	('suppressing', 'NegReg', (55, 66))	('Akt', 'Gene', '207', (38, 41))	('4-MU', 'Chemical', 'MESH:D006923', (11, 15))	('HA', 'Chemical', 'MESH:D006820', (116, 118))	('ligand-receptor interaction', 'MPA', (69, 96))	('Akt', 'Gene', (38, 41))
12801	25304388	Although earlier studies showed that 4-MU exhibited its anti-tumor activity by suppressing the HA-CD44 interaction, this study demonstrated that 4-MU downregulated TP expression in ovarian cancer cells.	('downregulated', 'NegReg', (150, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (181, 195))	('4-MU', 'Chemical', 'MESH:D006923', (37, 41))	('4-MU', 'Var', (145, 149))	('ovarian cancer', 'Disease', 'MESH:D010051', (181, 195))	('CD44', 'Gene', '960', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('interaction', 'Interaction', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CD44', 'Gene', (98, 102))	('suppressing', 'NegReg', (79, 90))	('TP', 'Gene', '1890', (164, 166))	('ovarian cancer', 'Disease', (181, 195))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('rat', 'Species', '10116', (134, 137))	('HA', 'Chemical', 'MESH:D006820', (95, 97))	('tumor', 'Disease', (61, 66))	('4-MU', 'Chemical', 'MESH:D006923', (145, 149))
12802	25304388	This suggests that 4-MU may act as an angiogenesis inhibitor and have potential as a new drug in the therapeutic strategy for ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('4-MU', 'Chemical', 'MESH:D006923', (19, 23))	('rat', 'Species', '10116', (115, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (126, 140))	('4-MU', 'Var', (19, 23))	('ovarian cancer', 'Disease', (126, 140))	('angiogenesis', 'biological_process', 'GO:0001525', ('38', '50'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('angiogenesis', 'CPA', (38, 50))
12808	29069830	The selected signature composed by VAT1L, CALR, LINC01456, RP11-484L8.1, MIR196A1 and MIR148A, separated the training group patients into high-risk or low-risk subgroup with significantly different survival time (median survival: 35.3 months vs. 64.9 months, P < 0.001).	('CALR', 'Gene', '811', (42, 46))	('LINC01456', 'Gene', '105373144', (48, 57))	('RP11', 'Gene', '26121', (59, 63))	('patients', 'Species', '9606', (124, 132))	('MIR148A', 'Var', (86, 93))	('VAT1L', 'Gene', '57687', (35, 40))	('LINC01456', 'Gene', (48, 57))	('CALR', 'Gene', (42, 46))	('MIR196A1', 'Gene', (73, 81))	('MIR196A1', 'Gene', '406972', (73, 81))	('RP11', 'Gene', (59, 63))	('VAT1L', 'Gene', (35, 40))
12819	29069830	Two immune-associated lncRNA biomarkers (RP11-284N8.3.1 and AC104699.1.1) could independently predict the survival of patients with different ovarian cancer stages.	('RP11', 'Gene', '26121', (41, 45))	('predict', 'Reg', (94, 101))	('ovarian cancer', 'Disease', (142, 156))	('ovarian cancer', 'Phenotype', 'HP:0100615', (142, 156))	('RP11', 'Gene', (41, 45))	('AC104699.1.1', 'Var', (60, 72))	('patients', 'Species', '9606', (118, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
12824	29069830	BCL11A overexpression modulated by microRNA-30a could predict survival and relapse in non-small cell lung cancer.	('BCL11A', 'Gene', '53335', (0, 6))	('BCL11A', 'Gene', (0, 6))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (90, 112))	('microRNA-30a', 'Gene', '407029', (35, 47))	('cell lung cancer', 'Disease', (96, 112))	('relapse', 'CPA', (75, 82))	('microRNA-30a', 'Gene', (35, 47))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (86, 112))	('predict', 'Reg', (54, 61))	('overexpression', 'PosReg', (7, 21))	('survival', 'CPA', (62, 70))	('modulated', 'Var', (22, 31))	('cell lung cancer', 'Disease', 'MESH:D008175', (96, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
12839	29069830	Then the PCGs-lncRNAs-microRNAs combination composed by VAT1L, CALR, LINC01456, RP11-484L8.1, MIR196A1 and MIR148A with the max AUC was selected (Figure 2B, Table 2).	('LINC01456', 'Gene', '105373144', (69, 78))	('MIR196A1', 'Gene', (94, 102))	('MIR196A1', 'Gene', '406972', (94, 102))	('RP11', 'Gene', (80, 84))	('LINC01456', 'Gene', (69, 78))	('CALR', 'Gene', (63, 67))	('MIR148A', 'Var', (107, 114))	('RP11', 'Gene', '26121', (80, 84))	('VAT1L', 'Gene', '57687', (56, 61))	('PCGs', 'Chemical', '-', (9, 13))	('VAT1L', 'Gene', (56, 61))	('CALR', 'Gene', '811', (63, 67))
12874	29069830	VAT1L is mainly expressed in the brain and CALR mutation status defined subtypes of essential thrombocythemia with substantially different clinical course and outcomes, thus it could be a potential biomarker for myeloproliterative neoplasm.	('CALR', 'Gene', (43, 47))	('VAT1L', 'Gene', '57687', (0, 5))	('myeloproliterative neoplasm', 'Phenotype', 'HP:0005547', (212, 239))	('essential thrombocythemia', 'Disease', 'MESH:D013920', (84, 109))	('neoplasm', 'Disease', (231, 239))	('thrombocythemia', 'Phenotype', 'HP:0001894', (94, 109))	('CALR', 'Gene', '811', (43, 47))	('neoplasm', 'Phenotype', 'HP:0002664', (231, 239))	('mutation', 'Var', (48, 56))	('VAT1L', 'Gene', (0, 5))	('essential thrombocythemia', 'Disease', (84, 109))	('neoplasm', 'Disease', 'MESH:D009369', (231, 239))
12875	29069830	On the another hand, miR-148a played a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasion of transformed cells, promoting cell proliferation by targeting p27 in gastric cancer cells, and silencing of miR-148a in cancer-associated fibroblasts resulted in WNT10B-mediated stimulation of tumor cell motility.	('miR-148a', 'Gene', (246, 254))	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('gastric cancer', 'Disease', (207, 221))	('miR-148a', 'Gene', '406940', (21, 29))	('miR-148a', 'Gene', (21, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('168', '186'))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('WNT10B', 'Gene', (300, 306))	('cell motility', 'biological_process', 'GO:0048870', ('337', '350'))	('cancer', 'Disease', (215, 221))	('cell proliferation', 'CPA', (168, 186))	('gastric cancer', 'Disease', 'MESH:D013274', (207, 221))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('stimulation', 'PosReg', (316, 327))	('p27', 'Gene', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('promoting', 'PosReg', (68, 77))	('invasion of transformed cells', 'CPA', (127, 156))	('targeting', 'Var', (190, 199))	('gastric cancer', 'Phenotype', 'HP:0012126', (207, 221))	('cancer', 'Disease', (258, 264))	('WNT10B', 'Gene', '7480', (300, 306))	('silencing', 'Var', (233, 242))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Disease', (331, 336))	('p27', 'Gene', '3429', (200, 203))	('hepatospecific phenotype', 'MPA', (82, 106))	('suppressing', 'NegReg', (111, 122))	('promoting', 'PosReg', (158, 167))	('miR-148a', 'Gene', '406940', (246, 254))
12876	29069830	MiR-196 appears to be a vertebrate specific microRNA and it has been suggested that a rare SNP (rs11614913) that overlaps miR-196 has been found to be associated with non-small cell lung carcinoma.	('miR-196', 'Gene', (122, 129))	('non-small cell lung carcinoma', 'Disease', (167, 196))	('rs11614913', 'Var', (96, 106))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (171, 196))	('associated', 'Reg', (151, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (167, 196))	('rs11614913', 'Mutation', 'rs11614913', (96, 106))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (167, 196))
12877	29069830	MiR-196 is correlated with metastasis and prognosis of human colorectal cancer, and may serve as an emerging cancer biomarker for digestive tract cancers.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colorectal cancer', 'Disease', (61, 78))	('MiR-196', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (55, 60))	('cancer', 'Disease', (109, 115))	('tract cancers', 'Disease', 'MESH:D014571', (140, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('tract cancers', 'Disease', (140, 153))	('correlated', 'Reg', (11, 21))	('cancer', 'Disease', (72, 78))
12903	29069830	The primer sequences of VAT1L, CALR, LINC01456, RP11-484L8.1 for PCR, and MIR196A1, MIR148A for RT-PCR were shown in Supplementary Table 3, and ACTB (beta-actin) was used as the internal control.	('CALR', 'Gene', '811', (31, 35))	('RP11', 'Gene', (48, 52))	('MIR196A1', 'Gene', (74, 82))	('RP11', 'Gene', '26121', (48, 52))	('VAT1L', 'Gene', '57687', (24, 29))	('MIR196A1', 'Gene', '406972', (74, 82))	('beta-actin', 'Gene', '728378', (150, 160))	('beta-actin', 'Gene', (150, 160))	('LINC01456', 'Gene', '105373144', (37, 46))	('ACTB', 'Gene', (144, 148))	('CALR', 'Gene', (31, 35))	('ACTB', 'Gene', '60', (144, 148))	('MIR148A', 'Var', (84, 91))	('VAT1L', 'Gene', (24, 29))	('LINC01456', 'Gene', (37, 46))
13004	33635867	Results also showed that ENPP1 gene was highly expressed in A2780, CaoV3, OVCAR3, SKOV3 and 3ao (Fig 2A).	('OVCAR3', 'Gene', '761', (74, 80))	('SKOV3', 'CellLine', 'CVCL:0532', (82, 87))	('OVCAR3', 'Gene', (74, 80))	('ENPP1', 'Gene', (25, 30))	('A2780', 'Var', (60, 65))	('ENPP1', 'Gene', '5167', (25, 30))
13007	33635867	After 48h of PC-1 siRNA transfection, A2780 cells were collected to extract RNA and protein for qRT-PCR and Western Blot analysis.	('PC-1', 'Gene', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('transfection', 'Var', (24, 36))	('PC-1', 'Gene', '5167', (13, 17))
13015	33635867	We found that after transfection of PC-1 siRNA, the expression of PCNA mRNA in A2780 and SKOV3 was down regulated by 55.47% and 39.19%, respectively(Fig 4D), and the expression of MMP9 mRNA was down regulated by 62.97% and 46.98%, respectively (Fig 4E).	('down regulated', 'NegReg', (99, 113))	('PCNA', 'molecular_function', 'GO:0003892', ('66', '70'))	('A2780', 'Var', (79, 84))	('MMP9', 'Gene', (180, 184))	('expression', 'MPA', (52, 62))	('SKOV3', 'Gene', (89, 94))	('MMP9', 'Gene', '4318', (180, 184))	('PC-1', 'Gene', '5167', (36, 40))	('PCNA', 'Gene', (66, 70))	('down regulated', 'NegReg', (194, 208))	('SKOV3', 'CellLine', 'CVCL:0532', (89, 94))	('MMP9', 'molecular_function', 'GO:0004229', ('180', '184'))	('expression', 'MPA', (166, 176))	('PC-1', 'Gene', (36, 40))	('PCNA', 'Gene', '5111', (66, 70))
13017	33635867	In addition, change of migratory ability with ENPP1 knockdown was measured with a wound-healing assay.	('migratory ability', 'CPA', (23, 40))	('ENPP1', 'Gene', '5167', (46, 51))	('knockdown', 'Var', (52, 61))	('wound-healing', 'biological_process', 'GO:0042060', ('82', '95'))	('ENPP1', 'Gene', (46, 51))
13020	33635867	Consistent with the wound healing, transwell migration/Matrigel invasion assay also showed that ENPP1 knockdown weakened the invasion and migration capacities of A2780 cells.	('ENPP1', 'Gene', '5167', (96, 101))	('weakened', 'NegReg', (112, 120))	('wound healing', 'biological_process', 'GO:0042060', ('20', '33'))	('knockdown', 'Var', (102, 111))	('ENPP1', 'Gene', (96, 101))
13046	33635867	In the study of lung cancer, it was found that when ENPP1 gene was knocked out in lung cancer cell lines, the expression of a large number of stem cell markers decreased, including ABCG2, SOX2, NANOG, and CD44.	('NANOG', 'Gene', '79923', (194, 199))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('decreased', 'NegReg', (160, 169))	('NANOG', 'Gene', (194, 199))	('ENPP1', 'Gene', '5167', (52, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('knocked out', 'Var', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SOX2', 'Gene', (188, 192))	('expression', 'MPA', (110, 120))	('ENPP1', 'Gene', (52, 57))	('SOX2', 'Gene', '6657', (188, 192))	('ABCG2', 'Gene', (181, 186))	('ABCG2', 'Gene', '9429', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('lung cancer', 'Disease', (82, 93))	('lung cancer', 'Disease', (16, 27))
