30	33664587	It is presently considered that there exist three categories of breast cancer stem cell (CSC): an ALDH+ epithelial-like CSC; CD44+/CD24- mesenchymal-like CSCs; and, a hybrid epithelial/mesenchymal-like ALDH+/CD44+/CD24- (reviewed in detail in).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('CD44+/CD24-', 'Var', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
32	33664587	This expression of stem-like markers was also supported by Gerhard et al, with most of their series showing positivity for CD44 and loss of CD24, as well as an enrichment for vimentin and loss of the claudins and E-cadherin.	('loss', 'Var', (132, 136))	('claudins', 'Protein', (200, 208))	('CD44', 'Gene', (123, 127))	('E-cadherin', 'Gene', (213, 223))	('E-cadherin', 'Gene', '999', (213, 223))	('loss', 'NegReg', (188, 192))	('CD24', 'Gene', (140, 144))	('vimentin', 'Gene', '7431', (175, 183))	('vimentin', 'Gene', (175, 183))
34	33664587	Notably, MpBC have a high frequency of PIK3CA mutations (see below) and these mutations correlate with poor response to neoadjuvant chemotherapy in breast cancer subtypes broadly, and this holds true in the metastatic setting.	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', '5290', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('MpBC', 'Chemical', '-', (9, 13))	('PIK3CA', 'Gene', (39, 45))	('response', 'MPA', (108, 116))
37	33664587	PI-3 Kinase and Ras signaling pathway mutations have been shown to be early events in MpBC pathogenesis.	('Ras signaling pathway', 'Pathway', (16, 37))	('MpBC', 'Disease', (86, 90))	('PI-3', 'Gene', (0, 4))	('MpBC', 'Chemical', '-', (86, 90))	('mutations', 'Var', (38, 47))
39	33664587	Other than TP53 and PIK3CA, the most frequently identified mutations across multiple cohorts occur in PTEN, NF1, HRAS, PIK3R1.	('NF1', 'Gene', '4763', (108, 111))	('PIK3R1', 'Gene', '5295', (119, 125))	('PIK3R1', 'Gene', (119, 125))	('TP53', 'Gene', '7157', (11, 15))	('PIK3CA', 'Gene', (20, 26))	('TP53', 'Gene', (11, 15))	('PIK3CA', 'Gene', '5290', (20, 26))	('HRAS', 'Gene', '3265', (113, 117))	('mutations', 'Var', (59, 68))	('PTEN', 'Gene', (102, 106))	('HRAS', 'Gene', (113, 117))	('NF1', 'Gene', (108, 111))	('PTEN', 'Gene', '5728', (102, 106))
40	33664587	Emerging data support that the various morphologic elements feature subtly different mutation profiles, with for example, a lack of PIK3CA mutations found in those MpBC with chondroid differentiation.	('chondroid differentiation', 'CPA', (174, 199))	('mutations', 'Var', (139, 148))	('MpBC', 'Chemical', '-', (164, 168))	('lack', 'NegReg', (124, 128))	('PIK3CA', 'Gene', (132, 138))	('PIK3CA', 'Gene', '5290', (132, 138))
41	33664587	Chondroid tumors were also shown to lack mutations in TERT promoters.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('TERT', 'Gene', '7015', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Chondroid tumors', 'Phenotype', 'HP:0030431', (0, 16))	('Chondroid tumors', 'Disease', 'MESH:D008949', (0, 16))	('lack', 'NegReg', (36, 40))	('Chondroid tumors', 'Disease', (0, 16))	('TERT', 'Gene', (54, 58))
43	33664587	An increase in mutations in Wnt pathway genes has been reported for MpBCs, with WISP3/CCN6 mutations more frequently seen in the epithelial components, and 3/7 CTNNB1 mutations present only in the spindle compartment of the tumor.	('CCN6', 'Gene', (86, 90))	('mutations', 'MPA', (15, 24))	('WISP3', 'Gene', '8838', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (224, 229))	('WISP3', 'Gene', (80, 85))	('CTNNB1', 'Gene', (160, 166))	('CTNNB1', 'Gene', '1499', (160, 166))	('CCN6', 'Gene', '8838', (86, 90))	('mutations', 'Var', (91, 100))	('Wnt pathway', 'Pathway', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('increase', 'PosReg', (3, 11))	('MpBC', 'Chemical', '-', (68, 72))
46	33664587	Genetic differences unique to the UCS were reported, with a significant enrichment for mutations in FBXW7 and PPP2R1A, and HER2 amplifications, while shared genomic features included alterations in TP53, PIK3CA, PTEN and EMT-related Wnt and Notch signalling components.	('UCS', 'Phenotype', 'HP:0002891', (34, 37))	('PIK3CA', 'Gene', '5290', (204, 210))	('alterations', 'Reg', (183, 194))	('PPP2R1A', 'Gene', '5518', (110, 117))	('PPP2R1A', 'Gene', (110, 117))	('PTEN', 'Gene', '5728', (212, 216))	('FBXW7', 'Gene', '55294', (100, 105))	('HER2', 'Gene', (123, 127))	('TP53', 'Gene', '7157', (198, 202))	('FBXW7', 'Gene', (100, 105))	('PTEN', 'Gene', (212, 216))	('HER2', 'Gene', '2064', (123, 127))	('PIK3CA', 'Gene', (204, 210))	('TP53', 'Gene', (198, 202))	('mutations', 'Var', (87, 96))
56	33664587	A 25% response rate (complete/partial response) was achieved in MpBC treated with temsirolimus/everolimus in combination with standard chemotherapy and a 21% objective response rate was also reported for the regimen of doxorubicin, bevacizumab and temsirolimus/everolimus, however genetic analysis showed that while PI3K pathway alterations were associated with a significant improvement in objective response rate (31% vs 0%) they were not associated with an improved clinical benefit rate (44% vs 45%).	('everolimus', 'Chemical', 'MESH:D000068338', (261, 271))	('temsirolimus', 'Chemical', 'MESH:C401859', (248, 260))	('PI3K pathway', 'Pathway', (316, 328))	('bevacizumab', 'Chemical', 'MESH:D000068258', (232, 243))	('improvement', 'PosReg', (376, 387))	('objective response', 'MPA', (391, 409))	('doxorubicin', 'Chemical', 'MESH:D004317', (219, 230))	('everolimus', 'Chemical', 'MESH:D000068338', (95, 105))	('temsirolimus', 'Chemical', 'MESH:C401859', (82, 94))	('alterations', 'Var', (329, 340))	('MpBC', 'Chemical', '-', (64, 68))
149	29056442	Prior taxane/platinum use (2-year SAR rate, 62.1% versus 39.7%, P =0.019), absence of prior whole pelvic irradiation (52.2% versus 31.6%, P = 0.004), distant recurrence (54.6% versus 26.8%, P = 0.001), and disease-free interval >=6 months (61.9% versus 40.0%, P = 0.002) were statistically associated with improved SAR with taxane/platinum regimen as the first-line salvage chemotherapy.	('SAR', 'Species', '2698737', (315, 318))	('taxane', 'Chemical', 'MESH:C080625', (324, 330))	('SAR', 'Species', '2698737', (34, 37))	('absence', 'Var', (75, 82))	('platinum', 'Chemical', 'MESH:D010984', (331, 339))	('improved', 'PosReg', (306, 314))	('SAR', 'MPA', (315, 318))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('taxane', 'Chemical', 'MESH:C080625', (6, 12))
190	29056442	Survival after recurrence was higher in TP regimen compared to non-TP regimen.	('higher', 'PosReg', (30, 36))	('Survival', 'MPA', (0, 8))	('TP', 'Chemical', '-', (67, 69))	('TP', 'Chemical', '-', (40, 42))	('TP regimen', 'Var', (40, 50))
236	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
250	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (245, 251))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
258	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
268	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('TRIM44', 'Gene', '54765', (18, 24))	('hallmark characteristics', 'MPA', (70, 94))	('change', 'Reg', (60, 66))	('cancers', 'Disease', (111, 118))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
270	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (0, 6))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
272	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
273	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('cyclin', 'Gene', (111, 117))	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', '5111', (111, 117))	('cyclin', 'Gene', '5111', (125, 131))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', (125, 131))
275	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('p27', 'Gene', '10671', (64, 67))	('TRIM44', 'Gene', '54765', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('inhibited', 'NegReg', (91, 100))	('TRIM44', 'Gene', (14, 20))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
276	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('activated', 'PosReg', (99, 108))	('glioma', 'Disease', (112, 118))	('p21', 'Gene', (22, 25))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
277	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('TRIM44', 'Gene', (0, 6))	('cancer', 'Disease', (118, 124))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
278	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
289	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('activate', 'PosReg', (158, 166))	('knockdown', 'Var', (39, 48))	('DDIT4', 'Gene', (130, 135))	('NUPR1', 'Gene', (89, 94))	('CADM1', 'Gene', (103, 108))	('TNFSF10', 'Gene', '8743', (117, 124))	('TRIM44', 'Gene', '54765', (32, 38))	('CADM1', 'Gene', '23705', (103, 108))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('CDK19', 'Gene', '23097', (96, 101))	('NUPR1', 'Gene', '26471', (89, 94))	('DDIT4', 'Gene', '54541', (130, 135))	('dysregulation', 'MPA', (72, 85))
298	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', (84, 90))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
305	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
320	32067422	Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lung cancer', 'Disease', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', '1956', (118, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Disease', (231, 237))	('Human', 'Species', '9606', (112, 117))	('epidermal growth factor receptor', 'Gene', (118, 150))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('EGFR', 'Gene', (243, 247))	('cancer', 'Disease', (96, 102))
321	32067422	Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (206, 213))	('EGFR', 'Gene', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
323	32067422	The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene.	('mutations', 'Var', (117, 126))	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'Var', (180, 195))	('cancer', 'Disease', (47, 53))	('expression', 'MPA', (165, 175))	('amplification/deletion', 'Var', (131, 153))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Reg', (156, 164))
325	32067422	EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
327	32067422	Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain.	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
328	32067422	Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.	('rat', 'Species', '10116', (52, 55))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('rat', 'Species', '10116', (40, 43))	('Glioblastoma multiforme', 'Disease', (0, 23))	('mutations', 'Var', (113, 122))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Furin', 'Gene', '5045', (135, 140))	('Furin', 'Gene', (135, 140))
329	32067422	Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.	('gene amplification', 'Var', (27, 45))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('increased', 'PosReg', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('expression', 'MPA', (65, 75))	('EGFR', 'Gene', (60, 64))	('glioma', 'Disease', (10, 16))
330	32067422	Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (135, 142))	('Colon and pancreatic adenocarcinoma', 'Disease', 'MESH:D003110', (0, 35))	('associated', 'Reg', (113, 123))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (10, 35))	('expression', 'MPA', (84, 94))	('short', 'NegReg', (129, 134))
332	32067422	DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('expression', 'MPA', (48, 58))	('associated', 'Reg', (27, 37))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (43, 47))
334	32067422	While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.	('rat', 'Species', '10116', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('leads to', 'Reg', (171, 179))	('increased', 'PosReg', (86, 95))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deregulation', 'MPA', (129, 141))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('affects', 'Reg', (142, 149))	('mutations', 'Var', (6, 15))
336	32067422	Five functional domains are characterized for EGFR according to the database of protein families (Pfam, http://pfam.xfam.org/protein/P00533): Recep_L (57-168aa), Furin-like (177-338aa), Recep_L (361-481aa), GF_recep_IV (505-637aa), and Pkinase_Tyr domains (712-968aa).	('177-338aa', 'Var', (174, 183))	('712-968aa', 'Var', (257, 266))	('Furin', 'Gene', (162, 167))	('Furin', 'Gene', '5045', (162, 167))	('505-637aa', 'Var', (220, 229))
338	32067422	Upon stimulation by its ligands, dimerization (both homodimerization and heterodimerization) of EGFR results in its intracellular tyrosine kinase activation and autophosphorylation at multiple tyrosine residues, which activates a number of downstream signaling cascades that not only promote proliferation, growth, and survival of normal cells but also contribute to processes that are crucial to cancer progression, including angiogenesis, metastasis, and apoptosis [4, 5].	('cancer', 'Disease', (397, 403))	('activation', 'PosReg', (146, 156))	('proliferation', 'CPA', (292, 305))	('promote', 'PosReg', (284, 291))	('tyrosine', 'Chemical', 'MESH:D014443', (193, 201))	('EGFR', 'Gene', (96, 100))	('dimerization', 'Var', (33, 45))	('survival', 'CPA', (319, 327))	('metastasis', 'CPA', (441, 451))	('growth', 'CPA', (307, 313))	('activates', 'PosReg', (218, 227))	('contribute', 'Reg', (353, 363))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('autophosphorylation', 'MPA', (161, 180))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('intracellular tyrosine kinase', 'MPA', (116, 145))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('rat', 'Species', '10116', (299, 302))
340	32067422	It is frequently activated by gene mutation, amplification, or overexpression through abnormal regulation in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene mutation', 'Var', (30, 43))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (45, 58))	('overexpression', 'PosReg', (63, 77))
342	32067422	In cancers like non-small-cell lung cancer (NSCLC) [13] and colon adenocarcinoma (COAD) [14], EGFR mutation status is considered as a poor prognostic factor, which is often associated with a more aggressive behavior and decreased patient survival.	('COAD', 'Disease', (82, 86))	('lung cancer', 'Disease', (31, 42))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('aggressive behavior', 'Phenotype', 'HP:0000718', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patient', 'Species', '9606', (230, 237))	('mutation', 'Var', (99, 107))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('colon adenocarcinoma', 'Disease', (60, 80))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('EGFR', 'Gene', (94, 98))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
345	32067422	Such treatments are very effective and provide significantly improved patient outcomes, particularly for lung adenocarcinoma (LUAD) patients with EGFR mutations [20, 21].	('improved', 'PosReg', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('patient', 'Species', '9606', (70, 77))	('lung adenocarcinoma', 'Disease', (105, 124))	('EGFR', 'Gene', (146, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))
347	32067422	Although many literature reports are available on EGFR mutation, overexpression, or amplification for particular cancer types [12, 13, 14, 23, 24], a simultaneous comprehensive profiling over multiple cancer types to explore their similarity and difference is not available.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
350	32067422	We first examined the patterns of EGFR mutations, including single nucleotide variant (SNV) and short insertion/deletion (indel), across tumors and their implications for targeted therapies.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('single nucleotide variant', 'Var', (60, 85))	('EGFR', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('short insertion/deletion', 'Var', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
354	32067422	The mutation data included SNVs, indels, and CNVs (defined by GISTIC 2.0 as following for log ratio value: -2/-1 = deletion; 0 = diploid; 1 = gain; 2 = amplification).	('deletion', 'Var', (115, 123))	('rat', 'Species', '10116', (94, 97))	('gain', 'PosReg', (142, 146))
364	32067422	The prognostic values of EGFR alterations and its CpG methylation were analyzed with Cox proportional hazard model.	('alterations', 'Var', (30, 41))	('EGFR', 'Gene', (25, 29))	('rat', 'Species', '10116', (34, 37))
365	32067422	The overall EGFR mutation frequency was 2.8% (320/11,410) for all tumor samples and 2.4% (268/11,314) for all patients across the 32 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', (12, 16))	('patients', 'Species', '9606', (110, 118))
366	32067422	The most common tumors with EGFR mutations were glioblastoma multiforme (GBM, 26.8%), LUAD (14.4%), diffuse large B-cell lymphoma (DLBC, 8.3%), and skin cutaneous melanoma (SKCM, 6.5%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 171))	('skin cutaneous melanoma', 'Disease', (148, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('B-cell lymphoma', 'Disease', (114, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('LUAD', 'Disease', (86, 90))	('glioblastoma multiforme', 'Disease', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (48, 71))
367	32067422	On the contrary, kidney chromophobe cell carcinoma (KICH), mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), and uveal melanoma (UVM) showed almost no EGFR mutations (Figure 1A).	('mesothelioma', 'Disease', (59, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('THCA', 'Phenotype', 'HP:0002890', (158, 162))	('thymoma', 'Disease', (123, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (173, 187))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('UCS', 'Phenotype', 'HP:0002891', (189, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('UVM', 'Phenotype', 'HP:0007716', (215, 218))	('melanoma', 'Disease', (205, 213))	('thyroid carcinoma', 'Disease', (139, 156))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('kidney chromophobe cell carcinoma', 'Disease', (17, 50))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (80, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('kidney chromophobe cell carcinoma', 'Disease', 'MESH:C538614', (17, 50))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('thymoma', 'Disease', 'MESH:D013945', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('mutations', 'Var', (242, 251))	('THYM', 'Phenotype', 'HP:0100522', (132, 136))	('carcinosarcoma', 'Disease', (173, 187))
369	32067422	The 320 EGFR somatic mutations (from 268 tumor samples) were observed across all cancer types and were widely distributed along different functional domains of EGFR gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', (81, 87))	('observed', 'Reg', (61, 69))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (21, 30))
371	32067422	The location distribution of these EGFR mutations was dramatically different among different cancers (Figure 1B, Supplementary Table S2).	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('different', 'Reg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
372	32067422	Mutations in GBM and brain lower-grade glioma (LGG) were most commonly located in the Furin-like domain, about 5 times more than the mutations located in the Pkinase_Tyr domain.	('glioma', 'Disease', (39, 45))	('GBM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', (86, 91))	('located', 'Reg', (71, 78))	('Furin', 'Gene', '5045', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
373	32067422	On the contrary, mutations in NSCLC were primarily in the Pkinase_Tyr domain, especially for LUAD, which amounted to four fifths of all mutations.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('NSCLC', 'Disease', (30, 35))	('mutations', 'Var', (17, 26))
374	32067422	Mutations in stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), and SKCM were mostly in other domains whose functions were less known.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', (21, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('neck squamous cell carcinoma', 'Disease', (53, 81))
375	32067422	The 289aa in the Furin-like domain was the most frequently mutated position, which was observed in 27 samples (3 samples with A289D, 1 with A289I, 1 with A289N, 6 with A289T, 15 with A289V, and 1 with A289Rfs*9).	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (201, 210))	('A289V', 'Var', (183, 188))	('A289D', 'Mutation', 'p.A289D', (126, 131))	('A289I', 'Mutation', 'p.A289I', (140, 145))	('Furin', 'Gene', (17, 22))	('A289N', 'Mutation', 'p.A289N', (154, 159))	('A289I', 'Var', (140, 145))	('Furin', 'Gene', '5045', (17, 22))	('A289N', 'Var', (154, 159))	('A289T', 'Mutation', 'rs769696078', (168, 173))	('A289V', 'Mutation', 'p.A289V', (183, 188))	('A289D', 'Var', (126, 131))	('A289T', 'Var', (168, 173))
376	32067422	A289V is known to be oncogenic, while other mutation types (A289D/T/N/I) are likely oncogenic.	('A289V', 'Mutation', 'p.A289V', (0, 5))	('A289V', 'Var', (0, 5))	('A289D/T/N/I', 'Var', (60, 71))	('A289D', 'Mutation', 'p.A289D', (60, 65))
377	32067422	The only other tumor with mutations at this position was HNSC (1 sample with A289T and 1 with A289Rfs*9), and their importance was little known to this cancer.	('A289Rfs*', 'Var', (94, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('HNSC', 'Phenotype', 'HP:0012288', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('A289T', 'Mutation', 'rs769696078', (77, 82))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('A289T', 'Var', (77, 82))	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (94, 103))
378	32067422	The second most mutated position was 598aa in the GF_recep_IV domain: 16 GBMs had G598V, 2 GBMs had G598A, and 1 esophageal squamous cell carcinoma (ESCC) had G598E.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('G598V', 'Mutation', 'rs139236063', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('G598A', 'Mutation', 'rs139236063', (100, 105))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('G598E', 'Mutation', 'p.G598E', (159, 164))	('G598A', 'Var', (100, 105))	('G598E', 'Var', (159, 164))	('G598V', 'Var', (82, 87))
379	32067422	Most mutations in LUAD (35 of 45 mutations) were located in the Pkinase_Tyr domain, especially at the positions of 858aa (8 samples with L858R) and 746-750aa (6 with E746_A750del, 2 with L747_E749del, and 1 with L747_T751del) (Figure 1E).	('E746_A750del', 'Var', (166, 178))	('L747_T751del', 'Var', (212, 224))	('L747_T751del', 'Mutation', 'p.747,751delT', (212, 224))	('L747_E749del', 'Var', (187, 199))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('LUAD', 'Gene', (18, 22))	('E746_A750del', 'Mutation', 'p.746,750delA', (166, 178))	('L747_E749del', 'Mutation', 'p.747,749delE', (187, 199))
381	32067422	All Level 1 mutations were found in NSCLC (28 in LUAD and 2 in lung squamous cell carcinoma [LUSC]), and these mutations were concentrated in exons 19-21, which included L858R, L861Q, G719A, S768I, L833F, E796_A750del, L747_E749del, E709_T710delinsD, L747_T751del, and T751_E758del (Figure 3).	('S768I', 'Var', (191, 196))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('L747_T751del', 'Var', (251, 263))	('E709_T710delinsD', 'Mutation', 'p.709,710delinsT,D', (233, 249))	('L833F', 'Mutation', 'p.L833F', (198, 203))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('T751_E758del', 'Mutation', 'p.751,758delE', (269, 281))	('E709_T710delinsD', 'Var', (233, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('S768I', 'Mutation', 'rs121913465', (191, 196))	('rat', 'Species', '10116', (133, 136))	('L833F', 'Var', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('L747_T751del', 'Mutation', 'p.747,751delT', (251, 263))	('G719A', 'Mutation', 'rs121913428', (184, 189))	('L747_E749del', 'Mutation', 'p.747,749delE', (219, 231))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('L858R', 'Var', (170, 175))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('NSCLC', 'Disease', (36, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('L747_E749del', 'Var', (219, 231))	('E796_A750del', 'Var', (205, 217))	('L861Q', 'Mutation', 'rs121913444', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('G719A', 'Var', (184, 189))	('E796_A750del', 'Mutation', 'p.796,750delA', (205, 217))	('L861Q', 'Var', (177, 182))	('T751_E758del', 'Var', (269, 281))
385	32067422	The combined EGFR mutation and CNV frequency in all tumors was about 7.0% (746 of 11,314 patients, 748 of 11,410 samples).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
387	32067422	Other cancers with dominantEGFR amplification but at much lower amplification rate included ESCA (13.0%), HNSC (9.4%), STAD (5.2%), LGG (5.4%), LUSC (6.4%), and BLCA (4.4%).	('LUSC', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ESCA', 'Disease', (92, 96))	('dominantEGFR', 'Var', (19, 31))	('amplification', 'Var', (32, 45))	('BLCA', 'Disease', (161, 165))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('rat', 'Species', '10116', (78, 81))	('LGG', 'Disease', (132, 135))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('HNSC', 'Disease', (106, 110))	('STAD', 'Disease', (119, 123))
389	32067422	Over half of the mutations (47 of 82 mutations) in the Furin-like domain were accompanied by EGFR amplification, while nearly half of mutations (40 of 85 mutations) in the Pkinase_Tyr domain had copy gain.	('copy', 'MPA', (195, 199))	('EGFR amplification', 'MPA', (93, 111))	('mutations', 'Var', (37, 46))	('Furin', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('Furin', 'Gene', '5045', (55, 60))
390	32067422	In order to evaluate the clinical significance of EGFR alterations, we analyzed patient survival for pan-cancer and for each cancer type separately by alteration status (mutations and CNVs alone or in combination).	('rat', 'Species', '10116', (155, 158))	('alterations', 'Var', (55, 66))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (141, 144))	('patient', 'Species', '9606', (80, 87))
391	32067422	When all tumors were analyzed together, patients with any EGFR alteration had significantly shorter median OS and DFS than those without EGFR alteration (both P < 0.001, Supplementary Figure S1).	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (146, 149))	('DFS', 'CPA', (114, 117))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('alteration', 'Var', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (92, 99))	('median OS', 'MPA', (100, 109))
392	32067422	When analysis was performed for CNV and mutation separately, the presence of either aberration was associated with shortened patients' OS and DFS (all P < 0.001, Supplementary Figure S2 and S3).	('DFS', 'CPA', (142, 145))	('presence', 'Var', (65, 73))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (53, 56))	('patients', 'Species', '9606', (125, 133))
393	32067422	For survival association in individual cancer types, only those cancer types with at least 10 tumor samples containing either EGFR mutations or CNVs were included in the analysis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (39, 45))	('EGFR', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
394	32067422	Among patients with HNSC, LGG, or LUAD, EGFR amplification was associated with short survival (Figure 6A).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('HNSC', 'Disease', (20, 24))	('short survival', 'MPA', (79, 93))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (6, 14))	('HNSC', 'Phenotype', 'HP:0012288', (20, 24))	('LGG', 'Disease', (26, 29))	('amplification', 'Var', (45, 58))
396	32067422	Not surprisingly, EGFR-amplified tumors had significantly higher EGFR expression than those without EGFR amplification in all 9 cancers types (all P < 0.001, Figure 6C); however, there was no much EGFR expression difference between tumors with or without EGFR mutations except that EGFR mutation status was associated with significantly increased EGFR expression in GBM (P = 0.024) and LUAD (P = 0.001, Figure 6D).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutation', 'Var', (287, 295))	('increased', 'PosReg', (337, 346))	('cancers', 'Disease', (128, 135))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('EGFR', 'Gene', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('LUAD', 'Phenotype', 'HP:0030078', (386, 390))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (33, 39))	('EGFR expression', 'MPA', (347, 362))	('tumors', 'Disease', (232, 238))
416	32067422	In individual cancer type analysis, most tumor types had the similar patterns of methylation association with gene expression in promoter and gene body, but a few others had predominant hypomethylation in both regions, such as GBM, LUSC, PRAD, THYM, KIRC, and KICH (Supplementary Figure S5).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('THYM', 'Phenotype', 'HP:0100522', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('hypomethylation', 'Var', (186, 201))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('gene expression', 'MPA', (110, 125))
417	32067422	Survival analysis for all tumors with tumor type as a covariate only found 2 CpG sites (cg07311521 and cg16751451) significantly associated with OS, and both were in the promoter region (TSS1500).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('associated with', 'Reg', (129, 144))	('cg16751451', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cg07311521', 'Var', (88, 98))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))
420	32067422	For both cancer types, the CpGs with significant associations were mostly located in the gene body, where higher CpG methylation was associated with a better outcome.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('higher', 'PosReg', (106, 112))	('methylation', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('CpG', 'MPA', (113, 116))
422	32067422	GBM had the highest rate of EGFR alterations, and amplification was the primary alteration.	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('EGFR', 'MPA', (28, 32))	('rat', 'Species', '10116', (20, 23))
425	32067422	Other common tumor types with EGFR alterations include ESCA, HNSC, LGG, LUSC, and BLCA, all with similar characteristics: alteration frequency of about 5.0% and amplification as a dominant type.	('tumor', 'Disease', (13, 18))	('alterations', 'Var', (35, 46))	('EGFR', 'Gene', (30, 34))	('alteration', 'Var', (122, 132))	('LUSC', 'Disease', (72, 76))	('BLCA', 'Disease', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (61, 65))	('ESCA', 'Disease', (55, 59))	('LGG', 'Disease', (67, 70))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HNSC', 'Disease', (61, 65))
427	32067422	On the other side of the spectrum, tumors such as DLBC and SKCM mainly had SNV mutations but rarely CNV; tumors including KIRC, MESO, THCA, THYM, UCS and UVM almost had no EGFR alterations.	('tumors', 'Disease', (105, 111))	('THCA', 'Phenotype', 'HP:0002890', (134, 138))	('THYM', 'Phenotype', 'HP:0100522', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('THYM', 'Disease', (140, 144))	('rat', 'Species', '10116', (181, 184))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('THCA', 'Disease', (134, 138))	('UVM', 'Phenotype', 'HP:0007716', (154, 157))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UCS', 'Disease', (146, 149))	('SNV', 'Gene', (75, 78))	('MESO', 'Disease', (128, 132))
428	32067422	Mutations in the Furin-like and Pkinase_Tyr domains accounted for most of EGFR single nucleotide or indel mutations.	('single nucleotide', 'Var', (79, 96))	('Furin', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', '5045', (17, 22))	('EGFR', 'Gene', (74, 78))
429	32067422	However, the Pkinase_Tyr domain was far more important in terms of targeted therapy with TKIs as 90% EGFR mutations in LUAD occurred in this region, particularly the exon 19 deletion and the L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (191, 196))	('L858R point', 'Var', (191, 202))	('LUAD', 'Gene', (119, 123))	('mutations', 'Var', (106, 115))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('exon 19 deletion', 'Var', (166, 182))
430	32067422	Mutations in these regions are proven predictive markers for effective TKI therapy for NSCLC in clinical practice [7, 33, 34, 35], with significantly prolonged survival as compared with traditional combination chemotherapy [21, 36, 37].	('NSCLC', 'Disease', (87, 92))	('prolonged', 'PosReg', (150, 159))	('survival', 'MPA', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
432	32067422	For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34, 40, 41, 42].	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('EGFR', 'Gene', (19, 23))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (65, 68))
433	32067422	In this large TCGA dataset, the combined alteration rate (amplification, deletion, or mutation) reached 67.3% in GBM.	('rat', 'Species', '10116', (52, 55))	('deletion', 'Var', (73, 81))	('rat', 'Species', '10116', (45, 48))	('mutation', 'Var', (86, 94))
435	32067422	Compared with LUAD, most EGFR mutations in GBM were located in extracellular domain or single-span transmembrane segment, which was known to be associated with tumorigenesis but not responsiveness to TKIs.	('associated with', 'Reg', (144, 159))	('EGFR', 'Gene', (25, 29))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('GBM', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (160, 165))
436	32067422	Although EGFR amplification was a predictor of poor prognosis for several cancer types, it was not significantly associated with GBM, consistent with the paradox phenomenon reported in the literature [46].	('rat', 'Species', '10116', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EGFR', 'Gene', (9, 13))	('GBM', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (14, 27))
437	32067422	Both amplification and high expression of EGFR were correlated with short patient survival in this dataset as reported previously [49, 50].	('amplification', 'Var', (5, 18))	('patient', 'Species', '9606', (74, 81))	('EGFR', 'Gene', (42, 46))	('short patient survival', 'CPA', (68, 90))
438	32067422	More interestingly, we found that LGG had the highest number of CpGs whose methylation level was associated with patient survival (i.e., hypermethylation of CpGs in the gene body with better survival), which has not been reported before.	('patient', 'Species', '9606', (113, 120))	('methylation', 'MPA', (75, 86))	('hypermethylation', 'Var', (137, 153))	('patient survival', 'CPA', (113, 129))	('associated', 'Reg', (97, 107))
439	32067422	COAD and PAAD had very few EGFR mutations in this TCGA dataset.	('PAAD', 'Phenotype', 'HP:0006725', (9, 13))	('COAD', 'Disease', (0, 4))	('EGFR', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('COAD', 'Disease', 'MESH:D029424', (0, 4))
440	32067422	However, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (70, 77))	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', (14, 18))	('high', 'Var', (9, 13))
442	32067422	Squamous cell carcinomas in the head and neck (HNSC), lung (LUSC), and esophagus (ESCA) have some commonalities: significantly increased EGFR expression, high frequency of EGFR amplification, and low rate of SNV/indel mutations.	('EGFR', 'Gene', (137, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('amplification', 'Var', (177, 190))	('rat', 'Species', '10116', (200, 203))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('EGFR', 'Gene', (172, 176))	('Squamous cell carcinomas', 'Phenotype', 'HP:0002860', (0, 24))	('HNSC', 'Phenotype', 'HP:0012288', (47, 51))	('Squamous cell carcinomas', 'Disease', 'MESH:D002294', (0, 24))	('Squamous cell carcinomas', 'Disease', (0, 24))	('esophagus', 'Disease', (71, 80))	('expression', 'MPA', (142, 152))	('lung', 'Disease', (54, 58))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