13049	33635867	These studies explain our experimental results very well, because of the molecular biological function of ENPP1 gene, ovarian cancer cells with high expression of ENPP1 protein are more prone to metastasis and rapidly proliferate to form metastatic foci, which leads to later stage and indicates poorer prognosis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ovarian cancer', 'Disease', (118, 132))	('high expression', 'Var', (144, 159))	('ENPP1', 'Gene', '5167', (163, 168))	('ENPP1', 'Gene', (106, 111))	('protein', 'Protein', (169, 176))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('more prone', 'PosReg', (181, 191))	('ENPP1', 'Gene', '5167', (106, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('metastasis', 'CPA', (195, 205))	('ENPP1', 'Gene', (163, 168))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))
13119	31035447	Recently, microRNAs (miRNAs), which consist of short-sequence RNAs that do not encode a protein, have emerged as new biomarkers in the clinical diagnosis and treatment of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (171, 185))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('RNAs', 'Gene', (62, 66))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('short-sequence', 'Var', (47, 61))	('ovarian cancer', 'Disease', (171, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (171, 185))
13173	31035447	A tumor suppressor gene is defined as a gene whose normal role serves to inhibit tumorigenesis, whereas its loss, mutation, or loss of function allows an activated oncogene to function and cause cancer.	('loss of function', 'NegReg', (127, 143))	('loss', 'NegReg', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('2', '18'))	('cancer', 'Disease', (195, 201))	('cause', 'Reg', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('function', 'MPA', (176, 184))	('tumor', 'Disease', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('mutation', 'Var', (114, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('2', '18'))	('tumor', 'Disease', (81, 86))	('inhibit', 'NegReg', (73, 80))
13200	31035447	miRNAs regulate the invasion and metastasis of ovarian cancer, and the abnormal expression of miRNA is closely related to the invasion and metastasis of ovarian cancer.	('related', 'Reg', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('miR', 'Gene', '220972', (0, 3))	('metastasis of ovarian cancer', 'Disease', (33, 61))	('metastasis of ovarian cancer', 'Disease', (139, 167))	('invasion', 'CPA', (126, 134))	('miR', 'Gene', (0, 3))	('invasion', 'CPA', (20, 28))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('expression', 'MPA', (80, 90))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (33, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (153, 167))	('abnormal', 'Var', (71, 79))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (139, 167))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
13205	31035447	have an important influence, and the abnormal expression of miRNA can change the ability of tumor invasion and metastasis by regulating the extracellular matrix.	('abnormal expression', 'Var', (37, 56))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('change', 'Reg', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('regulating', 'Reg', (125, 135))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('140', '160'))	('extracellular matrix', 'MPA', (140, 160))	('tumor', 'Disease', (92, 97))
13229	31035447	miR-429 belongs to one of the members of the miR-200 family, and the cells not only undergo morphological changes but also transform from mesenchymal cells to epithelial cells after the transfection of miR-429.	('miR-429', 'Gene', '554210', (202, 209))	('miR-429', 'Gene', '554210', (0, 7))	('miR', 'Gene', '220972', (202, 205))	('miR', 'Gene', (202, 205))	('miR-429', 'Gene', (202, 209))	('transform', 'Reg', (123, 132))	('miR', 'Gene', (0, 3))	('miR-429', 'Gene', (0, 7))	('miR', 'Gene', (45, 48))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', '220972', (45, 48))	('transfection', 'Var', (186, 198))
13281	31035447	Notably, whereas increasing the expression level of miR-21 in cisplatin-sensitive cancer cells increased the proliferation of ovarian cancer cells, targeting miR-21 reduced the tumorigenic characteristics of the cisplatin-resistant cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('miR-21', 'Gene', (52, 58))	('cancer', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('proliferation', 'CPA', (109, 122))	('expression', 'MPA', (32, 42))	('tumor', 'Disease', (177, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('ovarian cancer', 'Disease', 'MESH:D010051', (126, 140))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miR-21', 'Gene', '406991', (158, 164))	('targeting', 'Var', (148, 157))	('reduced', 'NegReg', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('ovarian cancer', 'Disease', (126, 140))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('miR-21', 'Gene', '406991', (52, 58))	('increased', 'PosReg', (95, 104))	('miR-21', 'Gene', (158, 164))
13284	31035447	The potential anti-tumor effects following miR-29a transfection were inferred through downstream molecular expression and the apoptosis of ovarian cancer cells.	('miR-29a', 'Gene', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('ovarian cancer', 'Disease', (139, 153))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('transfection', 'Var', (51, 63))	('tumor', 'Disease', (19, 24))	('ovarian cancer', 'Disease', 'MESH:D010051', (139, 153))	('miR-29a', 'Gene', '407021', (43, 50))
13285	31035447	observed that the expression of let-7a was significantly lower in patients with ovarian cancer who were sensitive to platinum and paclitaxel compared with those who were resistant to those agents; on the other hand, the high expression of let-7a was associated with an increased survival rate in patients receiving chemotherapy based on platinum alone but a lower survival in those receiving combination therapy.	('ovarian cancer', 'Disease', (80, 94))	('let-7a', 'Gene', (239, 245))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('platinum', 'Chemical', 'MESH:D010984', (337, 345))	('platinum', 'Chemical', 'MESH:D010984', (117, 125))	('increased', 'PosReg', (269, 278))	('patients', 'Species', '9606', (296, 304))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('high', 'Var', (220, 224))	('expression', 'MPA', (18, 28))	('paclitaxel', 'Chemical', 'MESH:D017239', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lower', 'NegReg', (358, 363))	('survival', 'MPA', (279, 287))	('patients', 'Species', '9606', (66, 74))	('lower', 'NegReg', (57, 62))
13429	21761824	Two genes, the proto-oncogene SRC encoding a non receptor tyrosine kinase and AKR1C1, which encodes an enzyme involved in phase 1 metabolism, were positively correlated with poor PFS, therefore linking their upregulation with poor PFS.	('metabolism', 'biological_process', 'GO:0008152', ('130', '140'))	('poor', 'Var', (174, 178))	('SRC', 'Gene', (30, 33))	('AKR1C1', 'Gene', '1645', (78, 84))	('AKR1C1', 'Gene', (78, 84))
13434	21761824	For example, C:G to A:T transversion mutations were identified to be among the most predominant type of these mutations in many cancers, including ovarian cancer.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('mutations', 'Var', (110, 119))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('predominant', 'Reg', (84, 95))	('C:G to', 'Var', (13, 19))	('ovarian cancer', 'Disease', (147, 161))
13464	21761824	In support of this paradoxical observation, multiple other studies have shown an association of TIMP1 expression with poor prognosis in several cancers including breast, renal, colorectal, and papillary thyroid cancers as well as non-Hodgkin lymphoma.	('non-Hodgkin lymphoma', 'Disease', (230, 250))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (230, 250))	('papillary thyroid cancers', 'Disease', (193, 218))	('colorectal', 'Disease', (177, 187))	('expression', 'Var', (102, 112))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (230, 250))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('TIMP1', 'Gene', '7076', (96, 101))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (193, 218))	('breast', 'Disease', (162, 168))	('lymphoma', 'Phenotype', 'HP:0002665', (242, 250))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('association', 'Reg', (81, 92))	('cancers', 'Disease', (211, 218))	('renal', 'Disease', (170, 175))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (234, 250))	('TIMP1', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (193, 218))
13500	31368906	In addition, LGSC and serous borderline tumors have relatively frequent point mutations in the KRAS and BRAF genes.	('LGSC', 'Disease', (13, 17))	('KRAS', 'Gene', '3845', (95, 99))	('borderline tumors', 'Disease', 'MESH:D012569', (29, 46))	('BRAF', 'Gene', '673', (104, 108))	('KRAS', 'Gene', (95, 99))	('point mutations', 'Var', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('BRAF', 'Gene', (104, 108))	('borderline tumors', 'Disease', (29, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
13502	31368906	In contrast, type II ovarian carcinoma is a high-grade epithelial malignant tumor, which almost always harbors a TP53 mutation and lacks obvious benign and/or borderline tumors, except for in rare cases.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('type II ovarian carcinoma', 'Disease', (13, 38))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('borderline tumors', 'Disease', 'MESH:D012569', (159, 176))	('epithelial malignant tumor', 'Phenotype', 'HP:0031492', (55, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (170, 175))	('TP53', 'Gene', '7157', (113, 117))	('borderline tumors', 'Disease', (159, 176))	('mutation', 'Var', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('type II ovarian carcinoma', 'Disease', 'MESH:D010051', (13, 38))	('TP53', 'Gene', (113, 117))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (21, 38))	('harbors', 'Reg', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
13505	31368906	Similar to HGSC, STIC shows a high frequency of TP53 mutations.	('TP53', 'Gene', '7157', (48, 52))	('STIC', 'Disease', (17, 21))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('STIC', 'Disease', 'MESH:D002278', (17, 21))
13506	31368906	Moreover, concurrent STIC and HGSC have identical TP53 mutations and other genetic alternations, suggesting that TP53 dysfunction in the fallopian tubal cells triggers high-grade serous carcinogenesis.	('STIC', 'Disease', (21, 25))	('TP53', 'Gene', '7157', (50, 54))	('dysfunction', 'Var', (118, 129))	('TP53', 'Gene', '7157', (113, 117))	('TP53', 'Gene', (50, 54))	('high-grade serous carcinogenesis', 'Disease', (168, 200))	('triggers', 'Reg', (159, 167))	('TP53', 'Gene', (113, 117))	('STIC', 'Disease', 'MESH:D002278', (21, 25))
13530	31368906	Unlike the extrauterine serous carcinoma, all other uterine serous carcinomas are considered high-grade malignancies, which most probably harbor a TP53 mutation.	('serous carcinomas', 'Disease', (60, 77))	('harbor', 'Reg', (138, 144))	('TP53', 'Gene', (147, 151))	('serous carcinoma', 'Disease', 'MESH:D018284', (24, 40))	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('serous carcinomas', 'Disease', 'MESH:D018284', (60, 77))	('malignancies', 'Disease', (104, 116))	('serous carcinoma', 'Disease', 'MESH:D018284', (60, 76))	('serous carcinoma', 'Disease', (24, 40))	('TP53', 'Gene', '7157', (147, 151))	('mutation', 'Var', (152, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
13541	31368906	TP53 mutation analysis of such cases identified 3 mutational patterns: identical TP53 mutations (10/21 cases), discordant TP53 mutations (5/21 cases), and mixed TP53 mutations (6/21 cases).	('mutations', 'Var', (86, 95))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (122, 126))	('TP53', 'Gene', (161, 165))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (122, 126))	('TP53', 'Gene', '7157', (161, 165))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
13542	31368906	The identical cases showed that TP53 mutation in SEIC was compatible to that in extrauterine serous cancer and lacked STIC, indicating that these cases were probably of endometrial origin.	('SEIC', 'Disease', 'MESH:D016889', (49, 53))	('mutation', 'Var', (37, 45))	('TP53', 'Gene', '7157', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('STIC', 'Disease', 'MESH:D002278', (118, 122))	('SEIC', 'Disease', (49, 53))	('TP53', 'Gene', (32, 36))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('SEIC', 'Phenotype', 'HP:0012887', (49, 53))	('STIC', 'Disease', (118, 122))
13543	31368906	In contrast, discordant cases contained the TP53 mutation that was identical to that observed in STIC, not SEIC, and displayed extensive involvement of extrauterine cancer compared with identical cases, suggesting that these cases were likely of tubal origin.	('SEIC', 'Phenotype', 'HP:0012887', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('STIC', 'Disease', 'MESH:D002278', (97, 101))	('mutation', 'Var', (49, 57))	('SEIC', 'Disease', 'MESH:D016889', (107, 111))	('involvement', 'Reg', (137, 148))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('TP53', 'Gene', '7157', (44, 48))	('SEIC', 'Disease', (107, 111))	('STIC', 'Disease', (97, 101))	('TP53', 'Gene', (44, 48))
13544	31368906	Mixed cases, whose metastatic sites contained 2 independent TP53 mutations, were considered synchronous primary endometrial and tubal serous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('tubal serous carcinoma', 'Disease', 'MESH:D005184', (128, 150))	('tubal serous carcinoma', 'Disease', (128, 150))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
13551	31368906	Hereditary cancer syndromes comprise ~10% of all cancer cases and arise from germline mutation of cancer-related genes, whose dysfunction leads to a predisposition to cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('leads to', 'Reg', (138, 146))	('cancer', 'Disease', (167, 173))	('Hereditary cancer syndromes', 'Disease', 'MESH:D009386', (0, 27))	('arise from', 'Reg', (66, 76))	('germline mutation', 'Var', (77, 94))	('Hereditary cancer syndromes', 'Disease', (0, 27))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', (49, 55))
13552	31368906	Hereditary breast and ovarian cancers principally arise from BRCA1/2 germline mutation.	('ovarian cancers', 'Phenotype', 'HP:0100615', (22, 37))	('BRCA1', 'Gene', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('Hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (0, 37))	('germline mutation', 'Var', (69, 86))	('BRCA1', 'Gene', '672', (61, 66))	('arise from', 'Reg', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
13553	31368906	The estimated lifetime ovarian cancer risk is 44% and 17% for BRCA1 and BRCA2 mutation carriers, respectively.	('BRCA2', 'Gene', (72, 77))	('mutation', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('BRCA1', 'Gene', '672', (62, 67))	('ovarian cancer', 'Disease', (23, 37))	('BRCA2', 'Gene', '675', (72, 77))	('BRCA1', 'Gene', (62, 67))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))
13562	31368906	BRCA1/2 dysfunction leads to homologous recombination deficiency (HRD), which results in a condition where the cells are unable to utilize the homologous recombination repair pathway when double strand breaks occur.	('BRCA1', 'Gene', (0, 5))	('homologous recombination', 'biological_process', 'GO:0035825', ('29', '53'))	('leads to', 'Reg', (20, 28))	('recombination deficiency', 'Disease', 'MESH:C535296', (40, 64))	('dysfunction', 'Var', (8, 19))	('BRCA1', 'Gene', '672', (0, 5))	('homologous recombination', 'biological_process', 'GO:0035825', ('143', '167'))	('recombination deficiency', 'Disease', (40, 64))
13564	31368906	In fact, The Cancer Genome Atlas (TCGA) study revealed that sporadic BRCA1/2 mutation and epigenetically BRCA1 silencing accounts for ~6% and 11.5% of all HGSC cases, respectively.	('BRCA1', 'Gene', (105, 110))	('silencing', 'NegReg', (111, 120))	('BRCA1', 'Gene', '672', (69, 74))	('mutation', 'Var', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('BRCA1', 'Gene', (69, 74))	('HGSC', 'Disease', (155, 159))	('BRCA1', 'Gene', '672', (105, 110))
13567	31368906	Although germline BRCA1/2 mutation accounts for ~25% of hereditary breast and ovarian cancers, evidence of other candidate genes involved in inherited cancer has subsequently emerged.	('BRCA1', 'Gene', '672', (18, 23))	('mutation', 'Var', (26, 34))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (56, 93))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('inherited cancer', 'Disease', (141, 157))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ovarian cancers', 'Phenotype', 'HP:0100615', (78, 93))	('BRCA1', 'Gene', (18, 23))	('inherited cancer', 'Disease', 'MESH:D009386', (141, 157))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
13572	31368906	Germline TP53 mutation predisposes adult females to breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('predisposes', 'Reg', (23, 34))	('breast cancer', 'Disease', (52, 65))	('TP53', 'Gene', '7157', (9, 13))	('mutation', 'Var', (14, 22))	('TP53', 'Gene', (9, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))
13573	31368906	In contrast, the ovarian cancer risk of germline TP53 mutation is not significant enough to recommend the mutant carrier for prophylactic adnexal surgery despite the prevalence in HGSC.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('TP53', 'Gene', '7157', (49, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('TP53', 'Gene', (49, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('ovarian cancer', 'Disease', (17, 31))	('carrier', 'molecular_function', 'GO:0005215', ('113', '120'))	('HGSC', 'Disease', (180, 184))	('germline', 'Var', (40, 48))
13574	31368906	This evidence suggests that TP53 mutation is essential in the early phase of high-grade serous carcinogenesis but another driving force is required for it to progress to the malignant form.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('high-grade serous carcinogenesis', 'Disease', (77, 109))
13579	31368906	Apart from their main histology, TP53 mutation is also detected in the SET variant, whereas BRCA dysregulation is frequently associated with the SET variant compared with conventional HGSC.	('detected', 'Reg', (55, 63))	('variant', 'Var', (75, 82))	('BRCA dysregulation', 'Disease', (92, 110))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))	('BRCA dysregulation', 'Disease', 'OMIM:604370', (92, 110))
13590	31368906	Aberrant p53 expression detected by immunohistochemistry has been known to be a surrogate marker of TP53 mutation in ovarian serous carcinoma.	('TP53', 'Gene', '7157', (100, 104))	('mutation', 'Var', (105, 113))	('ovarian serous carcinoma', 'Disease', (117, 141))	('Aberrant', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('expression', 'MPA', (13, 23))	('TP53', 'Gene', (100, 104))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (117, 141))
13591	31368906	Aberrant p53 expression is mainly divided into 2 distinctive patterns: diffuse positive (overexpression) and diffuse negative (complete absence).	('Aberrant', 'Var', (0, 8))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))
13592	31368906	The diffuse p53 positivity and negativity are believed to be associated with gain-of-function and loss-of-function p53, respectively.	('loss-of-function', 'NegReg', (98, 114))	('gain-of-function', 'PosReg', (77, 93))	('p53', 'Gene', (115, 118))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (115, 118))	('diffuse', 'Var', (4, 11))	('p53', 'Gene', '7157', (12, 15))	('negativity', 'Var', (31, 41))	('positivity', 'Var', (16, 26))
13593	31368906	Interestingly, the pattern of aberrant p53 expression is closely related to the specific type of TP53 mutation.	('aberrant', 'Var', (30, 38))	('TP53', 'Gene', '7157', (97, 101))	('mutation', 'Var', (102, 110))	('TP53', 'Gene', (97, 101))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('expression', 'MPA', (43, 53))
13594	31368906	Most of the p53 overexpression is linked to TP53 missense mutation, which is located at the DNA binding domain.	('missense mutation', 'Var', (49, 66))	('overexpression', 'PosReg', (16, 30))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('DNA binding', 'molecular_function', 'GO:0003677', ('92', '103'))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))
13595	31368906	In contrast, complete p53 absence tends to arise from insertion and/or deletion of the TP53 gene.	('absence', 'NegReg', (26, 33))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('p53', 'Gene', (22, 25))	('deletion', 'Var', (71, 79))	('p53', 'Gene', '7157', (22, 25))	('insertion', 'Var', (54, 63))
13596	31368906	Therefore, the kind of aberrant p53 expression is also a precise predictor of the type of TP53 mutation.	('expression', 'MPA', (36, 46))	('TP53', 'Gene', '7157', (90, 94))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('TP53', 'Gene', (90, 94))	('aberrant', 'Var', (23, 31))
13597	31368906	Recently, other p53 immunohistochemical types arising from TP53 mutations have been reported.	('TP53', 'Gene', (59, 63))	('p53', 'Gene', (16, 19))	('p53', 'Gene', '7157', (16, 19))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', '7157', (59, 63))
13598	31368906	The third aberrant immunophenotype, cytoplasmic p53 expression results from a TP53 mutation that is located at nuclear localized domains.	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (48, 51))	('results from', 'Reg', (63, 75))	('mutation', 'Var', (83, 91))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))
13600	31368906	Conversely, the wild-type p53 expression pattern is rarely observed with a TP53 mutation due to truncated or 3' splicing mutations.	('splicing', 'biological_process', 'GO:0045292', ('112', '120'))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('TP53', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (75, 79))	('mutation', 'Var', (80, 88))