447	32067422	Our analysis provides a comprehensive view of EGFR mutation, abnormal expression, DNA methylation, and their interplay and clinical implications for 32 cancer types covering over ten thousand tumor samples.	('cancer', 'Disease', (152, 158))	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
448	32067422	While some alternations are involved more in tumorigenesis, others are more therapeutic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('involved', 'Reg', (28, 36))	('alternations', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
449	32067422	Some cancer types have a higher frequency of EGFR alternations where mutation, amplification, or abnormal expression is associated with outcome or indicated for clinical action.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (45, 49))	('alternations', 'Var', (50, 62))	('cancer', 'Disease', (5, 11))	('abnormal expression', 'MPA', (97, 116))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (79, 92))
452	32251318	However, the functions of the many variants of these proteins in cancer remain incompletely understood.	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (35, 43))
454	32251318	Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('netrin', 'Gene', (100, 106))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (178, 186))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('Corpus Endometrial Carcinoma', 'Disease', (149, 177))	('patients', 'Species', '9606', (86, 94))
462	32251318	HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma.	('inhibits', 'NegReg', (4, 12))	('RAF', 'Gene', '22882', (49, 52))	('HGF', 'Gene', (0, 3))	('RAF', 'Gene', (49, 52))	('treatment of', 'MPA', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HGF', 'Gene', '3082', (0, 3))	('melanoma', 'Disease', (60, 68))	('RAF', 'Gene', '22882', (30, 33))	('mutant', 'Var', (53, 59))	('RAF', 'Gene', (30, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
481	32251318	Mutations in the netrins were identified in the 33 cancers included in TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('netrins', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('identified', 'Reg', (30, 40))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
482	32251318	At the cancer level, netrins associated with uterine corpus endometrial carcinoma (UCEC) exhibited the highest number of mutations (54), followed by colon adenocarcinoma (COAD) (49), skin cutaneous melanoma (SKCM) (47), stomach adenocarcinoma (STAD) (42), lung adenocarcinoma (LUAD) (38), and lung squamous cell carcinoma (LUSC)(36).	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Disease', (7, 13))	('associated', 'Reg', (29, 39))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('stomach adenocarcinoma', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (220, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('corpus endometrial carcinoma', 'Disease', (53, 81))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('colon adenocarcinoma (COAD) (49), skin cutaneous melanoma', 'Disease', 'MESH:D029424', (149, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('netrins', 'Gene', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
483	32251318	The total mutation rates of Netrin family members in the above six cancers were 10.19%, 12.28%, 10.06%, 9.61%, 6.70% and 7.32%, respectively.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Netrin family', 'Gene', (28, 41))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
485	32251318	However, the hot spot mutation P201Qfs*15 of NTN3 was identified in three patients, each with a different cancer (ESCA, STAD, UCEC), and encodes a truncated protein.	('STAD', 'Disease', (120, 124))	('P201Qfs*15', 'Var', (31, 41))	('NTN3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('ESCA', 'Phenotype', 'HP:0011459', (114, 118))	('cancer', 'Disease', (106, 112))	('NTN3', 'Gene', '4917', (45, 49))
486	32251318	E59K, one of the hotspot mutations of NTN4, was detected in four patients with three cancers (READ, COAD, and UCEC) and both VEST3 and REVEL algorithms indicated this change was dual-damaging.	('READ', 'Disease', (94, 98))	('detected', 'Reg', (48, 56))	('COAD', 'Disease', (100, 104))	('NTN4', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('E59K', 'Var', (0, 4))	('cancers', 'Disease', (85, 92))	('NTN4', 'Gene', '59277', (38, 42))	('E59K', 'Mutation', 'rs762617558', (0, 4))	('patients', 'Species', '9606', (65, 73))	('READ', 'Disease', '-', (94, 98))	('COAD', 'Disease', 'MESH:D029424', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
487	32251318	The hot spot mutation X342_splice of NTN5 occurred in two cancers (SKCM and UCEC) in two patients, and also encodes a truncated protein.	('occurred', 'Reg', (42, 50))	('NTN5', 'Gene', '126147', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NTN5', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', (58, 65))	('X342_splice', 'Var', (22, 33))
488	32251318	The hot spot mutation R238C/H of NTNG1 was detected in three patients with three cancers (COAD, STAD, and UCEC), and R238C was predicted as damaging in VEST3 and REVEL algorithms.	('STAD', 'Disease', (96, 100))	('R238C', 'SUBSTITUTION', 'None', (117, 122))	('R238C', 'Var', (117, 122))	('NTNG1', 'Gene', '22854', (33, 38))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('NTNG1', 'Gene', (33, 38))	('R238C', 'Mutation', 'p.R238C', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('patients', 'Species', '9606', (61, 69))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('R238C', 'Var', (22, 27))	('COAD', 'Disease', (90, 94))	('R238C', 'Mutation', 'p.R238C', (22, 27))	('R238C', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
489	32251318	The NTNG2 hotspot mutation D226N/Rfs*141 occurred in three patients with three cancers (LAML, GBM, and COAD), and NTN1 hotspot mutation P459T was detected in three patients with two cancers (STAD, READ).The mutations in NTN1, NTN3, NTN4, NTNG1, and NTNG2 were mainly in the laminin-N domain, and most mutations of NTN5 were concentrated in the laminin_EGF2 domain.	('NTNG1', 'Gene', '22854', (238, 243))	('NTNG2', 'Gene', (249, 254))	('NTN1', 'Gene', '9423', (114, 118))	('P459T', 'Mutation', 'rs376278603', (136, 141))	('NTN4', 'Gene', (232, 236))	('NTN1', 'Gene', (220, 224))	('COAD', 'Disease', (103, 107))	('NTN5', 'Gene', (314, 318))	('D226N', 'SUBSTITUTION', 'None', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (59, 67))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('NTN5', 'Gene', '126147', (314, 318))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (79, 86))	('NTN1', 'Gene', '9423', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NTN4', 'Gene', '59277', (232, 236))	('NTNG2', 'Gene', '84628', (4, 9))	('D226N', 'Var', (27, 32))	('NTN3', 'Gene', '4917', (226, 230))	('NTNG2', 'Gene', '84628', (249, 254))	('NTNG1', 'Gene', (238, 243))	('NTN1', 'Gene', (114, 118))	('READ', 'Disease', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('READ', 'Disease', '-', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NTN3', 'Gene', (226, 230))	('NTNG2', 'Gene', (4, 9))
490	32251318	After screening by genetic ancestry groups and non-synonymous mutations, 62 patients had complete mutation information (64 mutations) for NTN1, 34 patients were included with complete mutation information (37 mutations) for NTN3, and 107 patients had complete mutation information (120 mutations) for NTN4.	('NTN4', 'Gene', (301, 305))	('patients', 'Species', '9606', (76, 84))	('NTN3', 'Gene', '4917', (224, 228))	('NTN1', 'Gene', (138, 142))	('NTN3', 'Gene', (224, 228))	('NTN4', 'Gene', '59277', (301, 305))	('NTN1', 'Gene', '9423', (138, 142))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (123, 132))
491	32251318	Additionally, the data included 33 patients with 33 mutations in NTN5, 152 patient and 161 mutations in NTNG1, and 91 patients with 98 mutations in (Fig.	('mutations', 'Var', (52, 61))	('NTNG1', 'Gene', '22854', (104, 109))	('patient', 'Species', '9606', (75, 82))	('patient', 'Species', '9606', (35, 42))	('NTN5', 'Gene', '126147', (65, 69))	('patients', 'Species', '9606', (35, 43))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (118, 126))	('NTN5', 'Gene', (65, 69))	('NTNG1', 'Gene', (104, 109))
492	32251318	By comparing the data, we found that up to four netrin family members in individual patients contained mutations in four patients, three UCEC patients and one STAD patient with mutations in both NTN1 and NTNG2.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('NTNG2', 'Gene', (204, 209))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (121, 128))	('NTNG2', 'Gene', '84628', (204, 209))	('patient', 'Species', '9606', (142, 149))	('contained', 'Reg', (93, 102))	('NTN1', 'Gene', (195, 199))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (121, 129))	('patient', 'Species', '9606', (84, 91))	('NTN1', 'Gene', '9423', (195, 199))
493	32251318	In cancer studies with at least five mutations in members of netrin genes (Fig.	('netrin genes', 'Gene', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
494	32251318	2b), UCEC patients were one of the two highest among the cancers associated with the netrin family mutations, with most mutations in NTNG1.	('NTNG1', 'Gene', '22854', (133, 138))	('UCEC', 'Disease', (5, 9))	('NTNG1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (10, 18))
495	32251318	SKCM has the most mutations in NTN4.	('NTN4', 'Gene', '59277', (31, 35))	('NTN4', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
496	32251318	2c), the highest number of cancer mutations among the four genetic ancestry groups was UCEC, and the netrin family mutations in STAD were mainly distributed in EAA and NA.	('netrin family', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (34, 43))
497	32251318	Most netrin mutations in COAD occur in EA and AA.	('mutations', 'Var', (12, 21))	('COAD', 'Disease', (25, 29))	('COAD', 'Disease', 'MESH:D029424', (25, 29))	('netrin', 'Gene', (5, 11))
498	32251318	2d,e) revealed that most mutations in netrins were in the laminin N-terminal domain, except for NTN5.	('NTN5', 'Gene', '126147', (96, 100))	('mutations', 'Var', (25, 34))	('netrins', 'Gene', (38, 45))	('NTN5', 'Gene', (96, 100))
499	32251318	In the laminin EGF domains of NTN1, NTN3, NTN4, and NTN5, most mutations were in the laminin EGF-like 2 domain.	('mutations', 'Var', (63, 72))	('NTN4', 'Gene', (42, 46))	('NTN3', 'Gene', '4917', (36, 40))	('NTN5', 'Gene', '126147', (52, 56))	('NTN4', 'Gene', '59277', (42, 46))	('NTN3', 'Gene', (36, 40))	('NTN1', 'Gene', (30, 34))	('NTN1', 'Gene', '9423', (30, 34))	('NTN5', 'Gene', (52, 56))
500	32251318	In the NTNG1 laminin EGF domains, the mutation of laminin EGF-like 3 was the most frequent, and in the NTNG2 laminin EGF domains, the mutation of laminin EGF-like 1 was the most frequent.	('NTNG2', 'Gene', (103, 108))	('mutation', 'Var', (134, 142))	('frequent', 'Reg', (82, 90))	('frequent', 'Reg', (178, 186))	('laminin EGF-like 3', 'Gene', (50, 68))	('NTNG1', 'Gene', '22854', (7, 12))	('mutation', 'Var', (38, 46))	('NTNG2', 'Gene', '84628', (103, 108))	('NTNG1', 'Gene', (7, 12))
501	32251318	The mutations in the NTR domain were mainly concentrated in NTN1 and 4.	('NTR', 'Gene', (21, 24))	('NTN1', 'Gene', (60, 64))	('NTN1', 'Gene', '9423', (60, 64))	('NTR', 'Gene', '4923', (21, 24))	('mutations', 'Var', (4, 13))
511	32251318	Additionally, MLK1 enhanced cancer cell migration and invasion by epigenetic activation of MMP9 transcription in lung cancer.	('cancer', 'Disease', (118, 124))	('lung cancer', 'Disease', (113, 124))	('invasion', 'CPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MLK1', 'Gene', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('epigenetic activation', 'Var', (66, 87))	('transcription', 'MPA', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MLK1', 'Gene', '4293', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('MMP9', 'Gene', (91, 95))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MMP9', 'Gene', '4318', (91, 95))	('enhanced', 'PosReg', (19, 27))
546	32251318	5c) showed the survival was worse for hypomethylation of NTN1 in kidney renal papillary cell carcinoma (KIRP) and worse for NTNG1 in kidney renal clear cell carcinoma (KIRC), which is consistent with the correlation of high expression of NTN1 in KIRP and NTNG1 in KIRC with worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('kidney renal papillary cell carcinoma', 'Disease', (65, 102))	('hypomethylation', 'Var', (38, 53))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (65, 102))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 166))	('NTN1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NTNG1', 'Gene', '22854', (255, 260))	('NTN1', 'Gene', '9423', (238, 242))	('NTN1', 'Gene', (57, 61))	('NTN1', 'Gene', '9423', (57, 61))	('NTNG1', 'Gene', (255, 260))	('NTNG1', 'Gene', '22854', (124, 129))	('kidney renal clear cell carcinoma', 'Disease', (133, 166))	('NTNG1', 'Gene', (124, 129))
549	32251318	Methylation of NTN1, NTN3, NTN4, NTN5, and NTNG1 was associated with radiation therapy and overall survival of LGG.	('NTN3', 'Gene', (21, 25))	('NTN4', 'Gene', (27, 31))	('NTNG1', 'Gene', '22854', (43, 48))	('Methylation', 'Var', (0, 11))	('NTNG1', 'Gene', (43, 48))	('NTN5', 'Gene', (33, 37))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('radiation therapy', 'CPA', (69, 86))	('NTN1', 'Gene', '9423', (15, 19))	('associated with', 'Reg', (53, 68))	('NTN3', 'Gene', '4917', (21, 25))	('NTN5', 'Gene', '126147', (33, 37))
551	32251318	In pan-kidney (KIRP and KIRC), methylation of NTN4 was associated with pathology T stage and overall survival of KIRP and KIRC.	('methylation', 'Var', (31, 42))	('associated', 'Reg', (55, 65))	('NTN4', 'Gene', '59277', (46, 50))	('NTN4', 'Gene', (46, 50))
552	32251318	Methylation of NTN1 and NTNG1 was associated with pathology T stage and pathology N stage of KIRP.	('associated', 'Reg', (34, 44))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('NTNG1', 'Gene', (24, 29))	('NTN1', 'Gene', '9423', (15, 19))	('NTNG1', 'Gene', '22854', (24, 29))
554	32251318	Methylation of NTN1 and NTN3 was associated with radiation therapy and pathology T stage of ESCA.	('NTN3', 'Gene', '4917', (24, 28))	('NTN3', 'Gene', (24, 28))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (33, 43))	('NTN1', 'Gene', '9423', (15, 19))	('radiation therapy', 'Disease', (49, 66))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))
555	32251318	Methylation of NTN3 was associated with pathology T stage, pathology N stage and number of lymph nodes of PRAD.	('Methylation', 'Var', (0, 11))	('NTN3', 'Gene', (15, 19))	('associated', 'Reg', (24, 34))	('NTN3', 'Gene', '4917', (15, 19))
556	32251318	Methylation of NTN1, NTN3, NTN4, and NTNG1 was associated with PAM50 typing of BRCA, and NTNG1 was also associated with ER.Status and PR.Status.	('NTNG1', 'Gene', (37, 42))	('ER.Status', 'Disease', (120, 129))	('BRCA', 'Gene', (79, 83))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (104, 114))	('NTN4', 'Gene', '59277', (27, 31))	('associated', 'Reg', (47, 57))	('NTNG1', 'Gene', '22854', (37, 42))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', '9423', (15, 19))	('NTN3', 'Gene', '4917', (21, 25))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))	('NTNG1', 'Gene', (89, 94))	('PAM50 typing', 'Var', (63, 75))	('NTN3', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (79, 83))	('NTN4', 'Gene', (27, 31))	('PR.Status', 'Disease', (134, 143))	('NTNG1', 'Gene', '22854', (89, 94))
557	32251318	In UCEC, methylation of NTN3, NTN4, NTNG1, and NTNG2 was associated with MSI phenotype.	('methylation', 'Var', (9, 20))	('NTN3', 'Gene', '4917', (24, 28))	('NTN4', 'Gene', (30, 34))	('MSI', 'Disease', '-', (73, 76))	('NTN3', 'Gene', (24, 28))	('NTNG2', 'Gene', '84628', (47, 52))	('NTNG1', 'Gene', '22854', (36, 41))	('NTN4', 'Gene', '59277', (30, 34))	('NTNG1', 'Gene', (36, 41))	('NTNG2', 'Gene', (47, 52))	('MSI', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))
561	32251318	Overexpression of EZH2 is also associated with the development of prostate cancer, and phosphorylated EZH2 can act as a co-activator of transcription factors, such as promoting the expression of AR.	('EZH2', 'Gene', (102, 106))	('EZH2', 'Gene', '2146', (102, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('expression', 'MPA', (181, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('EZH2', 'Gene', '2146', (18, 22))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('phosphorylated', 'Var', (87, 101))	('EZH2', 'Gene', (18, 22))	('AR', 'Gene', '367', (195, 197))	('prostate cancer', 'Disease', (66, 81))	('promoting', 'PosReg', (167, 176))
576	32251318	Among the many statistically significant results, hsa-miR-361-3p had the strongest inhibitory effect on NTN1 in TCGT (r = 0.612), hsa-miR-33a-5p had the strongest inhibitory effect on NTN4 in TCGT and ESCA (r = -0.494), and hsa-miR-20b-5p had the strongest inhibitory effect on NTNG1 in DLBC (r = -0.528).	('inhibitory effect', 'MPA', (83, 100))	('NTN4', 'Gene', '59277', (184, 188))	('NTN1', 'Gene', (104, 108))	('hsa-miR-361-3p', 'Gene', '100500908', (50, 64))	('NTN1', 'Gene', '9423', (104, 108))	('inhibitory effect', 'MPA', (163, 180))	('hsa-miR-33a-5p', 'Var', (130, 144))	('ESCA', 'Phenotype', 'HP:0011459', (201, 205))	('NTN4', 'Gene', (184, 188))	('NTNG1', 'Gene', '22854', (278, 283))	('hsa-miR-361-3p', 'Gene', (50, 64))	('NTNG1', 'Gene', (278, 283))	('BC', 'Phenotype', 'HP:0003002', (289, 291))
582	32251318	The expression of NTN5 was affected by eQTL in BRCA, COAD, KIRC, KIRP, LGG, PRAD, and THCA.	('expression', 'MPA', (4, 14))	('COAD', 'Disease', 'MESH:D029424', (53, 57))	('affected', 'Reg', (27, 35))	('eQTL', 'Var', (39, 43))	('NTN5', 'Gene', '126147', (18, 22))	('BRCA', 'Phenotype', 'HP:0003002', (47, 51))	('THCA', 'Phenotype', 'HP:0002890', (86, 90))	('BRCA', 'Gene', '672', (47, 51))	('COAD', 'Disease', (53, 57))	('NTN5', 'Gene', (18, 22))	('BRCA', 'Gene', (47, 51))
585	32251318	Of these, 186 (74.4%) NTNG1 eQTLs were associated with AIDS and 57 (22.9%) were associated with non-obstructive azoospermia.	('NTNG1', 'Gene', '22854', (22, 27))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('NTNG1', 'Gene', (22, 27))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('AIDS', 'Disease', (55, 59))	('non-obstructive azoospermia', 'Disease', (96, 123))	('associated', 'Reg', (80, 90))	('associated', 'Reg', (39, 49))	('AIDS', 'Disease', 'MESH:D000163', (55, 59))	('eQTLs', 'Var', (28, 33))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))
588	32251318	Further, three eQTLs (rs9894790, rs9901637, and rs11650713) were found to affect the binding of MYC, TCF12, EBF1, EGR1, and NR2F2.	('rs11650713', 'Var', (48, 58))	('rs11650713', 'Mutation', 'rs11650713', (48, 58))	('MYC', 'Gene', (96, 99))	('EBF1', 'Gene', '1879', (108, 112))	('TCF12', 'Gene', '6938', (101, 106))	('rs9894790', 'Var', (22, 31))	('TCF12', 'Gene', (101, 106))	('EGR1', 'Gene', (114, 118))	('MYC', 'Gene', '4609', (96, 99))	('NR2F2', 'Gene', '7026', (124, 129))	('affect', 'Reg', (74, 80))	('EGR1', 'Gene', '1958', (114, 118))	('rs9894790', 'Mutation', 'rs9894790', (22, 31))	('NR2F2', 'Gene', (124, 129))	('rs9901637', 'Mutation', 'rs9901637', (33, 42))	('rs9901637', 'Var', (33, 42))	('EBF1', 'Gene', (108, 112))	('binding', 'Interaction', (85, 92))
589	32251318	Additionally, high expression of NTN1 in thyroid carcinoma was correlated with a worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('high', 'Var', (14, 18))	('NTN1', 'Gene', '9423', (33, 37))	('NTN1', 'Gene', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
597	32251318	Highly expressed NTN4 is more sensitive to SRC inhibitors such as Dasatinib, WH-4-023, and AZD0530.	('NTN4', 'Gene', (17, 21))	('SRC', 'Gene', '6714', (43, 46))	('SRC', 'Gene', (43, 46))	('more', 'PosReg', (25, 29))	('NTN4', 'Gene', '59277', (17, 21))	('WH-4-023', 'Chemical', '-', (77, 85))	('AZD0530', 'Var', (91, 98))	('AZD0530', 'Chemical', 'MESH:C515233', (91, 98))	('Dasatinib', 'Chemical', 'MESH:D000069439', (66, 75))
609	32251318	In particular, ML162 and ML210 are compounds that target and change the mesenchymal state, inhibit GPX4 activity, and promote apoptosis.	('change', 'Reg', (61, 67))	('GPX4', 'Gene', (99, 103))	('GPX4', 'Gene', '2879', (99, 103))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'CPA', (126, 135))	('ML162', 'Var', (15, 20))	('mesenchymal state', 'CPA', (72, 89))	('promote', 'PosReg', (118, 125))	('ML210', 'Var', (25, 30))
618	32251318	Our findings are as follows: (1) members of the Netrin family are tightly regulated by multiple mechanisms at the genetic, transcriptional, and post-transcriptional levels; (2) mutations of members of the Netrin family correlate with tumor genetic characteristics; (3) Netrins may play important roles in the occurrence and development of endocrine system-related tumors and sex hormone targeting tumors; (4) Netrin family members may be promising prognostic indicators and potential therapeutic targets for lung and kidney cancer; (5) NTNG1 and NTNG2 are potential diagnostic markers and therapeutic targets that should be further studied systematically.	('tumor', 'Disease', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('kidney cancer', 'Disease', 'MESH:D007680', (517, 530))	('NTNG1', 'Gene', (536, 541))	('tumors', 'Disease', (364, 370))	('lung', 'Disease', (508, 512))	('NTNG2', 'Gene', '84628', (546, 551))	('tumors', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('NTNG1', 'Gene', '22854', (536, 541))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('kidney cancer', 'Phenotype', 'HP:0009726', (517, 530))	('kidney cancer', 'Disease', (517, 530))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('NTNG2', 'Gene', (546, 551))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
621	32251318	This study was the first comprehensive analysis of tumor genetic characteristics of mutations in members of the Netrin family.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Netrin', 'Gene', (112, 118))
622	32251318	We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
623	32251318	It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors and the regulatory localization of the NTR domain.	('interact', 'Interaction', (144, 152))	('truncating mutations', 'Var', (60, 80))	('NTR', 'Gene', '4923', (215, 218))	('missense', 'Var', (48, 56))	('NTR', 'Gene', (215, 218))	('Laminin', 'Protein', (104, 111))
626	32251318	Our mutation analysis found highly enriched mutation of netrin family genes in uterine corpus endometrial carcinoma.	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('corpus endometrial carcinoma', 'Disease', (87, 115))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('netrin family genes', 'Gene', (56, 75))
634	32251318	This study found that the NTN family not only has a high overall mutation rate in lung cancer, but that netrin activity is also closely related to the survival and clinical parameters of kidney cancer and non-small cell lung cancer.	('kidney cancer', 'Disease', (187, 200))	('clinical', 'Species', '191496', (164, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (205, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('related', 'Reg', (136, 143))	('lung cancer', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('kidney cancer', 'Disease', 'MESH:D007680', (187, 200))	('mutation', 'Var', (65, 73))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (187, 200))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
642	32251318	Here we find that the expression or methylation of NTNG1 and NTNG2 is associated with survival and other clinical parameters of more than 10 types of cancer.	('NTNG1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NTNG2', 'Gene', '84628', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('clinical', 'Species', '191496', (105, 113))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (150, 156))	('NTNG2', 'Gene', (61, 66))	('NTNG1', 'Gene', '22854', (51, 56))	('expression', 'MPA', (22, 32))	('methylation', 'Var', (36, 47))
643	32251318	There are also important epigenetic and transcriptional modifications of netrins that occur in pan-cancer that are related to the activation of the EMT pathway.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activation', 'PosReg', (130, 140))	('EMT', 'Gene', (148, 151))	('cancer', 'Disease', (99, 105))	('EMT', 'Gene', '3702', (148, 151))	('netrins', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic', 'Var', (25, 35))
645	32251318	It is worth noting that the mutations and potential mirRNA targeting of NTNG1 and NTNG2 in cancer exhibit rates that are much higher than those predicted for NTN1 and NTN4.	('NTN4', 'Gene', (167, 171))	('NTN1', 'Gene', '9423', (158, 162))	('NTNG2', 'Gene', '84628', (82, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (126, 132))	('NTN4', 'Gene', '59277', (167, 171))	('NTNG2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTNG1', 'Gene', '22854', (72, 77))	('NTNG1', 'Gene', (72, 77))	('mutations', 'Var', (28, 37))	('NTN1', 'Gene', (158, 162))
646	32251318	TCGA fusion transcripts analysis suggests the presence of fusion transcripts composed of NTNG1 or NTNG2 in multiple cancers.	('multiple cancers', 'Disease', (107, 123))	('NTNG2', 'Gene', '84628', (98, 103))	('NTNG1', 'Gene', '22854', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('NTNG1', 'Gene', (89, 94))	('fusion transcripts', 'Var', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NTNG2', 'Gene', (98, 103))
650	32251318	However, in some cancers, the selective inhibition of this receptor-dependent apoptosis pathway depends on the silencing of pro-apoptotic proteins.	('silencing', 'Var', (111, 120))	('receptor-dependent apoptosis pathway', 'Pathway', (59, 95))	('inhibition', 'NegReg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
707	32226771	Molecular data are now considered as an important part of pathologic evaluation, since type I carcinomas are associated with PTEN, KRAS, CTNNB1, and PIK3CA genetic mutations and MLH1 promoter hypermethylation, whereas serous carcinomas show mostly TP53 mutations.	('TP53', 'Gene', '7157', (248, 252))	('PTEN', 'Gene', (125, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('KRAS', 'Gene', '3845', (131, 135))	('CTNNB1', 'Gene', '1499', (137, 143))	('serous carcinomas', 'Disease', 'MESH:D018284', (218, 235))	('KRAS', 'Gene', (131, 135))	('PTEN', 'Gene', '5728', (125, 129))	('PIK3CA', 'Gene', '5290', (149, 155))	('associated', 'Reg', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('CTNNB1', 'Gene', (137, 143))	('TP53', 'Gene', (248, 252))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('type I carcinomas', 'Disease', 'MESH:D017827', (87, 104))	('MLH1', 'Gene', (178, 182))	('mutations', 'Var', (164, 173))	('serous carcinomas', 'Disease', (218, 235))	('type I carcinomas', 'Disease', (87, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('PIK3CA', 'Gene', (149, 155))	('MLH1', 'Gene', '4292', (178, 182))
708	32226771	Because of the limitations of this classification due to the wide molecular heterogeneity and, in turn, due to the discrepancy between the detected molecular pattern and tumor behavior, The Cancer Genome Atlas (TCGA) Research Network has gone further in the EC molecular landscape, providing more detailed molecular subclassifications, characterized, respectively by POLE mutation, mismatch repair deficiency, TP53 mutation, and a copy number low group without a specific driver mutation, each with a distinct prognosis: (i) POLE (ultra-mutated) tumors, (ii) microsatellite unstable (MSI) tumors, (iii) copy number high tumors with mostly TP53 mutations, and (iv) a remaining group without these alterations.	('mutations', 'Var', (644, 653))	('tumors', 'Phenotype', 'HP:0002664', (546, 552))	('MSI) tumors', 'Disease', 'MESH:D009369', (584, 595))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (589, 595))	('tumor', 'Phenotype', 'HP:0002664', (620, 625))	('TP53', 'Gene', (410, 414))	('high tumors', 'Disease', (615, 626))	('tumors', 'Disease', (620, 626))	('tumor', 'Phenotype', 'HP:0002664', (546, 551))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (190, 209))	('TP53', 'Gene', (639, 643))	('tumor', 'Disease', (589, 594))	('tumors', 'Disease', (546, 552))	('Cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (589, 594))	('tumors', 'Disease', 'MESH:D009369', (620, 626))	('Cancer Genome Atlas', 'Disease', (190, 209))	('copy number', 'Var', (603, 614))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('EC', 'Phenotype', 'HP:0012114', (258, 260))	('tumors', 'Disease', 'MESH:D009369', (546, 552))	('TP53', 'Gene', '7157', (410, 414))	('tumors', 'Phenotype', 'HP:0002664', (589, 595))	('tumor', 'Disease', (620, 625))	('TP53', 'Gene', '7157', (639, 643))	('tumor', 'Phenotype', 'HP:0002664', (589, 594))	('tumor', 'Disease', (546, 551))	('tumor', 'Disease', 'MESH:D009369', (620, 625))	('high tumors', 'Disease', 'MESH:D009369', (615, 626))	('tumors', 'Disease', (589, 595))	('tumors', 'Phenotype', 'HP:0002664', (620, 626))	('tumor', 'Disease', 'MESH:D009369', (546, 551))
733	32226771	Dysregulation of NLRP3 inflammasome is implicated in tumor pathogenesis and cancer progression of EC and has been proposed as a new therapeutic target for EC.	('EC', 'Phenotype', 'HP:0012114', (98, 100))	('implicated', 'Reg', (39, 49))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('EC', 'Phenotype', 'HP:0012114', (155, 157))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NLRP3', 'Gene', (17, 22))	('tumor', 'Disease', (53, 58))	('NLRP3', 'Gene', '114548', (17, 22))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
756	32226771	Dysregulation in cytotoxic and regulatory NK-cell balance is involved in recurrent miscarriage and preeclampsia and pathogenesis mechanisms.	('preeclampsia', 'Disease', (99, 111))	('miscarriage', 'Phenotype', 'HP:0005268', (83, 94))	('recurrent miscarriage', 'Phenotype', 'HP:0200067', (73, 94))	('Dysregulation', 'Var', (0, 13))	('NK', 'Gene', '42273', (42, 44))	('involved', 'Reg', (61, 69))	('recurrent', 'Disease', (73, 82))	('preeclampsia', 'Phenotype', 'HP:0100602', (99, 111))
813	32226771	An unbalanced Th1/Th2 and/or Th17/Treg ratios have been associated to several pregnancy complications, including preeclampsia and recurrent miscarriage.	('preeclampsia', 'Disease', (113, 125))	('Th1', 'Gene', '51497', (29, 32))	('unbalanced', 'Var', (3, 13))	('Th1', 'Gene', (14, 17))	('associated', 'Reg', (56, 66))	('preeclampsia', 'Phenotype', 'HP:0100602', (113, 125))	('recurrent miscarriage', 'Disease', (130, 151))	('Th1', 'Gene', (29, 32))	('Treg', 'Chemical', '-', (34, 38))	('miscarriage', 'Phenotype', 'HP:0005268', (140, 151))	('pregnancy complications', 'Disease', (78, 101))	('Th1', 'Gene', '51497', (14, 17))	('recurrent miscarriage', 'Phenotype', 'HP:0200067', (130, 151))
838	32226771	PD-1/PD-L1 pathway dysregulation is involved in preeclampsia (increase PD-L1 expression in Th17 cells and higher PD-1 expression in Treg cells) and recurrent miscarriage (decreased decidual PD-L1 expression).	('dysregulation', 'Var', (19, 32))	('recurrent miscarriage', 'Disease', (148, 169))	('decreased', 'NegReg', (171, 180))	('expression', 'MPA', (77, 87))	('Th1', 'Gene', '51497', (91, 94))	('increase PD', 'Phenotype', 'HP:0008151', (62, 73))	('preeclampsia', 'Phenotype', 'HP:0100602', (48, 60))	('recurrent miscarriage', 'Phenotype', 'HP:0200067', (148, 169))	('PD-L1', 'Gene', (71, 76))	('higher', 'PosReg', (106, 112))	('PD-1/PD-L1 pathway', 'Pathway', (0, 18))	('preeclampsia', 'Disease', (48, 60))	('Th1', 'Gene', (91, 94))	('miscarriage', 'Phenotype', 'HP:0005268', (158, 169))	('expression', 'MPA', (118, 128))	('Treg', 'Chemical', '-', (132, 136))	('PD-1', 'Gene', (113, 117))	('increase', 'PosReg', (62, 70))
869	32226771	On the other hand, EC TME reshapes NK-cell phenotype and function to promote tumor progression and acquire a decidual-like and proangiogenic phenotype/function in patients with various cancers.	('EC TME', 'Var', (19, 25))	('EC', 'Phenotype', 'HP:0012114', (19, 21))	('patients', 'Species', '9606', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('decidual-like and', 'CPA', (109, 126))	('NK', 'Gene', '42273', (35, 37))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('TME', 'Chemical', '-', (22, 25))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('promote', 'PosReg', (69, 76))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('tumor', 'Disease', (77, 82))	('cancers', 'Disease', (185, 192))
888	32226771	TAM presence is mostly associated with LVSI, myometrial invasion, and lymph node metastases, showing a proangiogenic phenotype.	('TAM', 'Gene', (0, 3))	('LVSI', 'Disease', (39, 43))	('metastases', 'Disease', (81, 91))	('lymph node', 'Disease', (70, 80))	('TAM', 'Chemical', '-', (0, 3))	('myometrial', 'Disease', (45, 55))	('presence', 'Var', (4, 12))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('associated', 'Reg', (23, 33))
893	32226771	Also, in POLE ultra-mutated tumors associated with a high mutational burden, clinical beneficial effects have been shown, after pembrolizumab administration.	('beneficial effects', 'PosReg', (86, 104))	('ultra-mutated', 'Var', (14, 27))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('pembrolizumab', 'Chemical', 'MESH:C582435', (128, 141))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutational', 'Var', (58, 68))
972	31298514	Patients with MMMT were found to have a higher mean age compared with the other groups (62.40+-7.97 years vs 49.80+-5.87 years in LMS, 39.60+-13.22 years in ESS, and 51.89+-20.74 years in other sarcomas).	('LMS', 'Disease', (130, 133))	('LMS', 'Disease', 'MESH:D007890', (130, 133))	('Patients', 'Species', '9606', (0, 8))	('MMMT', 'Var', (14, 18))	('ESS', 'Disease', (157, 160))	('sarcomas', 'Disease', 'MESH:D012509', (194, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('sarcomas', 'Disease', (194, 202))	('LMS', 'Phenotype', 'HP:0100243', (130, 133))
1018	31298514	The number of patients with positive lymph nodes was low in our study, and survival times were found to be significantly shorter for those with positive lymph nodes.	('positive', 'Var', (144, 152))	('survival times', 'CPA', (75, 89))	('shorter', 'NegReg', (121, 128))	('patients', 'Species', '9606', (14, 22))
1038	31298514	We also found that the presence of residual tumor and positive Ki-67 decreased DFS; however, the decreases were not statistically significant for either comparison, presumably due to the low number of patients.	('patients', 'Species', '9606', (201, 209))	('Ki-67', 'Gene', (63, 68))	('decreased', 'NegReg', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('DFS', 'MPA', (79, 82))	('positive', 'Var', (54, 62))	('tumor', 'Disease', (44, 49))
1078	30985686	3), multifocal AFP+, multifocal CD56+, unifocal CD15+, unifocal P16+, P-CK+++, glypican 3+++ (Fig.	('AFP', 'Gene', '174', (15, 18))	('glypican 3', 'Gene', '2719', (79, 89))	('P16+', 'Var', (64, 68))	('CD56', 'Gene', '4684', (32, 36))	('glypican 3', 'Gene', (79, 89))	('CD15', 'Gene', (48, 52))	('CD56', 'Gene', (32, 36))	('CD15', 'Gene', '2526', (48, 52))	('P-CK+++', 'Var', (70, 77))	('AFP', 'Gene', (15, 18))