13603	31368906	Naturally, aberrant p53 expression was predominantly found in the distal fallopian tube and fimbria associated with TP53 mutation.	('p53', 'Gene', (20, 23))	('TP53', 'Gene', (116, 120))	('p53', 'Gene', '7157', (20, 23))	('fallopian tube', 'Disease', (73, 87))	('fimbria', 'cellular_component', 'GO:0009289', ('92', '99'))	('found', 'Reg', (53, 58))	('expression', 'MPA', (24, 34))	('aberrant', 'Var', (11, 19))	('fallopian tube', 'Disease', 'MESH:D005184', (73, 87))	('mutation', 'Var', (121, 129))	('TP53', 'Gene', '7157', (116, 120))
13605	31368906	Consequently, the p53 signature is a latent precursor of STIC because TP53 mutation is the main driving force in high-grade serous carcinogenesis, but it does not always seem to develop into STIC.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('STIC', 'Disease', (57, 61))	('STIC', 'Disease', 'MESH:D002278', (191, 195))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('TP53', 'Gene', (70, 74))	('STIC', 'Disease', 'MESH:D002278', (57, 61))	('STIC', 'Disease', (191, 195))
13607	31368906	To detect a null-type p53 signature is a diagnostic challenge because of the benign-like morphology and minimal molecular alteration.	('null-type', 'Var', (12, 21))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', (22, 25))
13611	31368906	Interestingly, TP53 mutation analysis revealed that majority of ESPs contained mutations identical to those of concurrent STIC-negative HGSC.	('ESPs', 'Disease', (64, 68))	('STIC', 'Disease', (122, 126))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('contained', 'Reg', (69, 78))	('STIC', 'Disease', 'MESH:D002278', (122, 126))	('mutations', 'Var', (79, 88))
13614	31368906	The original definition of SCOUT was, at least 30 distinctive secretory epithelial cells with BCL2 expression and without p53 expression, which were different from the background tubal epithelium that consisted of a mixture of secretory and ciliated cells.	('BCL2', 'molecular_function', 'GO:0015283', ('94', '98'))	('BCL2', 'Gene', '596', (94, 98))	('p53', 'Gene', '7157', (122, 125))	('expression', 'Var', (99, 109))	('BCL2', 'Gene', (94, 98))	('p53', 'Gene', (122, 125))
13623	31368906	Notably, the SET variant is closely associated with 2 unique features: BRCA1 mutation and tumor-infiltrating T lymphocytes.	('BRCA1', 'Gene', (71, 76))	('mutation', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('variant', 'Var', (17, 24))	('BRCA1', 'Gene', '672', (71, 76))	('associated', 'Reg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
13624	31368906	As described above, BRCA1 mutation is associated with HRD, suggesting that such a molecular feature is frail in platinum-based combined chemotherapy because of DNA repair system dysregulation.	('BRCA1', 'Gene', (20, 25))	('associated', 'Reg', (38, 48))	('mutation', 'Var', (26, 34))	('DNA repair', 'biological_process', 'GO:0006281', ('160', '170'))	('HRD', 'Disease', (54, 57))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('platinum', 'Chemical', 'MESH:D010984', (112, 120))	('BRCA1', 'Gene', '672', (20, 25))
13627	31368906	This study confirmed 2 notable refractory features: CCNE1 amplification and reversion of BRCA1/2 mutation.	('BRCA1', 'Gene', (89, 94))	('CCNE1', 'Gene', '898', (52, 57))	('mutation', 'Var', (97, 105))	('CCNE1', 'Gene', (52, 57))	('BRCA1', 'Gene', '672', (89, 94))	('amplification', 'Var', (58, 71))
13631	31368906	Consistent with the initial report, several groups described that the CCNE1 amplification or cyclin E1 overexpression is associated with unfavorable prognosis and therapy resistance.	('cyclin E1', 'Gene', (93, 102))	('cyclin', 'molecular_function', 'GO:0016538', ('93', '99'))	('CCNE1', 'Gene', '898', (70, 75))	('CCNE1', 'Gene', (70, 75))	('overexpression', 'PosReg', (103, 117))	('cyclin E1', 'Gene', '898', (93, 102))	('amplification', 'Var', (76, 89))
13632	31368906	Interestingly, CCNE1 amplification is found in ~20% of HGSCs and for the most part is exclusive of BRCA1/2 dysregulation.	('CCNE1', 'Gene', (15, 20))	('BRCA1', 'Gene', (99, 104))	('CCNE1', 'Gene', '898', (15, 20))	('amplification', 'Var', (21, 34))	('HGSCs', 'Disease', (55, 60))	('BRCA1', 'Gene', '672', (99, 104))
13634	31368906	These findings indicated that CCNE1 amplification is one of the essential molecular events in high-grade serous carcinogenesis.	('amplification', 'Var', (36, 49))	('high-grade serous carcinogenesis', 'Disease', (94, 126))	('CCNE1', 'Gene', '898', (30, 35))	('CCNE1', 'Gene', (30, 35))
13635	31368906	Reversion of BRCA1/2 mutation is a unique genetic event that leads to therapy resistance in cancer cells.	('leads to', 'Reg', (61, 69))	('cancer', 'Disease', (92, 98))	('BRCA1', 'Gene', (13, 18))	('therapy resistance', 'CPA', (70, 88))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA1', 'Gene', '672', (13, 18))
13636	31368906	Reversion of BRCA1/2 mutation stands for the secondary mutation that allows BRCA1/2-mutated cancer cells to restore to wild-type or nearly intact BRCA1/2 state, allowing these cancer cells to reacquire normal BRCA1/2 function, and resistance to chemotherapy.	('BRCA1', 'Gene', '672', (209, 214))	('cancer', 'Disease', (92, 98))	('BRCA1', 'Gene', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('BRCA1', 'Gene', '672', (146, 151))	('BRCA1', 'Gene', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('mutation', 'Var', (21, 29))	('BRCA1', 'Gene', '672', (76, 81))	('function', 'MPA', (217, 225))	('BRCA1', 'Gene', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA1', 'Gene', (76, 81))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('BRCA1', 'Gene', '672', (13, 18))
13637	31368906	Beside these genetic alterations, demethylation of the BRCA1 promotor region also restores BRCA1 expression and results in chemoresistance.	('BRCA1', 'Gene', (91, 96))	('results in', 'Reg', (112, 122))	('BRCA1', 'Gene', '672', (55, 60))	('restores', 'PosReg', (82, 90))	('demethylation', 'Var', (34, 47))	('chemoresistance', 'CPA', (123, 138))	('BRCA1', 'Gene', (55, 60))	('BRCA1', 'Gene', '672', (91, 96))	('demethylation', 'biological_process', 'GO:0070988', ('34', '47'))	('expression', 'MPA', (97, 107))
13638	31368906	Collectively, the BRCA1/2 mutation plays an important role in the early stage of high-grade serous carcinogenesis to form specific genomic patterns effectively.	('high-grade serous carcinogenesis', 'Disease', (81, 113))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (18, 23))	('mutation', 'Var', (26, 34))
13639	31368906	Meanwhile, this mutagenic phenotype, derived from BRCA1/2 mutation, is impeditive for cancer cell survival because of unavailability of the DNA repair system.	('BRCA1', 'Gene', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('DNA repair', 'biological_process', 'GO:0006281', ('140', '150'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutation', 'Var', (58, 66))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('BRCA1', 'Gene', '672', (50, 55))	('cancer', 'Disease', (86, 92))
13640	31368906	Therefore, reversion of the BRCA1/2 mutation is a reasonable genetic event in the late stage of high-grade serous carcinogenesis.	('high-grade serous carcinogenesis', 'Disease', (96, 128))	('BRCA1', 'Gene', (28, 33))	('BRCA1', 'Gene', '672', (28, 33))	('mutation', 'Var', (36, 44))
13704	24525512	One of these cases was mismatch repair-deficient tumor (MLH1-, PMS2-).	('mismatch repair', 'biological_process', 'GO:0006298', ('23', '38'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PMS2', 'Gene', (63, 67))	('deficient tumor', 'Disease', (39, 54))	('PMS2', 'Gene', '5395', (63, 67))	('mismatch', 'Var', (23, 31))	('MLH1', 'Gene', '4292', (56, 60))	('deficient tumor', 'Disease', 'MESH:D009369', (39, 54))	('MLH1', 'Gene', (56, 60))
13803	23800698	Fifteen patients with HGOSCs were identified to have wild-type TP53, which had significantly shorter survival and higher chemoresistance than those with mutated TP53.	('shorter', 'NegReg', (93, 100))	('survival', 'CPA', (101, 109))	('chemoresistance', 'CPA', (121, 136))	('TP53', 'Var', (63, 67))	('higher', 'PosReg', (114, 120))	('patients', 'Species', '9606', (8, 16))
13806	23800698	Using RNAseq data, it was found that EDA2R gene, a direct target of wild-type TP53, was highly up-regulated in samples with wild-type TP53 in comparison to samples with either nonsense or missense TP53 mutations.	('EDA2R', 'Gene', (37, 42))	('EDA2R', 'Gene', '60401', (37, 42))	('up-regulated', 'PosReg', (95, 107))	('TP53', 'Var', (134, 138))	('wild-type', 'Var', (124, 133))
13807	23800698	Patients with wild-type TP53 high grade ovarian serous carcinomas appeared to have a poorer survival and were more chemoresistant than those with mutated TP53.	('poorer', 'NegReg', (85, 91))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (40, 65))	('survival', 'CPA', (92, 100))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (40, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('Patients', 'Species', '9606', (0, 8))	('wild-type', 'Var', (14, 23))	('ovarian serous carcinomas', 'Disease', (40, 65))	('TP53', 'Var', (24, 28))	('chemoresistant', 'CPA', (115, 129))
13809	23800698	Many researchers have tried to correlate TP53 mutations with clinical outcomes for patients with ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('ovarian cancer', 'Disease', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('patients', 'Species', '9606', (83, 91))
13811	23800698	Recent exome sequencing analysis of 316 high-grade ovarian serous carcinomas (HGOSCs) identified mutations in the tumor repressor protein 53 (TP53) gene in 96% of all cases, which supports the idea that TP53 is a driver mutation in ovarian cancer.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('mutations', 'Var', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('tumor repressor protein 53', 'Gene', '7157', (114, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ovarian cancer', 'Disease', (232, 246))	('TP53', 'Gene', (142, 146))	('ovarian serous carcinomas', 'Disease', (51, 76))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (51, 76))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (51, 76))	('tumor repressor protein 53', 'Gene', (114, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (232, 246))	('ovarian cancer', 'Disease', 'MESH:D010051', (232, 246))
13812	23800698	The use of whole-exome sequencing and subsequent independent validation of TP53 mutations in The Cancer Genome Atlas (TCGA) ovarian cancer samples provide the most reliable data to date.	('mutations', 'Var', (80, 89))	('Cancer Genome Atlas (TCGA) ovarian cancer', 'Disease', 'MESH:D010051', (97, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('TP53', 'Gene', (75, 79))
13814	23800698	More interestingly, patients with wild-type TP53 ovarian cancer appeared to have a poorer survival and were more chemoresistant than those with mutated TP53.	('chemoresistant', 'CPA', (113, 127))	('poorer', 'NegReg', (83, 89))	('TP53', 'Var', (44, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (49, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('survival', 'CPA', (90, 98))	('ovarian cancer', 'Disease', (49, 63))
13828	23800698	Patients with wild-type TP53 had significantly poorer survival than those with mutated TP53 (Figure 1).	('survival', 'MPA', (54, 62))	('Patients', 'Species', '9606', (0, 8))	('poorer', 'NegReg', (47, 53))	('mutated', 'Var', (79, 86))
13829	23800698	The median overall survival for the patients with wild-type TP53 was 27 months, while the median survival for patients with mutated TP53 was 45 months.	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (110, 118))	('TP53', 'Var', (60, 64))	('mutated', 'Var', (124, 131))
13830	23800698	The mean follow-up time for patients with TP53 wild-type was 57 months and for TP53 mutation was 63 months (p value = 0.272, not significantly different).	('patients', 'Species', '9606', (28, 36))	('TP53', 'Var', (42, 46))	('TP53', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
13831	23800698	The median follow-up for patients with TP53 mutation was 62 months which is much longer than the median survival time for patients with TP53 mutation.	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (25, 33))	('mutation', 'Var', (44, 52))	('TP53', 'Gene', (39, 43))
13832	23800698	After adjustment for age and debulking status by Cox regression analysis, the difference in both overall and progression-free survival between mutated TP53 and wild-type TP53 was still significant (p=0.02 and 0.01, respectively).	('mutated', 'Var', (143, 150))	('Cox', 'Gene', '1351', (49, 52))	('Cox', 'Gene', (49, 52))	('TP53', 'Gene', (151, 155))
13833	23800698	Moreover, seven patients with wild-type TP53 appeared to be resistant to standard chemotherapy (carboplatin/taxane).	('wild-type TP53', 'Var', (30, 44))	('taxane', 'Chemical', 'MESH:C080625', (108, 114))	('patients', 'Species', '9606', (16, 24))	('TP53', 'Var', (40, 44))	('carboplatin', 'Chemical', 'MESH:D016190', (96, 107))	('resistant', 'MPA', (60, 69))
13839	23800698	Using somatic mutation level 3 TCGA data (validated mutations) for these 15 tumor samples with wild-type TP53, we identified 354 genes that were mutated (S5).	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutated', 'Var', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
13842	23800698	Since these mutations were more frequently found in epithelial ovarian cancers of other histological subtypes - BRAF in serous borderline tumors and low-grade serous carcinomas, CTNNB1 in endometrioid ovarian carcinomas, and PIK3CA and ARIDIA in clear cell carcinomas, misclassification of these wild-type TP53 tumors from other histological subtypes as high grade ovarian serous cystadenocarcinomas was less likely.	('tumors', 'Disease', (311, 317))	('carcinomas', 'Phenotype', 'HP:0030731', (257, 267))	('PIK3CA', 'Gene', '5290', (225, 231))	('endometrioid ovarian carcinomas', 'Disease', (188, 219))	('found', 'Reg', (43, 48))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('serous carcinomas', 'Disease', (159, 176))	('ovarian serous cystadenocarcinomas', 'Disease', (365, 399))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (52, 78))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (201, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (389, 398))	('ovarian serous cystadenocarcinomas', 'Phenotype', 'HP:0012887', (365, 399))	('carcinomas', 'Phenotype', 'HP:0030731', (389, 399))	('CTNNB1', 'Gene', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (201, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PIK3CA', 'Gene', (225, 231))	('clear cell carcinomas', 'Disease', (246, 267))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('serous carcinomas', 'Disease', 'MESH:D018284', (159, 176))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('ovarian cancers', 'Phenotype', 'HP:0100615', (63, 78))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (246, 267))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('endometrioid ovarian carcinomas', 'Disease', 'MESH:D016889', (188, 219))	('mutations', 'Var', (12, 21))	('tumors', 'Disease', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('ovarian serous cystadenocarcinomas', 'Disease', 'MESH:D018284', (365, 399))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('CTNNB1', 'Gene', '1499', (178, 184))	('epithelial ovarian cancers', 'Disease', (52, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
13843	23800698	Since mammalian cells has an RNA surveillance system (nonsense mediated mRNA decay) to eliminate faulty mRNA transcripts with nonsense mutations, we would expect that samples with nonsense TP53 mutation would have lower expression level of TP53 transcript and protein.	('mutation', 'Var', (194, 202))	('nonsense', 'Var', (180, 188))	('RNA surveillance', 'biological_process', 'GO:0071025', ('29', '45'))	('TP53', 'Gene', (189, 193))	('nonsense mediated mRNA decay', 'biological_process', 'GO:0000184', ('54', '82'))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('mammalian', 'Species', '9606', (6, 15))	('lower', 'NegReg', (214, 219))	('protein', 'cellular_component', 'GO:0003675', ('260', '267'))
13852	23800698	Although the progression of low-grade serous carcinoma to high-grade serous carcinoma is very rare, Vang et al found no TP53 mutations in a series of six ovarian serous carcinomas with both high-grade and low-grade components.	('mutations', 'Var', (125, 134))	('serous carcinoma', 'Disease', (69, 85))	('serous carcinoma', 'Disease', 'MESH:D018284', (38, 54))	('serous carcinoma', 'Disease', 'MESH:D018284', (69, 85))	('ovarian serous carcinomas', 'Disease', (154, 179))	('serous carcinoma', 'Disease', 'MESH:D018284', (162, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ovarian serous carcinomas', 'Phenotype', 'HP:0012887', (154, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (154, 179))	('serous carcinoma', 'Disease', (38, 54))	('TP53', 'Gene', (120, 124))
13853	23800698	Out of these 354 genes with mutations, 88 genes are involved in the pathogenesis of cancer, seven genes were involved in estrogen receptor signaling (Table 2), and six genes (DSCAML1, KIAA1012, TNN, MUC16, FBXW7, and KRAS) occurred in more than one wild-type TP53 samples (S5).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('pathogenesis', 'biological_process', 'GO:0009405', ('68', '80'))	('DSCAML1', 'Gene', '57453', (175, 182))	('KIAA1012', 'Gene', (184, 192))	('TNN', 'Gene', (194, 197))	('KRAS', 'Gene', '3845', (217, 221))	('MUC16', 'Gene', '94025', (199, 204))	('KIAA1012', 'Gene', '22878', (184, 192))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('FBXW7', 'Gene', (206, 211))	('involved', 'Reg', (109, 117))	('KRAS', 'Gene', (217, 221))	('DSCAML1', 'Gene', (175, 182))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('MUC16', 'Gene', (199, 204))	('mutations', 'Var', (28, 37))	('FBXW7', 'Gene', '55294', (206, 211))	('TNN', 'Gene', '63923', (194, 197))	('involved', 'Reg', (52, 60))
13856	23800698	In a recent study, FBXW7 mutation was found to be significantly correlated with positive lymph nodes in endometrial cancer.	('FBXW7', 'Gene', (19, 24))	('endometrial cancer', 'Disease', (104, 122))	('mutation', 'Var', (25, 33))	('endometrial cancer', 'Phenotype', 'HP:0012114', (104, 122))	('positive', 'Disease', (80, 88))	('endometrial cancer', 'Disease', 'MESH:D016889', (104, 122))	('FBXW7', 'Gene', '55294', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('correlated', 'Reg', (64, 74))
13857	23800698	By querying the TCGA uterine cancer study using the cBio Cancer Genomics Portal, we found that FBXW7 is more frequently mutated in more aggressive uterine serous carcinomas (33%) than that of uterine endometrioid cancer (12%).	('uterine cancer', 'Phenotype', 'HP:0010784', (21, 35))	('cancer', 'Disease', (29, 35))	('endometrioid cancer', 'Disease', 'MESH:D016889', (200, 219))	('FBXW7', 'Gene', '55294', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('FBXW7', 'Gene', (95, 100))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (200, 219))	('endometrioid cancer', 'Disease', (200, 219))	('serous carcinomas', 'Disease', 'MESH:D018284', (155, 172))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('serous carcinomas', 'Disease', (155, 172))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('mutated', 'Var', (120, 127))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
13859	23800698	Wild-type TP53 can also impair the effectiveness of chemotherapy against breast cancer.	('impair', 'NegReg', (24, 30))	('TP53', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('effectiveness', 'CPA', (35, 48))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('Wild-type', 'Var', (0, 9))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
13878	32117711	For example, the antisense RNA of ubiquitin carboxy-terminal hydrolase L1 (Uchl1) can participate in the translation and maintain the stability of Uchl1 mRNA.	('ubiquitin carboxy-terminal hydrolase L1', 'Gene', '7345', (34, 73))	('Uchl1', 'Gene', '7345', (147, 152))	('antisense RNA', 'molecular_function', 'GO:0009388', ('17', '30'))	('stability', 'MPA', (134, 143))	('ubiquitin', 'molecular_function', 'GO:0031386', ('34', '43'))	('translation', 'MPA', (105, 116))	('Uchl1', 'Gene', (147, 152))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('translation', 'biological_process', 'GO:0006412', ('105', '116'))	('ubiquitin carboxy-terminal hydrolase L1', 'Gene', (34, 73))	('antisense', 'Var', (17, 26))	('maintain', 'PosReg', (121, 129))	('participate', 'Reg', (86, 97))	('Uchl1', 'Gene', '7345', (75, 80))	('Uchl1', 'Gene', (75, 80))
13885	32117711	Its expression is regulated by methylation and abnormal splicing and is closely associated with the development and progression of various tumors.	('abnormal splicing', 'Var', (47, 64))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('expression', 'MPA', (4, 14))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('associated', 'Reg', (80, 90))	('methylation', 'Var', (31, 42))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('regulated', 'Reg', (18, 27))
13894	32117711	Moreover, WT1-AS can bind to microRNAs such as miR-203a-5p and miR-330-5p as a molecular decoy and can inhibit the translation of downstream genes, including TP53 (tumor protein p53) and FOXN2 (forkhead box N2), thereby regulating the biological behaviors of tumor cells.	('TP53', 'Gene', (158, 162))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('miR-203a-5p', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('translation', 'biological_process', 'GO:0006412', ('115', '126'))	('inhibit', 'NegReg', (103, 110))	('translation', 'MPA', (115, 126))	('forkhead box N2', 'Gene', '3344', (194, 209))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('regulating', 'Reg', (220, 230))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('TP53', 'Gene', '7157', (158, 162))	('forkhead box N2', 'Gene', (194, 209))	('FOXN2', 'Gene', '3344', (187, 192))	('p53', 'Gene', '7157', (178, 181))	('FOXN2', 'Gene', (187, 192))	('miR-330-5p', 'Var', (63, 73))	('tumor', 'Disease', (259, 264))	('p53', 'Gene', (178, 181))
13902	32117711	Patients with breast cancer with high WT1-AS expression also had poorer prognosis.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('high WT1-AS', 'Var', (33, 44))