1079	30985686	4), unifocal CEA+, beta-catenin (membrane)++, P53++, Ki67 positivity rate of approximately 90%, Mutl homolog (MLH)1+++, MutS protein homolog (MSH)2++, PMS2++ (PMS2 Postmeiotic Segregation), and MSH6+++.	('PMS2', 'Gene', (151, 155))	('PMS2', 'Gene', '5395', (151, 155))	('MSH6+++', 'Var', (194, 201))	('PMS2', 'Gene', (159, 163))	('P53++', 'Var', (46, 51))	('CEA', 'Gene', (13, 16))	('beta-catenin', 'Gene', (19, 31))	('CEA', 'Gene', '1084', (13, 16))	('beta-catenin', 'Gene', '1499', (19, 31))	('PMS2', 'Gene', '5395', (159, 163))
1128	30123978	Histologic subtypes were categorized using ICD-O-3 codes as follows: serous carcinoma (8441, 8460, 8461); clear cell carcinoma (8310, 8005); carcinosarcoma/malignant mixed Mullerian tumor (8950, 8951, 8980, 8981), high-grade endometrioid (8140, 8210, 8211, 8260, 8261, 8262, 8263, 8340, 8380, 8381, 8382, 8383, 8384, 8560, 8570, restricted to cases with grade coded as high)4; and mixed (8323, 8255) high-grade uterine cancer.	('serous carcinoma', 'Disease', (69, 85))	('8950', 'Var', (189, 193))	('high-grade endometrioid', 'Disease', (214, 237))	('clear cell carcinoma', 'Disease', (106, 126))	('serous carcinoma', 'Disease', 'MESH:D018284', (69, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinosarcoma', 'Disease', 'MESH:D002296', (141, 155))	('Mullerian tumor', 'Disease', 'MESH:D002296', (172, 187))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (106, 126))	('8140', 'Var', (239, 243))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (419, 425))	('carcinosarcoma', 'Disease', (141, 155))	('uterine cancer', 'Phenotype', 'HP:0010784', (411, 425))	('cancer', 'Disease', (419, 425))	('Mullerian tumor', 'Disease', (172, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
1156	30123978	Non-Hispanic black patients had a worse 5-year disease-specific survival (DSS) when compared to other racial/ethnic groups (Figure 2).	('worse', 'NegReg', (34, 39))	('patients', 'Species', '9606', (19, 27))	('Non-Hispanic', 'Var', (0, 12))	('DSS', 'Chemical', '-', (74, 77))	('disease-specific survival', 'CPA', (47, 72))
1159	30123978	However, when time to treatment was between 2 and 4 weeks or greater than 4 weeks, NH black patients had a significantly worse DSS compared to patients of other race/ethnicity (P < 0.0001, P < 0.0001, respectively; Figure 3).	('DSS', 'Chemical', '-', (127, 130))	('NH black', 'Var', (83, 91))	('DSS', 'MPA', (127, 130))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (143, 151))
1189	30123978	Molecular differences between endometrial cancers in NH black and NH white women has been studied previously and included identifying differences in p53 mutations, Her2/neu expression, and PTEN mutations.	('PTEN', 'Gene', (189, 193))	('endometrial cancers', 'Disease', (30, 49))	('p53', 'Gene', (149, 152))	('Her2/neu', 'Gene', (164, 172))	('PTEN', 'Gene', '5728', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (153, 162))	('women', 'Species', '9606', (75, 80))	('p53', 'Gene', '7157', (149, 152))	('Her2/neu', 'Gene', '2064', (164, 172))	('mutations', 'Var', (194, 203))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('expression', 'MPA', (173, 183))	('endometrial cancer', 'Phenotype', 'HP:0012114', (30, 48))	('endometrial cancers', 'Disease', 'MESH:D016889', (30, 49))
1190	30123978	Mutations in tumor suppressor gene p53 are associated with overall poorer prognosis.	('tumor', 'Disease', (13, 18))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('associated', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
1195	30123978	Black patients were more likely to have copy number variant (CNV)-high (serous-type) tumors than other racial groups.	('tumors', 'Disease', (85, 91))	('copy number variant', 'Var', (40, 59))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
1197	30123978	Both mutation and somatic copy number alteration revealed a significant amount of TP53 mutations in black patients.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('patients', 'Species', '9606', (106, 114))	('mutations', 'Var', (87, 96))
1219	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
1248	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
1265	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
1282	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('cytolytic levels', 'MPA', (156, 172))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
1307	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
1308	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('PRF1', 'Gene', (188, 192))
1312	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
1313	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('GSE13876', 'Var', (192, 200))	('TCGA-UCEC', 'Disease', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
1314	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('improved', 'PosReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
1315	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
1318	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
1320	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
1326	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('GSE10846', 'Var', (10, 18))	('PRF1', 'Var', (120, 124))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
1327	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
1365	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
1370	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('non-small cell lung cancer', 'Disease', (139, 165))	('blockage', 'Var', (56, 64))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
1378	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
1384	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('arginase', 'Protein', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('tumor', 'Disease', (53, 58))	('Inhibition', 'Var', (0, 10))	('enhance', 'PosReg', (40, 47))
1398	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
1402	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('viral infection', 'Disease', (183, 198))	('tumor', 'Disease', (212, 217))	('mutations', 'Var', (144, 153))
1409	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('THYM', 'Disease', (157, 161))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('improved', 'PosReg', (109, 117))	('tumor', 'Disease', (8, 13))	('LUAD/LUSC', 'Disease', (163, 172))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
1410	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('GZMA', 'Gene', (90, 94))	('associated', 'Reg', (123, 133))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
1442	29464067	Two individuals with breast cancer (4.2% of cases) and one with ovarian cancer (5.3% of cases) carried germline BRCA2 mutations.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('ovarian cancer', 'Disease', 'MESH:D010051', (64, 78))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (21, 34))	('BRCA2', 'Gene', (112, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('ovarian cancer', 'Disease', (64, 78))	('BRCA2', 'Gene', '675', (112, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
1445	29464067	In addition, 18 breast or ovarian tumors (18/70, 26%), including the three cases with germline BRCA2 mutations, exhibited a predominant "BRCAness" mutational signature, an indicator of functional BRCA1/BRCA2 deficiency.	('BRCA2', 'Gene', '675', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (101, 110))	('breast or ovarian tumors', 'Disease', (16, 40))	('BRCA1/BRCA2 deficiency', 'Disease', (196, 218))	('BRCA2', 'Gene', '675', (202, 207))	('breast or ovarian tumors', 'Disease', 'MESH:D001943', (16, 40))	('ovarian tumor', 'Phenotype', 'HP:0100615', (26, 39))	('ovarian tumors', 'Phenotype', 'HP:0100615', (26, 40))	('BRCA2', 'Gene', (95, 100))	('BRCA1/BRCA2 deficiency', 'Disease', 'OMIM:604370', (196, 218))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('BRCA2', 'Gene', (202, 207))
1447	29464067	Thus, mutational processes and aberrant genes in AYA tumors are largely shared with those identified in non-AYA tumors.	('aberrant genes', 'Var', (31, 45))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('AYA tumors', 'Disease', (49, 59))	('AYA tumors', 'Disease', 'MESH:D009369', (49, 59))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('AYA tumors', 'Disease', (108, 118))	('AYA tumors', 'Disease', 'MESH:D009369', (108, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
1465	29464067	Exome sequencing data generated from non-tumor DNA from 73/76 cases (three ovarian tumor cases without informed consent for germline mutation analysis were excluded) were analyzed to identify germline mutations in 25 known cancer susceptibility genes.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', (41, 46))	('ovarian tumor', 'Disease', (75, 88))	('tumor', 'Disease', (83, 88))	('ovarian tumor', 'Phenotype', 'HP:0100615', (75, 88))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('ovarian tumor', 'Disease', 'MESH:D010051', (75, 88))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('germline mutations', 'Var', (192, 210))	('cancer', 'Disease', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
1466	29464067	Germline mutations were identified in three cases: 2/48 cases with breast (4.2%) and 1/19 cases with ovarian (5.3%) cancer carried pathogenic deleterious germline mutations in the BRCA2 gene.	('pathogenic', 'Reg', (131, 141))	('germline', 'Var', (154, 162))	('cancer', 'Disease', (116, 122))	('BRCA2', 'Gene', '675', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('breast', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRCA2', 'Gene', (180, 185))
1468	29464067	A high tumor mutation burden (TMB), recently defined as > 10 SNVs/Mb, was found in two breast carcinomas (BR15-035T, TMB = 50.4 and BR15-045T, TMB = 16.4) and an ovarian carcinoma (OV15-005T, TMB = 250.9).	('ovarian carcinoma', 'Disease', (162, 179))	('TMB', 'Chemical', '-', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (162, 179))	('breast carcinomas', 'Disease', 'MESH:D001943', (87, 104))	('breast carcinomas', 'Disease', (87, 104))	('BR15-035T', 'Var', (106, 115))	('TMB', 'Chemical', '-', (192, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('breast carcinomas', 'Phenotype', 'HP:0003002', (87, 104))	('breast carcinoma', 'Phenotype', 'HP:0003002', (87, 103))	('TMB', 'Chemical', '-', (143, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('tumor', 'Disease', (7, 12))	('BR15-045T', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('TMB', 'Chemical', '-', (30, 33))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (162, 179))
1469	29464067	Deleterious germline and somatic mutations, i.e., nonsense and frameshift insertion/deletion (indel) alterations, in six hypermutator genes consisting of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and two DNA polymerase genes with proofreading function, POLD and POLE, were examined as potentially responsible for high TMB, since their aberration is established as associated with high TMB in a variety of human cancers.	('MSH2', 'Gene', '4436', (194, 198))	('MLH1', 'Gene', (188, 192))	('cancers', 'Phenotype', 'HP:0002664', (431, 438))	('alterations', 'Var', (101, 112))	('TMB', 'Chemical', '-', (338, 341))	('cancers', 'Disease', (431, 438))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('MLH1', 'Gene', '4292', (188, 192))	('PMS2', 'Gene', (210, 214))	('cancers', 'Disease', 'MESH:D009369', (431, 438))	('indel', 'Chemical', '-', (94, 99))	('associated', 'Reg', (384, 394))	('frameshift', 'Var', (63, 73))	('MSH2', 'Gene', (194, 198))	('TMB', 'Chemical', '-', (405, 408))	('human', 'Species', '9606', (425, 430))	('PMS2', 'Gene', '5395', (210, 214))	('MSH6', 'Gene', (200, 204))	('MSH6', 'Gene', '2956', (200, 204))
1474	29464067	In the second largest group (N = 18; 24%) COSMIC-signature 3 (associated with BRCA1 and BRCA2 mutations) was predominant; all three cases with germline BRCA2 mutations were included in this group.	('mutations', 'Var', (94, 103))	('associated', 'Reg', (62, 72))	('BRCA2', 'Gene', '675', (152, 157))	('BRCA2', 'Gene', (88, 93))	('BRCA1', 'Gene', '672', (78, 83))	('BRCA2', 'Gene', '675', (88, 93))	('BRCA1', 'Gene', (78, 83))	('BRCA2', 'Gene', (152, 157))
1476	29464067	Case OV15-005T with the somatic MSH6 mutation showed strong identity with the COSMIC-signature 6 cluster associated with MMR deficiency.	('MMR deficiency', 'Disease', 'MESH:C536143', (121, 135))	('mutation', 'Var', (37, 45))	('MSH6', 'Gene', (32, 36))	('MSH6', 'Gene', '2956', (32, 36))	('MMR deficiency', 'Disease', (121, 135))
1477	29464067	BR15-035T showed strong identity with an unknown signature pattern enriched in CpC to CpA mutations.	('mutations', 'Var', (90, 99))	('CpC', 'Disease', (79, 82))	('CpA', 'Gene', '1357', (86, 89))	('BR15-035T', 'Var', (0, 9))	('CpA', 'Gene', (86, 89))
1480	29464067	Among the ovarian tumors, KRAS mutations were more frequent in mucinous tumors than in other types (7/8 vs. 2/14; P = 0.0015 by Fisher's exact test).	('ovarian tumors', 'Disease', (10, 24))	('ovarian tumors', 'Phenotype', 'HP:0100615', (10, 24))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ovarian tumors', 'Disease', 'MESH:D010051', (10, 24))	('mucinous tumors', 'Disease', 'MESH:D002288', (63, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('ovarian tumor', 'Phenotype', 'HP:0100615', (10, 23))	('KRAS', 'Gene', (26, 30))	('frequent', 'Reg', (51, 59))	('KRAS', 'Gene', '3845', (26, 30))	('mucinous tumors', 'Disease', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
1481	29464067	PIK3CA and ARID1A mutations were more frequent in clear cell or endometrioid tumors than in other types (6/7 vs. 4/15 and 4/7 vs. 3/15; P = 0.016 and 0.11, respectively), consistent with previous studies of all-age-group ovarian tumors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('ovarian tumor', 'Phenotype', 'HP:0100615', (221, 234))	('clear cell', 'Disease', (50, 60))	('endometrioid tumors', 'Disease', (64, 83))	('ARID1A', 'Gene', '8289', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('ARID1A', 'Gene', (11, 17))	('ovarian tumors', 'Disease', (221, 235))	('endometrioid tumors', 'Disease', 'MESH:D016889', (64, 83))	('ovarian tumors', 'Phenotype', 'HP:0100615', (221, 235))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ovarian tumors', 'Disease', 'MESH:D010051', (221, 235))	('frequent', 'Reg', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('mutations', 'Var', (18, 27))
1482	29464067	Mutations in CTNNB1, PTEN, and ARID1A were recurrent among the six uterine tumors (50%, 50%, and 33%, respectively), which is also consistent with previous reports from all-age-group uterine tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('CTNNB1', 'Gene', '1499', (13, 19))	('ARID1A', 'Gene', '8289', (31, 37))	('uterine tumors', 'Phenotype', 'HP:0010784', (183, 197))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('CTNNB1', 'Gene', (13, 19))	('ARID1A', 'Gene', (31, 37))	('Mutations', 'Var', (0, 9))	('uterine tumors', 'Phenotype', 'HP:0010784', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PTEN', 'Gene', (21, 25))	('tumors', 'Disease', (191, 197))	('PTEN', 'Gene', '5728', (21, 25))	('tumors', 'Disease', (75, 81))
1483	29464067	These findings indicate that aberrations in the same sets of genes contribute to breast, ovarian, and uterine tumorigenesis in both AYA and non-AYA individuals.	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('AYA', 'Chemical', '-', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('aberrations', 'Var', (29, 40))	('AYA', 'Chemical', '-', (132, 135))	('ovarian', 'Disease', (89, 96))	('breast', 'Disease', (81, 87))	('contribute', 'Reg', (67, 77))
1485	29464067	The increased genome copy numbers of both loci in this case, together with the location of these two genes neighboring CCDC170 on chromosome 6q25, suggest that this fusion was generated by tandem duplication of the ARMT1-CCDC170-ESR1 locus, as identified in breast cancers bearing the recurrent ESR1-CCDC170 fusion.	('breast cancers', 'Disease', 'MESH:D001943', (258, 272))	('breast cancers', 'Disease', (258, 272))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('CCDC170', 'Gene', (300, 307))	('CCDC170', 'Gene', (221, 228))	('ARMT1', 'Gene', (215, 220))	('ARMT1', 'Gene', '79624', (215, 220))	('breast cancers', 'Phenotype', 'HP:0003002', (258, 272))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('CCDC170', 'Gene', '80129', (119, 126))	('CCDC170', 'Gene', '80129', (300, 307))	('CCDC170', 'Gene', '80129', (221, 228))	('tandem duplication', 'Var', (189, 207))	('ESR1', 'Gene', '2099', (295, 299))	('ESR1', 'Gene', (295, 299))	('ESR1', 'Gene', '2099', (229, 233))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('ESR1', 'Gene', (229, 233))	('CCDC170', 'Gene', (119, 126))
1486	29464067	Hot spot activating mutations in the PIK3CA, KRAS, BRAF, and AKT1 genes, copy number gains in HER2, and deleterious BRCA1, BRCA2, PTEN, and ARID1A mutations were considered actionable gene aberrations (Figure 3), since drugs targeting the molecules encoded by these loci are available or being developed in clinical trials.	('BRCA1', 'Gene', (116, 121))	('mutations', 'Var', (147, 156))	('ARID1A', 'Gene', '8289', (140, 146))	('copy number', 'Var', (73, 84))	('AKT1', 'Gene', '207', (61, 65))	('BRCA2', 'Gene', '675', (123, 128))	('gains', 'PosReg', (85, 90))	('PTEN', 'Gene', (130, 134))	('PIK3CA', 'Gene', '5290', (37, 43))	('HER2', 'Gene', '2064', (94, 98))	('AKT1', 'Gene', (61, 65))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (130, 134))	('mutations', 'Var', (20, 29))	('KRAS', 'Gene', '3845', (45, 49))	('ARID1A', 'Gene', (140, 146))	('activating', 'PosReg', (9, 19))	('BRCA2', 'Gene', (123, 128))	('BRCA1', 'Gene', '672', (116, 121))	('KRAS', 'Gene', (45, 49))	('PIK3CA', 'Gene', (37, 43))	('HER2', 'Gene', (94, 98))
1490	29464067	Germline mutations in 25 genes established as involved in hereditary tumors were detected only in a small fraction of patients: 4.2% of cases with breast tumors and 5.3% of those with ovarian tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ovarian tumors', 'Disease', (184, 198))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('ovarian tumors', 'Phenotype', 'HP:0100615', (184, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('hereditary tumors', 'Disease', (58, 75))	('breast tumors', 'Phenotype', 'HP:0100013', (147, 160))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('ovarian tumors', 'Disease', 'MESH:D010051', (184, 198))	('Germline', 'Var', (0, 8))	('breast tumors', 'Disease', (147, 160))	('breast tumors', 'Disease', 'MESH:D001943', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('patients', 'Species', '9606', (118, 126))	('ovarian tumor', 'Phenotype', 'HP:0100615', (184, 197))	('hereditary tumors', 'Disease', 'MESH:D009386', (58, 75))
1492	29464067	Thus, germline mutations in those susceptibility genes may contribute to the development of a smaller subset of sporadic AYA tumors in females in Japan than in those in the US.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('AYA tumors', 'Disease', (121, 131))	('germline mutations', 'Var', (6, 24))	('AYA tumors', 'Disease', 'MESH:D009369', (121, 131))	('contribute', 'Reg', (59, 69))
1493	29464067	It was noted that two individuals with breast cancer with germline BRCA2 mutation also carried another deleterious germline mutation, respectively.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('carried', 'Reg', (87, 94))	('BRCA2', 'Gene', (67, 72))	('BRCA2', 'Gene', '675', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('mutation', 'Var', (73, 81))	('breast cancer', 'Disease', (39, 52))
1494	29464067	Double germline mutations have been observed in several US patients (Supplementary Table 2), therefore, their pathogenic and clinical significance in AYA-tumors should be further investigated in larger sets of samples.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('AYA-tumors', 'Disease', 'MESH:D009369', (150, 160))	('Double germline mutations', 'Var', (0, 25))	('patients', 'Species', '9606', (59, 67))	('AYA-tumors', 'Disease', (150, 160))
1497	29464067	By contrast, a substantial proportion of the cases (24%) bore a signature of mutagenesis associated with BRCA1 and BRCA2 deficiency, which is exclusively observed in breast, ovarian, and pancreatic tumors.	('BRCA1 and BRCA2 deficiency', 'Disease', 'OMIM:604370', (105, 131))	('pancreatic tumors', 'Disease', 'MESH:D010190', (187, 204))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('observed', 'Reg', (154, 162))	('breast', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('pancreatic tumors', 'Disease', (187, 204))	('mutagenesis', 'Var', (77, 88))	('ovarian', 'Disease', (174, 181))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (187, 204))
1500	29464067	The breast cancer case, BR-035T, showed a signature highly enriched in CpC to CpA mutations.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CpC', 'Disease', (71, 74))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('CpA', 'Gene', '1357', (78, 81))	('mutations', 'Var', (82, 91))	('CpA', 'Gene', (78, 81))
1502	29464067	Consistent with the mutational signature data, AYA tumors showed mutations in the same set of genes as non-AYA tumors.	('AYA tumors', 'Disease', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('AYA tumors', 'Disease', 'MESH:D009369', (47, 57))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('AYA tumors', 'Disease', (107, 117))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('AYA tumors', 'Disease', 'MESH:D009369', (107, 117))	('mutations', 'Var', (65, 74))
1503	29464067	Deleterious mutations in GATA3, an activating SF3B1 mutation (K700E), and an activating AKT1 mutation (E17K) were observed in eight (16.7%), three (6.3%), and three (6.3%) breast tumors, respectively.	('K700E', 'Var', (62, 67))	('SF3B1', 'Gene', '23451', (46, 51))	('GATA3', 'Gene', (25, 30))	('GATA3', 'Gene', '2625', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('activating', 'PosReg', (35, 45))	('K700E', 'Mutation', 'rs559063155', (62, 67))	('breast tumors', 'Phenotype', 'HP:0100013', (172, 185))	('SF3B1', 'Gene', (46, 51))	('breast tumors', 'Disease', 'MESH:D001943', (172, 185))	('E17K', 'Mutation', 'rs121434592', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('AKT1', 'Gene', '207', (88, 92))	('activating', 'PosReg', (77, 87))	('AKT1', 'Gene', (88, 92))	('breast tumors', 'Disease', (172, 185))
1506	29464067	In the present study, significant fractions of breast (50%), ovarian (77%), and uterine (83%) tumors had actionable gene mutations and gains (Figure 3), while actionable oncogene fusions, as frequently observed in AYA lung tumors, were not discovered.	('lung tumors', 'Disease', 'MESH:D008175', (218, 229))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('mutations', 'Var', (121, 130))	('gains', 'PosReg', (135, 140))	('uterine', 'Disease', (80, 87))	('tumors', 'Disease', (223, 229))	('lung tumors', 'Disease', (218, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('lung tumors', 'Phenotype', 'HP:0100526', (218, 229))	('gene mutations', 'Var', (116, 130))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('breast', 'Disease', (47, 53))	('AYA', 'Chemical', '-', (214, 217))	('ovarian', 'Disease', (61, 68))
1510	29464067	Several types of gene fusions including ESR1 have been reported in ER+ breast cancers.	('gene fusions', 'Var', (17, 29))	('breast cancers', 'Disease', 'MESH:D001943', (71, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('reported', 'Reg', (55, 63))	('ESR1', 'Gene', '2099', (40, 44))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ESR1', 'Gene', (40, 44))	('breast cancers', 'Disease', (71, 85))
1520	29464067	The remaining three, OV15-016, OV15-017, and OV15-018, only provided informed consent for somatic mutation analysis, in which non-tumor DNA is used as a reference to identify somatic mutations in tumor DNA; these three patients did not give consent for germline mutation analysis, where non-tumor tissue DNA is used for detection of germline mutations.	('OV15-018', 'Var', (45, 53))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (291, 296))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
1529	29464067	Somatic insertion/deletion (indel) mutations were called using the GATK Somatic Indel Detector, while germline SNVs and indels were called using the GATK program (https://www.broadinstitute.org/gatk/).	('indel', 'Chemical', '-', (120, 125))	('insertion/deletion', 'Var', (8, 26))	('indel', 'Chemical', '-', (28, 33))	('mutations', 'Var', (35, 44))
1530	29464067	Pathogenic germline mutations in 25 known cancer susceptibility genes were defined as "pathogenic variants" deposited in the ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/), and as deleterious variations, i.e., nonsense SNVs and frameshift indel variants.	('frameshift indel', 'Var', (237, 253))	('nonsense SNVs', 'Var', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Pathogenic', 'Reg', (0, 10))	('indel', 'Chemical', '-', (248, 253))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
1536	29464067	AYA adolescent and young adult CGC Cancer Gene Census COSMIC Catalogue of Somatic Mutations in Cancer ER estrogen receptor HER2 human epidermal growth factor receptor 2 indel insertion/deletion ILC invasive lobular carcinoma JUH Jikei University Hospital MMR mismatch repair NCCH National Cancer Center Hospital NMF non-negative matrix factorization PgR progesterone receptor SNV single nucleotide variant TMB tumor mutation burden	('tumor', 'Disease', 'MESH:D009369', (410, 415))	('Cancer', 'Disease', 'MESH:D009369', (95, 101))	('AYA', 'Chemical', '-', (0, 3))	('HER2', 'Gene', (123, 127))	('indel', 'Chemical', '-', (169, 174))	('PgR', 'Gene', (350, 353))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Phenotype', 'HP:0002664', (289, 295))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Disease', (289, 295))	('human', 'Species', '9606', (128, 133))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (207, 224))	('epidermal growth factor receptor 2', 'Gene', '2064', (134, 168))	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('HER2', 'Gene', '2064', (123, 127))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (198, 224))	('PgR', 'Gene', '5241', (350, 353))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer', 'Disease', 'MESH:D009369', (289, 295))	('TMB', 'Chemical', '-', (406, 409))	('progesterone receptor', 'Gene', (354, 375))	('epidermal growth factor receptor 2', 'Gene', (134, 168))	('progesterone receptor', 'Gene', '5241', (354, 375))	('Cancer', 'Disease', (95, 101))	('single nucleotide variant', 'Var', (380, 405))	('invasive lobular carcinoma', 'Disease', (198, 224))	('tumor', 'Disease', (410, 415))
1541	28126714	By integrating patient mutation data, we found that while mutation burden was associated with immune infiltration differences between distinct tumor types, additional factors likely explained differences between tumors originating from the same tissue.	('patient', 'Species', '9606', (15, 22))	('associated', 'Reg', (78, 88))	('mutation burden', 'Var', (58, 73))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('immune infiltration', 'MPA', (94, 113))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (212, 217))
1561	28126714	Second, we investigate the factors driving tumor immunogenicity by examining the associations between mutation load and immune infiltration in a pan-cancer and tumor type-specific manner.	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutation', 'Var', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (160, 165))
1590	28126714	The resulting pCLSup and pCLSdn are normalized through a permutation-based method where the gene labels in vector g are permuted 1000 times resulting in 1000 permuted gene expression vectors (g1, g2, ..., g1000).	('g1', 'Var', (192, 194))	('g1000', 'Var', (205, 210))	('expression vectors', 'Species', '29278', (172, 190))
1599	28126714	The hazard ratio from each Cox proportional hazards model was used to determine the sign of the z-score, with a hazard ratio > 1 corresponding to a z-score > 0 and a hazard ratio < 1 corresponding to a z-score < 0.	('Cox', 'Gene', '1351', (27, 30))	('z-score > 0', 'Var', (148, 159))	('Cox', 'Gene', (27, 30))
1630	28126714	Neoantigens created by nonsynonymous somatic mutations have been linked to higher levels of T cell infiltration and response to immunotherapy in several tumor types.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('higher', 'PosReg', (75, 81))	('nonsynonymous somatic mutations', 'Var', (23, 54))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('T cell infiltration', 'MPA', (92, 111))
1633	28126714	Dropping these five tumor types considerably improved the relationship between mutation burden and CD8+ T cell infiltration (R = 0.69, P = 1e-3; Fig.	('relationship', 'Interaction', (58, 70))	('CD8', 'Gene', (99, 102))	('improved', 'PosReg', (45, 53))	('CD8', 'Gene', '925', (99, 102))	('P = 1e-3', 'Gene', '1423;5394', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('mutation', 'Var', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('P = 1e-3', 'Gene', (135, 143))	('tumor', 'Disease', (20, 25))
1634	28126714	This result supported the link between mutation burden and CD8+ T cell infiltration, though additional factors took precedence in some tumor types.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('mutation burden', 'Var', (39, 54))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
1636	28126714	Of the 23 tumor types examined, only colon adenocarcinoma, uterine carcinosarcoma, and cervical squamous cell carcinoma had significant relationships between CD8+ T cell level and mutation load (P < 0.10, Spearman correlation).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('squamous cell carcinoma', 'Disease', (96, 119))	('carcinosarcoma', 'Disease', (67, 81))	('only colon adenocarcinoma', 'Disease', (32, 57))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('CD8', 'Gene', (158, 161))	('tumor', 'Disease', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('CD8', 'Gene', '925', (158, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('relationships', 'Interaction', (136, 149))	('mutation load', 'Var', (180, 193))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('carcinosarcoma', 'Disease', 'MESH:D002296', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('only colon adenocarcinoma', 'Disease', 'MESH:D003110', (32, 57))
1646	28126714	These associations indicated that mutation burden is a driver of general immune infiltration, but other factors are likely more relevant in some tumor types.	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('mutation', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))
1659	28126714	Most interestingly, macrophage infiltration was associated with poor patient prognosis in 9 cancer types and showed trends toward negative survival associations in several other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('macrophage infiltration', 'Var', (20, 43))	('patient', 'Species', '9606', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
1686	28126714	While mutation load was previously linked to CD8+ T cell infiltration and an overall decrease in tumor purity, links between mutation load and other immune cell subsets remained unclear.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutation load', 'Var', (6, 19))	('decrease', 'NegReg', (85, 93))	('tumor', 'Disease', (97, 102))	('CD8', 'Gene', (45, 48))	('CD8', 'Gene', '925', (45, 48))
1688	28126714	However, when excluding five outlier tumor types from our analysis, we found that mutation load was correlated with infiltration by CD8+ T cells, B cells, NK cells, and macrophages, implicating a role for mutation load in the overall tumor immune response.	('mutation load', 'Var', (82, 95))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('infiltration', 'CPA', (116, 128))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
1691	28126714	In support of this finding, we found that in nearly all cancer types, patients sharing a diagnosis did not exhibit an association between mutation load and immune infiltration.	('patients', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (138, 146))	('association', 'Interaction', (118, 129))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
1692	28126714	Exceptions to this were in colorectal and endometrial cancers, where MSI-based genomic instability was associated with increased immune infiltration.	('immune infiltration', 'MPA', (129, 148))	('colorectal and endometrial cancers', 'Disease', 'MESH:D016889', (27, 61))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('genomic instability', 'Var', (79, 98))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('increased', 'PosReg', (119, 128))
1702	28126714	VISTA is constitutively and highly expressed in MDSCs and VISTA blockade has been shown to reduce their number, while also resulting in increased maturation of dendritic cells and stimulation of T cell-based anti-tumor immunity.	('tumor', 'Disease', (213, 218))	('blockade', 'Var', (64, 72))	('reduce', 'NegReg', (91, 97))	('number', 'MPA', (104, 110))	('VISTA', 'Gene', (0, 5))	('VISTA', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('VISTA', 'Gene', '64115', (0, 5))	('increased', 'PosReg', (136, 145))	('stimulation', 'PosReg', (180, 191))	('maturation of dendritic cells', 'CPA', (146, 175))	('VISTA', 'Gene', '64115', (58, 63))
1718	29023197	We identified 281 RBPs to be enriched for mutations (GEMs) in at least one cancer type.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('RBP', 'Gene', (18, 21))	('RBP', 'Gene', '57794', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (42, 51))
1719	29023197	GEM RBPs were found to undergo frequent frameshift and inframe deletions as well as missense, nonsense and silent mutations when compared to those that are not enriched for mutations.	('nonsense', 'Var', (94, 102))	('RBP', 'Gene', (4, 7))	('RBP', 'Gene', '57794', (4, 7))	('frameshift', 'Var', (40, 50))	('missense', 'Var', (84, 92))
1721	29023197	Using the OncodriveFM framework, we also identified more than 200 candidate driver RBPs that were found to accumulate functionally impactful mutations in at least one cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('mutations', 'Var', (141, 150))	('cancer', 'Disease', (167, 173))	('RBP', 'Gene', (83, 86))	('RBP', 'Gene', '57794', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
1730	29023197	Given the importance of regulatory molecules like RBPs in controlling gene expression, it is evident that any deviation from normal function of these proteins can lead to various disorders including cancer.	('RBP', 'Gene', '57794', (50, 53))	('deviation', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('various disorders', 'Disease', (171, 188))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('RBP', 'Gene', (50, 53))	('lead to', 'Reg', (163, 170))	('various disorders', 'Disease', 'MESH:C566351', (171, 188))
1735	29023197	An increased expression of this protein facilitates the inclusion of exon5 in the pre-mRNA of CD44 - a cell surface protein involved in cancer proliferation.	('increased', 'PosReg', (3, 12))	('CD44', 'Gene', (94, 98))	('expression', 'MPA', (13, 23))	('exon5', 'Protein', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('CD44', 'Gene', '960', (94, 98))	('facilitates', 'PosReg', (40, 51))	('inclusion', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