13905	32117711	Knocking down WT1-AS expression can significantly reduce tumor cell proliferation and migration.	('Knocking down', 'Var', (0, 13))	('reduce', 'NegReg', (50, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('WT1-AS', 'Gene', (14, 20))
13906	32117711	However, WT1-AS is significantly downregulated in tumors such as gastric cancer, cervical cancer, liver cancer, and kidney cancer; and its biological functions are also quite different.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('kidney cancer', 'Disease', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('liver cancer', 'Disease', 'MESH:D006528', (98, 110))	('downregulated', 'NegReg', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('liver cancer', 'Phenotype', 'HP:0002896', (98, 110))	('liver cancer', 'Disease', (98, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('kidney cancer', 'Disease', 'MESH:D007680', (116, 129))	('WT1-AS', 'Var', (9, 15))	('cervical cancer', 'Disease', 'MESH:D002583', (81, 96))	('cervical cancer', 'Disease', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('gastric cancer', 'Disease', (65, 79))	('kidney cancer', 'Phenotype', 'HP:0009726', (116, 129))	('tumors', 'Disease', (50, 56))
13913	32117711	Moreover, a subsequent study revealed that WT1-AS expression can be used as an independent predictor of ccRCC prognosis and that patients with high WT1-AS expression had poorer prognosis.	('ccRCC', 'Disease', 'MESH:D002292', (104, 109))	('WT1-AS', 'Var', (43, 49))	('patients', 'Species', '9606', (129, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('ccRCC', 'Disease', (104, 109))
13917	32117711	analyzed the differential expression of lncRNAs in various histological subtypes of ovarian cancer and found that non-serous ovarian cancer had a greater degree of epigenetic WT1-AS inactivation than ovarian serous adenocarcinoma.	('ovarian cancer', 'Disease', (125, 139))	('ovarian cancer', 'Disease', (84, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (125, 139))	('epigenetic', 'Var', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
13943	32117711	Silencing WT1-AS in ovarian serous adenocarcinoma cell lines can inhibit tumor cell proliferation and downregulate the expression of various oncogenes.	('expression', 'MPA', (119, 129))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('downregulate', 'NegReg', (102, 114))	('tumor', 'Disease', (73, 78))	('WT1-AS', 'Gene', (10, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('inhibit', 'NegReg', (65, 72))	('Silencing', 'Var', (0, 9))	('oncogenes', 'Gene', (141, 150))
13946	32117711	The above studies demonstrate that WT1-AS is closely associated with many biological behaviors such as tumor cell proliferation, cell cycle arrest, and resistance to cell death, and that WT1-AS plays different roles in various tumors.	('cell death', 'biological_process', 'GO:0008219', ('166', '176'))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', (103, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (129, 146))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('129', '146'))	('resistance to cell death', 'CPA', (152, 176))	('associated', 'Reg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('cell cycle arrest', 'CPA', (129, 146))	('WT1-AS', 'Var', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
13950	32117711	reported that WT1-AS knockdown in the SiHa and CaSKi cervical cancer cell lines increased the invasive and migration abilities of these tumor cells, whereas WT1-AS overexpression attenuated their invasive and migration abilities; Dai et al.	('CaSKi', 'CellLine', 'CVCL:1100', (47, 52))	('cervical cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('increased', 'PosReg', (80, 89))	('SiHa', 'CellLine', 'CVCL:0032', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('knockdown', 'Var', (21, 30))	('tumor', 'Disease', (136, 141))	('cervical cancer', 'Disease', 'MESH:D002583', (53, 68))
13951	32117711	found that patients with gastric cancer with low WT1-AS expression were more likely to have local invasion and distant metastasis, whereas WT1-AS overexpression in the HGC7901 and HS-746T gastric cancer cell lines attenuated cell invasion and migration.	('gastric cancer', 'Phenotype', 'HP:0012126', (188, 202))	('local invasion', 'CPA', (92, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('HGC7901', 'CellLine', 'CVCL:1279', (168, 175))	('HS-746T', 'CellLine', 'CVCL:0333', (180, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('gastric cancer', 'Disease', (188, 202))	('attenuated', 'NegReg', (214, 224))	('patients', 'Species', '9606', (11, 19))	('gastric cancer', 'Disease', 'MESH:D013274', (188, 202))	('low', 'Var', (45, 48))	('gastric cancer', 'Disease', (25, 39))	('distant metastasis', 'CPA', (111, 129))
13955	32117711	Figure 3 summarizes all the reported mechanisms of WT1-AS in malignant tumors.	('WT1-AS', 'Var', (51, 57))	('malignant tumors', 'Disease', (61, 77))	('malignant tumors', 'Disease', 'MESH:D009369', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
13969	20965493	DNA methylation is an important mechanism in the regulation of gene function and serves as an epigenetic marker for tumor detection, classification and prognostication.	('methyl', 'Chemical', 'MESH:C051224', (4, 10))	('regulation', 'biological_process', 'GO:0065007', ('49', '59'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
13973	20965493	This protection is critical, since methylation of CpG islands is usually associated with loss of expression of that particular gene.	('methyl', 'Chemical', 'MESH:C051224', (35, 41))	('methylation', 'Var', (35, 46))	('loss of', 'NegReg', (89, 96))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('expression', 'MPA', (97, 107))
13975	20965493	For example, hypermethylation in the promoters of CDKN2 (p16), VHL, WT1 and MLH1 occurs in many solid tumors and is associated with loss of its expression, indicating that aberrant DNA methylation is one of the main mechanisms in the pathogenesis of human cancer.	('WT1', 'Gene', (68, 71))	('loss', 'NegReg', (132, 136))	('cancer', 'Disease', (256, 262))	('VHL', 'Disease', 'MESH:D006623', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('methyl', 'Chemical', 'MESH:C051224', (185, 191))	('CDKN2', 'Gene', '1029', (50, 55))	('WT1', 'Gene', '7490', (68, 71))	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('methyl', 'Chemical', 'MESH:C051224', (18, 24))	('expression', 'MPA', (144, 154))	('hypermethylation', 'Var', (13, 29))	('MLH1', 'Gene', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('p16', 'Gene', (57, 60))	('solid tumors', 'Disease', (96, 108))	('VHL', 'Disease', (63, 66))	('p16', 'Gene', '1029', (57, 60))	('DNA methylation', 'biological_process', 'GO:0006306', ('181', '196'))	('MLH1', 'Gene', '4292', (76, 80))	('CDKN2', 'Gene', (50, 55))	('pathogenesis', 'biological_process', 'GO:0009405', ('234', '246'))	('human', 'Species', '9606', (250, 255))	('solid tumors', 'Disease', 'MESH:D009369', (96, 108))
13976	20965493	To this end, 5-azacitidine has been shown to demethylate DR4 resulting in its re-expression, which leads in turn to enhanced sensitivity of platinum-resistant ovarian cancer cells to carboplatin through induction of apoptosis.	('ovarian cancer', 'Disease', (159, 173))	('enhanced', 'PosReg', (116, 124))	('DR4', 'Gene', '3126', (57, 60))	('5-azacitidine', 'Chemical', 'MESH:D001374', (13, 26))	('demethylate', 'Var', (45, 56))	('apoptosis', 'CPA', (216, 225))	('DR4', 'Gene', (57, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (159, 173))	('sensitivity', 'MPA', (125, 136))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('203', '225'))	('methyl', 'Chemical', 'MESH:C051224', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('carboplatin', 'Chemical', 'MESH:D016190', (183, 194))	('platinum', 'Chemical', 'MESH:D010984', (140, 148))	('ovarian cancer', 'Disease', 'MESH:D010051', (159, 173))	('re-expression', 'MPA', (78, 91))
13977	20965493	Aberrant methylation of multiple CpG islands is frequently observed in ovarian carcinoma compared with normal ovarian surface epithelium or benign ovarian neoplasms.	('benign ovarian neoplasms', 'Disease', (140, 164))	('benign ovarian neoplasms', 'Disease', 'MESH:D010051', (140, 164))	('Aberrant', 'Var', (0, 8))	('neoplasm', 'Phenotype', 'HP:0002664', (155, 163))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (71, 88))	('methyl', 'Chemical', 'MESH:C051224', (9, 15))	('ovarian neoplasms', 'Phenotype', 'HP:0100615', (147, 164))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (71, 88))	('ovarian carcinoma', 'Disease', (71, 88))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation', 'MPA', (9, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('neoplasms', 'Phenotype', 'HP:0002664', (155, 164))	('observed', 'Reg', (59, 67))
13978	20965493	For example, frequent CpG island hypermethylation in BRCA1, RASSF1A, and OPCML is detected in ovarian carcinoma and plays a role in tumor development.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (94, 111))	('role', 'Reg', (124, 128))	('RASSF1A', 'Gene', '11186', (60, 67))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ovarian carcinoma', 'Disease', (94, 111))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('OPCML', 'Gene', '4978', (73, 78))	('tumor', 'Disease', (132, 137))	('BRCA1', 'Gene', '672', (53, 58))	('hypermethylation', 'Var', (33, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('RASSF1A', 'Gene', (60, 67))	('methyl', 'Chemical', 'MESH:C051224', (38, 44))	('BRCA1', 'Gene', (53, 58))	('OPCML', 'Gene', (73, 78))
13980	20965493	Moreover, DNA methylation in certain gene promoters has been found to be a reliable epigenetic marker to predict treatment outcome in several types of human cancer including ovarian carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('methyl', 'Chemical', 'MESH:C051224', (14, 20))	('human', 'Species', '9606', (151, 156))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (174, 191))	('cancer', 'Disease', (157, 163))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (174, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('DNA methylation', 'biological_process', 'GO:0006306', ('10', '25'))	('DNA', 'Var', (10, 13))	('ovarian carcinoma', 'Disease', (174, 191))
13981	20965493	Thus, it has been suggested that DNA methylation changes have implications for ovarian cancer diagnosis, prognostication and treatment.	('methylation changes', 'Var', (37, 56))	('implications', 'Reg', (62, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('DNA methylation', 'biological_process', 'GO:0006306', ('33', '48'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('methyl', 'Chemical', 'MESH:C051224', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('ovarian cancer', 'Disease', (79, 93))	('changes', 'Var', (49, 56))
13997	20965493	Significant Analysis of Microarrays (SAM) analysis was implemented on two groups of methylation data for identifying the statistically significant hypermethylated or hypomethylated loci.	('hypomethylated', 'Var', (166, 180))	('methyl', 'Chemical', 'MESH:C051224', (84, 90))	('methyl', 'Chemical', 'MESH:C051224', (152, 158))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('methyl', 'Chemical', 'MESH:C051224', (170, 176))	('hypermethylated', 'Var', (147, 162))
13998	20965493	To assess the alterations in the overall methylation pattern among different clusters of tumor groups, we calculated the number of genes showing hypomethylation and hypermethylation in each sample.	('methyl', 'Chemical', 'MESH:C051224', (41, 47))	('methyl', 'Chemical', 'MESH:C051224', (149, 155))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('methyl', 'Chemical', 'MESH:C051224', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('hypermethylation', 'Var', (165, 181))
14010	20965493	The overall methylation pattern demonstrated that more genes were hypermethylated in the cystadenoma/SBT/LG serous carcinoma group than in the HG serous carcinoma group (p< 0.0001) (Fig.	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('hypermethylated', 'Var', (66, 81))	('cystadenoma', 'Disease', 'MESH:D003537', (89, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('cystadenoma', 'Disease', (89, 100))	('methyl', 'Chemical', 'MESH:C051224', (12, 18))	('methyl', 'Chemical', 'MESH:C051224', (71, 77))	('HG serous carcinoma', 'Disease', 'MESH:D018284', (143, 162))	('LG serous carcinoma', 'Disease', 'MESH:D018284', (105, 124))	('LG serous carcinoma', 'Disease', (105, 124))	('HG serous carcinoma', 'Disease', (143, 162))
14013	20965493	There were a number of genes showing aberrant methylation in HG serous carcinomas (both primary and recurrent tumors) as compared to other samples (Fig.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('serous carcinomas', 'Disease', (64, 81))	('HG serous carcinoma', 'Disease', 'MESH:D018284', (61, 80))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('methyl', 'Chemical', 'MESH:C051224', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('HG serous carcinoma', 'Disease', (61, 80))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('serous carcinomas', 'Disease', 'MESH:D018284', (64, 81))
14029	20965493	In contrast, HG serous carcinomas are highly aggressive, rarely harbor mutations in KRAS/BRAF/ERBB2 but have a high frequency of TP53 mutations.	('serous carcinomas', 'Disease', (16, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('KRAS', 'Gene', (84, 88))	('TP53', 'Gene', '7157', (129, 133))	('HG serous carcinoma', 'Disease', 'MESH:D018284', (13, 32))	('mutations', 'Var', (71, 80))	('KRAS', 'Gene', '3845', (84, 88))	('BRAF', 'Gene', '673', (89, 93))	('mutations', 'Var', (134, 143))	('BRAF', 'Gene', (89, 93))	('TP53', 'Gene', (129, 133))	('ERBB2', 'Gene', '2064', (94, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('HG serous carcinoma', 'Disease', (13, 32))	('serous carcinomas', 'Disease', 'MESH:D018284', (16, 33))	('ERBB2', 'Gene', (94, 99))
14047	20965493	This study also provides new clues about how aberrant promoter methylation participates in the pathogenesis of ovarian serous neoplasms.	('methyl', 'Chemical', 'MESH:C051224', (63, 69))	('promoter', 'Protein', (54, 62))	('ovarian serous neoplasms', 'Phenotype', 'HP:0012887', (111, 135))	('neoplasm', 'Phenotype', 'HP:0002664', (126, 134))	('aberrant', 'Var', (45, 53))	('ovarian serous neoplasm', 'Phenotype', 'HP:0012887', (111, 134))	('participates', 'Reg', (75, 87))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('ovarian serous neoplasms', 'Disease', 'MESH:D010051', (111, 135))	('pathogenesis', 'biological_process', 'GO:0009405', ('95', '107'))	('ovarian serous neoplasms', 'Disease', (111, 135))
14050	20965493	Based on the supervised analysis, we identified several genes whose methylation patterns are associated with the development of recurrent HG serous carcinoma.	('HG serous carcinoma', 'Disease', (138, 157))	('associated', 'Reg', (93, 103))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('methylation patterns', 'Var', (68, 88))	('methyl', 'Chemical', 'MESH:C051224', (68, 74))	('HG serous carcinoma', 'Disease', 'MESH:D018284', (138, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
14052	20965493	For example, hypermethylation in the promoters of FLT4 and KIT and hypomethylation in the promoters of TGF-beta1, gastrin-releasing peptide receptor occur more frequently in recurrent than primary untreated HG serous carcinomas.	('HG serous carcinoma', 'Disease', (207, 226))	('hypomethylation', 'Var', (67, 82))	('KIT', 'Gene', (59, 62))	('TGF-beta1', 'Gene', (103, 112))	('methyl', 'Chemical', 'MESH:C051224', (18, 24))	('methyl', 'Chemical', 'MESH:C051224', (71, 77))	('serous carcinomas', 'Disease', 'MESH:D018284', (210, 227))	('hypermethylation', 'Var', (13, 29))	('gastrin-releasing peptide receptor', 'Gene', '2925', (114, 148))	('TGF-beta1', 'Gene', '7040', (103, 112))	('HG serous carcinoma', 'Disease', 'MESH:D018284', (207, 226))	('KIT', 'molecular_function', 'GO:0005020', ('59', '62'))	('recurrent', 'Disease', (174, 183))	('FLT4', 'Gene', (50, 54))	('FLT4', 'Gene', '2324', (50, 54))	('gastrin-releasing peptide receptor', 'Gene', (114, 148))	('serous carcinomas', 'Disease', (210, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))
14057	20965493	We also identified several candidate hypomethylated and hypermethylated genes that may be involved in the development of recurrent HG serous carcinoma and in the progression from SBT to LG serous carcinoma.	('SBT', 'Disease', (179, 182))	('methyl', 'Chemical', 'MESH:C051224', (41, 47))	('hypermethylated', 'Var', (56, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('HG serous carcinoma', 'Disease', (131, 150))	('hypomethylated', 'Var', (37, 51))	('methyl', 'Chemical', 'MESH:C051224', (61, 67))	('LG serous carcinoma', 'Disease', 'MESH:D018284', (186, 205))	('LG serous carcinoma', 'Disease', (186, 205))	('involved', 'Reg', (90, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('HG serous carcinoma', 'Disease', 'MESH:D018284', (131, 150))
14068	31308737	High expression of DYNLT3 mRNA was related to poor overall survival and progression free survival, especially in serous ovarian cancer patients.	('overall survival', 'CPA', (51, 67))	('DYNLT3', 'Gene', '6990', (19, 25))	('poor', 'NegReg', (46, 50))	('patients', 'Species', '9606', (135, 143))	('High', 'Var', (0, 4))	('serous ovarian cancer', 'Disease', (113, 134))	('progression free survival', 'CPA', (72, 97))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('DYNLT3', 'Gene', (19, 25))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (113, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
14145	31308737	For serous ovarian cancer patients, high expression of DYNLT3 mRNA was associated with poor OS (HR (95% CI) =1.22 (1.02-1.46), P=0.026) and PFS (HR (95% CI) =1.2 (1.04-1.39), P=0.012).	('high expression', 'Var', (36, 51))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (4, 25))	('DYNLT3', 'Gene', (55, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('poor OS', 'Disease', (87, 94))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('DYNLT3', 'Gene', '6990', (55, 61))	('serous ovarian cancer', 'Disease', (4, 25))	('PFS', 'Disease', (140, 143))
14146	31308737	For endometrioid ovarian cancer patients, high expression of DYNLT3 mRNA was related to improved PFS (HR (95% CI) =0.25 (0.1-0.64), P=0.0018) but not related to OS (HR (95% CI) =447,707,887.65 (0-lnf), P=0.057).	('DYNLT3', 'Gene', '6990', (61, 67))	('endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (4, 31))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('high expression', 'Var', (42, 57))	('endometrioid ovarian cancer', 'Disease', (4, 31))	('PFS', 'MPA', (97, 100))	('improved', 'PosReg', (88, 96))	('DYNLT3', 'Gene', (61, 67))
14152	31308737	Conversely, cell proliferation in the DYNLT3 knockdown group (OD value: 0.90+-0.18) was significantly inhibited compared with that in the knockdown blank control group (OD value: 1.17+-0.12) and the knockdown vector control group (OD value: 1.15+-0.23) (Figure 4A).	('DYNLT3', 'Gene', (38, 44))	('inhibited', 'NegReg', (102, 111))	('DYNLT3', 'Gene', '6990', (38, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('12', '30'))	('cell proliferation', 'CPA', (12, 30))	('knockdown', 'Var', (45, 54))
14157	31308737	As expected, the number of migrated cells was appreciably reduced in the DYNLT3 knockdown group (healed area: 40.56+-5.15%) compared with that in the knockdown blank control group (healed area: 62.96+-7.46%) and the knockdown vector control group (healed area: 65.27+-7.27%) (P<0.05) (Figure 5A).	('DYNLT3', 'Gene', '6990', (73, 79))	('knockdown', 'Var', (80, 89))	('reduced', 'NegReg', (58, 65))	('DYNLT3', 'Gene', (73, 79))
14162	31308737	Conversely, the fluorescence intensity of Ki-67 in the DYNLT3 knockdown group was significantly decreased compared with that in the knockdown blank control group and the knockdown vector control group (P<0.05) (Figure 6A).	('Ki-67', 'Gene', (42, 47))	('decreased', 'NegReg', (96, 105))	('DYNLT3', 'Gene', (55, 61))	('DYNLT3', 'Gene', '6990', (55, 61))	('Ki-67', 'Chemical', '-', (42, 47))	('fluorescence intensity', 'MPA', (16, 38))	('knockdown', 'Var', (62, 71))
14165	31308737	On the contrary, the Ezrin protein level tended to decrease when DYNLT3 was knocked down (P<0.05).	('Ezrin', 'Gene', '7430', (21, 26))	('DYNLT3', 'Gene', (65, 71))	('Ezrin', 'Gene', (21, 26))	('decrease', 'NegReg', (51, 59))	('DYNLT3', 'Gene', '6990', (65, 71))	('knocked down', 'Var', (76, 88))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
14179	31308737	However, in endometrioid ovarian cancer patients, high expression of DYNLT3 mRNA was related to improved PFS but was not related to OS.	('high expression', 'Var', (50, 65))	('improved', 'PosReg', (96, 104))	('patients', 'Species', '9606', (40, 48))	('DYNLT3', 'Gene', (69, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('DYNLT3', 'Gene', '6990', (69, 75))	('endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (12, 39))	('PFS', 'MPA', (105, 108))	('endometrioid ovarian cancer', 'Disease', (12, 39))
14213	31308737	Another study reported that knockout of dynein light chain roadblock-type 1 (DYNLRB1) decreased the paracrine effect of colon cancer cell secretory factors in conditioned medium and fibroblast coculture, the invasion and migration of colon cancer cells and the expression of the metastasis-related protein Ezrin, which is regulated by extracellular regulated protein kinases.	('migration', 'CPA', (221, 230))	('colon cancer', 'Disease', 'MESH:D015179', (234, 246))	('knockout', 'Var', (28, 36))	('extracellular', 'cellular_component', 'GO:0005576', ('335', '348'))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('dynein light chain roadblock-type 1', 'Gene', (40, 75))	('Ezrin', 'Gene', (306, 311))	('colon cancer', 'Disease', (234, 246))	('invasion', 'CPA', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('dynein light chain roadblock-type 1', 'Gene', '83658', (40, 75))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('expression', 'MPA', (261, 271))	('Ezrin', 'Gene', '7430', (306, 311))	('DYNLRB1', 'Gene', (77, 84))	('decreased', 'NegReg', (86, 95))	('DYNLRB1', 'Gene', '83658', (77, 84))	('protein', 'cellular_component', 'GO:0003675', ('359', '366'))	('protein', 'cellular_component', 'GO:0003675', ('298', '305'))	('colon cancer', 'Phenotype', 'HP:0003003', (234, 246))	('dynein', 'molecular_function', 'GO:0003777', ('40', '46'))	('colon cancer', 'Disease', (120, 132))