1742	29023197	Mutational analysis of all the genes in the human genome across 12 cancer types identified SF3B1, U2AF1 and PCBP1 - RBPs involved in splicing to be significantly mutated in multiple cancers suggesting their role in causing cancer phenotypes.	('human', 'Species', '9606', (44, 49))	('SF3B1', 'Gene', (91, 96))	('PCBP1', 'Gene', (108, 113))	('U2AF1', 'Gene', (98, 103))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('RBP', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('SF3B1', 'Gene', '23451', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('U2AF1', 'Gene', '7307', (98, 103))	('multiple cancers', 'Disease', 'MESH:D009369', (173, 189))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutated', 'Var', (162, 169))	('PCBP1', 'Gene', '5093', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (67, 73))	('multiple cancers', 'Disease', (173, 189))	('RBP', 'Gene', '57794', (116, 119))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
1743	29023197	Furthermore, APOBEC3B - an important protein in the RNA editing mechanism was found to be upregulated and frequently mutated in cancers of bladder, cervix, lung, head and neck and breast.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutated', 'Var', (117, 124))	('cancers of bladder', 'Disease', (128, 146))	('cervix', 'Disease', (148, 154))	('cancers of bladder', 'Disease', 'MESH:D001749', (128, 146))	('APOBEC3B', 'Gene', (13, 21))	('APOBEC3B', 'Gene', '9582', (13, 21))	('breast', 'Disease', (180, 186))	('lung', 'Disease', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('upregulated', 'PosReg', (90, 101))
1744	29023197	Also notable are the mutations in the gene coding for RBM10 in lung cancer which was found to misregulate the alternative splicing of NUMB protein- a critical regulator of the Notch pathway and hence leading to irregular cell proliferation in lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('lung cancers', 'Phenotype', 'HP:0100526', (243, 255))	('lung cancer', 'Disease', (63, 74))	('RBM10', 'Gene', '8241', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('alternative splicing', 'MPA', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('NUMB', 'Gene', (134, 138))	('irregular cell proliferation', 'CPA', (211, 239))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('misregulate', 'Var', (94, 105))	('mutations', 'Var', (21, 30))	('irregular cell proliferation', 'Phenotype', 'HP:0031377', (211, 239))	('NUMB', 'Gene', '8650', (134, 138))	('lung cancers', 'Disease', 'MESH:D008175', (243, 255))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('RBM10', 'Gene', (54, 59))	('lung cancers', 'Disease', (243, 255))	('leading to', 'Reg', (200, 210))
1746	29023197	Hence, to expand the current understanding of mutations in these genes, we performed a systematic analyses of somatic mutations occurring in ~1300 RBPs in ~6000 tumor samples across 26 cancer types.	('tumor', 'Disease', (161, 166))	('RBP', 'Gene', (147, 150))	('RBP', 'Gene', '57794', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
1748	29023197	We then analyzed the exome sequencing data of 26 cancer types to identify candidate drivers and integrated their transcriptome profiles to assess alterations in their expression due to mutation.	('expression', 'MPA', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutation', 'Var', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
1752	29023197	Secondly, we identify Genes Enriched for Mutations (GEMs) in a given cancer using a Fisher's exact test that calculates the probability of observing mutations in a given gene against a genomic background (Fig.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Mutations', 'Var', (41, 50))	('cancer', 'Disease', (69, 75))
1753	29023197	Finally, we identify RBPs that accumulate high functionally-impactful mutations using OncodriveFM approach (Fig.	('RBP', 'Gene', (21, 24))	('mutations', 'Var', (70, 79))	('RBP', 'Gene', '57794', (21, 24))
1754	29023197	1C) (See Materials and Methods) that relies on SIFT, PPH2 and Mutation Assessor to estimate the functional impact of individual mutations.	('mutations', 'Var', (128, 137))	('SIFT', 'Disease', 'None', (47, 51))	('SIFT', 'Disease', (47, 51))
1755	29023197	It does so by computing the bias towards the accumulation of high-impact mutations across the cancer in the cohort as a signal of their involvement in tumorogenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
1759	29023197	Overall, we find the mutational frequency of Non-RBPs to be significantly higher than that of RBPs in ~70% of the cancer types studied (Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('higher', 'PosReg', (74, 80))	('RBP', 'Gene', (49, 52))	('RBP', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('RBP', 'Gene', '57794', (49, 52))	('RBP', 'Gene', '57794', (94, 97))	('mutational', 'Var', (21, 31))	('cancer', 'Disease', (114, 120))
1775	29023197	S1D), suggesting that these observations could reveal common mechanisms of dysregulation at post-transcriptional level with in members of these cancer type clusters due to mutations in RBPs.	('mutations', 'Var', (172, 181))	('cancer type clusters', 'Disease', (144, 164))	('RBP', 'Gene', (185, 188))	('RBP', 'Gene', '57794', (185, 188))	('cancer type clusters', 'Disease', 'MESH:D003027', (144, 164))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
1777	29023197	1B to identify Genes Enriched for Mutations (GEMs) in a given cancer type (see Materials and Methods).	('Mutations', 'Var', (34, 43))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
1778	29023197	This identified 281 genes encoding for RBPs to be significantly enriched for mutations in at least one cancer (see Fig.	('RBP', 'Gene', '57794', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('RBP', 'Gene', (39, 42))
1779	29023197	3A for RBPs enriched for mutations in at least 4 cancers and Fig.	('mutations', 'Var', (25, 34))	('RBP', 'Gene', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('RBP', 'Gene', '57794', (7, 10))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
1781	29023197	Comparison of GEM and non-GEM RBPs with corresponding gene sets for non-RBPs, for differences in the GC content and exome length, revealed that while GC content does not contribute to the extent of mutations in RBPs (p = 0.496, Wilcoxon test), it was found to be significantly different (p = 4.21e-08, Wilcoxon test) between GEM and non-GEM groups for non-RBPs (Fig.	('RBP', 'Gene', '57794', (30, 33))	('RBP', 'Gene', (356, 359))	('RBP', 'Gene', '57794', (72, 75))	('RBP', 'Gene', '57794', (356, 359))	('mutations', 'Var', (198, 207))	('RBP', 'Gene', (72, 75))	('RBP', 'Gene', (211, 214))	('RBP', 'Gene', '57794', (211, 214))	('different', 'Reg', (277, 286))	('RBP', 'Gene', (30, 33))
1783	29023197	These observations suggest that while GC content has no significant influence on the extent of mutations in RBPs, exome length might be higher for GEM RBPs, however it does not necessarily determine whether a gene is a GEM since non-RBPs GEMs exhibited significantly lower exome lengths.	('RBP', 'Gene', (233, 236))	('RBP', 'Gene', (151, 154))	('higher', 'PosReg', (136, 142))	('exome lengths', 'MPA', (273, 286))	('exome length', 'MPA', (114, 126))	('RBP', 'Gene', '57794', (151, 154))	('RBP', 'Gene', '57794', (233, 236))	('RBP', 'Gene', (108, 111))	('RBP', 'Gene', '57794', (108, 111))	('mutations', 'Var', (95, 104))	('lower', 'NegReg', (267, 272))
1784	29023197	Among the GEM RBPs, we identified KMT2C (MLL3), a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes, to be enriched for mutations in 40% of the cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('RBP', 'Gene', (14, 17))	('tumor', 'Disease', (93, 98))	('MLL3', 'Gene', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mutations', 'Var', (195, 204))	('KMT2C', 'Gene', '58508', (34, 39))	('cancer', 'Disease', (219, 225))	('KMT2C', 'Gene', (34, 39))	('RBP', 'Gene', '57794', (14, 17))	('MLL3', 'Gene', '58508', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
1786	29023197	Furthermore, PLEC (plectin) - an abundantly expressed versatile protein that links different elements of the cytoskeleton was also seen to be enriched for mutations in 11 cancer types including lung, head and neck, bladder and pancreas.	('plectin', 'Gene', '5339', (19, 26))	('mutations', 'Var', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('PLEC', 'Gene', '5339', (13, 17))	('lung', 'Disease', (194, 198))	('PLEC', 'Gene', (13, 17))	('plectin', 'Gene', (19, 26))	('bladder and pancreas', 'Disease', 'MESH:D001749', (215, 235))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
1789	29023197	Also notable is the gene encoding for EPPK1 which was seen to be mutated in ~40% of the cancers including cancers of cervix, colon, head and neck, pancreas etc.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('pancreas', 'Disease', (147, 155))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (88, 95))	('EPPK1', 'Gene', '83481', (38, 43))	('cancers', 'Disease', (106, 113))	('EPPK1', 'Gene', (38, 43))	('colon', 'Disease', (125, 130))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutated', 'Var', (65, 72))
1791	29023197	Further, functional analysis of RBPs enriched for mutations identified diverse pathways including translation, mRNA splicing and apoptosis to be over-represented (p < 0.01, Fig.	('apoptosis', 'CPA', (129, 138))	('mutations', 'Var', (50, 59))	('translation', 'MPA', (98, 109))	('over-represented', 'PosReg', (145, 161))	('RBP', 'Gene', (32, 35))	('mRNA splicing', 'MPA', (111, 124))	('RBP', 'Gene', '57794', (32, 35))
1793	29023197	As different genes are susceptible to undergo different kinds of mutations at varied frequency, we aimed to identify mutation types that RBPs enriched for mutations (GEM-RBPs) frequently undergo when compared to RBPs that are not enriched for mutations (NonGEM-RBPs) (See Materials and Methods).	('RBP', 'Gene', (212, 215))	('mutations', 'Var', (155, 164))	('RBP', 'Gene', (137, 140))	('RBP', 'Gene', '57794', (212, 215))	('RBP', 'Gene', (261, 264))	('RBP', 'Gene', '57794', (137, 140))	('RBP', 'Gene', '57794', (261, 264))	('RBP', 'Gene', (170, 173))	('RBP', 'Gene', '57794', (170, 173))
1794	29023197	In particular, we quantified the mutation frequencies of nine different classes of mutations namely Frameshift mutations - Deletion and Insertion, Inframe Deletion, Inframe Insertion, Missense, Nonsense, Nonstop, Silent and Splice Site for all the RBPs across cancer samples (Materials and Methods, Table S2).	('Inframe Deletion', 'Var', (147, 163))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('RBP', 'Gene', (248, 251))	('cancer', 'Disease', (260, 266))	('Nonstop', 'Var', (204, 211))	('Missense', 'Var', (184, 192))	('RBP', 'Gene', '57794', (248, 251))	('Insertion', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Nonsense', 'Var', (194, 202))	('Frameshift mutations - Deletion', 'Var', (100, 131))
1795	29023197	Our analysis clearly revealed that RBPs frequently and significantly undergo Frameshift deletion, Inframe deletion, Missense, Nonsense and Silent mutations (Fig.	('Frameshift deletion', 'Var', (77, 96))	('Silent mutations', 'Var', (139, 155))	('Inframe deletion', 'Var', (98, 114))	('RBP', 'Gene', (35, 38))	('RBP', 'Gene', '57794', (35, 38))	('Missense', 'Var', (116, 124))	('undergo', 'Reg', (69, 76))
1797	29023197	Abundance of Frameshift deletions in GEM-RBPs clearly indicates that deletion mutations causing change in reading frame thereby resulting in different translation than the original polypeptide, could be a frequent mechanism of dysregulation.	('deletion mutations', 'Var', (69, 87))	('RBP', 'Gene', (41, 44))	('RBP', 'Gene', '57794', (41, 44))	('Frameshift deletions', 'Var', (13, 33))	('resulting in different', 'Reg', (128, 150))	('translation', 'MPA', (151, 162))	('reading frame', 'MPA', (106, 119))
1798	29023197	Also, a significant difference in the frequency of nonsense mutations - which introduce a premature termination codon (PTC) in the gene; between the two groups indicate the importance of these mutations in triggering the mechanism of nonsense mediate decay (NMD) of RBPs enriched for mutations in several cancers.	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('cancers', 'Disease', (305, 312))	('mutations', 'Var', (193, 202))	('RBP', 'Gene', (266, 269))	('RBP', 'Gene', '57794', (266, 269))
1800	29023197	This study showed that mutations that change the reading frame and introduce a premature termination codon cause a severe form of the disease as the whole transcript is eliminated by NMD, whereas mutations that did not give rise to a PTC resulted in a milder form of muscular dystrophy.	('muscular dystrophy', 'Disease', (267, 285))	('muscular dystrophy', 'Disease', 'MESH:D009136', (267, 285))	('cause', 'Reg', (107, 112))	('premature termination codon', 'MPA', (79, 106))	('mutations', 'Var', (23, 32))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (267, 285))	('eliminated', 'NegReg', (169, 179))
1801	29023197	A similar mechanism could be leading to the dysregulation of RBPs that are enriched for mutations in several cancer phenotypes, due to the higher mutational rate of nonsense mutations in GEM-RBPs (Fig.	('nonsense mutations', 'Var', (165, 183))	('RBP', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('RBP', 'Gene', '57794', (61, 64))	('mutational rate', 'MPA', (146, 161))	('cancer', 'Disease', (109, 115))	('dysregulation', 'MPA', (44, 57))	('RBP', 'Gene', (191, 194))	('RBP', 'Gene', '57794', (191, 194))	('higher', 'PosReg', (139, 145))
1802	29023197	Likewise, missense mutations that result in a change in the amino acid composition and inframe deletions which although do not change the frame of transcription but can result in a dysfunctional protein form could contribute to the loss of function phenotypes in RBPs enriched for mutations.	('dysfunctional', 'Disease', (181, 194))	('dysfunctional', 'Disease', 'MESH:D006331', (181, 194))	('amino acid composition', 'MPA', (60, 82))	('protein form', 'MPA', (195, 207))	('change', 'Reg', (46, 52))	('missense mutations', 'Var', (10, 28))	('RBP', 'Gene', '57794', (263, 266))	('RBP', 'Gene', (263, 266))	('result', 'Reg', (169, 175))
1803	29023197	In addition to identifying Genes Enriched for Mutations (GEMs), which can comprise of both synonymous and nonsynonymous somatic mutations in a cancer genome, we aimed to uncover RBPs that exhibit a bias towards the accumulation of nonsynonymous mutations with high functional impact during tumorigenesis, as a means to uncover likely driver RBPs.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('RBP', 'Gene', (178, 181))	('RBP', 'Gene', '57794', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('cancer', 'Disease', (143, 149))	('RBP', 'Gene', (341, 344))	('nonsynonymous mutations', 'Var', (231, 254))	('RBP', 'Gene', '57794', (341, 344))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('accumulation', 'PosReg', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (290, 295))
1804	29023197	Driver genes are known to provide a significant growth advantage to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('genes', 'Var', (7, 12))	('growth advantage', 'CPA', (48, 64))
1806	29023197	A significant trend towards the accumulation of such functional mutations is calculated as FM bias - signal of positive selection during cancer development (See Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
1813	29023197	We predict AHNAK to be a candidate driver in 12 cancers including head and neck squamous carcinoma, lung adenocarcinoma, lung squamous carcinoma, breast cancers (See Table S3) suggesting the impact of nonsynonymous mutations on protein function and thus misregulating pathways responsible for cellular growth and hence leading to a cancer phenotype.	('lung squamous carcinoma', 'Disease', (121, 144))	('lung adenocarcinoma', 'Disease', (100, 119))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (75, 98))	('cancers', 'Disease', (153, 160))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('leading to', 'Reg', (319, 329))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('pathways', 'Pathway', (268, 276))	('nonsynonymous mutations', 'Var', (201, 224))	('protein', 'Protein', (228, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('breast cancers', 'Disease', (146, 160))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', (48, 55))	('misregulating', 'Reg', (254, 267))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('impact', 'Reg', (191, 197))	('AHNAK', 'Gene', '79026', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('cancer', 'Disease', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('AHNAK', 'Gene', (11, 16))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('neck squamous carcinoma', 'Disease', (75, 98))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
1814	29023197	Another striking example is AGO2 which was found to accumulate functional mutations in cancers of breast, skin, lung and stomach.	('AGO2', 'Gene', '27161', (28, 32))	('cancers of breast', 'Disease', 'MESH:D001943', (87, 104))	('stomach', 'Disease', (121, 128))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('skin', 'Disease', (106, 110))	('AGO2', 'Gene', (28, 32))	('cancers of breast', 'Disease', (87, 104))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('lung', 'Disease', (112, 116))
1821	29023197	Interestingly, we find the gene encoding SF3B1 - an important splicing factor to be frequently mutated and accumulating functional mutations in uveal melanoma (UVM) which is in accordance with a study that showed the impact of SF3B1 mutations on alternative splicing in uveal melanomas.	('uveal melanomas', 'Disease', (270, 285))	('uveal melanomas', 'Phenotype', 'HP:0007716', (270, 285))	('melanomas', 'Phenotype', 'HP:0002861', (276, 285))	('SF3B1', 'Gene', '23451', (227, 232))	('splicing factor', 'Gene', (62, 77))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('SF3B1', 'Gene', (41, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Disease', (144, 158))	('splicing factor', 'Gene', '10569', (62, 77))	('uveal melanomas', 'Disease', 'MESH:C536494', (270, 285))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('SF3B1', 'Gene', '23451', (41, 46))	('mutations', 'Var', (131, 140))	('SF3B1', 'Gene', (227, 232))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('mutations', 'Var', (233, 242))
1822	29023197	Furthermore, recurrent missense mutation at R625 in patients with uveal melanoma was observed suggesting an oncogenic role of this mutation (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('missense mutation at R625', 'Var', (23, 48))	('patients', 'Species', '9606', (52, 60))
1825	29023197	Also, recurrent missense mutations at S34 in the zf-CCCH domain was observed to be highly recurrent in patients with LAML (Fig.	('missense mutations at S34', 'Var', (16, 41))	('patients', 'Species', '9606', (103, 111))	('LAML', 'Disease', (117, 121))
1826	29023197	To identify if mutations in an RBP gene affects its RNA levels, we performed pan-cancer expression analysis for all the candidate RBP drivers between patient cohorts containing these mutations and cohorts that don't carry such mutations (See Materials and Methods).	('RBP', 'Gene', (130, 133))	('patient', 'Species', '9606', (150, 157))	('mutations', 'Var', (183, 192))	('affects', 'Reg', (40, 47))	('RBP', 'Gene', '57794', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('mutations', 'Var', (15, 24))	('RBP', 'Gene', (31, 34))	('cancer', 'Disease', (81, 87))	('RBP', 'Gene', '57794', (31, 34))	('RNA levels', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
1828	29023197	Of these, CDKN2A, a cyclin-dependent kinase inhibitor 2A known to stabilize the tumor suppressor protein p53 was observed to have higher levels of RNA in mutated samples when compared to the non-mutated samples (Fold change = 3.9, p = 1.26E-11, Wilcox test).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CDKN2A', 'Gene', '1029', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('higher', 'PosReg', (130, 136))	('tumor', 'Disease', (80, 85))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (20, 56))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (20, 56))	('mutated', 'Var', (154, 161))	('levels', 'MPA', (137, 143))	('CDKN2A', 'Gene', (10, 16))	('RNA', 'MPA', (147, 150))
1829	29023197	Additionally, two distinct RNA helicases - DDX5 and DHX9 were found to have significantly different expression profiles between mutated and non-mutated cohorts.	('RNA helicases', 'Protein', (27, 40))	('expression profiles', 'MPA', (100, 119))	('mutated', 'Var', (128, 135))	('different', 'Reg', (90, 99))	('DDX5', 'Gene', (43, 47))	('DHX9', 'Gene', (52, 56))	('DDX5', 'Gene', '1655', (43, 47))	('DHX9', 'Gene', '1660', (52, 56))
1831	29023197	RBM10 was seen to be 2 fold down regulated in mutated samples when compared to the non-mutated samples.	('mutated', 'Var', (46, 53))	('down regulated', 'NegReg', (28, 42))	('RBM10', 'Gene', (0, 5))	('RBM10', 'Gene', '8241', (0, 5))
1832	29023197	We hypothesize that the lower expression in the mutated samples could be a result of the presence of truncated transcripts due to several non-sense mutations in the gene encoding for RBM10 (Fig.	('mutations', 'Var', (148, 157))	('expression', 'MPA', (30, 40))	('lower', 'NegReg', (24, 29))	('RBM10', 'Gene', '8241', (183, 188))	('RBM10', 'Gene', (183, 188))
1833	29023197	Hence, mutations in the RBP gene might not only lead to abnormal subcellular localization, defective binding to RNA but also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('conferring', 'Reg', (179, 189))	('mutations', 'Var', (7, 16))	('RNA', 'Protein', (112, 115))	('defective', 'NegReg', (91, 100))	('subcellular localization', 'MPA', (65, 89))	('protein-protein interactions', 'MPA', (141, 169))	('RBP', 'Gene', (24, 27))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('RBP', 'Gene', '57794', (24, 27))	('binding', 'Interaction', (101, 108))	('lead', 'Reg', (48, 52))	('abnormal', 'Reg', (56, 64))	('lead', 'Reg', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('altered', 'Reg', (133, 140))
1843	29023197	Higher degree, betweenness and closeness of drivers when compared to the non-drivers indicates that they form an integral part of the protein-protein interaction network of RBPs and thus mutations in them could significantly contribute to causing lethal phenotypes by potentially disrupting the formation of RNP complexes.	('disrupting', 'NegReg', (280, 290))	('contribute', 'Reg', (225, 235))	('formation', 'MPA', (295, 304))	('RNP', 'Gene', (308, 311))	('mutations', 'Var', (187, 196))	('RNP', 'Gene', '55599', (308, 311))	('RBP', 'Gene', (173, 176))	('causing', 'Reg', (239, 246))	('RBP', 'Gene', '57794', (173, 176))
1846	29023197	Hence, mutations in them may not only affect the expression, defective binding to RNA but can also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('cancer', 'Disease', (166, 172))	('defective', 'NegReg', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('RNA', 'Protein', (82, 85))	('lead to altered', 'Reg', (99, 114))	('expression', 'MPA', (49, 59))	('conferring', 'Reg', (153, 163))	('protein-protein interactions', 'MPA', (115, 143))	('binding', 'Interaction', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('affect', 'Reg', (38, 44))	('mutations', 'Var', (7, 16))
1854	29023197	This RBP interacts with CDC5L and SF3A1 in LUAD whereas it interacts with SNRNP300 and SF3B3 in COAD suggesting that different combinations of RBP mutated complexes could be contributing to disruption in different post-transcriptional sub-networks leading to varying cancer phenotypes.	('COAD', 'Disease', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('disruption', 'Reg', (190, 200))	('LUAD', 'Disease', (43, 47))	('RBP', 'Gene', (5, 8))	('leading to', 'Reg', (248, 258))	('RBP', 'Gene', '57794', (143, 146))	('CDC5L', 'Gene', (24, 29))	('post-transcriptional sub-networks', 'Pathway', (214, 247))	('SF3B3', 'Gene', (87, 92))	('mutated', 'Var', (147, 154))	('contributing', 'Reg', (174, 186))	('CDC5L', 'Gene', '988', (24, 29))	('interacts', 'Reg', (9, 18))	('cancer', 'Disease', (267, 273))	('SF3B3', 'Gene', '23450', (87, 92))	('SF3A1', 'Gene', '10291', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('COAD', 'Disease', 'MESH:D029424', (96, 100))	('RBP', 'Gene', '57794', (5, 8))	('RNP', 'Gene', '55599', (76, 79))	('RBP', 'Gene', (143, 146))	('SF3A1', 'Gene', (34, 39))	('RNP', 'Gene', (76, 79))
1858	29023197	Hence, to understand if the mutations in these proteins are truly deleterious and/or can have a phenotypic impact in breast cancer, we choose SF3B1 and PRPF8 to study their effect on breast cancer cell lines.	('PRPF8', 'Gene', (152, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('SF3B1', 'Gene', '23451', (142, 147))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('SF3B1', 'Gene', (142, 147))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('PRPF8', 'Gene', '10594', (152, 157))	('breast cancer', 'Disease', (183, 196))	('mutations', 'Var', (28, 37))
1862	29023197	Despite inefficient knockdown of SF3B1 (Fig.	('knockdown', 'Var', (20, 29))	('SF3B1', 'Gene', (33, 38))	('SF3B1', 'Gene', '23451', (33, 38))
1863	29023197	8A), CD44+/CD24+ cells were reproducibly reduced upon SF3B1 knockdown (Fig.	('CD24', 'Gene', (11, 15))	('reduced', 'NegReg', (41, 48))	('SF3B1', 'Gene', (54, 59))	('CD44', 'Gene', (5, 9))	('SF3B1', 'Gene', '23451', (54, 59))	('knockdown', 'Var', (60, 69))	('CD24', 'Gene', '100133941', (11, 15))	('CD44', 'Gene', '960', (5, 9))
1864	29023197	By contrast, SF3B1 knockdown cells displayed elevated levels of CD24 compared with control luciferase siRNA transfected cells (Fig.	('CD24', 'Gene', '100133941', (64, 68))	('SF3B1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('CD24', 'Gene', (64, 68))	('SF3B1', 'Gene', '23451', (13, 18))	('elevated', 'PosReg', (45, 53))	('levels', 'MPA', (54, 60))
1865	29023197	Similar results were obtained upon knockdown of PRPF8 in these cells (Fig.	('knockdown', 'Var', (35, 44))	('PRPF8', 'Gene', '10594', (48, 53))	('PRPF8', 'Gene', (48, 53))
1866	29023197	Interestingly, SF3B1 or PRPF8 knockdown in MDA-MB-231 cell line, which represents mesenchymal stem like triple negative breast cancer, had no effect on CD44+/CD24- status (Fig.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('CD44', 'Gene', (152, 156))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('SF3B1', 'Gene', '23451', (15, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('CD24', 'Gene', '100133941', (158, 162))	('CD24', 'Gene', (158, 162))	('PRPF8', 'Gene', '10594', (24, 29))	('PRPF8', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (43, 53))	('SF3B1', 'Gene', (15, 20))	('CD44', 'Gene', '960', (152, 156))
1870	29023197	Consistent with this possibility, recent studies have demonstrated SF3B1 mutation (K700E) in breast cancer, preferentially in estrogen receptor positive breast cancer, to be a driver mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('SF3B1', 'Gene', '23451', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('K700E', 'Mutation', 'rs559063155', (83, 88))	('breast cancer', 'Disease', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('SF3B1', 'Gene', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('K700E', 'Var', (83, 88))	('breast cancer', 'Disease', (153, 166))
1874	29023197	Dysregulation of these proteins has been implicated in several disorders including cancer although the causes of such dysregulation is poorly understood.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
1876	29023197	Our computational analysis revealed that RBPs have an average of ~3 mutations per Mb across 26 cancers and enabled the identification of 281 RBPs to be enriched for mutations in at least one cancer type.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('RBP', 'Gene', (41, 44))	('cancer', 'Disease', (95, 101))	('cancers', 'Disease', (95, 102))	('RBP', 'Gene', '57794', (41, 44))	('RBP', 'Gene', (141, 144))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('RBP', 'Gene', '57794', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
1877	29023197	Among these, genes encoding for EPPK1, KMT2C, AHNAK and PLEC were found to be enriched for mutations in at least 10 cancers suggesting common players in mediating cancer phenotypes in different tissues.	('PLEC', 'Gene', '5339', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('EPPK1', 'Gene', '83481', (32, 37))	('PLEC', 'Gene', (56, 60))	('EPPK1', 'Gene', (32, 37))	('AHNAK', 'Gene', '79026', (46, 51))	('KMT2C', 'Gene', '58508', (39, 44))	('cancer', 'Disease', (116, 122))	('KMT2C', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('cancer', 'Disease', (163, 169))	('AHNAK', 'Gene', (46, 51))
1878	29023197	GC content and exome length were not found to play a major role in contributing to the mutational frequency of RBPs in majority of the studied cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutational', 'Var', (87, 97))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('RBP', 'Gene', (111, 114))	('RBP', 'Gene', '57794', (111, 114))
1881	29023197	Our analyses also revealed that RBPs enriched for mutations in atleast one cancer type were seen to be undergoing frequent Frameshift and Inframe deletions, missense, nonsense and silent mutations when compared to those that are not enriched, revealing the abundance of these variant types in mutated RBPs as significant contributor for malfunction in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (352, 358))	('cancer', 'Disease', (75, 81))	('atleast', 'Gene', (63, 70))	('RBP', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('RBP', 'Gene', (301, 304))	('RBP', 'Gene', '57794', (301, 304))	('missense', 'Var', (157, 165))	('RBP', 'Gene', '57794', (32, 35))
1885	29023197	We show that the presence of non-synonymous mutations correlate with change in the RNA levels of a significant fraction of driver RBPs (15% of the drivers), when cancer samples are grouped by the presence of mutations in an RBP irrespective of the cancer type.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('RBP', 'Gene', (130, 133))	('RBP', 'Gene', '57794', (130, 133))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('RBP', 'Gene', (224, 227))	('RBP', 'Gene', '57794', (224, 227))	('change', 'Reg', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('presence', 'Var', (17, 25))	('non-synonymous mutations', 'Var', (29, 53))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('RNA levels', 'MPA', (83, 93))
1888	29023197	Our knock down experiments indicated that deletion of either of these RBPs resulted in MCF7 cells, which are estrogen receptor positive, to exhibit reduced stem cell features.	('MCF7', 'CellLine', 'CVCL:0031', (87, 91))	('stem cell features', 'CPA', (156, 174))	('reduced', 'NegReg', (148, 155))	('RBP', 'Gene', (70, 73))	('RBP', 'Gene', '57794', (70, 73))	('MCF7', 'Gene', (87, 91))	('deletion', 'Var', (42, 50))
1896	29023197	This analysis should form a foundation to help us uncover the mutational spectrum of RBPs and their wiring dynamics in different cancer types thereby leading to dysregulation of post-transcriptional regulatory networks and also emphasizes the potential of various proteins of the splicesomal machinery as possible drug targets in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutational', 'Var', (62, 72))	('RBP', 'Gene', (85, 88))	('RBP', 'Gene', '57794', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('leading to', 'Reg', (150, 160))	('cancer', 'Disease', (129, 135))	('dysregulation', 'MPA', (161, 174))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('post-transcriptional', 'Pathway', (178, 198))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
1905	29023197	Genes with corrected p < 0.01 and odds ratio < 1 were classified as Genes Enriched in Mutations (GEMs) in a given cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Mutations', 'Var', (86, 95))	('cancer', 'Disease', (114, 120))
1907	29023197	We then obtained the mutation frequency of these genes in each cancer type for nine different variant classes viz - Inframe deletion, Inframe insertion, Frameshift deletion, Frameshift Insertion, Missense mutation, Nonsense mutation, Nonstop mutation, Silent and Splice Site mutations.	('Inframe insertion', 'Var', (134, 151))	('Frameshift deletion', 'Var', (153, 172))	('Nonsense mutation', 'Var', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Nonstop mutation', 'Var', (234, 250))	('Frameshift Insertion', 'Var', (174, 194))	('cancer', 'Disease', (63, 69))	('Missense mutation', 'Var', (196, 213))
1908	29023197	Variants were classified into the above mentioned categories based on the annotations provided in the downloaded MAF files.	('MAF', 'Gene', '4094', (113, 116))	('MAF', 'Gene', (113, 116))	('Variants', 'Var', (0, 8))
1910	29023197	Upon obtaining the mutation frequencies in each cancer type for all the variant classes, we pooled the mutational frequencies of RBPs enriched for mutations across the cancers into one bin named as GEM-RBPs (Fig.	('RBP', 'Gene', (129, 132))	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RBP', 'Gene', '57794', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('RBP', 'Gene', (202, 205))	('RBP', 'Gene', '57794', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Disease', (48, 54))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
1926	29023197	Further, genes were categorized as drivers - if they are predicted to be candidate drivers in at least two cancer types and the remaining RBPs are termed nondrivers.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RBP', 'Gene', (138, 141))	('RBP', 'Gene', '57794', (138, 141))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('genes', 'Var', (9, 14))	('cancer', 'Disease', (107, 113))
1937	29023197	Antibodies against SF3B1 (cat# 14434S, Cell Signaling), PRPF8 (Cat#Ab190347, Abcam), CD24 (Cat#555428, BD Biosciences) and CD44 (Cat#559942, BD Biosciences) were used as per instructions from manufacturers.	('Cat#Ab190347', 'Var', (63, 75))	('CD44', 'Gene', '960', (123, 127))	('SF3B1', 'Gene', '23451', (19, 24))	('cat# 14434S', 'Var', (26, 37))	('CD24', 'Gene', '100133941', (85, 89))	('CD44', 'Gene', (123, 127))	('CD24', 'Gene', (85, 89))	('PRPF8', 'Gene', (56, 61))	('PRPF8', 'Gene', '10594', (56, 61))	('SF3B1', 'Gene', (19, 24))
2040	27157039	The European Society of Urogenital Radiology guidelines recommend MRI in high and intermediate risk cancers, in suspected advanced disease and before lymph node sampling.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('MRI', 'Var', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
2101	27157039	Further, metastases from endometrial cancer rather than a second primary in the ovaries should be suspected in bilateral ovarian involvement in small size of the ovarian mass or in multinodularity of the ovaries.	('endometrial cancer', 'Disease', (25, 43))	('metastases', 'Disease', (9, 19))	('endometrial cancer', 'Disease', 'MESH:D016889', (25, 43))	('multinodularity', 'Var', (181, 196))	('ovaries', 'Disease', (204, 211))	('ovaries', 'Disease', 'MESH:D010051', (204, 211))	('metastases', 'Disease', 'MESH:D009362', (9, 19))	('ovaries', 'Disease', 'MESH:D010051', (80, 87))	('bilateral ovarian involvement', 'Disease', 'MESH:D010051', (111, 140))	('endometrial cancer', 'Phenotype', 'HP:0012114', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('bilateral ovarian involvement', 'Disease', (111, 140))	('ovaries', 'Disease', (80, 87))	('ovarian mass', 'Disease', (162, 174))	('ovarian mass', 'Disease', 'MESH:D010049', (162, 174))
2160	26793768	Immunohistochemically, the great majority of pPNET/ES demonstrate CD99 and FLI1 positivity, and cytogenetics demonstrate the characteristic t(11;22)(q24;q12) translocation and EWSR1/FLI1 gene fusion.	('FLI1', 'Gene', (182, 186))	('t(11;22)(q24;q12', 'Var', (140, 156))	('EWSR1', 'Gene', (176, 181))	('CD99', 'Gene', '4267', (66, 70))	('FLI1', 'Gene', '2313', (182, 186))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (140, 157))	('EWSR1', 'Gene', '2130', (176, 181))	('CD99', 'Gene', (66, 70))	('FLI1', 'Gene', (75, 79))	('FLI1', 'Gene', '2313', (75, 79))	('pPNET/ES', 'Gene', (45, 53))
2176	26793768	The presence of neoplastic endothelial proliferation and VEGF positivity within the tumor provides a rational explanation to the effectiveness of this novel chemotherapy modality against uterine cPNET.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('positivity', 'Var', (62, 72))	('uterine cPNET', 'Disease', (187, 200))	('tumor', 'Disease', (84, 89))	('VEGF', 'Gene', (57, 61))	('neoplastic endothelial proliferation', 'CPA', (16, 52))	('VEGF', 'Gene', '7422', (57, 61))
2186	25926074	Moreover, we identified the progesterone receptor (PR), a potent endometrial tumor suppressor, as a direct target of miR-888.	('PR', 'Gene', '5241', (51, 53))	('progesterone receptor', 'Gene', (28, 49))	('endometrial tumor', 'Disease', 'MESH:D016889', (65, 82))	('miR-888', 'Var', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('endometrial tumor', 'Disease', (65, 82))	('progesterone receptor', 'Gene', '5241', (28, 49))
2189	25926074	Because of their restricted expression in spermatogonia and the presence of a blood-testis barrier, expression of CT antigens in cancer often induces a tumor-directed immune response.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('induces', 'Reg', (142, 149))	('expression', 'Var', (100, 110))
2203	25926074	Our objective in this study was to determine whether miR-888 is a CT-X antigen and to understand its role in EC.	('miR-888', 'Var', (53, 60))	('EC', 'Phenotype', 'HP:0012114', (109, 111))	('CT-X', 'Gene', '1593', (66, 70))	('CT-X', 'Gene', (66, 70))
2204	25926074	MiR-888 is a primate-specific miRNA that evolved through gene translocation and duplication events on the X chromosome similar to other CT antigen genes.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('MiR-888', 'Gene', '100126306', (0, 7))	('duplication', 'Var', (80, 91))	('MiR-888', 'Gene', (0, 7))
2206	25926074	In addition, we describe a novel mechanism of PR inhibition in EC through miR-888.	('PR', 'Gene', '5241', (46, 48))	('EC', 'Phenotype', 'HP:0012114', (63, 65))	('inhibition', 'NegReg', (49, 59))	('miR-888', 'Var', (74, 81))
2260	25926074	UCEC tumors that had positive expression of miR-888 were substantially more likely to be grade 3 tumors than UCEC tumors with undetectable miR-888 levels (Table 1, P = .001).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('grade', 'Disease', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('positive expression', 'Var', (21, 40))	('tumors', 'Disease', (97, 103))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('EC', 'Phenotype', 'HP:0012114', (111, 113))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('EC', 'Phenotype', 'HP:0012114', (2, 4))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('miR-888', 'Var', (44, 51))
2267	25926074	Thus, these data suggest that miR-888 is associated with an aggressive tumor phenotype.	('associated', 'Reg', (41, 51))	('aggressive tumor', 'Disease', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('aggressive tumor', 'Disease', 'MESH:D001523', (60, 76))	('miR-888', 'Var', (30, 37))
2285	25926074	To investigate the role of miR-888 regulation of PR, we chose to use the ECC-1 and Ishikawa EC cells because they had a low level of miR-888 expression (Figure S1) and are positive for PR expression .	('EC', 'Phenotype', 'HP:0012114', (92, 94))	('miR-888', 'Var', (133, 140))	('PR', 'Gene', '5241', (49, 51))	('EC', 'Phenotype', 'HP:0012114', (73, 75))	('expression', 'MPA', (141, 151))	('PR', 'Gene', '5241', (185, 187))
2290	25926074	Western blots were quantified by densitometry using ImageJ software, and a significant decrease in PR protein was observed with miR-888 transfection, but not EV transfection, relative to the mock-transfected controls in the ECC-1 (Figure 6D) and Ishikawa (Figure 6E) cell lines.	('transfection', 'Var', (136, 148))	('EC', 'Phenotype', 'HP:0012114', (224, 226))	('decrease', 'NegReg', (87, 95))	('EV', 'Chemical', '-', (158, 160))	('PR', 'Gene', '5241', (99, 101))	('miR-888', 'Gene', (128, 135))
2315	25926074	In a panel of eight different types of tumors, miR-888 was most predominantly expressed in EC.	('tumors', 'Disease', (39, 45))	('miR-888', 'Var', (47, 54))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('EC', 'Phenotype', 'HP:0012114', (91, 93))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
2326	25926074	The miR-888-dependent decrease in PR protein expression and 3'UTR luciferase reporter activity that we report here was relatively modest.	('activity', 'MPA', (86, 94))	('miR-888-dependent', 'Var', (4, 21))	('decrease', 'NegReg', (22, 30))	('PR', 'Gene', '5241', (34, 36))
2330	25926074	performed protein arrays after knockout of miR-223 and found that a large number of targets were only reduced by about 30%.	('miR-223', 'Gene', (43, 50))	('miR-223', 'Gene', '407008', (43, 50))	('knockout', 'Var', (31, 39))
2466	22247805	Normal or reactive lymph nodes and bowel mucosa are also hyperintense on DWI of the female pelvic cavity.	('hyperintense', 'PosReg', (57, 69))	('bowel mucosa', 'Disease', 'MESH:D015212', (35, 47))	('bowel mucosa', 'Disease', (35, 47))	('DWI', 'Var', (73, 76))
2631	21876648	It has been reported that tamoxifen induces endometrial K-ras oncogene codon 12 mutations, which are considered important in endometrial carcinogenesis.	('K-ras', 'Gene', (56, 61))	('K-ras', 'Gene', '3845', (56, 61))	('mutations', 'Var', (80, 89))	('tamoxifen', 'Chemical', 'MESH:D013629', (26, 35))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (125, 151))	('endometrial carcinogenesis', 'Disease', (125, 151))
2635	21876648	dG-N2-tamoxifen adducts display a high miscoding and mutagenic potential and generate primarily G- to T-transversions in mammalian cells.	('mammalian', 'Species', '9606', (121, 130))	('miscoding', 'MPA', (39, 48))	('dG-N2-tamoxifen', 'Chemical', '-', (0, 15))	('mutagenic potential', 'CPA', (53, 72))	('adducts', 'Var', (16, 23))
2636	21876648	Such tamoxifen adducts, if not repaired, may cause mutations, leading to the development of endometrial cancers.	('mutations', 'Var', (51, 60))	('endometrial cancers', 'Disease', 'MESH:D016889', (92, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('endometrial cancers', 'Disease', (92, 111))	('cause', 'Reg', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('endometrial cancer', 'Phenotype', 'HP:0012114', (92, 110))	('tamoxifen', 'Chemical', 'MESH:D013629', (5, 14))
2708	21876648	The annual rate was 3.05 malignancies per 1,000 women treated with tamoxifen versus 0.76 malignancies per 1,000 women receiving placebo.	('tamoxifen', 'Var', (67, 76))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('malignancies', 'Disease', 'MESH:D009369', (25, 37))	('tamoxifen', 'Chemical', 'MESH:D013629', (67, 76))	('women', 'Species', '9606', (112, 117))	('malignancies', 'Disease', (89, 101))	('malignancies', 'Disease', (25, 37))	('women', 'Species', '9606', (48, 53))
2711	21876648	Most studies have found that the increased relative risk of developing endometrial cancer for women taking tamoxifen is two to four times higher than that of an age-matched population (.	('women', 'Species', '9606', (94, 99))	('endometrial cancer', 'Phenotype', 'HP:0012114', (71, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('endometrial cancer', 'Disease', (71, 89))	('tamoxifen', 'Chemical', 'MESH:D013629', (107, 116))	('endometrial cancer', 'Disease', 'MESH:D016889', (71, 89))	('tamoxifen', 'Var', (107, 116))
2714	21876648	In a more recent update of NSABP trials of patients with breast cancer, the rate of endometrial cancer was 1.26 per 1,000 patient years in women treated with tamoxifen versus 0.58 per 1,000 in the placebo group.	('breast cancer', 'Disease', (57, 70))	('women', 'Species', '9606', (139, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('patient', 'Species', '9606', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (43, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (158, 167))	('patient', 'Species', '9606', (122, 129))	('endometrial cancer', 'Disease', (84, 102))	('tamoxifen', 'Var', (158, 167))	('endometrial cancer', 'Phenotype', 'HP:0012114', (84, 102))	('endometrial cancer', 'Disease', 'MESH:D016889', (84, 102))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
2721	21876648	reported that 67% of the corpus cancers that developed in 15 tamoxifen-treated breast cancer patients were high-grade or unfavorable histologic subtypes, compared with 24% of those that developed in 38 breast cancer patients who had not received tamoxifen.	('corpus cancers', 'Disease', 'MESH:D009369', (25, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('patients', 'Species', '9606', (93, 101))	('tamoxifen', 'Chemical', 'MESH:D013629', (61, 70))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('tamoxifen', 'Chemical', 'MESH:D013629', (246, 255))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Disease', (202, 215))	('patients', 'Species', '9606', (216, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('corpus cancers', 'Disease', (25, 39))	('tamoxifen-treated', 'Var', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
2732	21876648	Oncogene changes, such as K-ras mutation, c-erbB2/neu gene amplification, and cyclin D1 and p53 overexpression have also been observed in tamoxifen-related endometrial cancers.	('endometrial cancers', 'Disease', 'MESH:D016889', (156, 175))	('neu', 'Gene', '2064', (50, 53))	('c-erbB2', 'Gene', '2064', (42, 49))	('c-erbB2', 'Gene', (42, 49))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('K-ras', 'Gene', '3845', (26, 31))	('amplification', 'Var', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('observed', 'Reg', (126, 134))	('cyclin D1', 'Gene', (78, 87))	('endometrial cancer', 'Phenotype', 'HP:0012114', (156, 174))	('cyclin D1', 'Gene', '595', (78, 87))	('neu', 'Gene', (50, 53))	('K-ras', 'Gene', (26, 31))	('tamoxifen', 'Chemical', 'MESH:D013629', (138, 147))	('overexpression', 'PosReg', (96, 110))	('p53', 'Gene', '7157', (92, 95))	('p53', 'Gene', (92, 95))	('endometrial cancers', 'Disease', (156, 175))
2751	21876648	Similarly, in a separate trial of high-risk women without breast cancer taking tamoxifen as part of a breast cancer prevention trial with a median follow-up of 6.9 years, there were 4 sarcomas (17 per 100,000 patient years) in the tamoxifen group versus none in the placebo group.	('breast cancer', 'Disease', (102, 115))	('patient', 'Species', '9606', (209, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('sarcomas', 'Disease', 'MESH:D012509', (184, 192))	('women', 'Species', '9606', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (184, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('tamoxifen', 'Chemical', 'MESH:D013629', (79, 88))	('sarcomas', 'Disease', (184, 192))	('tamoxifen', 'Chemical', 'MESH:D013629', (231, 240))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('tamoxifen', 'Var', (231, 240))
2859	33889702	Additionally, our tumor was diffusely positive for p53, consistent with a TP53 mutation.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('tumor', 'Disease', (18, 23))	('positive', 'Reg', (38, 46))	('TP53', 'Gene', '7157', (74, 78))	('mutation', 'Var', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('TP53', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
2864	33889702	The suggested mechanisms of extra-gonadal YST histogenesis include: (1) misplaced or arrested migration of germ cells during embryogenesis, (2) reverse migration of germ cells, (3) aberrant or retro-differentiation of somatic tumor cells to more primitive ones, (4) specialized differentiation from a somatic carcinoma, (5) arising from residual fetal tissue following incomplete abortion, and (6) metastasis from an occult primary germ cell tumor of the gonad.	('carcinoma', 'Disease', (309, 318))	('tumor', 'Disease', 'MESH:D009369', (442, 447))	('aberrant', 'Var', (181, 189))	('incomplete abortion', 'Phenotype', 'HP:0005268', (369, 388))	('germ cell tumor', 'Phenotype', 'HP:0100728', (432, 447))	('tumor', 'Phenotype', 'HP:0002664', (442, 447))	('specialized differentiation', 'CPA', (266, 293))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('carcinoma', 'Disease', 'MESH:D009369', (309, 318))	('tumor', 'Disease', (442, 447))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('metastasis', 'CPA', (398, 408))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('tumor', 'Disease', (226, 231))
2867	33889702	Although no adjacent coexisting conventional endometrial carcinoma was identified in our case, the YST had evidence of a mutated TP53 gene which is more consistent with a high-grade endometrial carcinoma than with a germ cell tumor.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (182, 203))	('endometrial carcinoma', 'Disease', (45, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('germ cell tumor', 'Phenotype', 'HP:0100728', (216, 231))	('mutated', 'Var', (121, 128))	('endometrial carcinoma', 'Disease', (182, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('TP53', 'Gene', '7157', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (45, 66))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (182, 203))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('TP53', 'Gene', (129, 133))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (45, 66))	('tumor', 'Disease', (226, 231))
2884	33300026	It is estimated that ~70 000 lesions occur in genomic DNA in each human cell per day, most of which (75%) originate from oxidation reactions with endogenous byproducts of metabolism and base hydrolysis.	('human', 'Species', '9606', (66, 71))	('lesions', 'Var', (29, 36))	('originate from', 'Reg', (106, 120))
2885	33300026	To counteract the continuous threat these lesions pose to genome stability, cells have evolved a wide-ranging arsenal of repair programs, including DNA base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), translesion synthesis (TLS) and strand break repair (homologous recombination and various non-homologous end joining pathways), which together act upon particular types of lesion or at specific phases of the cell cycle to prevent mutations in DNA and cell death.	('mutations', 'Var', (467, 476))	('death', 'Disease', 'MESH:D003643', (493, 498))	('death', 'Disease', (493, 498))	('DNA', 'Gene', (480, 483))
2889	33300026	Indeed, despite the fact that replication-associated mutations have been linked to high frequencies of single base-pair substitutions (SBSs) in human cancers, mutational landscapes in cancer genomes are highly heterogeneous.	('cancer', 'Disease', (184, 190))	('human', 'Species', '9606', (144, 149))	('single base-pair substitutions', 'Var', (103, 133))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('replication-associated', 'Disease', (30, 52))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
2893	33300026	We showed that NEIL1 becomes stabilized on chromatin after site-specific (Lys296-298) acetylation, and accumulates almost exclusively at highly transcribed genomic regions as well as the transcription start sites (TSS) of weakly expressed genes, some of which are associated with poor prognosis when overexpressed in cancer.	('acetylation', 'Var', (86, 97))	('NEIL1', 'Gene', (15, 20))	('accumulates', 'PosReg', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('Lys296-298) acetylation', 'Var', (74, 97))	('Lys296', 'Chemical', '-', (74, 80))	('acetyl', 'Chemical', '-', (86, 92))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
2894	33300026	Bioinformatic analyses using cancer genome datasets and human germline population mutation datasets provide, with unprecedented resolution, information on the relationship between local variations in single base substitution (SBS) rates and ChIP-seq AcNEIL1 occupancy, both in cancer genomes and the germline.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('human', 'Species', '9606', (56, 61))	('variations', 'Var', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
2958	33300026	For XRCC1, we downloaded the original fastq file from the GEO (https://www.ncbi.nlm.nih.gov/geo/) repository (GSE95302, file SRR5282040) and processed it according to the pipeline we used here.	('GSE95302', 'Var', (110, 118))	('XRCC1', 'Gene', (4, 9))	('XRCC1', 'Gene', '7515', (4, 9))
2960	33300026	The file for OGG1 was GSM2357433_CP-Sample_Flag-OGG1-Con-2.tdf from the GEO record GSM2357433; the file was first converted to a bedGraph format using the 'igvtools tdftobedgraph'and then to bigWig.	('OGG1', 'Gene', '4968', (48, 52))	('GSM2357433', 'Var', (83, 93))	('OGG1', 'Gene', (13, 17))	('OGG1', 'Gene', '4968', (13, 17))	('OGG1', 'Gene', (48, 52))
2967	33300026	To this end we divided patients with each tumor type into two groups: group 1, with expression of gene x above the mean; and group 2, with expression of gene x below or at the mean value.	('tumor', 'Disease', (42, 47))	('patients', 'Species', '9606', (23, 31))	('gene x', 'Var', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('expression', 'MPA', (84, 94))	('below', 'NegReg', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
2980	33300026	We recently showed that p300 acetylates NEIL1 (herein referred to as AcNEIL1) at residues Lys296, Lys297 and Lys298, which serves to increase DG activity and stabilize the enzyme on chromatin-bound complexes.	('Lys298', 'Var', (109, 115))	('Lys297', 'Chemical', '-', (98, 104))	('Lys296', 'Var', (90, 96))	('p300', 'Gene', (24, 28))	('Lys296', 'Chemical', '-', (90, 96))	('NEIL1', 'Gene', (40, 45))	('DG activity', 'MPA', (142, 153))	('Lys297', 'Var', (98, 104))	('p300', 'Gene', '2033', (24, 28))	('increase', 'PosReg', (133, 141))	('Lys298', 'Chemical', '-', (109, 115))	('acetyl', 'Chemical', '-', (29, 35))	('stabilize', 'MPA', (158, 167))
2983	33300026	STED of human colorectal adenocarcinoma HCT116 cells labeled with anti-AcNEIL1 or anti-total-NEIL1 antibodies showed strong AcNEIL1 nuclear localization, as opposed to diffuse staining in nuclei and cytoplasm for non-acetylated NEIL1.	('anti-total-NEIL1', 'Var', (82, 98))	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('AcNEIL1', 'Gene', (124, 131))	('colorectal adenocarcinoma', 'Disease', (14, 39))	('nuclear localization', 'MPA', (132, 152))	('acetyl', 'Chemical', '-', (217, 223))	('anti-AcNEIL1', 'Var', (66, 78))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (14, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('human', 'Species', '9606', (8, 13))	('TE', 'Chemical', 'MESH:D013691', (1, 3))
2993	33300026	H3K27Ac (Figure 1Dii) colocalized with AcNEIL1 on condensed chromosomes to a greater extent than total histone H3 (Figure 1Diii) and, likewise, AcNEIL1 yielded stronger fluorescent signal than total NEIL1 in nuclei (Supplementary Figure S2A, green trace).	('H3K27Ac', 'Protein', (0, 7))	('H3K27Ac', 'Chemical', '-', (0, 7))	('AcNEIL1', 'Var', (144, 151))	('fluorescent signal', 'MPA', (169, 187))	('stronger', 'PosReg', (160, 168))
3042	33300026	We therefore analyzed ~25.4 million SBSs specific to tumor samples, including 5.6 million coding region mutations and 19.8 million non-coding variants.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
3043	33300026	We conclude that transcription is an intrinsically mutagenic process, and that chromatin-bound AcNEIL1 is the active DG form of NElL1 in the context of BERosomes, which is responsible for the repair of oxidative DNA damage and the prevention of base-pair change accumulations, particularly transversion mutations at A:T base pairs.	('transversion mutations', 'Var', (290, 312))	('NElL1', 'Gene', (128, 133))	('NElL1', 'Gene', '4745', (128, 133))
3044	33300026	After establishing that the local variations in mutation rates observed in cancer genomes coincide with segmental AcNEIL1 occupancy, we next addressed whether similar patterns exist for genetic variations between populations.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
3045	33300026	We selected SweGen, a database of single nucleotide polymorphisms (SNPs) in the Swedish population, which is comparable in size (~23 million SNPs) to the cancer dataset.	('single nucleotide polymorphisms', 'Var', (34, 65))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))
3046	33300026	No qualitative differences were observed in the genome-wide distribution of SNPs as a function of AcNEIL1 ICS compared with those observed for cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SNPs', 'Disease', (76, 80))	('AcNEIL1 ICS', 'Var', (98, 109))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
3047	33300026	Quantitatively, the frequency of incurring base changes at low AcNEIL1 (<500 000 ICS) was greater in cancer than in the germline, particularly for A>T and A>C transversions (Supplementary Figure S9C).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('A>C transversions', 'Var', (155, 172))	('A>T', 'Var', (147, 150))	('cancer', 'Disease', (101, 107))	('base changes', 'MPA', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
3048	33300026	We surveyed the Human Gene Mutation Database (HGMD) to assess the frequency of variants at G4 DNA motifs in 5'-UTRs known to cause or predispose toward inherited disease.	('G4 DNA', 'Gene', (91, 97))	('variants', 'Var', (79, 87))	('inherited disease', 'Disease', (152, 169))	('cause', 'Reg', (125, 130))	('Human', 'Species', '9606', (16, 21))	('inherited disease', 'Disease', 'MESH:D030342', (152, 169))
3053	33300026	The AcNEIL1 acetyl acceptors, Lys296, Lys297 and Lys298, are embedded within an intrinsically unstructured carboxyl-terminal (C-ter) domain (Supplementary Figure S10B), whose disordered nature has been well-conserved (Supplementary Figure S10B-D) despite the high degree of ordered protein folds expected among thermophilic lifeforms.	('acetyl', 'Chemical', '-', (12, 18))	('Lys297', 'Chemical', '-', (38, 44))	('Lys298', 'Chemical', '-', (49, 55))	('S10B', 'SUBSTITUTION', 'None', (162, 166))	('S10B', 'Var', (239, 243))	('Lys298', 'Var', (49, 55))	('Lys297', 'Var', (38, 44))	('Lys296', 'Var', (30, 36))	('S10B', 'SUBSTITUTION', 'None', (239, 243))	('Lys296', 'Chemical', '-', (30, 36))	('S10B', 'Var', (162, 166))
3059	33300026	The observed loading and stabilization of AcNEIL1 on chromatin is critically dependent upon PTM at three consecutive lysine residues (Lys297-299), an acetylation center that appears to be the result of consolidation among variable amino acids in protostomes, probably occurring during the Cambrian explosion, ~540 million years ago, during a transition from sulfur to oxygen as an energy source.	('AcNEIL1', 'Gene', (42, 49))	('acetyl', 'Chemical', '-', (150, 156))	('oxygen', 'Chemical', 'MESH:D010100', (368, 374))	('Lys297-299', 'Var', (134, 144))	('sulfur', 'Chemical', 'MESH:D013455', (358, 364))	('Lys297', 'Chemical', '-', (134, 140))	('lysine', 'Chemical', 'MESH:D008239', (117, 123))
3061	33300026	C>T (G>A) substitutions occur frequently at methylated CpG dinucleotides, particularly in single-stranded DNA where deamination of 5-methylcytosine to thymine, which produces G:T mismatches resulting in mutations (i.e.	('C>T (G>A', 'Gene', (0, 8))	('G:T mismatches', 'Var', (175, 189))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (131, 147))	('thymine', 'Chemical', 'MESH:D013941', (151, 158))	('mismatches', 'Var', (179, 189))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (55, 72))	('mutations', 'Var', (203, 212))	('substitutions', 'Var', (10, 23))
3063	33300026	C>T transitions also arise from stable cytosine oxidation products, such as 5-hydroxycytosine.	('5-hydroxycytosine', 'Chemical', 'MESH:C017400', (76, 93))	('cytosine oxidation', 'MPA', (39, 57))	('5-hydroxycytosine', 'MPA', (76, 93))	('C>T', 'Var', (0, 3))	('cytosine', 'Chemical', 'MESH:D003596', (39, 47))	('cytosine', 'Chemical', 'MESH:D003596', (85, 93))	('arise', 'Reg', (21, 26))
3069	33300026	Regarding transcription-associated mutagenesis, the tumor suppressor TP53, the most commonly mutated gene associated with cancer, strikingly resides within the most highly transcribed 1-Mb domain in the human genome, raising the intriguing possibility that susceptibility to human cancer may stem, in part, from intrinsic genome architecture.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutagenesis', 'Var', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('human', 'Species', '9606', (203, 208))	('tumor', 'Disease', (52, 57))	('TP53', 'Gene', (69, 73))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('human', 'Species', '9606', (275, 280))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
3071	33300026	Studies on the mutagenic potential of formamidopyrimidines have suggested that direct base misincorporation can generate both transition and transversion mutations.	('transversion mutations', 'CPA', (141, 163))	('misincorporation', 'Var', (91, 107))	('formamidopyrimidines', 'Chemical', '-', (38, 58))	('transition', 'MPA', (126, 136))
3072	33300026	TG blocks DNA replication and its bypass, aided by translesion synthesis polymerases, can yield mutations when Poltheta is utilized.	('yield', 'Reg', (90, 95))	('TG', 'Chemical', 'MESH:C029389', (0, 2))	('DNA replication', 'CPA', (10, 25))	('mutations', 'Var', (96, 105))
3077	33300026	Our analysis that Hox overexpression, and especially AcNEIL1-containing Hox gene reactivation in low grade glioma, contributes to poor survival strengthens the growing support for their key role in tumorigenesis.	('Hox', 'Gene', '42536', (72, 75))	('Hox', 'Gene', (72, 75))	('overexpression', 'PosReg', (22, 36))	('survival', 'MPA', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('poor', 'NegReg', (130, 134))	('reactivation', 'Var', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Hox', 'Gene', (18, 21))	('tumor', 'Disease', (198, 203))	('glioma', 'Disease', (107, 113))	('Hox', 'Gene', '42536', (18, 21))
3078	33300026	Neil1-/- (or Neil2-/-) mouse embryoid bodies display neural defects, the downregulation of key developmental genes, including Hox genes, elevated levels of reactive oxygen species (ROS) and a pro-apoptotic TP53-associated DNA damage response.	('neural defects', 'CPA', (53, 67))	('pro-apoptotic', 'PosReg', (192, 205))	('Neil2', 'Gene', (13, 18))	('Neil1-/-', 'Var', (0, 8))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (156, 179))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('elevated', 'PosReg', (137, 145))	('TP53-associated', 'CPA', (206, 221))	('mouse', 'Species', '10090', (23, 28))	('levels of reactive oxygen species', 'MPA', (146, 179))	('elevated levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (137, 179))	('Hox', 'Gene', '42536', (126, 129))	('downregulation', 'NegReg', (73, 87))	('Neil2', 'Gene', '382913', (13, 18))	('Hox', 'Gene', (126, 129))
3081	33300026	The altered expression and mutations associated with polycomb complexes have also been linked to cancer, and it will be of interest to determine the extent to which escape from NEIL1 damage repair beyond the early developmental stages may contribute to tumorigenesis.	('mutations', 'Var', (27, 36))	('NEIL1', 'Gene', (177, 182))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('contribute', 'Reg', (239, 249))	('linked', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (253, 258))	('expression', 'MPA', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
3092	33067881	The panoramic picture of pepsinogen gene family with pan-cancer The panoramic picture of pepsinogen gene family with pan-cancer It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers.	('correlation', 'Reg', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('related', 'Reg', (364, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('PGs', 'Chemical', 'MESH:D010715', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGs', 'Chemical', 'MESH:D010715', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('gastric cancer', 'Disease', (297, 311))	('ectopic', 'Var', (338, 345))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('cancer', 'Disease', (305, 311))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Disease', (121, 127))
3094	33067881	This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.	('human', 'Species', '9606', (175, 180))	('copy number variation', 'Var', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PGs', 'Chemical', 'MESH:D010715', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('PGs', 'Gene', (143, 146))	('cancer', 'Disease', (181, 187))
3095	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('CCLE', 'Chemical', '-', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('Oncomine', 'Chemical', '-', (54, 62))	('tumor', 'Disease', (134, 139))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('PGs', 'Gene', (255, 258))	('cancers', 'Disease', (394, 401))	('cancer', 'Disease', (394, 400))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (286, 292))
3100	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('PGC', 'Gene', (120, 123))	('signal transduction pathways', 'Pathway', (81, 109))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('inhibition', 'NegReg', (62, 72))	('PGC', 'Gene', '5225', (120, 123))	('PGs', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
3106	33067881	Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (180, 185))	('PGC', 'Gene', '5225', (39, 42))	('mutated', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('copy number amplification', 'MPA', (143, 168))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (80, 128))	('PGC', 'Gene', (39, 42))
3107	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', (0, 3))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
3111	33067881	The variation of copy number of PGC gene could affect the PGC expression.	('PGC', 'Gene', (58, 61))	('variation', 'Var', (4, 13))	('copy number', 'Var', (17, 28))	('expression', 'MPA', (62, 72))	('PGC', 'Gene', '5225', (32, 35))	('PGC', 'Gene', (32, 35))	('affect', 'Reg', (47, 53))	('PGC', 'Gene', '5225', (58, 61))
3113	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancer', 'Disease', (268, 274))	('cancers', 'Disease', (375, 382))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('tumor', 'Disease', (123, 128))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('copy number variation', 'Var', (212, 233))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('PGs', 'Gene', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', (375, 381))	('CCLE', 'Chemical', '-', (57, 61))
3133	33067881	In this study, by using the multilevel data from TCGA based Pan-Cancer Atlas, Oncomine and Cancer Cell Line Encyclopedia (CCLE), we focused on the elucidating expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their prediction/diagnosis/prognosis potential in pan-cancer.	('Cancer', 'Disease', (91, 97))	('Cancer', 'Disease', (64, 70))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('-cancer', 'Disease', 'MESH:D009369', (325, 332))	('-cancer', 'Disease', (325, 332))	('Oncomine', 'Chemical', '-', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (264, 267))	('copy number variation', 'Var', (239, 260))	('PGs', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
3134	33067881	We totally collected the information of 33 different kinds of tumors in TCGA database (http://cancergenome.nih.gov/), including the information of TPM (Transcripts Per Kilobase Million) expression, mutation, and copy number variation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('copy number variation', 'Var', (212, 233))	('TPM', 'Gene', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (198, 206))
3139	33067881	CCLE database(https://portals.broadinstitute.org/ccle)was used to identify the PGs expression, mutation, and copy number variation in different cancer cell lines, including all 431 cell lines from six cancer types.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('CCLE', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('PGs', 'Chemical', 'MESH:D010715', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PGs', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (95, 103))
3152	33067881	The frequency of CNV in each cancer type and cell lines was calculated as the proportion of CNV amplification and deletion.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (114, 122))
3164	33067881	The results showed that in stomach adenocarcinoma and lung squamous cell carcinoma, high expression of PG is a protective factor, and high expression can reduce the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('reduce', 'NegReg', (154, 160))	('high expression', 'Var', (134, 149))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (27, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('stomach adenocarcinoma', 'Disease', (27, 49))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))
3175	33067881	The results show that PGs expression was significantly related to the activation or inhibition of many carcinogenic pathways (Figure 7A), in which PGC and PGA5 are more likely to be associated with carcinogenic processes.	('PGC', 'Gene', (147, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (198, 210))	('associated', 'Reg', (182, 192))	('inhibition', 'NegReg', (84, 94))	('carcinogenic', 'Disease', (198, 210))	('expression', 'Var', (26, 36))	('PGA5', 'Gene', (155, 159))	('PGs', 'Gene', (22, 25))	('PGA5', 'Gene', '5222', (155, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (103, 115))	('carcinogenic', 'Disease', (103, 115))	('activation', 'PosReg', (70, 80))	('related', 'Reg', (55, 62))	('PGs', 'Chemical', 'MESH:D010715', (22, 25))	('PGC', 'Gene', '5225', (147, 150))
3199	33067881	The results showed that PGC gene mutations frequently occurred in uterine corpus endometrial carcinoma and stomach adenocarcinoma (Figure 10A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PGC', 'Gene', '5225', (24, 27))	('PGC', 'Gene', (24, 27))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (81, 129))	('mutations', 'Var', (33, 42))	('occurred', 'Reg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))
3202	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('PGA5', 'Gene', '5222', (16, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA4', 'Gene', (6, 10))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
3203	33067881	In addition, CCLE database analysis revealed the mutation status of PGs in different human cancer cell lines, which showed that there were frequent mutations of PGs in colorectal cancer and gastric cancer cell lines (Figure 11).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('PGs', 'Chemical', 'MESH:D010715', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PGs', 'Gene', (161, 164))	('CCLE', 'Chemical', '-', (13, 17))	('mutations', 'Var', (148, 157))	('PGs', 'Chemical', 'MESH:D010715', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('human', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (179, 185))	('gastric cancer', 'Disease', (190, 204))