14280	28506269	Tumors can release exosomes mimicking membranous material, resulting in the deletion of reactive lymphocytes.	('deletion', 'Var', (76, 84))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('reactive lymphocytes', 'CPA', (88, 108))
14307	28506269	At the same time, miR-30a-5p knockdown significantly inhibited OC cell proliferation and migration.	('inhibited', 'NegReg', (53, 62))	('miR-30a', 'Gene', '407029', (18, 25))	('knockdown', 'Var', (29, 38))	('miR-30a', 'Gene', (18, 25))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('OC cell proliferation', 'CPA', (63, 84))	('OC', 'Phenotype', 'HP:0100615', (63, 65))
14325	28506269	For example, high miR-21, miR-23b and miR-29a levels were associated with poor progression-free survival, whereas high miR-21 expression was correlated to poor overall survival.	('miR-21', 'Gene', (119, 125))	('miR-23b', 'Gene', (26, 33))	('miR-21', 'Gene', '406991', (18, 24))	('high', 'Var', (13, 17))	('progression-free survival', 'CPA', (79, 104))	('poor', 'NegReg', (74, 78))	('miR-29a', 'Gene', (38, 45))	('miR-29a', 'Gene', '407021', (38, 45))	('miR-21', 'Gene', (18, 24))	('miR-21', 'Gene', '406991', (119, 125))	('miR-23b', 'Gene', '407011', (26, 33))
14503	21997682	If mutation of KRAS or BRAF occurs in any of these lesions an APST develops.	('BRAF', 'Gene', '673', (23, 27))	('KRAS', 'Gene', (15, 19))	('BRAF', 'Gene', (23, 27))	('mutation', 'Var', (3, 11))	('KRAS', 'Gene', '3845', (15, 19))
14544	21997682	Case #4 A 49-year-old woman G1P0010 was admitted with a history of an abnormal Pap smear and an endometrial biopsy diagnosed as simple hyperplasia with no atypia.	('woman', 'Species', '9606', (22, 27))	('hyperplasia', 'Disease', (135, 146))	('G1P0010', 'Var', (28, 35))	('Pap', 'molecular_function', 'GO:0043751', ('79', '82'))	('hyperplasia', 'Disease', 'MESH:D006965', (135, 146))
14588	19419571	We obtained high-resolution 500K SNP array data for 52 ovarian tumors and identified the most statistically significant minimal genomic regions with the most prevalent and highest-level copy number alterations (recurrent CNAs).	('ovarian tumors', 'Disease', (55, 69))	('ovarian tumors', 'Phenotype', 'HP:0100615', (55, 69))	('ovarian tumor', 'Phenotype', 'HP:0100615', (55, 68))	('ovarian tumors', 'Disease', 'MESH:D010051', (55, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('copy number alterations', 'Var', (186, 209))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
14597	19419571	As somatic DNA copy number alterations (CNAs) can indicate the presence of genes involved in tumorigenesis, studies of DNA instability in ovarian cancers could potentially lead to identification of causal genes and thus therapeutic targets.	('copy', 'Var', (15, 19))	('ovarian cancers', 'Disease', 'MESH:D010051', (138, 153))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('tumor', 'Disease', (93, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('lead', 'Reg', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancers', 'Phenotype', 'HP:0100615', (138, 153))	('ovarian cancers', 'Disease', (138, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
14598	19419571	Indeed, several groups have used genomic technologies to systematically survey copy number changes in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancer', 'Disease', (102, 116))	('copy number changes', 'Var', (79, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))
14600	19419571	The Affymetrix 10K single nucleotide polymorphism (SNP) arrays, with the average resolution of 210 kb, have also been used to measure copy number changes in ovarian serous carcinoma.	('ovarian serous carcinoma', 'Disease', (157, 181))	('copy number changes', 'Var', (134, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (157, 181))
14606	19419571	We have applied Affymetrix 500K SNP Chips to survey and compare copy number alterations (CNAs) in fresh-frozen ovarian tumor samples, of several subtypes, from 52 patients.	('patients', 'Species', '9606', (163, 171))	('ovarian tumor', 'Disease', 'MESH:D010051', (111, 124))	('ovarian tumor', 'Disease', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Chip', 'Gene', (36, 40))	('ovarian tumor', 'Phenotype', 'HP:0100615', (111, 124))	('copy number alterations', 'Var', (64, 87))	('Chip', 'Gene', '34433', (36, 40))
14624	19419571	GISTIC is similar in spirit to the STAC, CMAR and MCR methods in that it seeks to select the genomic regions containing the most important copy number alterations.	('CMAR', 'Gene', (41, 45))	('CMAR', 'Gene', '6687', (41, 45))	('copy number alterations', 'Var', (139, 162))
14625	19419571	In brief, GISTIC scores each probeset across the genome for the frequency with which it shows copy gain, times the average level of cancer/normal log2 ratio for the samples showing copy gain.	('cancer', 'Disease', (132, 138))	('copy', 'Var', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('gain', 'PosReg', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
14644	19419571	These tumors are characterized by a dearth of CNAs, with the exception of gains on chromosome 8 in seven of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('gains', 'Var', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
14658	19419571	More importantly, the distribution of tumor-associated copy number alterations in the genome is not uniform (Fig.	('copy number alterations', 'Var', (55, 78))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
14677	19419571	PRKCI has been shown to be a target of amplification in ovarian cancer that contributes to transformation in cooperation with mutant Ras in addition to contributing to anchorage independent growth.	('anchorage independent growth', 'CPA', (168, 196))	('amplification', 'Var', (39, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('contributes', 'Reg', (76, 87))	('PRKCI', 'Gene', (0, 5))	('contributing', 'Reg', (152, 164))	('transformation', 'CPA', (91, 105))	('PRKCI', 'Gene', '5584', (0, 5))	('ovarian cancer', 'Disease', 'MESH:D010051', (56, 70))	('ovarian cancer', 'Disease', (56, 70))	('mutant', 'Var', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
14686	19419571	Of these PARD6B, BCAS4, and KCNG1 are expressed greater than two-fold higher in cancer samples with the amplification relative to normal (Fig.	('PARD6B', 'Gene', (9, 15))	('BCAS4', 'Gene', (17, 22))	('PARD6B', 'Gene', '84612', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('KCNG1', 'Gene', '3755', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('BCAS4', 'Gene', '55653', (17, 22))	('higher', 'PosReg', (70, 76))	('KCNG1', 'Gene', (28, 33))	('cancer', 'Disease', (80, 86))	('amplification', 'Var', (104, 117))
14692	19419571	Amplification of 20q13 may be particularly heterogeneous as AURKA , TGIF2, PTPN1 and ZNF217 , and ADRM1 , and other genes, have been cited as drivers of 20q13 amplification in ovarian cancer.	('Amplification', 'Var', (0, 13))	('PTPN1', 'Gene', (75, 80))	('ADRM1', 'Gene', '11047', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('TGIF2', 'Gene', '60436', (68, 73))	('AURKA', 'Gene', '6790', (60, 65))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('ZNF217', 'Gene', (85, 91))	('ADRM1', 'Gene', (98, 103))	('ZNF217', 'Gene', '7764', (85, 91))	('PTPN1', 'Gene', '5770', (75, 80))	('TGIF2', 'Gene', (68, 73))	('ovarian cancer', 'Disease', (176, 190))	('AURKA', 'Gene', (60, 65))
14694	19419571	Of these, 8 genes showed a significant decrease in expression in tumor samples with this deletion relative to tumors samples without this deletion: ARSD, ARSE, MXRA5, PRKX, LOC729137, NLGN4X, HDHD1A, and STS (see Additional files 7, 8).	('decrease', 'NegReg', (39, 47))	('LOC729137', 'Var', (173, 182))	('ARSD', 'Gene', (148, 152))	('deletion', 'Var', (89, 97))	('expression', 'MPA', (51, 61))	('HDHD1A', 'Gene', '8226', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('PRKX', 'Gene', '5613', (167, 171))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('ARSD', 'Gene', '414', (148, 152))	('PRKX', 'Gene', (167, 171))	('MXRA5', 'Gene', '25878', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('ARSE', 'Gene', (154, 158))	('MXRA5', 'Gene', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('HDHD1A', 'Gene', (192, 198))	('ARSE', 'Gene', '415', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (110, 115))	('NLGN4X', 'Gene', (184, 190))	('NLGN4X', 'Gene', '57502', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
14701	19419571	Interestingly the deletion of the death receptors TNFRSF10A and TNFRSF10B on chromosome 8p did not correlate with the amplification of their ligand TNFSF10 on chromsome 3q.	('TNFRSF10B', 'Gene', (64, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('TNFRSF10A', 'Gene', (50, 59))	('TNFSF10', 'Gene', (148, 155))	('TNFSF10', 'Gene', '8743', (148, 155))	('TNFRSF10B', 'Gene', '8795', (64, 73))	('TNFRSF10A', 'Gene', '8797', (50, 59))	('ligand', 'molecular_function', 'GO:0005488', ('141', '147'))	('deletion', 'Var', (18, 26))
14702	19419571	We have applied high-resolution SNP arrays to survey the diversity of copy number alterations in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('ovarian cancer', 'Disease', (97, 111))	('copy number alterations', 'Var', (70, 93))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))
14709	19419571	For example, amplified CLND11 is reported as under-expressed when compared to our whole ovary normal samples, but is over-expressed when comparing LCM ovarian cancer and normal fallopian epithelium.	('over-expressed', 'PosReg', (117, 131))	('amplified CLND11', 'Var', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('LCM ovarian cancer', 'Disease', (147, 165))	('CLND11', 'Var', (23, 29))	('LCM ovarian cancer', 'Disease', 'MESH:D010051', (147, 165))
14710	19419571	The relatively minor expression change in tumors with MYC amplification may be due to over-expression of MYC in a subset of the non-amplified tumors through alternate mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('over-expression', 'PosReg', (86, 101))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('expression', 'MPA', (21, 31))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('MYC', 'Gene', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('MYC', 'Protein', (105, 108))	('amplification', 'Var', (58, 71))
14713	19419571	While MYC and PVT1 knock-downs both reduced proliferation of breast and ovarian cancer cell lines with amplification and over-expression of MYC and PVT1, knock-down of PVT1 in these lines also elicited a strong apoptotic response.	('knock-down', 'Var', (154, 164))	('MYC', 'Gene', (140, 143))	('over-expression', 'PosReg', (121, 136))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('elicited', 'Reg', (193, 201))	('PVT1', 'Gene', (168, 172))	('amplification', 'Var', (103, 116))	('proliferation of breast and ovarian cancer', 'Disease', 'MESH:D010051', (44, 86))	('PVT1', 'Gene', (148, 152))	('reduced', 'NegReg', (36, 43))	('apoptotic response', 'CPA', (211, 229))	('knock-downs', 'Var', (19, 30))