3204	33067881	In order to explore whether PGC self-variation affects its expression, we analyzed the correlation between PGs mutation, CNV, and PGs expression.	('PGs', 'Gene', (107, 110))	('PGC', 'Gene', '5225', (28, 31))	('PGC', 'Gene', (28, 31))	('PGs', 'Chemical', 'MESH:D010715', (130, 133))	('expression', 'MPA', (59, 69))	('PGs', 'Chemical', 'MESH:D010715', (107, 110))	('mutation', 'Var', (111, 119))
3205	33067881	The results showed that PGs mutations did not affect the PGs expression in all cancers.	('cancers', 'Disease', (79, 86))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PGs', 'Chemical', 'MESH:D010715', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('mutations', 'Var', (28, 37))	('PGs', 'Gene', (24, 27))
3208	33067881	In this study, we used the multilevel data of TCGA, Oncomine, and CCLE to reveal the expression and activated pathways, mutation, and copy number variation, prognostic potential of PGs in all 33 types of tumors and 431 cell lines, aiming to clarify the important role of PGs in tumorigenesis and development of cancers.	('Oncomine', 'Chemical', '-', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number variation', 'Var', (134, 155))	('tumor', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('CCLE', 'Chemical', '-', (66, 70))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('tumor', 'Disease', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (181, 184))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
3209	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('PGC', 'Gene', (328, 331))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('affect', 'Reg', (338, 344))	('immune cell infiltration', 'CPA', (273, 297))	('cancer', 'Disease', (245, 251))	('PGs', 'Chemical', 'MESH:D010715', (62, 65))	('copy number variation', 'Var', (303, 324))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PGC', 'Gene', '5225', (328, 331))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('associated', 'Reg', (211, 221))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
3228	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
3230	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
3251	33067881	The results showed that the overall average mutation rate of PGs was 0%-5.3%, and the mutation rate of PGC was higher in stomach adenocarcinoma and endometrial carcinoma.	('higher', 'Reg', (111, 117))	('PGC', 'Gene', '5225', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PGs', 'Chemical', 'MESH:D010715', (61, 64))	('PGC', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('mutation', 'Var', (86, 94))	('stomach adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 169))
3252	33067881	It is worth noticed that all PGC, PGA3, and PGA5 genes had a certain degree of mutation in endometrial carcinoma, which is a tumor with high global mutation rate.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PGA3', 'Gene', (34, 38))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('PGA3', 'Chemical', '-', (34, 38))	('PGA5', 'Gene', (44, 48))	('mutation', 'Var', (79, 87))	('PGC', 'Gene', '5225', (29, 32))	('PGC', 'Gene', (29, 32))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PGA5', 'Gene', '5222', (44, 48))
3253	33067881	31  In addition, CCLE-based analysis of human cancer cell lines showed that most of the PGs mutations were found in colorectal adenocarcinoma and stomach adenocarcinoma cell lines, suggesting PGs mutation may be the key events in tumorigenesis and development of both gastric cancer and colorectal adenocarcinoma.	('CCLE', 'Chemical', '-', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('gastric cancer', 'Disease', (268, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (192, 195))	('mutations', 'Var', (92, 101))	('PGs', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (88, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('colorectal adenocarcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D000230', (116, 168))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('found', 'Reg', (107, 112))	('colorectal adenocarcinoma', 'Disease', (287, 312))
3254	33067881	In this study, we also found that there was extensive copy number amplification in various tumor types, which may be related to its widespread expression in various tissues.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy number amplification', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
3256	33067881	The results showed that there was no correlation between PGs mutation and PGs expression in cancer cells.	('PGs', 'Chemical', 'MESH:D010715', (74, 77))	('cancer', 'Disease', (92, 98))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (61, 69))	('PGs', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
3257	33067881	However, previous studies in our lab have found that PGC gene insertion-deletion fragment polymorphism and single nucleotide polymorphism from human germline cells can affect PGC expression.	('PGC', 'Gene', (175, 178))	('human', 'Species', '9606', (143, 148))	('expression', 'MPA', (179, 189))	('insertion-deletion fragment polymorphism', 'Var', (62, 102))	('single nucleotide polymorphism', 'Var', (107, 137))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (175, 178))
3259	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
3311	29044542	Women who received the combination of carboplatin/paclitaxel for neoadjuvant chemotherapy had a statistically significantly improved survival compared to those who did not receive this regimen: PFS, median time 8.6 versus 6.6 months, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, 36.0 versus 9.1 months, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002.	('Women', 'Species', '9606', (0, 5))	('carboplatin/paclitaxel', 'Var', (38, 60))	('carboplatin', 'Chemical', 'MESH:D016190', (38, 49))	('improved', 'PosReg', (124, 132))	('survival', 'MPA', (133, 141))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))
3378	32377091	When we consider the relationship between omental micrometastasis and adnexal metastasis, we found that the rates of micrometastasis in omentum were higher in patients with adnexal metastasis, but the difference was not significant (%5 and %13, p=0.223) (Table 3).	('adnexal', 'Disease', (173, 180))	('omental micrometastasis', 'Disease', (42, 65))	('omental micrometastasis', 'Disease', 'MESH:D061206', (42, 65))	('micrometastasis', 'Var', (117, 132))	('higher', 'PosReg', (149, 155))	('patients', 'Species', '9606', (159, 167))
3396	31977292	The SWI/SNF complex mutations in gynecologic cancers: molecular mechanisms and models The SWI/SNF (Mating Type SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression.	('gene expression', 'MPA', (267, 282))	('chromatin structure', 'MPA', (235, 254))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('control', 'Reg', (259, 266))	('SWI/SNF', 'Gene', (90, 97))	('modulate', 'Reg', (226, 234))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('interact', 'Interaction', (174, 182))	('Sucrose', 'Chemical', 'MESH:D013395', (118, 125))	('cancers', 'Disease', (45, 52))	('mutations', 'Var', (20, 29))
3397	31977292	Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
3398	31977292	These SWI/SNF mutations occur at different stages of tumour development and are restricted to unique histologic types of gynecologic cancer.	('SWI/SNF', 'Gene', (6, 13))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('occur', 'Reg', (24, 29))	('tumour', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
3399	31977292	Thus, the SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression.	('promote', 'PosReg', (91, 98))	('SWI/SNF', 'Gene', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('progression', 'CPA', (133, 144))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (18, 27))
3400	31977292	In this review, we will summarize the current knowledge of SWI/SNF mutations in gynecologic cancer development to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.	('SWI/SNF', 'Gene', (59, 66))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
3405	31977292	In addition to finding common well-studied tumor suppressors and oncogenes, genomic analysis of gynecologic cancers has identified frequent mutations of genes encoding subunits of the SWI/SNF (Mating Type SWItch/Sucrose Non-Fermentable) chromatin remodeling complex.	('died', 'Disease', 'MESH:D003643', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Sucrose', 'Chemical', 'MESH:D013395', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (140, 149))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Disease', (43, 48))	('died', 'Disease', (38, 42))	('cancers', 'Disease', (108, 115))
3406	31977292	Some mutations, such as SMARCA4/BRG1, occur as a germline event and function as a classic tumor suppressor and key driver in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (136, 158))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (125, 145))	('BRG1', 'Gene', (32, 36))	('hypercalcemic type', 'Disease', (160, 178))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutations', 'Var', (5, 14))	('carcinoma of the ovary', 'Disease', (136, 158))	('BRG1', 'Gene', '6597', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
3407	31977292	Other mutations occur either early during the transformation or as a late event during the progression of gynecologic cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('occur', 'Reg', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (6, 15))
3408	31977292	These studies suggest specific roles of mutations in the SWI/SNF complex during multiple steps of gynecologic cancer development.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (40, 49))	('roles', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('SWI/SNF', 'Gene', (57, 64))
3409	31977292	In this review, we will summarize the current knowledge of SWI/SNF mutations in gynecologic cancer development to provide insights into both molecular pathogenesis and the potential treatment implications of these disease.	('SWI/SNF', 'Gene', (59, 66))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
3419	31977292	The BAF complex displayed a strong enrichment in active enhancers (H3K27ac and H3K4me1) and primed enhancers (H3K4me1), suggestive of their key roles in enhancer regulation, whereas the PBAF complex had the strongest presence in active promoters (H3K27ac and H3K4me3).	('H3K4me3', 'Var', (259, 266))	('BAF', 'Chemical', '-', (187, 190))	('H3K4me1', 'Var', (79, 86))	('enhancers', 'PosReg', (56, 65))	('H3K27ac', 'Var', (67, 74))	('BAF', 'Chemical', '-', (4, 7))	('H3K27ac', 'Var', (247, 254))
3421	31977292	Given its pivotal role in regulating diverse pathways, it is not surprising that mutations impacting SWI/SNF function occur in a broad spectrum of cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('function', 'MPA', (109, 117))	('SWI/SNF', 'Gene', (101, 108))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('mutations', 'Var', (81, 90))	('occur', 'Reg', (118, 123))	('cancers', 'Disease', (147, 154))
3422	31977292	Indeed, data from The Cancer Genome Atlas (TCGA) has shown that mutations of the SWI/SNF subunits are found in about 20% of all cancers, a rate that approaches the frequency of TP53 mutations.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('Cancer', 'Disease', (22, 28))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancers', 'Disease', (128, 135))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', '7157', (177, 181))	('found', 'Reg', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', (177, 181))	('SWI/SNF', 'Gene', (81, 88))
3427	31977292	Mutations in the SWI/SNF complexes have been reported in multiple types of gynecologic cancers (Figure.	('cancers', 'Disease', (87, 94))	('SWI/SNF', 'Gene', (17, 24))	('reported', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
3428	31977292	These mutations, which impact different subunits of the complex, arise at different stages of tumor development and thus may play distinct roles in each tumor type.	('play', 'Reg', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mutations', 'Var', (6, 15))
3429	31977292	In contrast, the inactivating mutations of SMARCA4, SMARCB1 or ARID1A/B genes are late events in the development of endometrial cancer that may promote disease progression.	('SMARCB1', 'Gene', '6598', (52, 59))	('endometrial cancer', 'Disease', 'MESH:D016889', (116, 134))	('inactivating mutations', 'Var', (17, 39))	('SMARCB1', 'Gene', (52, 59))	('promote', 'PosReg', (144, 151))	('endometrial cancer', 'Disease', (116, 134))	('ARID1A/B', 'Gene', '8289', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('endometrial cancer', 'Phenotype', 'HP:0012114', (116, 134))	('ARID1A/B', 'Gene', (63, 71))	('SMARCA4', 'Gene', (43, 50))
3430	31977292	In this section, we will summarize the current understanding of SWI/SNF mutations in gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('mutations', 'Var', (72, 81))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SWI/SNF', 'Gene', (64, 71))
3442	31977292	We and others have discovered that, unlike most common ovarian malignancies, the genome of SCCOHT is diploid with inactivating germline and/or somatic mutations of the SMARCA4 gene as the only recurrent feature and the likely driver event in ~90% of SCCOHT tumors.	('inactivating', 'Var', (114, 126))	('SCCOHT tumors', 'Disease', (250, 263))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('SMARCA4', 'Gene', (168, 175))	('ovarian malignancies', 'Disease', 'MESH:D010049', (55, 75))	('SCCOHT tumors', 'Disease', 'MESH:D009369', (250, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('ovarian malignancies', 'Phenotype', 'HP:0100615', (55, 75))	('ovarian malignancies', 'Disease', (55, 75))	('mutations', 'Var', (151, 160))
3444	31977292	Through IHC analysis of over 3000 primary gynecologic tumors, we further demonstrated that loss of SMARCA4, either alone or together with SMARCA2, is highly sensitive and specific for the diagnosis of SCCOHT, thus providing a definitive tool for SCCOHT diagnosis.	('SMARCA4', 'Gene', (99, 106))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SMARCA2', 'Gene', (138, 145))	('SMARCA2', 'Gene', '6595', (138, 145))	('SCCOHT', 'Disease', (201, 207))	('loss', 'Var', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
3446	31977292	SCCOHTs share both histological and genetic similarities to malignant rhabdoid tumors of the kidney, soft tissues and brain, which are tumors caused by mutations in SMARCB1.	('SMARCB1', 'Gene', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mutations', 'Var', (152, 161))	('malignant rhabdoid tumors of the kidney', 'Disease', (60, 99))	('malignant rhabdoid tumors of the kidney', 'Disease', 'MESH:D018335', (60, 99))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('SMARCB1', 'Gene', '6598', (165, 172))	('caused by', 'Reg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
3458	31977292	Research from our group and others has shown that somatic mutations in the ARID1A gene, encoding an accessory subunit of the SWI/SNF chromatin remodeling complex, commonly occur in both CCOC and ENOC, resulting in complete loss of ARID1A protein expression in ~50% of CCOC and 30% of ENOC.	('mutations', 'Var', (58, 67))	('CCOC', 'Chemical', '-', (186, 190))	('ARID1A', 'Gene', (75, 81))	('occur', 'Reg', (172, 177))	('CCOC', 'Chemical', '-', (268, 272))	('ARID1A', 'Gene', (231, 237))	('loss', 'NegReg', (223, 227))
3462	31977292	Moreover, ARID1A loss is significantly associated with genetic alterations that activate the PI3K/AKT signaling pathway in CCOC, such as PTEN loss and/or gain-of-function mutations of PIK3CA gene, suggesting a cooperative role of ARID1A inactivation and PI3K/AKT activation in malignant transformation of premalignant lesions.	('PTEN loss', 'Disease', (137, 146))	('AKT', 'Gene', '207', (259, 262))	('malignant transformation of premalignant lesions', 'Disease', (277, 325))	('CCOC', 'Chemical', '-', (123, 127))	('ARID1A', 'Gene', (10, 16))	('gain-of-function', 'PosReg', (154, 170))	('AKT', 'Gene', '207', (98, 101))	('PTEN loss', 'Disease', 'MESH:D006223', (137, 146))	('AKT', 'Gene', (259, 262))	('PIK3CA', 'Gene', (184, 190))	('activate', 'PosReg', (80, 88))	('mutations', 'Var', (171, 180))	('loss', 'NegReg', (17, 21))	('CCOC', 'Disease', (123, 127))	('AKT', 'Gene', (98, 101))	('malignant transformation of premalignant lesions', 'Disease', 'MESH:D009369', (277, 325))
3465	31977292	The genomic landscapes of sporadic EECs and HGSECs have been elucidated by TCGA and ourselves, in which mutations of ARID1A occurs in about 30-50% of low grade EEC, 40-60% of high grade EEC and a much lower frequency in HGSEC and endometrial carcinosarcoma.	('mutations', 'Var', (104, 113))	('HGSEC', 'Disease', (220, 225))	('EEC', 'Chemical', '-', (160, 163))	('endometrial carcinosarcoma', 'Phenotype', 'HP:0012114', (230, 256))	('EEC', 'Phenotype', 'HP:0012114', (160, 163))	('EEC', 'Phenotype', 'HP:0012114', (186, 189))	('endometrial carcinosarcoma', 'Disease', 'MESH:D002296', (230, 256))	('EEC', 'Chemical', '-', (35, 38))	('ARID1A', 'Gene', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('low grade EEC', 'Disease', (150, 163))	('occurs', 'Reg', (124, 130))	('endometrial carcinosarcoma', 'Disease', (230, 256))	('EEC', 'Phenotype', 'HP:0012114', (35, 38))	('EEC', 'Chemical', '-', (186, 189))
3469	31977292	Mutation of ARID1A was observed in 22% (7/32) of CCEC along with protein loss, in agreement with an earlier report by Fadare et al..	('loss', 'NegReg', (73, 77))	('CCEC', 'Disease', (49, 53))	('observed', 'Reg', (23, 31))	('Mutation', 'Var', (0, 8))	('ARID1A', 'Gene', (12, 18))	('CCEC', 'Chemical', '-', (49, 53))	('protein', 'MPA', (65, 72))
3470	31977292	Thus, ARID1A mutations occurs at differential frequencies in most common types of endometrial carcinomas, with a significant enrichment in EEC.	('EEC', 'Chemical', '-', (139, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (82, 103))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (82, 104))	('EEC', 'Phenotype', 'HP:0012114', (139, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('EEC', 'Disease', (139, 142))	('endometrial carcinomas', 'Disease', (82, 104))	('ARID1A', 'Gene', (6, 12))	('mutations', 'Var', (13, 22))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (82, 104))
3476	31977292	Patients with Lynch syndrome, one of the most prevalent hereditary cancer predisposition syndromes arising from a germline mutation in one of the four microsatellite repair genes (MLH1, MSH2, MSH6, PMS2), have a 40-60% lifetime risk of developing ECs.	('Lynch syndrome', 'Disease', (14, 28))	('hereditary cancer', 'Disease', 'MESH:D009369', (56, 73))	('mutation', 'Var', (123, 131))	('arising from', 'Reg', (99, 111))	('Lynch syndrome', 'Disease', 'MESH:D003123', (14, 28))	('MSH6', 'Gene', '2956', (192, 196))	('PMS2', 'Gene', '5395', (198, 202))	('hereditary cancer', 'Disease', (56, 73))	('MLH1', 'Gene', '4292', (180, 184))	('ECs', 'Disease', (247, 250))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('MSH2', 'Gene', (186, 190))	('PMS2', 'Gene', (198, 202))	('MLH1', 'Gene', (180, 184))	('MSH6', 'Gene', (192, 196))	('MSH2', 'Gene', '4436', (186, 190))
3480	31977292	This discrepancy may be attributed to the size and origin of different Lynch syndrome kindreds that may carry distinct mutations of mismatch repair genes.	('Lynch syndrome', 'Disease', 'MESH:D003123', (71, 85))	('Lynch syndrome', 'Disease', (71, 85))	('mutations', 'Var', (119, 128))
3491	31977292	These include inactivating mutations in SMARCA4 resulting in loss of SMARCA4 protein in 30-40% of DDEC, inactivation of SMARCB1 resulting in loss of SMARCB1 protein in 2-7% of DDEC, or co-inactivation of ARID1A and ARID1B resulting in concurrent loss of ARID1A and ARID1B proteins in 28% of DDEC.	('ARID1B', 'Gene', '57492', (265, 271))	('inactivating mutations', 'Var', (14, 36))	('SMARCB1', 'Gene', (149, 156))	('ARID1B', 'Gene', (265, 271))	('ARID1B', 'Gene', '57492', (215, 221))	('loss', 'NegReg', (141, 145))	('loss', 'NegReg', (61, 65))	('SMARCA4', 'Gene', (69, 76))	('inactivation', 'Var', (104, 116))	('protein', 'Protein', (77, 84))	('ARID1B', 'Gene', (215, 221))	('loss', 'NegReg', (246, 250))	('SMARCB1', 'Gene', (120, 127))	('co-inactivation', 'Var', (185, 200))	('SMARCB1', 'Gene', '6598', (120, 127))	('SMARCA4', 'Gene', (40, 47))	('protein', 'Protein', (157, 164))	('SMARCB1', 'Gene', '6598', (149, 156))
3494	31977292	Furthermore, mutational loss of SMARCA4, SMARCB1 or ARID1A/ARID1B is often associated with loss of the expression of SMARCA2 protein, the alternative ATPase of the SWI/SNF complex, through non-genetic mechanisms.	('mutational loss', 'Var', (13, 28))	('SMARCB1', 'Gene', (41, 48))	('ATPase', 'Gene', (150, 156))	('SMARCA2', 'Gene', '6595', (117, 124))	('ARID1B', 'Gene', (59, 65))	('expression', 'MPA', (103, 113))	('protein', 'Protein', (125, 132))	('ARID1B', 'Gene', '57492', (59, 65))	('SMARCA4', 'Gene', (32, 39))	('loss', 'NegReg', (91, 95))	('SMARCA2', 'Gene', (117, 124))	('ATPase', 'Gene', '1769', (150, 156))	('SMARCB1', 'Gene', '6598', (41, 48))
3495	31977292	Such SWI/SNF mutations are also implicated in undifferentiated carcinomas of ovary, urinary tract, gastrointestinal tract and kidney, suggesting that the SWI/SNF deficiency acquired during tumor progression may be a widespread mechanism that promotes cancer dedifferentiation.	('tumor', 'Disease', (189, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('SNF deficiency', 'Phenotype', 'HP:0025457', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('implicated', 'Reg', (32, 42))	('SNF deficiency', 'Disease', 'MESH:D007153', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('undifferentiated carcinomas of ovary', 'Disease', 'MESH:D010051', (46, 82))	('undifferentiated carcinomas of ovary', 'Disease', (46, 82))	('SNF deficiency', 'Disease', (158, 172))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (251, 257))	('SWI/SNF', 'Gene', (5, 12))	('promotes', 'PosReg', (242, 250))
3504	31977292	discovered SMARCA4 mutations and/or protein loss in 5 cases of undifferentiated uterine sarcoma with a median age of diagnosis of 33 years old, close to that of SCCOHT.	('SMARCA4', 'Gene', (11, 18))	('mutations', 'Var', (19, 28))	('loss', 'NegReg', (44, 48))	('protein', 'Protein', (36, 43))	('undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (63, 95))	('undifferentiated uterine sarcoma', 'Disease', (63, 95))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (80, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
3517	31977292	studied the clinicopathologic, IHC, and molecular genetic features of 14 SMARCB1-deficient vulvar neoplasms and uncovered that the proximal-type epithelioid sarcoma was the predominant subtype with SMARCB1 deficiency, followed by myoepithelial carcinoma.	('died', 'Disease', (3, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('SMARCB1', 'Gene', (73, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (233, 253))	('SMARCB1', 'Gene', '6598', (198, 205))	('deficiency', 'Var', (206, 216))	('SMARCB1', 'Gene', (198, 205))	('SMARCB1-deficient vulvar neoplasms', 'Disease', (73, 107))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('myoepithelial carcinoma', 'Disease', (230, 253))	('vulvar neoplasms', 'Phenotype', 'HP:0030416', (91, 107))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (230, 253))	('SMARCB1-deficient vulvar neoplasms', 'Disease', 'MESH:D014846', (73, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('died', 'Disease', 'MESH:D003643', (3, 7))	('sarcoma', 'Disease', (157, 164))	('SMARCB1', 'Gene', '6598', (73, 80))
3521	31977292	Despite this, future study of a large number of cases are required to fully characterize the clinicopathologic, immunophenotypic and genomic features of these two entities and address whether SMARCB1 inactivation is the only recurrent driver event, as seen in epithelioid sarcomas at other anatomic sites.	('sarcomas', 'Phenotype', 'HP:0100242', (272, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('sarcomas', 'Disease', (272, 280))	('SMARCB1', 'Gene', '6598', (192, 199))	('SMARCB1', 'Gene', (192, 199))	('inactivation', 'Var', (200, 212))	('sarcomas', 'Disease', 'MESH:D012509', (272, 280))
3526	31977292	Supporting this, analysis of transcriptomic profiles from the ARID1A wild-type and mutant CCOC failed to identify a canonical signaling process that was distinct between wild-type and ARID1A mutant tumors.	('CCOC', 'Chemical', '-', (90, 94))	('mutant', 'Var', (83, 89))	('CCOC', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Disease', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
3527	31977292	found that loss of ARID1A was significantly correlated with advanced FIGO stage and high CA125 levels and a shorter progression-free survival in 60 patients of CCOC that received platinum-based chemotherapy.	('patients', 'Species', '9606', (148, 156))	('progression-free survival', 'CPA', (116, 141))	('CCOC', 'Chemical', '-', (160, 164))	('CA125', 'Gene', '94025', (89, 94))	('loss', 'Var', (11, 15))	('shorter', 'NegReg', (108, 115))	('FIGO', 'Disease', (69, 73))	('CA125', 'Gene', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (179, 187))	('ARID1A', 'Gene', (19, 25))
3540	31977292	demonstrated that ARID1A mutations correlated with a better outcome in endometrial carcinoma.	('mutations', 'Var', (25, 34))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (71, 92))	('ARID1A', 'Gene', (18, 24))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (71, 92))	('endometrial carcinoma', 'Disease', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
3542	31977292	further investigated whether such correlation reflects the enrichment of ARID1A mutations in MSI tumor.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('ARID1A', 'Gene', (73, 79))
3543	31977292	It was unveiled that ARID1A mutation status was not significantly associated with survival in patients with MSI tumors, but was associated with a better prognosis in patients with MSS tumors, implying that ARID1A mutation status may predict patient outcome in MSS endometrial cancer.	('mutation', 'Var', (28, 36))	('MSS tumors', 'Disease', (180, 190))	('predict', 'Reg', (233, 240))	('patients', 'Species', '9606', (94, 102))	('MSI tumors', 'Disease', (108, 118))	('patient', 'Species', '9606', (94, 101))	('patient', 'Species', '9606', (166, 173))	('endometrial cancer', 'Phenotype', 'HP:0012114', (264, 282))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('MSS endometrial cancer', 'Disease', 'MESH:D016889', (260, 282))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('MSI tumors', 'Disease', 'MESH:D009369', (108, 118))	('MSS endometrial cancer', 'Disease', (260, 282))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('patient', 'Species', '9606', (241, 248))	('ARID1A', 'Gene', (21, 27))	('MSS tumors', 'Disease', 'MESH:D013132', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (166, 174))
3545	31977292	Although DDEC displayed a worse outcome than grade 3 endometrial cancer, our initial comparison between 15 DDEC with intact SMARCA4/SMARCB1 and 15 DDEC with loss of SMARCA4 or SMARCB1 did not identify significant differences in disease-specific survival.	('SMARCB1', 'Gene', '6598', (176, 183))	('SMARCB1', 'Gene', (132, 139))	('SMARCA4', 'Gene', (165, 172))	('SMARCB1', 'Gene', '6598', (132, 139))	('SMARCB1', 'Gene', (176, 183))	('endometrial cancer', 'Disease', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('intact', 'Var', (117, 123))	('endometrial cancer', 'Phenotype', 'HP:0012114', (53, 71))	('loss', 'NegReg', (157, 161))	('endometrial cancer', 'Disease', 'MESH:D016889', (53, 71))
3581	31977292	Given the strong association of ARID1A loss and PIK3CA or PTEN mutations in endometriosis-associated ovarian cancer, it is plausible that such mutations may be present in this endometriosis cell line.	('mutations', 'Var', (63, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('endometriosis', 'Phenotype', 'HP:0030127', (176, 189))	('PIK3CA', 'Gene', (48, 54))	('endometriosis', 'Disease', 'MESH:D004715', (76, 89))	('loss', 'NegReg', (39, 43))	('endometriosis-associated ovarian cancer', 'Disease', 'MESH:D004715', (76, 115))	('endometriosis', 'Disease', (176, 189))	('endometriosis', 'Disease', (76, 89))	('endometriosis', 'Disease', 'MESH:D004715', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('endometriosis-associated ovarian cancer', 'Disease', (76, 115))	('ARID1A', 'Gene', (32, 38))	('endometriosis', 'Phenotype', 'HP:0030127', (76, 89))	('PTEN', 'Gene', '19211', (58, 62))	('PTEN', 'Gene', (58, 62))
3586	31977292	Since within the normal uterine environment, endometrial epithelial progenitor cells undergo terminal differentiation with a preference towards secretory cells, it is speculated that the local ovarian microenvironment of each patient, which holds distinct differentiation pressure, may determine the differentiation of ARID1A-deficient biopotential premalignant progenitor cells of endometriotic cysts and together with accumulated additional mutations or epigenetic changes to drive their malignant transformation towards either ENOC or CCOC, respectively (Figure 4).	('CCOC', 'Chemical', '-', (538, 542))	('patient', 'Species', '9606', (226, 233))	('ARID1A-deficient', 'Gene', (319, 335))	('ENOC', 'Disease', (530, 534))	('epigenetic changes', 'Var', (456, 474))	('determine', 'Reg', (286, 295))	('malignant transformation', 'CPA', (490, 514))	('CCOC', 'Disease', (538, 542))	('mutations', 'Var', (443, 452))
3588	31977292	Recently, we and others have demonstrated that TOV112D and OVK18, two ENOC cell lines, are likely DDEC cell lines derived from dedifferentiated carcinomas of the ovary based on their lack of expression of both SMARCA4 and SMARCA2 and histological reevaluation of original tumor material (Karnezis et al., manuscript in preparation).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (272, 277))	('SMARCA2', 'Gene', (222, 229))	('SMARCA2', 'Gene', '6595', (222, 229))	('TOV112D', 'Var', (47, 54))	('SMARCA4', 'Gene', (210, 217))	('carcinomas of the ovary', 'Disease', (144, 167))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas of the ovary', 'Disease', 'MESH:D010051', (144, 167))	('OVK18', 'Gene', (59, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
3590	31977292	As ARID1A/ARID1B-dual deficient DDEC has intact PBAF and GBAF complexes and SMARCB1-deficient DDEC has functional GBAF complex, whereas SMARCA4-deficient DDEC loses ATPase activity of all SWI/SNF complexes completely (Figure 5), it is plausible to propose that inactivation of the BAF complexes is sufficient to stall the differentiation of cancer initiating cells and drive histological dedifferentiation.	('ARID1B', 'Gene', (10, 16))	('BAF', 'Chemical', '-', (115, 118))	('stall', 'NegReg', (312, 317))	('BAF', 'Chemical', '-', (281, 284))	('ARID1B', 'Gene', '57492', (10, 16))	('BAF', 'Chemical', '-', (49, 52))	('cancer', 'Disease', (341, 347))	('SMARCB1', 'Gene', '6598', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('SMARCB1', 'Gene', (76, 83))	('SMARCA4-deficient DDEC loses', 'Disease', 'MESH:D011504', (136, 164))	('SMARCA4-deficient DDEC loses', 'Disease', (136, 164))	('GBAF', 'Chemical', '-', (114, 118))	('GBAF', 'Chemical', '-', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('histological dedifferentiation', 'CPA', (375, 405))	('activity', 'MPA', (172, 180))	('ATPase', 'Gene', (165, 171))	('inactivation', 'Var', (261, 273))	('BAF', 'Chemical', '-', (58, 61))	('drive', 'Reg', (369, 374))	('ATPase', 'Gene', '1769', (165, 171))
3594	31977292	Efforts from several teams have attempted to determine whether inactivation of ARID1A is sufficient to drive the development of ovarian cancer and whether co-existing mutations are required to synergize with ARID1A loss to promote tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('ovarian cancer', 'Disease', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('inactivation', 'Var', (63, 75))	('loss', 'NegReg', (215, 219))	('drive', 'Reg', (103, 108))	('tumor', 'Disease', (231, 236))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('ARID1A', 'Gene', (79, 85))	('ARID1A', 'Gene', (208, 214))	('promote', 'PosReg', (223, 230))	('ovarian cancer', 'Disease', 'MESH:D010051', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
3595	31977292	reported that adenoviral-mediated co-depletion of Pten and Arid1a in ovarian surface epithelium of the Ptenfl/fl;Arid1afl/fl mice induces ovarian hyperplasia as early as 2 months after genetic depletion, which drives the development of undifferentiated or endometrioid carcinoma of the ovary in 6/13 mice examined at 6 months and 7/9 mice at 8-9 months.	('Pten', 'Gene', (50, 54))	('Pten', 'Gene', '19211', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('ovarian hyperplasia', 'Disease', 'MESH:D006965', (138, 157))	('induces', 'Reg', (130, 137))	('mice', 'Species', '10090', (334, 338))	('ovarian hyperplasia', 'Disease', (138, 157))	('mice', 'Species', '10090', (125, 129))	('undifferentiated or endometrioid carcinoma of the ovary', 'Disease', 'MESH:D010051', (236, 291))	('co-depletion', 'Var', (34, 46))	('Arid1afl/fl', 'Var', (113, 124))	('mice', 'Species', '10090', (300, 304))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (256, 278))	('Pten', 'Gene', (103, 107))	('Arid1a', 'Gene', (59, 65))	('Pten', 'Gene', '19211', (103, 107))
3596	31977292	Noteworthy, inactivation of one or both alleles of Arid1a in ovarian surface epithelium prolonged the survival of tumor-bearing Apc/Pten-deficient mice and promoted cancer cell differentiation to more closely resemble the histology of human ovarian endometrioid cancer.	('Pten', 'Gene', '19211', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('inactivation', 'Var', (12, 24))	('mice', 'Species', '10090', (147, 151))	('Arid1a', 'Gene', (51, 57))	('survival', 'CPA', (102, 110))	('tumor', 'Disease', (114, 119))	('Apc', 'Gene', (128, 131))	('promoted', 'PosReg', (156, 164))	('cancer', 'Disease', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Apc', 'Gene', '11789', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('human ovarian endometrioid cancer', 'Disease', (235, 268))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (249, 268))	('human ovarian endometrioid cancer', 'Disease', 'MESH:D016889', (235, 268))	('prolonged', 'PosReg', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('Pten', 'Gene', (132, 136))
3597	31977292	found that inactivation of Arid1a and expression of Pik3ca H1047R activating mutation in ovarian surface epithelium of the Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R mice rapidly develop primary ovarian tumor with a 7.5 week latency and clear cell carcinoma-like histopathology.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('Pik3ca', 'Gene', '18706', (145, 151))	('H1047R', 'SUBSTITUTION', 'None', (152, 158))	('ovarian tumor', 'Phenotype', 'HP:0100615', (188, 201))	('primary', 'CPA', (180, 187))	('Pik3ca', 'Gene', (52, 58))	('H1047R', 'Var', (59, 65))	('Pik3ca', 'Gene', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('develop', 'PosReg', (172, 179))	('ovarian tumor', 'Disease', (188, 201))	('clear cell carcinoma', 'Disease', (230, 250))	('inactivation', 'Var', (11, 23))	('ovarian tumor', 'Disease', 'MESH:D010051', (188, 201))	('Pik3ca', 'Gene', '18706', (52, 58))	('H1047R', 'SUBSTITUTION', 'None', (59, 65))	('H1047R', 'Var', (152, 158))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (230, 250))	('mice', 'Species', '10090', (159, 163))	('Arid1a', 'Gene', (27, 33))
3598	31977292	In contrast, mice with deletion of Pten or Arid1a or activation of Pik3ca.H1047R alone did not develop ovarian lesions except that activation of Pik3ca.H1047R led to development of hyperplasia in ovarian surface epithelium.	('Pten', 'Gene', (35, 39))	('mice', 'Species', '10090', (13, 17))	('Pik3ca', 'Gene', (67, 73))	('Pten', 'Gene', '19211', (35, 39))	('Pik3ca', 'Gene', '18706', (145, 151))	('deletion', 'Var', (23, 31))	('ovarian lesions', 'Disease', 'MESH:D010049', (103, 118))	('ovarian lesions', 'Disease', (103, 118))	('hyperplasia', 'Disease', 'MESH:D006965', (181, 192))	('Pik3ca', 'Gene', '18706', (67, 73))	('ovarian lesions', 'Phenotype', 'HP:0100615', (103, 118))	('Arid1a', 'Gene', (43, 49))	('ovarian surface epithelium', 'CPA', (196, 222))	('hyperplasia', 'Disease', (181, 192))	('Pik3ca', 'Gene', (145, 151))
3604	31977292	As ARID1A is also frequently mutated in endometrial carcinomas, inactivation of Arid1a, alone or in combination with genetic mutations of other genes (such as Pten, Pik3ca), in specific mouse cre strains in which the cre expression is driven by endometrial tissue specific promoters (i.e.	('inactivation', 'Var', (64, 76))	('Arid1a', 'Gene', (80, 86))	('Pten', 'Gene', (159, 163))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (40, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Pten', 'Gene', '19211', (159, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (40, 61))	('endometrial carcinomas', 'Disease', (40, 62))	('mouse', 'Species', '10090', (186, 191))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (40, 62))	('Pik3ca', 'Gene', (165, 171))	('Pik3ca', 'Gene', '18706', (165, 171))
3608	31977292	These putative tissue-specific GEMMs will open the opportunity for better understanding how inactivation of ARID1A interacts with other genetic mutations as well as ovarian microenvironment to drive transformation of precursor cells through comparison of the gene expression profiles and epigenetic states of tumor cells to those of the precursor cells that can be identified by lineage tracking markers.	('inactivation', 'Var', (92, 104))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('ARID1A', 'Gene', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
3609	31977292	reported that inactivation of Smarca4 using a Wap-cre line, which activates cre expression in granulosa cells of mouse ovary and multiple lineages of mouse uterus, led to frequent development of ovarian cyst and a low incidence of endometrial cancer.	('ovarian cyst', 'Disease', 'MESH:D010048', (195, 207))	('Wap', 'Gene', (46, 49))	('ovarian cyst', 'Phenotype', 'HP:0000138', (195, 207))	('inactivation', 'Var', (14, 26))	('Smarca4', 'Gene', (30, 37))	('ovarian cyst', 'Disease', (195, 207))	('endometrial cancer', 'Disease', (231, 249))	('endometrial cancer', 'Phenotype', 'HP:0012114', (231, 249))	('Wap', 'Gene', '22373', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mouse', 'Species', '10090', (113, 118))	('led to', 'Reg', (164, 170))	('mouse', 'Species', '10090', (150, 155))	('endometrial cancer', 'Disease', 'MESH:D016889', (231, 249))	('activates', 'PosReg', (66, 75))
3611	31977292	Therefore, inactivation of Smarca4 cannot drive the transformation of ovarian granulosa cells, but has the ability to transform unknown lineage in uterus.	('transform', 'Reg', (118, 127))	('ovarian granulosa', 'Disease', (70, 87))	('ovarian granulosa', 'Disease', 'MESH:D010049', (70, 87))	('inactivation', 'Var', (11, 23))	('Smarca4', 'Gene', (27, 34))
3615	31977292	Furthermore, additional inactivation of Smarca4 or the BAF complex through dual inactivation of Arid1a/Arid1b will likely promote the development of undifferentiated cancer resembling human DDEC in GEMMs of well differentiated endometrial cancer, such as Pgr-Cre:Ptenfl/fl GEMM mice.	('undifferentiated cancer', 'Disease', 'MESH:D009369', (149, 172))	('promote', 'PosReg', (122, 129))	('Pgr', 'Gene', (255, 258))	('human', 'Species', '9606', (184, 189))	('endometrial cancer', 'Phenotype', 'HP:0012114', (227, 245))	('Smarca4', 'Gene', (40, 47))	('BAF', 'Chemical', '-', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('Arid1b', 'Gene', (103, 109))	('endometrial cancer', 'Disease', (227, 245))	('Arid1b', 'Gene', '57492', (103, 109))	('Pten', 'Gene', (263, 267))	('endometrial cancer', 'Disease', 'MESH:D016889', (227, 245))	('Pten', 'Gene', '19211', (263, 267))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('inactivation', 'Var', (24, 36))	('mice', 'Species', '10090', (278, 282))	('Pgr', 'Gene', '5241', (255, 258))	('undifferentiated cancer', 'Disease', (149, 172))
3616	31977292	These models will offer great opportunities for better understanding the context-specific tumor suppressive roles of distinct SWI/SNF mutations in gynecologic cancers.	('cancers', 'Disease', (159, 166))	('SWI/SNF', 'Gene', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('mutations', 'Var', (134, 143))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
3617	31977292	Although SWI/SNF gene mutations occur in nearly 20% of all human cancers, most SWI/SNF gene mutations are loss of function mutations, including nonsense, frameshift and large deletions, that lead to concurrent loss of their protein expression.	('human', 'Species', '9606', (59, 64))	('cancers', 'Disease', (65, 72))	('loss of function', 'NegReg', (106, 122))	('protein expression', 'MPA', (224, 242))	('SWI/SNF gene', 'Gene', (79, 91))	('large deletions', 'Var', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (92, 101))	('frameshift', 'Var', (154, 164))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('nonsense', 'Var', (144, 152))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('loss', 'NegReg', (210, 214))
3618	31977292	Consequently, many efforts have been invested to identify synthetic lethal targets that are conferred by these SWI/SNF mutations on cancer cells, which has been summarized in details in several reviews.	('cancer', 'Disease', (132, 138))	('SWI/SNF', 'Gene', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
3631	31977292	Mutations of several SWI/SNF subunits have been discovered in multiple gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('discovered', 'Reg', (48, 58))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('SWI/SNF', 'Gene', (21, 28))
3632	31977292	The frequency and inactivating nature of these mutations supports that the SWI/SNF complexes are bona fide tumor suppressors in gynecologic tissues, which also define unique vulnerabilities that warrants further clinical investigations.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (47, 56))	('SWI/SNF', 'Gene', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
3633	31977292	These SWI/SNF mutations may function as either the sole driver event (SCCOHT), a malignant transformation-permitting early event (CCOC/ENOC/EEC) or a late progression event (DDEC) in distinct gynecologic cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('SWI/SNF', 'Gene', (6, 13))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('EEC', 'Chemical', '-', (140, 143))	('CCOC', 'Chemical', '-', (130, 134))	('EEC', 'Phenotype', 'HP:0012114', (140, 143))	('mutations', 'Var', (14, 23))
3635	31977292	The SWI/SNF mutations appears to have a value in predicting the worse outcome of DDEC patients even though a large number of cases are required to validate its clinical utility.	('DDEC', 'Disease', (81, 85))	('mutations', 'Var', (12, 21))	('SWI/SNF', 'Gene', (4, 11))	('patients', 'Species', '9606', (86, 94))
3637	31977292	Furthermore, the pathogenic roles of the SWI/SNF mutations are far beyond being fully understood in gynecologic cancers.	('mutations', 'Var', (49, 58))	('SWI/SNF', 'Gene', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
3638	31977292	The fact that specific subunits are mutated in specific gynecologic malignancies implies that the SWI/SNF complexes function in context-specific manners.	('mutated', 'Var', (36, 43))	('malignancies', 'Disease', (68, 80))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))
3642	31977292	The understanding of SWI/SNF complex mutations and their cellular interactions will be pivotal to developing novel treatment strategies for these gynecologic malignancies, particularly those which portend poor prognoses and often only have conventional platinum-based chemotherapy as a therapeutic option.	('SWI/SNF complex', 'Gene', (21, 36))	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('gynecologic', 'Disease', (146, 157))	('platinum', 'Chemical', 'MESH:D010984', (253, 261))	('malignancies', 'Disease', (158, 170))	('mutations', 'Var', (37, 46))
3646	31992951	We analysed their morphology and immunohistochemical expression of hMLH1, hPMS2, hMSH2, MSH6, and p53 as well as the presence of mutations in TP53 and promoter methylation of the hMLH1.	('hMSH2', 'Gene', '4436', (81, 86))	('hMLH1', 'Gene', (179, 184))	('hPMS2', 'Gene', (74, 79))	('hMLH1', 'Gene', '4292', (67, 72))	('TP53', 'Gene', '7157', (142, 146))	('mutations', 'Var', (129, 138))	('TP53', 'Gene', (142, 146))	('hMSH2', 'Gene', (81, 86))	('hMLH1', 'Gene', '4292', (179, 184))	('MSH6', 'Gene', (88, 92))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))	('hPMS2', 'Gene', '5395', (74, 79))	('hMLH1', 'Gene', (67, 72))	('MSH6', 'Gene', '2956', (88, 92))	('promoter', 'MPA', (151, 159))
3651	31992951	We demonstrated MLH1 promoter hypermethylation in uterine CS, leading to loss of MLH1 immunostaining.	('loss', 'NegReg', (73, 77))	('MLH1', 'Gene', '4292', (16, 20))	('MLH1', 'Gene', '4292', (81, 85))	('MLH1', 'Gene', (16, 20))	('MLH1', 'Gene', (81, 85))	('CS', 'Disease', 'MESH:D002296', (58, 60))	('hypermethylation', 'Var', (30, 46))
3653	31992951	It is likely that uterine CS may develop in two independent molecular pathways in association with either chromosomal or microsatellite instability.	('CS', 'Disease', 'MESH:D002296', (26, 28))	('microsatellite instability', 'Var', (121, 147))	('chromosomal', 'Var', (106, 117))	('develop', 'Reg', (33, 40))
3664	31992951	TP53 mutations seem to be crucial for CS pathogenesis.	('CS', 'Disease', 'MESH:D002296', (38, 40))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
3672	31992951	According to the current point of view, we considered a strong/diffuse (> 75% of tumour cell nuclei) and a completely negative stain as p53 defect indicative of its mutation, (missense and nonsense, respectively), whereas a patchy/scattered pattern was regarded as a marker of normal p53 function.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('p53', 'Gene', '7157', (136, 139))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('tumour', 'Disease', (81, 87))	('missense', 'Var', (176, 184))	('p53', 'Gene', (284, 287))	('p53', 'Gene', '7157', (284, 287))	('nonsense', 'Var', (189, 197))	('p53', 'Gene', (136, 139))
3689	31992951	Interestingly, we observed that in all three cases with defective MMR, there was no immunohistochemical evidence of any p53 defect; on the other hand, all uterine tumours with defective p53 were positive for MMR proteins.	('MMR proteins', 'Protein', (208, 220))	('uterine tumours', 'Disease', (155, 170))	('uterine tumours', 'Disease', 'MESH:D014594', (155, 170))	('p53', 'Gene', '7157', (120, 123))	('positive', 'Reg', (195, 203))	('defective', 'Var', (176, 185))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('p53', 'Gene', (186, 189))	('p53', 'Gene', '7157', (186, 189))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('p53', 'Gene', (120, 123))
3690	31992951	Thus, in the next step, we tested the MLH1 promoter methylation status and TP53 mutations in our cohort (one case was excluded due to the lack of representative material for further analyses).	('mutations', 'Var', (80, 89))	('MLH1', 'Gene', '4292', (38, 42))	('MLH1', 'Gene', (38, 42))	('tested', 'Reg', (27, 33))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
3691	31992951	TP53 mutation was detected in 8/19 tumours (42.1%), whereas MLH1 promoter hypermethylation occurred in 4/19 cases (21%).	('tumours', 'Disease', (35, 42))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('MLH1', 'Gene', '4292', (60, 64))	('MLH1', 'Gene', (60, 64))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('mutation', 'Var', (5, 13))
3693	31992951	TP53 mutations were found exclusively in regions responsible for DNA binding, and some of them had been previously observed in uterine CS.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('DNA binding', 'Interaction', (65, 76))	('mutations', 'Var', (5, 14))	('CS', 'Disease', 'MESH:D002296', (135, 137))
3695	31992951	Correlation between p53 and hMLH1 defect in uterine CS, assessed by Spearman's rank-correlation, was -0.40849 (p = 0.0825).	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('hMLH1', 'Gene', (28, 33))	('CS', 'Disease', 'MESH:D002296', (52, 54))	('hMLH1', 'Gene', '4292', (28, 33))	('defect', 'Var', (34, 40))
3697	31992951	It is well known that MMR-deficiency and TP53 mutations, either gain or loss of function, may lead to the development of the sarcomatous component, for example through TGF-bsignalling (by MMR deficiency) or miRNA.	('TP53', 'Gene', '7157', (41, 45))	('TGF-bsignalling', 'CPA', (168, 183))	('TP53', 'Gene', (41, 45))	('loss of', 'NegReg', (72, 79))	('mutations', 'Var', (46, 55))	('sarcomatous component', 'Disease', 'MESH:D018316', (125, 146))	('MMR-deficiency', 'Gene', (22, 36))	('sarcomatous component', 'Disease', (125, 146))	('lead to', 'Reg', (94, 101))	('gain', 'PosReg', (64, 68))	('miRNA', 'CPA', (207, 212))
3703	31992951	The two main mechanisms of MMR loss in cancer are sequence mutations and epigenetic changes.	('cancer', 'Disease', (39, 45))	('loss', 'NegReg', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('MMR', 'Gene', (27, 30))	('epigenetic changes', 'Var', (73, 91))	('sequence mutations', 'Var', (50, 68))
3704	31992951	Extensive parallel sequencing of 22 uterine CSs revealed MLH1 frameshift mutation in one case (5%) and MSH6 nonsense mutation in three cases (15%).	('nonsense mutation', 'Var', (108, 125))	('MSH6', 'Gene', (103, 107))	('frameshift mutation', 'Var', (62, 81))	('MLH1', 'Gene', '4292', (57, 61))	('MLH1', 'Gene', (57, 61))	('MSH6', 'Gene', '2956', (103, 107))	('CSs', 'Disease', (44, 47))	('CSs', 'Disease', 'MESH:D002296', (44, 47))
3705	31992951	A recent comprehensive epigenetic analysis of 57 uterine CS cases revealed MLH1 epigenetic silencing in two tumours exhibiting MSI, discovering a novel important mechanism responsible for MMR deficiency in uterine CS.	('tumours', 'Disease', (108, 115))	('CS', 'Disease', 'MESH:D002296', (57, 59))	('MLH1', 'Gene', '4292', (75, 79))	('MLH1', 'Gene', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('MSI', 'Gene', (127, 130))	('epigenetic silencing', 'Var', (80, 100))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('MSI', 'Gene', '5928', (127, 130))	('CS', 'Disease', 'MESH:D002296', (214, 216))
3706	31992951	Our study reports another four cases of MLH1 promoter methylation in CS, which supports these findings.	('methylation', 'Var', (54, 65))	('MLH1', 'Gene', '4292', (40, 44))	('CS', 'Disease', 'MESH:D002296', (69, 71))	('MLH1', 'Gene', (40, 44))
3710	31992951	Only one tumour from our cases presented with MLH1 hypermethylation and TP53 mutation; however, it was still positive immunohistochemically.	('MLH1', 'Gene', (46, 50))	('tumour', 'Disease', (9, 15))	('hypermethylation', 'Var', (51, 67))	('TP53', 'Gene', '7157', (72, 76))	('mutation', 'Var', (77, 85))	('TP53', 'Gene', (72, 76))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('MLH1', 'Gene', '4292', (46, 50))
3712	31992951	These findings are consistent with another study that demonstrated a higher frequency of p53 defects in CS with serous differentiation when compared with CS with an endometrioid epithelial component.	('defects', 'Var', (93, 100))	('CS', 'Disease', 'MESH:D002296', (154, 156))	('serous differentiation', 'CPA', (112, 134))	('p53', 'Gene', (89, 92))	('CS', 'Disease', 'MESH:D002296', (104, 106))	('p53', 'Gene', '7157', (89, 92))
3713	31992951	Genetic studies showed that the overall mutation profile of uterine CS corresponds to the mutation profiles of either serous (mutation of TP53 and PPP2R1A) or endometrioid carcinomas (mutation of PTEN and ARID1A).	('PPP2R1A', 'Gene', (147, 154))	('serous', 'Disease', (118, 124))	('PPP2R1A', 'Gene', '5518', (147, 154))	('TP53', 'Gene', '7157', (138, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('CS', 'Disease', 'MESH:D002296', (68, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('endometrioid carcinomas', 'Disease', (159, 182))	('TP53', 'Gene', (138, 142))	('endometrioid carcinomas', 'Disease', 'MESH:D018269', (159, 182))	('PTEN', 'Gene', (196, 200))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (159, 182))	('PTEN', 'Gene', '5728', (196, 200))	('ARID1A', 'Gene', (205, 211))	('ARID1A', 'Gene', '8289', (205, 211))	('mutation', 'Var', (184, 192))
3714	31992951	Nevertheless, these findings are not supported by other studies that failed to demonstrate any inverse associations between mutations in MMR genes and TP53.	('TP53', 'Gene', '7157', (151, 155))	('MMR', 'Gene', (137, 140))	('mutations', 'Var', (124, 133))	('TP53', 'Gene', (151, 155))
3715	31992951	We conclude that epigenetic loss of hMLH1 expression may be an element of pathogenesis in some cases of uterine CS.	('CS', 'Disease', 'MESH:D002296', (112, 114))	('hMLH1', 'Gene', (36, 41))	('hMLH1', 'Gene', '4292', (36, 41))	('epigenetic loss', 'Var', (17, 32))	('pathogenesis', 'Reg', (74, 86))
3717	31992951	This association may indicate the existence of two distinct pathways of uterine CS development: through microsatellite or chromosomal instability.	('chromosomal instability', 'Phenotype', 'HP:0040012', (122, 145))	('microsatellite', 'Var', (104, 118))	('chromosomal instability', 'Var', (122, 145))	('CS', 'Disease', 'MESH:D002296', (80, 82))
3731	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('tumor', 'Disease', (16, 21))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
3732	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('hypermethylation', 'Var', (11, 27))	('H3K9me3', 'Protein', (181, 188))	('histone H3', 'Protein', (99, 109))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
3747	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
3777	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('MDA-MB468', 'Var', (177, 186))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('HER2', 'Gene', '2064', (193, 197))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
3799	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('multiple cancer', 'Disease', (181, 196))	('altered', 'Var', (53, 60))	('reduced', 'NegReg', (82, 89))	('expression', 'MPA', (90, 100))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('upregulation', 'PosReg', (165, 177))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))
3833	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('aberrant splicing', 'Var', (3, 20))	('ZNFs', 'Chemical', '-', (130, 134))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
3836	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
3837	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
3838	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
3843	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('ZNF273', 'Gene', (0, 6))	('partial deletion', 'Var', (30, 46))	('ZNF273', 'Gene', '10793', (0, 6))
3848	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
3906	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
3907	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
3909	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
3924	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
3925	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (207, 221))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', (188, 191))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
3936	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
3960	29530001	During embryonic development, RPs are expressed at different levels across tissue types, and loss of RPs due to mutation or targeted knockdown produces specific developmental abnormalities in plants, invertebrates, and vertebrates.	('RPs', 'Gene', (101, 104))	('mutation', 'Var', (112, 120))	('loss', 'NegReg', (93, 97))	('developmental abnormalities', 'Disease', (161, 188))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (161, 188))	('developmental abnormalities', 'Disease', 'MESH:D006130', (161, 188))
3965	29530001	Indeed, an entire class of diseases has been shown to be associated with haploinsufficient expression or mutation in individual RPs.	('mutation', 'Var', (105, 113))	('haploinsufficient', 'Disease', (73, 90))	('haploinsufficient', 'Disease', 'MESH:D058495', (73, 90))	('associated', 'Reg', (57, 67))	('RPs', 'Gene', (128, 131))
3969	29530001	The developmental abnormalities of the ribosomopathies are variable and associate with specific RP loss or mutation.	('developmental abnormalities of the ribosomopathies', 'Disease', 'MESH:D006130', (4, 54))	('RP loss', 'Disease', (96, 103))	('developmental abnormalities of the ribosomopathies', 'Disease', (4, 54))	('RP loss', 'Disease', 'MESH:C538365', (96, 103))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (4, 31))	('mutation', 'Var', (107, 115))
3972	29530001	We have recently shown that RP transcripts (RPTs) were dysregulated in two murine models of hepatoblastoma and hepatocellular carcinoma (HCC) in a tumor-specific manner and in patterns unrelated to tumor growth rates.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('dysregulated', 'Var', (55, 67))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('murine', 'Species', '10090', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('hepatoblastoma and hepatocellular carcinoma', 'Disease', 'MESH:D018197', (92, 135))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('tumor', 'Disease', (198, 203))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (92, 106))
3974	29530001	Perturbations of several individual RPs have been found in numerous human cancers, including those of the breast, pancreas, bladder, brain and many other tissues.	('bladder', 'Disease', (124, 131))	('breast', 'Disease', (106, 112))	('numerous human cancers', 'Disease', 'MESH:D009369', (59, 81))	('brain', 'Disease', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('found', 'Reg', (50, 55))	('RPs', 'Protein', (36, 39))	('pancreas', 'Disease', (114, 122))	('numerous human cancers', 'Disease', (59, 81))	('Perturbations', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
3975	29530001	Mutations and deletions of RP-encoding genes have also been found in endometrial cancer, colorectal cancer, glioma, and various hematopoietic malignancies.	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('endometrial cancer', 'Disease', (69, 87))	('glioma', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('hematopoietic malignancies', 'Disease', (128, 154))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('endometrial cancer', 'Phenotype', 'HP:0012114', (69, 87))	('RP-encoding genes', 'Gene', (27, 44))	('deletions', 'Var', (14, 23))	('found', 'Reg', (60, 65))	('Mutations', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('endometrial cancer', 'Disease', 'MESH:D016889', (69, 87))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (128, 154))
3976	29530001	5q- abnormality associated with myelodysplastic syndrome and the accompanying haploinsufficiency of RPS14 is considered one of the prototype "acquired" ribosomopathies that are often classified together with DBA, SDS and other inherited ribosomopathies.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (32, 56))	('haploinsufficiency', 'Disease', 'MESH:D058495', (78, 96))	('SDS', 'Disease', 'MESH:D000081003', (213, 216))	('RPS14', 'Gene', (100, 105))	('SDS', 'Disease', (213, 216))	('haploinsufficiency', 'Disease', (78, 96))	('myelodysplastic syndrome', 'Disease', (32, 56))	('RPS14', 'Gene', '6208', (100, 105))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (32, 56))	('inherited ribosomopathies', 'Disease', 'MESH:D030342', (227, 252))	('inherited ribosomopathies', 'Disease', (227, 252))	('associated', 'Reg', (16, 26))	('5q- abnormality', 'Var', (0, 15))
3997	29530001	When comparing relative expression of other RPTs between these clusters and other tumors from the same cohorts, all five clusters with high RPL8 and RPL30 also displayed, on average, lower relative expression of RPL10 and higher relative expression of RPL7.	('high', 'Var', (135, 139))	('RPL7', 'Gene', '6129', (252, 256))	('tumors', 'Disease', (82, 88))	('RPL10', 'Gene', '6134', (212, 217))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('higher', 'PosReg', (222, 228))	('RPL7', 'Gene', (252, 256))	('RPL10', 'Gene', (212, 217))	('RPL8', 'Gene', '6132', (140, 144))	('RPL8', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('RPL30', 'Gene', '6156', (149, 154))	('lower', 'NegReg', (183, 188))	('expression', 'MPA', (198, 208))	('expression', 'MPA', (238, 248))	('RPL30', 'Gene', (149, 154))
3999	29530001	The frequency of amplifications and deletions in RP genes were compared between clusters of tumors in each TCGA cohort using chi-squared tests and adjusted for 5% false discovery rate.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('deletions', 'Var', (36, 45))	('RP genes', 'Gene', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
4031	29530001	Excluding thyroid cancers, all other tumor clusters with low RPL3 also shared 11 other similarly co-regulated RPTs.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('thyroid cancers', 'Disease', (10, 25))	('RPL3', 'Gene', (61, 65))	('thyroid cancers', 'Disease', 'MESH:D013964', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('low', 'Var', (57, 60))	('tumor', 'Disease', (37, 42))	('RPL3', 'Gene', '6122', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
4038	29530001	For example, 48% of tumors in kidney clear cell carcinoma Cluster 3 possessed deletions of RPL12, RPL35, and RPL7A on 9q33-34.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('RPL7A', 'Gene', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('RPL35', 'Gene', (98, 103))	('tumors in kidney clear cell carcinoma Cluster', 'Disease', (20, 65))	('RPL12', 'Gene', (91, 96))	('RPL35', 'Gene', '11224', (98, 103))	('RPL12', 'Gene', '6136', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors in kidney clear cell carcinoma Cluster', 'Disease', 'MESH:C538614', (20, 65))	('deletions', 'Var', (78, 87))	('RPL7A', 'Gene', '6130', (109, 114))
4039	29530001	Similarly, half of brain cancers in Cluster 1 possessed a 1p/19q13 co-deletion, compared to nearly 100% of tumors in Cluster 5 with this deletion (Table 2).	('brain cancer', 'Phenotype', 'HP:0030692', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('brain cancers', 'Disease', (19, 32))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('brain cancers', 'Disease', 'MESH:D001932', (19, 32))	('1p/19q13 co-deletion', 'Var', (58, 78))
4058	29530001	In addition to their tissue-specific patterning, virtually all tumors showed perturbations of RPT expression that readily allowed them to be distinguished from the normal tissues from which they originated.	('perturbations', 'Var', (77, 90))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('RPT', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('expression', 'MPA', (98, 108))
4062	29530001	Aside from potentially altering translation, the notion that altered RP expression might influence the behaviors of both normal tissues and tumors is not new.	('altered', 'Var', (61, 68))	('behaviors of', 'CPA', (103, 115))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('translation', 'MPA', (32, 43))	('influence', 'Reg', (89, 98))	('RP expression', 'Protein', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('altering', 'Reg', (23, 31))
4064	29530001	It has been proposed that subsequent circumvention of this TP53-mediated senescence by mutation and/or dysregulation of the p19ARF/MDM2/TP53 pathway is responsible for the propensity for eventual neoplastic progression [.	('TP53', 'Gene', '7157', (59, 63))	('p19ARF', 'Gene', '1029', (124, 130))	('TP53', 'Gene', (59, 63))	('p19ARF', 'Gene', (124, 130))	('TP53', 'Gene', '7157', (136, 140))	('neoplastic progression [', 'CPA', (196, 220))	('dysregulation', 'Var', (103, 116))	('mutation', 'Var', (87, 95))	('TP53', 'Gene', (136, 140))
4081	29530001	As with RPL3, deregulated RPS4X has been previously associated with various tumors and tumor phenotypes, including subgroups of colorectal carcinoma, a myelodysplasia risk signature and poor prognosis in bladder cancer.	('RPS4X', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RPL3', 'Gene', '6122', (8, 12))	('tumor', 'Disease', (76, 81))	('myelodysplasia', 'Phenotype', 'HP:0002863', (152, 166))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('myelodysplasia', 'Disease', 'MESH:D009190', (152, 166))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (204, 218))	('bladder cancer', 'Disease', (204, 218))	('RPS4X', 'Gene', '6191', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (87, 92))	('associated', 'Reg', (52, 62))	('tumors', 'Disease', (76, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (204, 218))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('RPL3', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('colorectal carcinoma', 'Disease', (128, 148))	('myelodysplasia', 'Disease', (152, 166))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (128, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('deregulated', 'Var', (14, 25))
4082	29530001	Interestingly, some of our tumor clusters with altered RPS4X expression were comprised of a greater proportion of females than males (Table 1 and Table 3), perhaps reflecting RPS4X's residence on the X chromosome.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('RPS4X', 'Gene', '6191', (175, 180))	('RPS4X', 'Gene', (175, 180))	('RPS4X', 'Gene', '6191', (55, 60))	('RPS4X', 'Gene', (55, 60))	('expression', 'MPA', (61, 71))	('altered', 'Var', (47, 54))
4088	29530001	In contrast, kidney clear cell carcinomas with high RPL13 expression tended to be of higher pathologic grade and were associated with significantly poorer survival (Tables 1 and 3, and Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('kidney clear cell carcinomas', 'Disease', (13, 41))	('high', 'Var', (47, 51))	('RPL13', 'Gene', '6137', (52, 57))	('RPL13', 'Gene', (52, 57))	('kidney clear cell carcinomas', 'Disease', 'MESH:C538614', (13, 41))	('poorer', 'NegReg', (148, 154))	('survival', 'MPA', (155, 163))
4091	29530001	Virtually all tumors with this expression pattern possessed co-amplification of a region on 8q22-24 that includes RPL8, RPL30, and the oncogenes MYC and PVT1.	('RPL8', 'Gene', (114, 118))	('PVT1', 'Gene', '5820', (153, 157))	('MYC', 'Gene', (145, 148))	('co-amplification', 'Var', (60, 76))	('RPL30', 'Gene', '6156', (120, 125))	('RPL30', 'Gene', (120, 125))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('MYC', 'Gene', '4609', (145, 148))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('PVT1', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('RPL8', 'Gene', '6132', (114, 118))
4092	29530001	Amplification of this region has been previously described in breast cancers and correlates with chemoresistance and metastasis.	('chemoresistance', 'CPA', (97, 112))	('Amplification', 'Var', (0, 13))	('described', 'Reg', (49, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('breast cancers', 'Disease', (62, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('correlates', 'Reg', (81, 91))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('metastasis', 'CPA', (117, 127))
4097	29530001	Amplification of a region on 11q13 that contains RPS3, occurring in a cluster of breast cancers and HCCs, has been previously described in both cancers and is thought to confer unfavorable prognosis due to amplification of the adjacent oncogene EMS1.	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cluster of breast cancers', 'Disease', (70, 95))	('HCCs', 'Disease', (100, 104))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('EMS1', 'Gene', '2017', (245, 249))	('RPS3', 'Gene', '6188', (49, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('RPS3', 'Gene', (49, 53))	('Amplification', 'Var', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('EMS1', 'Gene', (245, 249))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cluster of breast cancers', 'Disease', 'MESH:D001943', (70, 95))
4098	29530001	The co-deletion of 19q13 along with 1p, which together includes 12 RP genes, has been described in low-grade gliomas and confers a favorable prognosis.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('co-deletion', 'Var', (4, 15))	('described', 'Reg', (86, 95))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('19q13', 'Gene', (19, 24))
4104	29530001	Although the means by which altered RPT patterns influence the pathogenesis and/or behavior of tumors remain incompletely understood, several non-mutually exclusive mechanisms can be envisioned.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('altered', 'Var', (28, 35))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RPT', 'Protein', (36, 39))	('influence', 'Reg', (49, 58))	('tumors', 'Disease', (95, 101))
4106	29530001	Changes in ribosome affinity for IRES elements have been shown to reduce translation of tumor suppressors such as p27 and TP53 and to promote cancer development.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('TP53', 'Gene', (122, 126))	('ribosome affinity', 'Protein', (11, 28))	('promote', 'PosReg', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TP53', 'Gene', '7157', (122, 126))	('p27', 'Gene', '3429', (114, 117))	('p27', 'Gene', (114, 117))	('Changes', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reduce', 'NegReg', (66, 72))	('translation', 'MPA', (73, 84))	('tumor', 'Disease', (88, 93))	('cancer', 'Disease', (142, 148))
4108	29530001	In addition to their stabilization of TP53 mediated by binding to and inactivating MDM2, specific RPs have been shown to inactivate Myc; to inhibit the Myc target Lin28B; to activate NF-kappaB, cyclins, and cyclin-dependent kinases and to regulate a variety of other tumorigenic functions and immunogenic pathways.	('cyclin-dependent', 'Enzyme', (207, 223))	('TP53', 'Gene', (38, 42))	('Lin28B', 'Gene', '389421', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('MDM2', 'Gene', (83, 87))	('RPs', 'Var', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('Myc', 'Gene', '4609', (152, 155))	('inactivate', 'NegReg', (121, 131))	('Myc', 'Gene', (132, 135))	('inactivating', 'NegReg', (70, 82))	('TP53', 'Gene', '7157', (38, 42))	('cyclins', 'Enzyme', (194, 201))	('inhibit', 'NegReg', (140, 147))	('Lin28B', 'Gene', (163, 169))	('activate', 'PosReg', (174, 182))	('regulate', 'Reg', (239, 247))	('Myc', 'Gene', '4609', (132, 135))	('binding', 'Interaction', (55, 62))	('immunogenic', 'CPA', (293, 304))	('NF-kappaB', 'Pathway', (183, 192))	('tumor', 'Disease', (267, 272))	('Myc', 'Gene', (152, 155))
4113	29530001	As this is a cross-sectional study, we also recognize that causality cannot be inferred, and it remains unknown whether altered RPT expression is an early or late event in tumorigenesis despite its predictive value.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('RPT', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('altered', 'Var', (120, 127))
4115	29530001	Finally, additional molecular analyses of the identified t-SNE clusters with whole-transcriptome sequencing data, pathway analysis, whole-genome DNA mutation data, and DNA methylation patterning may offer additional insights into the biological mechanisms that link altered RPT expression with tumor phenotypes.	('tumor', 'Disease', (294, 299))	('RPT', 'Gene', (274, 277))	('expression', 'MPA', (278, 288))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('altered', 'Var', (266, 273))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))
4122	29133752	Proportion of Uterine Malignant Tumors in Patients with Laparoscopic Myomectomy: A National Multicenter Study in China The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma; therefore, the use of morcellation is limited in the USA.	('cause', 'Reg', (204, 209))	('morcellation', 'Var', (187, 199))	('Tumors', 'Phenotype', 'HP:0002664', (32, 38))	('sarcoma', 'Disease', (269, 276))	('Uterine Malignant Tumors', 'Phenotype', 'HP:0010784', (14, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('Malignant Tumors', 'Disease', (22, 38))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (261, 276))	('Patients', 'Species', '9606', (42, 50))	('sarcoma', 'Disease', 'MESH:D012509', (269, 276))	('fibroids', 'CPA', (210, 218))	('pelvic dissemination', 'CPA', (222, 242))	('metastasis', 'CPA', (247, 257))	('Malignant Tumors', 'Disease', 'MESH:D018198', (22, 38))
4135	29133752	Furthermore, previous studies reported that power morcellation had a risk of dispersing missed fragments all over the pelvic cavity, which can negatively affect patient prognosis and cause a range of complications.	('power morcellation', 'Var', (44, 62))	('patient', 'Species', '9606', (161, 168))	('affect', 'Reg', (154, 160))	('cause', 'Reg', (183, 188))	('dispersing', 'MPA', (77, 87))
4139	29133752	According to the International Classification of Diseases (ICD)-10 disease code, the primary diagnosis code is D25 (myoma).	('myoma', 'Disease', (116, 121))	('D25', 'Var', (111, 114))	('myoma', 'Disease', 'MESH:D009214', (116, 121))
4183	28893210	To develop subtype specific diagnostic biomarkers, genes overexpressed in subtype I (LMOD1, 1:20, Sigma, CAT#HPA028325) and subtype II (ARL4C, 1:120, Sigma, CAT#HPA028927) ULMS were selected for immunohistochemistry staining (IHC) based on SAM-seq result and the antibody availability.	('ARL4C', 'Gene', (136, 141))	('CAT#HPA028325', 'Var', (105, 118))	('LMOD1', 'Gene', '25802', (85, 90))	('LMS', 'Phenotype', 'HP:0100243', (173, 176))	('ULMS', 'Phenotype', 'HP:0002891', (172, 176))	('overexpressed', 'PosReg', (57, 70))	('ARL4C', 'Gene', '10123', (136, 141))	('LMOD1', 'Gene', (85, 90))
4211	28893210	CDK6 (Cyclin-dependent kinase 6) is a cell cycle regulator and forms a complex with cyclin D to initiate G1 to S phase transition by phosphorylating and inactivating Rb.	('Rb', 'Chemical', 'MESH:D012413', (166, 168))	('inactivating', 'NegReg', (153, 165))	('phosphorylating', 'Var', (133, 148))	('CDK6', 'Gene', (0, 4))	('Cyclin-dependent kinase 6', 'Gene', '1021', (6, 31))	('CDK6', 'Gene', '1021', (0, 4))	('Cyclin-dependent kinase 6', 'Gene', (6, 31))
4223	27339696	Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma.	('liver tumors', 'Disease', (74, 86))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (298, 328))	('liver hepatocellular carcinoma', 'Disease', (298, 328))	('KMT2B', 'Gene', '9757', (42, 47))	('liver tumors', 'Phenotype', 'HP:0002896', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('integration', 'Var', (23, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (304, 328))	('KMT2B', 'Gene', (42, 47))	('liver tumors', 'Disease', 'MESH:D008113', (74, 86))	('HBV', 'Gene', (19, 22))
4224	27339696	Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer.	('cervical cancer', 'Disease', (110, 125))	('found', 'Reg', (33, 38))	('HPV', 'Species', '10566', (80, 83))	('PTPN13', 'Gene', '5783', (100, 106))	('HPV integrations', 'Var', (80, 96))	('PTPN13', 'Gene', (100, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
4225	27339696	Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences.	('HBV', 'Gene', (39, 42))	('HHV4', 'Species', '10376', (30, 34))	('HHV4', 'Gene', (30, 34))	('variants', 'Var', (43, 51))	('associated', 'Reg', (61, 71))
4228	27339696	The Cancer Genome Atlas (TCGA) Pan-Cancer project has discovered numerous somatic mutations in key cancer genes.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('mutations', 'Var', (82, 91))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
4230	27339696	Also, mutational signatures related to endogenous and exogenous DNA damage have been found in different cancer types, such as the APOBEC-associated cytosine deaminase mutational signature and smoking-related cytosine-to-adenine signatures.	('cytosine', 'Chemical', 'MESH:D003596', (208, 216))	('adenine', 'Chemical', 'MESH:D000225', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('APOBEC-associated', 'Gene', (130, 147))	('mutational', 'Var', (167, 177))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cytosine', 'Chemical', 'MESH:D003596', (148, 156))
4240	27339696	Three important issues are explicitly addressed in the present study: 1) differential viral expression and integration patterns between tumors and adjacent normal samples, 2) the discovery and implications of novel rare viral insertions and 3) differences among ethnicities that may point to environmental influences on viral sequence evolution.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('viral', 'MPA', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('insertions', 'Var', (226, 236))	('integration', 'MPA', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('differences', 'Reg', (244, 255))
4260	27339696	However, we did observe some exceptional cases that were positive for two different viruses, for example, one STAD case having HHV4 and HHV5, one LIHC case having HBV and HPV16 (Fig.	('HHV5', 'Var', (136, 140))	('HPV16', 'Species', '333760', (171, 176))	('HHV4', 'Species', '10376', (127, 131))	('HHV5', 'Species', '10359', (136, 140))	('HHV4', 'Var', (127, 131))
4261	27339696	S3A) and one BLCA with having HPV6 and HPV11 (Fig.	('HPV11', 'Var', (39, 44))	('HPV6', 'Var', (30, 34))	('HPV11', 'Species', '10580', (39, 44))	('HPV', 'Species', '10566', (30, 33))	('HPV', 'Species', '10566', (39, 42))
4267	27339696	The clinical-pathological information shows that patient DD-A1EH with only HBV in adjacent normal has a family history of cancer, and sample DD-A11A with HBV in tumor has no family history of cancer, which may indicate different cancer etiologies, i.e., inherited mutations and HBV infection, respectively.	('DD-A1EH', 'Var', (57, 64))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('patient', 'Species', '9606', (49, 56))	('HBV infection', 'Disease', (278, 291))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HBV infection', 'Disease', 'MESH:D006509', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
4285	27339696	Importantly, in these six tumors, we found three samples with HBV virus integration in KMT2B (MLL4), suggesting the integration sites in this gene are important for the development of liver cancer, consistent with other studies.	('important', 'Reg', (151, 160))	('integration', 'Var', (72, 83))	('KMT2B', 'Gene', '9757', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('MLL4', 'Gene', (94, 98))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('MLL4', 'Gene', '9757', (94, 98))	('KMT2B', 'Gene', (87, 92))	('liver cancer', 'Disease', (184, 196))	('tumors', 'Disease', (26, 32))
4296	27339696	For instance, we found that EBER-1 is highly expressed in BR-8676.	('EBER-1', 'Gene', (28, 34))	('BR-8676', 'Var', (58, 65))	('BR', 'Chemical', 'MESH:D001966', (58, 60))	('highly', 'PosReg', (38, 44))
4300	27339696	Because disruption of apoptosis can lead to tumor initiation, progression, or metastasis, RNA2.7 can be regarded as a viral oncogene.	('disruption', 'Var', (8, 18))	('lead to', 'Reg', (36, 43))	('progression', 'CPA', (62, 73))	('tumor initiation', 'Disease', 'MESH:D009369', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('metastasis', 'CPA', (78, 88))	('apoptosis', 'Protein', (22, 31))	('tumor initiation', 'Disease', (44, 60))
4306	27339696	E6/E7 were involved in binding and degrading p53/Rb proteins and their expression suggests that HPV16 may also play a role in the tumorgenesis in these LGG samples.	('play', 'Reg', (111, 115))	('E6/E7', 'Var', (0, 5))	('expression', 'MPA', (71, 81))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('binding', 'Interaction', (23, 30))	('HPV16', 'Species', '333760', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('LGG', 'Disease', (152, 155))	('HPV16', 'Gene', (96, 101))	('tumor', 'Disease', (130, 135))	('degrading', 'NegReg', (35, 44))
4307	27339696	Discordant read pair analysis using Pindel (see Methods) revealed a battery of genes having recurrent HPV integrations in several cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('integrations', 'Var', (106, 118))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('HPV', 'Species', '10566', (102, 105))	('HPV', 'Gene', (102, 105))
4315	27339696	The second hotpot of recurrent virus integration is at the RAD51B locus in 8 CESC samples, which include 3 samples with HPV16, 2 samples with HPV39, one with HPV18 and one with HPV45; interestingly, two HNSC tumors also harbor HPV16 integration at RAD51B.	('RAD51B', 'Gene', (59, 65))	('RAD51B', 'Gene', '5890', (248, 254))	('RAD51B', 'Gene', '5890', (59, 65))	('HNSC tumors', 'Disease', (203, 214))	('RAD51B', 'Gene', (248, 254))	('HPV', 'Species', '10566', (227, 230))	('HPV', 'Species', '10566', (142, 145))	('HPV16', 'Species', '333760', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('HPV', 'Species', '10566', (177, 180))	('HPV16 integration', 'Var', (227, 244))	('HPV16', 'Species', '333760', (227, 232))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('HNSC tumors', 'Disease', 'MESH:D009369', (203, 214))	('HPV', 'Species', '10566', (158, 161))	('HPV', 'Species', '10566', (120, 123))
4316	27339696	Whole-genome sequencing analysis reveals that HPV integration amplifies the somatic copy number of this region.	('HPV', 'Species', '10566', (46, 49))	('integration', 'Var', (50, 61))	('amplifies', 'PosReg', (62, 71))	('HPV', 'Gene', (46, 49))
4321	27339696	Three samples (C5-A1M9, DS-A7WF, LP-A5U3) with viral integration at ERBB2 locus showed significantly increased expression across all exons (P-value < 0.05) (Fig.	('increased', 'PosReg', (101, 110))	('viral integration', 'Var', (47, 64))	('ERBB2', 'Gene', '2064', (68, 73))	('ERBB2', 'Gene', (68, 73))	('expression', 'MPA', (111, 121))
4330	27339696	4C, HPV18 integrates at intron 1 of PTPN13 in sample EK-A2PK, while HPV16 integrates at exons 2 and 14 for samples WL-A834 and VS-A8QC, respectively.	('HPV', 'Species', '10566', (4, 7))	('PTPN13', 'Gene', (36, 42))	('integrates', 'Reg', (10, 20))	('HPV16', 'Species', '333760', (68, 73))	('VS-A8QC', 'Var', (127, 134))	('HPV18', 'Gene', (4, 9))	('integrates', 'Reg', (74, 84))	('HPV16', 'Gene', (68, 73))	('HPV', 'Species', '10566', (68, 71))	('PTPN13', 'Gene', '5783', (36, 42))
4331	27339696	The distinct virus integration sites and the consistent increase of the expression of the integrated or nearby exons provide strong evidence of novel recurrent HPV integrations within PTPN13.	('increase', 'PosReg', (56, 64))	('integrations', 'Var', (164, 176))	('expression', 'MPA', (72, 82))	('PTPN13', 'Gene', '5783', (184, 190))	('HPV', 'Species', '10566', (160, 163))	('HPV', 'Gene', (160, 163))	('PTPN13', 'Gene', (184, 190))
4336	27339696	For example, TERT was recently implicated by somatic events or viral integration in hepatocarcinogensis.	('TERT', 'Gene', (13, 17))	('hepatocarcinogensis', 'Disease', (84, 103))	('TERT', 'Gene', '7015', (13, 17))	('hepatocarcinogensis', 'Disease', 'None', (84, 103))	('viral integration', 'Var', (63, 80))
4337	27339696	Figure 4D and Table S2 show that the integration sites on KMT2B are between exon 3 and exon 8 and integrations often lead to increased expression of exons following these sites; this holds true for TERT, as well (Fig.	('increased', 'PosReg', (125, 134))	('KMT2B', 'Gene', '9757', (58, 63))	('TERT', 'Gene', '7015', (198, 202))	('integrations', 'Var', (98, 110))	('KMT2B', 'Gene', (58, 63))	('TERT', 'Gene', (198, 202))	('expression of exons', 'MPA', (135, 154))
4341	27339696	The average number of variants for HHV4, HBV and HPV16 are 121, 52 and 22, respectively.	('HBV', 'Gene', (41, 44))	('HPV16', 'Gene', (49, 54))	('HHV4', 'Species', '10376', (35, 39))	('HHV4', 'Gene', (35, 39))	('variants', 'Var', (22, 30))	('HPV16', 'Species', '333760', (49, 54))
4343	27339696	Using RPHM >= 1000 and sites with coverage >10X, we selected 50 variant sites for HBV across 50 HBV-positive LIHC samples, 101 variants across 24 HHV4-positive STAD samples, 17 variants across 60 HPV16-postive HNSC samples and 22 variants across 142 HPV16-positive CESC samples.	('variants', 'Var', (127, 135))	('HBV', 'Gene', (82, 85))	('HPV16', 'Species', '333760', (250, 255))	('HHV4', 'Species', '10376', (146, 150))	('variant', 'Var', (64, 71))	('HPV16', 'Species', '333760', (196, 201))
4344	27339696	Figure 5A shows the unsupervised clustering results for HHV4 variants across HHV4-positive samples with Caucasian and Asian cohorts separated in distinct groups.	('HHV4', 'Species', '10376', (56, 60))	('HHV4', 'Gene', (56, 60))	('HHV4-positive', 'Gene', (77, 90))	('HHV4', 'Species', '10376', (77, 81))	('variants', 'Var', (61, 69))
4345	27339696	Three variants, C   T at sites 343 and 454 and G   A at site 633, result in amino acid substitutions, L418F and P455S in HBV polymerase protein and R160K in S protein, respectively.	('R160K', 'Mutation', 'rs1222267645', (148, 153))	('R160K', 'Var', (148, 153))	('P455S', 'Var', (112, 117))	('HBV', 'Gene', (121, 124))	('P455S', 'Mutation', 'p.P455S', (112, 117))	('L418F', 'Mutation', 'p.L418F', (102, 107))	('L418F', 'Var', (102, 107))
4346	27339696	Variants C   T at sites 505 and 586 and A   G at site 616 are missense mutations, which lead to the respective amino acid substitutions H472Y, R499W and I509 V in HBV polymerase.	('R499W', 'Var', (143, 148))	('I509 V', 'Mutation', 'p.I509V', (153, 159))	('R499W', 'Mutation', 'rs199530208', (143, 148))	('H472Y', 'Mutation', 'p.H472Y', (136, 141))	('H472Y', 'Var', (136, 141))	('I509 V', 'Var', (153, 159))	('HBV polymerase', 'Enzyme', (163, 177))
4347	27339696	Finally, the tumor and adjacent normal pairs have the same variants for the sites observed in Fig.	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (13, 18))	('variants', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
4348	27339696	5B, except for sample DD-A116, in which HBV found in the tumor has an additional variant (A   G) at site 1034, leading to an amino acid substitution Q648R in the HBV polymerase.	('Q648R', 'Var', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Q648R', 'Mutation', 'rs1057519862', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('HBV polymerase', 'Enzyme', (162, 176))	('tumor', 'Disease', (57, 62))
4349	27339696	We also examined viral variation by cancer type by comparing HPV16 variants between CESC and HNSC samples.	('comparing', 'Reg', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('HPV16', 'Gene', (61, 66))	('HPV16', 'Species', '333760', (61, 66))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('examined', 'Reg', (8, 16))	('variants', 'Var', (67, 75))
4351	27339696	Most HPV16 variants overlap between the two cancer types, which suggests they reflect population diversity rather than tissue origin.	('HPV16', 'Gene', (5, 10))	('HPV16', 'Species', '333760', (5, 10))	('variants', 'Var', (11, 19))	('overlap', 'Reg', (20, 27))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
4354	27339696	We did not observe any strong correlation between HPV16 variants and ethnic group.	('variants', 'Var', (56, 64))	('HPV16', 'Species', '333760', (50, 55))	('HPV16', 'Gene', (50, 55))
4357	27339696	HPV subtypes in BLCA are HPV45, HPV51, HPV56 and HPV6 and virus abundance in four samples is especially high (RPHM > 104).	('HPV45', 'Var', (25, 30))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (25, 28))	('HPV', 'Species', '10566', (49, 52))	('HPV51', 'Var', (32, 37))	('HPV6', 'Var', (49, 53))	('HPV', 'Species', '10566', (32, 35))	('HPV', 'Species', '10566', (39, 42))	('HPV56', 'Var', (39, 44))
4367	27339696	For instance, recurrent HBV integrations in the KMT2B (MLL4) were observed in tumors, but none in adjacent normal samples.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('KMT2B', 'Gene', '9757', (48, 53))	('HBV', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MLL4', 'Gene', '9757', (55, 59))	('MLL4', 'Gene', (55, 59))	('integrations', 'Var', (28, 40))	('KMT2B', 'Gene', (48, 53))
4375	27339696	In addition, the analyses of virus variants in tumor samples reveal the association of virus variants and ethnicity groups for HBV in LIHC and HHV4 in STAD.	('HBV', 'Gene', (127, 130))	('HHV4', 'Gene', (143, 147))	('association', 'Interaction', (72, 83))	('variants', 'Var', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('LIHC', 'Disease', (134, 138))	('tumor', 'Disease', (47, 52))	('HHV4', 'Species', '10376', (143, 147))
4395	27339696	We used the contml tool from the PHYLIP toolkit (http://evolution.genetics.washington.edu/phylip.html) to construct phylogenetic trees based on variant allele fraction for HBV and HHV4.	('HHV4', 'Gene', (180, 184))	('variant', 'Var', (144, 151))	('HBV', 'Gene', (172, 175))	('HHV4', 'Species', '10376', (180, 184))
4423	22648069	The relationship of ERalpha phosphorylation (pS-104/106-ERalpha, p-S118-ERalpha, p-S167-ERalpha, p-S282-ERalpha, p-S294-ERalpha, p-T311-ERalpha, and p-S559-ERalpha) to clinical outcome after tamoxifen therapy suggests high phosphorylation status is associated with increased mortality.	('tamoxifen', 'Chemical', 'MESH:D013629', (191, 200))	('p-S118-ERalpha', 'Var', (65, 79))	('pS-104/106-ERalpha', 'Var', (45, 63))	('p-S559-ERalpha', 'Var', (149, 163))	('p-S294-ERalpha', 'Var', (113, 127))	('p-T311-ERalpha', 'Var', (129, 143))	('p-S167-ERalpha', 'Var', (81, 95))	('p-S282-ERalpha', 'Var', (97, 111))	('associated', 'Reg', (249, 259))
4424	22648069	ERalpha-S305 phosphorylation positive breast cancers are resistant to adjuvant tamoxifen treatment, while ERalpha-S305 phosphorylation negative tumors have improved recurrence-free survival with tamoxifen treatment.	('tumors', 'Disease', (144, 150))	('men', 'Species', '9606', (210, 213))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancers', 'Disease', 'MESH:D001943', (38, 52))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('breast cancers', 'Disease', (38, 52))	('men', 'Species', '9606', (94, 97))	('tamoxifen', 'Chemical', 'MESH:D013629', (195, 204))	('improved', 'PosReg', (156, 164))	('recurrence-free survival', 'CPA', (165, 189))	('ERalpha-S305', 'Var', (0, 12))	('ERalpha-S305', 'Var', (106, 118))	('tamoxifen', 'Chemical', 'MESH:D013629', (79, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
4428	22648069	Phosphorylation modifications of ERalpha affect survival in ERalpha-positive breast cancer and could be used to distinguish patients who are more likely to benefit from endocrine therapy alone from those who may be resistant.	('ERalpha', 'Gene', (33, 40))	('breast cancer', 'Disease', (77, 90))	('survival', 'MPA', (48, 56))	('ERalpha-positive', 'Gene', (60, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('patients', 'Species', '9606', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Phosphorylation modifications', 'Var', (0, 29))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('affect', 'Reg', (41, 47))
4431	22648069	In HER2-positive tumors, ERalpha and PR are associated with AR co-expression and lower proliferative activity, while AR-negative/ERalpha-negative tumors were associated with highest proliferative activity and histological grade.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('lower', 'NegReg', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('HER2-positive tumors', 'Disease', (3, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('HER2-positive tumors', 'Disease', 'MESH:D009369', (3, 23))	('ERalpha', 'Var', (25, 32))	('PR', 'Gene', '5241', (37, 39))	('AR', 'Gene', '367', (60, 62))	('proliferative activity', 'CPA', (87, 109))	('tumors', 'Disease', (146, 152))	('AR', 'Gene', '367', (117, 119))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
4435	22648069	ERbeta is regulated by transcriptional and post-transcriptional modifications; ERbeta mRNAs are transcribed from three promoters and variants of ERbeta1, ERbeta2 and ERbeta5 play a role in breast cancer.	('ERbeta1', 'Gene', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ERbeta2', 'Gene', (154, 161))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer', 'Disease', (189, 202))	('role', 'Reg', (181, 185))	('play', 'Reg', (174, 178))	('ERbeta5', 'Gene', (166, 173))	('variants', 'Var', (133, 141))
4442	22648069	In contrast, co-expression of ERbeta and HER2 associates with poorer prognosis in primary breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('poorer', 'NegReg', (62, 68))	('co-expression', 'Var', (13, 26))	('ERbeta', 'Protein', (30, 36))	('breast cancers', 'Phenotype', 'HP:0003002', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HER2', 'Gene', (41, 45))	('breast cancers', 'Disease', 'MESH:D001943', (90, 104))	('breast cancers', 'Disease', (90, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('HER2', 'Gene', '2064', (41, 45))
4445	22648069	One study has demonstrated that nuclear ERbeta-S105 phosphorylation is associated with better survival even in tamoxifen-resistant cases.	('phosphorylation', 'Var', (52, 67))	('survival', 'MPA', (94, 102))	('better', 'PosReg', (87, 93))	('tamoxifen', 'Chemical', 'MESH:D013629', (111, 120))	('nuclear ERbeta-S105', 'Protein', (32, 51))
4450	22648069	In contrast, CUE domain-containing protein-2 (CUEDC2) expression and ERalpha expression are inversely correlated with high CUEDC2 expression being a predictor of poor responsiveness to tamoxifen treatment.	('high', 'Var', (118, 122))	('expression', 'MPA', (77, 87))	('expression', 'MPA', (130, 140))	('CUEDC2', 'Gene', (46, 52))	('CUE domain-containing protein-2', 'Gene', (13, 44))	('CUEDC2', 'Gene', '79004', (46, 52))	('CUE domain-containing protein-2', 'Gene', '79004', (13, 44))	('CUEDC2', 'Gene', (123, 129))	('tamoxifen', 'Chemical', 'MESH:D013629', (185, 194))	('men', 'Species', '9606', (200, 203))	('CUEDC2', 'Gene', '79004', (123, 129))	('ERalpha', 'Gene', (69, 76))
4457	22648069	PBX1-transcriptional program is associated with poor outcome in patients and a study in cells with PBX1 knockdown no longer proliferate after estrogen.	('patients', 'Species', '9606', (64, 72))	('PBX1', 'Gene', (99, 103))	('PBX1', 'Gene', (0, 4))	('PBX1', 'Gene', '5087', (99, 103))	('knockdown', 'Var', (104, 113))	('PBX1', 'Gene', '5087', (0, 4))
4463	22648069	Additionally, the knockdown of ERbeta in MCF-10 and MCF-7 cells results in increased growth in a ligand-independent manner while overexpression of ERbeta allows MCF-7 cells to respond to tamoxifen and inhibit proliferation.	('proliferation', 'CPA', (209, 222))	('knockdown', 'Var', (18, 27))	('ERbeta', 'Gene', (31, 37))	('tamoxifen', 'Chemical', 'MESH:D013629', (187, 196))	('inhibit', 'NegReg', (201, 208))	('growth', 'MPA', (85, 91))	('MCF-10', 'CellLine', 'CVCL:5555', (41, 47))	('MCF-7', 'CellLine', 'CVCL:0031', (52, 57))	('increased', 'PosReg', (75, 84))	('respond to tamoxifen', 'MPA', (176, 196))	('MCF-7', 'CellLine', 'CVCL:0031', (161, 166))
4481	22648069	Studies have examined single-nucleotide polymorphisms (SNPs) for ERalpha and ERbeta to determine whether they confer risks for breast cancer development.	('ERalpha', 'Gene', (65, 72))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('single-nucleotide polymorphisms', 'Var', (22, 53))	('men', 'Species', '9606', (148, 151))	('breast cancer', 'Disease', (127, 140))	('ERbeta', 'Gene', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('risks', 'Reg', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
4482	22648069	Women with sporadic breast cancer more frequently (odds ratio (OR) = 1.99) carry the CC genotype of ERbeta promoter SNP rs2987983.	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (11, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('rs2987983', 'Mutation', 'rs2987983', (120, 129))	('sporadic breast cancer', 'Disease', (11, 33))	('ERbeta promoter', 'Gene', (100, 115))	('rs2987983', 'Var', (120, 129))
4483	22648069	A large cohort examining four htSNPs that tag the six major haploytpes of ERbeta demonstrated that the inherited variants in ERbeta are not associated with an appreciable (OR > 1.2) change in breast cancer risk in Caucasian women.	('ERbeta', 'Gene', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('variants', 'Var', (113, 121))	('women', 'Species', '9606', (224, 229))
4485	22648069	The rs1801132 and rs2234693 ERalpha polymorphisms confer a slight decreased breast cancer risk for CC and CC/CT carriers.	('rs1801132', 'Var', (4, 13))	('rs1801132', 'Mutation', 'rs1801132', (4, 13))	('decreased', 'NegReg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs2234693', 'Var', (18, 27))	('ERalpha', 'Gene', (28, 35))	('rs2234693', 'Mutation', 'rs2234693', (18, 27))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
4486	22648069	C325G SNP in ERalpha is associated with increased cancer risk (OR = 2.28) in women 50 years and younger; however, overall susceptibility to breast cancer was not found.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ERalpha', 'Gene', (13, 20))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('women', 'Species', '9606', (77, 82))	('C325G', 'Mutation', 'rs1801132', (0, 5))	('C325G SNP', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (147, 153))
4487	22648069	SNP rs2046210 at 6q25.1 in the ERalpha promoter only shows a weak association with breast cancer in Chinese and European ancestry women.	('SNP rs2046210', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('women', 'Species', '9606', (130, 135))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('rs2046210', 'Mutation', 'rs2046210', (4, 13))
4488	22648069	In a study of more than 55,000 breast cancer patients to look at SNP rs3020314 in ERalpha intron 4 found no large risks for increased breast cancer susceptibility in European populations.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ERalpha', 'Gene', (82, 89))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('000 breast cancer', 'Disease', 'MESH:D001943', (27, 44))	('patients', 'Species', '9606', (45, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('rs3020314', 'Var', (69, 78))	('000 breast cancer', 'Disease', (27, 44))	('rs3020314', 'Mutation', 'rs3020314', (69, 78))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
4505	22648069	ERbeta levels are inversely correlated with metastasis-associated gene 1 (MTA1) expression and in an in vitro cell model, overexpressing MTA1 reduces ERbeta levels.	('ERbeta levels', 'MPA', (150, 163))	('ERbeta levels', 'MPA', (0, 13))	('metastasis-associated gene 1 (MTA1', 'Gene', '9112', (44, 78))	('MTA1', 'Gene', (74, 78))	('MTA1', 'Gene', (137, 141))	('overexpressing', 'Var', (122, 136))	('reduces', 'NegReg', (142, 149))	('MTA1', 'Gene', '9112', (74, 78))	('MTA1', 'Gene', '9112', (137, 141))
4508	22648069	SNPs and methylation have been examined to determine whether they may be risk factors for ovarian cancer.	('methylation', 'Var', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ovarian cancer', 'Disease', (90, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('ovarian cancer', 'Disease', 'MESH:D010051', (90, 104))
4509	22648069	A comprehensive study of epithelial ovarian cancer in American white women examined 13 different SNPs in ERalpha and found the strongest association of rs2295190 for the mucinous subtype of ovarian cancer (OR = 1.32).	('association', 'Interaction', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('mucinous subtype of ovarian cancer', 'Disease', 'MESH:D010051', (170, 204))	('rs2295190', 'Mutation', 'rs2295190', (152, 161))	('mucinous subtype of ovarian cancer', 'Disease', (170, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (25, 50))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (25, 50))	('women', 'Species', '9606', (69, 74))	('rs2295190', 'Var', (152, 161))	('epithelial ovarian cancer', 'Disease', (25, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))
4510	22648069	The ERbeta rs1271572 polymorphism has an OR = 1.35 for the risk of development of invasive ovarian carcinoma in women <50 years and was strongest among women who had never used contraceptive steroids.	('women', 'Species', '9606', (152, 157))	('invasive ovarian carcinoma', 'Disease', (82, 108))	('women', 'Species', '9606', (112, 117))	('men', 'Species', '9606', (114, 117))	('rs1271572', 'Var', (11, 20))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (91, 108))	('rs1271572', 'Mutation', 'rs1271572', (11, 20))	('men', 'Species', '9606', (154, 157))	('invasive ovarian carcinoma', 'Disease', 'MESH:D010051', (82, 108))	('men', 'Species', '9606', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('steroids', 'Chemical', 'MESH:D013256', (191, 199))	('ERbeta', 'Gene', (4, 10))
4511	22648069	A study to characterize the role of haplotype diversity in ERbeta with the risk of ovarian cancer found five haplotypes with a frequency of >5 % in white subjects, but no association was observed for the risk of ovarian cancer.	('ERbeta', 'Gene', (59, 65))	('haplotype diversity', 'Var', (36, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (212, 226))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ovarian cancer', 'Disease', (83, 97))	('ovarian cancer', 'Disease', (212, 226))
4512	22648069	Promoter methylation analysis of ERbeta from treatment insensitive ovarian cancer cell lines revealed that promoter methylation is cell type-specific and that the loss of ERbeta isoform expression and inactivation correlates with aberrant promoter methylation.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('aberrant', 'Var', (230, 238))	('loss', 'NegReg', (163, 167))	('ovarian cancer', 'Disease', (67, 81))	('ERbeta', 'Protein', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('inactivation', 'NegReg', (201, 213))	('men', 'Species', '9606', (50, 53))	('promoter methylation', 'MPA', (239, 259))	('expression', 'MPA', (186, 196))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))
4513	22648069	Overall, a slight increase in ovarian cancer risk may be attributed to SNPs or altered methylation status of ERalpha or ERbeta.	('increase in ovarian cancer', 'Disease', 'MESH:D010051', (18, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ERalpha', 'Gene', (109, 116))	('SNPs', 'Var', (71, 75))	('altered', 'Reg', (79, 86))	('ERbeta', 'Protein', (120, 126))	('methylation', 'MPA', (87, 98))	('increase in ovarian cancer', 'Disease', (18, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))
4524	22648069	The co-expression of ERbeta and proline, glutamate- and leucine-rich protein 1 (PELP1/MNAR) in epithelial cells of carcinomas is a favorable prognostic factor.	('MNAR', 'Gene', '27043', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('co-expression', 'Var', (4, 17))	('carcinomas', 'Disease', 'MESH:D002277', (115, 125))	('PELP1', 'Gene', (80, 85))	('carcinomas', 'Disease', (115, 125))	('MNAR', 'Gene', (86, 90))	('PELP1', 'Gene', '27043', (80, 85))	('proline', 'Chemical', 'MESH:D011392', (32, 39))
4540	22648069	ERalpha (rs1801132, rs2077647, rs746432, rs2273206, rs851982, and rs2228480) and ERbeta (rs4986938, rs928554, rs8018687, and rs number not available for ESR2 5696 bp 3' of STP A >G) SNPs from multiple cohorts with large study participation observed little evidence for any association of ERalpha or ERbeta polymorphisms with prostate cancer risk.	('rs2077647', 'Var', (20, 29))	('rs851982', 'Mutation', 'rs851982', (52, 60))	('ESR2', 'Gene', (153, 157))	('rs2228480', 'Mutation', 'rs2228480', (66, 75))	('rs746432', 'Mutation', 'rs746432', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('rs4986938', 'Mutation', 'rs4986938', (89, 98))	('rs4986938', 'Var', (89, 98))	('rs1801132', 'Mutation', 'rs1801132', (9, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (325, 340))	('rs928554', 'Mutation', 'rs928554', (100, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (325, 340))	('ERbeta', 'Gene', (299, 305))	('rs2228480', 'Var', (66, 75))	('prostate cancer', 'Disease', (325, 340))	('rs1801132', 'Var', (9, 18))	('rs2273206', 'Mutation', 'rs2273206', (41, 50))	('rs2273206', 'Var', (41, 50))	('rs2077647', 'Mutation', 'rs2077647', (20, 29))	('rs851982', 'Var', (52, 60))	('association', 'Interaction', (273, 284))	('rs8018687', 'Mutation', 'rs8018687', (110, 119))	('ESR2', 'Gene', '2100', (153, 157))	('rs746432', 'Var', (31, 39))	('rs928554', 'Var', (100, 108))	('ERalpha', 'Gene', (288, 295))
4544	22648069	Examination of endometrial carcinomas by tissue microarray, fluorescence in situ hybridization (FISH), and immunohistochemistry demonstrates that the amplification of ERalpha is related to early-stage cancer, but in contrast, the absence of ERalpha correlates to death from disease.	('ERalpha', 'Gene', (167, 174))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('endometrial carcinomas', 'Disease', (15, 37))	('cancer', 'Disease', (201, 207))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (15, 37))	('related', 'Reg', (178, 185))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (15, 36))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (15, 37))	('amplification', 'Var', (150, 163))	('death', 'Disease', 'MESH:D003643', (263, 268))	('death', 'Disease', (263, 268))
4557	22648069	Polymorphic variations of ERalpha (rs2234670, rs2234693, and rs9340799) suggest decreased endometrial cancer risk most strongly with rs9340799 (OR = 0.75 for heterozygous and OR = 0.53 for homozygous).	('rs2234670', 'Mutation', 'rs2234670', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('endometrial cancer', 'Disease', (90, 108))	('rs9340799', 'Mutation', 'rs9340799', (133, 142))	('rs9340799', 'Mutation', 'rs9340799', (61, 70))	('endometrial cancer', 'Phenotype', 'HP:0012114', (90, 108))	('decreased', 'NegReg', (80, 89))	('endometrial cancer', 'Disease', 'MESH:D016889', (90, 108))	('rs9340799', 'Var', (133, 142))	('rs9340799', 'Var', (61, 70))	('rs2234693', 'Mutation', 'rs2234693', (46, 55))	('rs2234693', 'Var', (46, 55))	('rs2234670', 'Var', (35, 44))	('ERalpha', 'Gene', (26, 33))
4558	22648069	These results suggest that intronic variation in ERalpha, depending on the SNP, confers risk or protection to endometrial cancer.	('intronic variation', 'Var', (27, 45))	('endometrial cancer', 'Disease', (110, 128))	('ERalpha', 'Gene', (49, 56))	('endometrial cancer', 'Disease', 'MESH:D016889', (110, 128))	('endometrial cancer', 'Phenotype', 'HP:0012114', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
4585	22648069	SNPs associated with ERalpha (rs2234693-T/C SNP, dinucleotide (TA)(n) repeat), and ERbeta (dinucleotide (CA)(n) repeat) revealed ERalpha longer (TA)(n) repeats correlated with susceptibility to stage I-II endometriosis, and ERbeta shorter (CA)(n) repeats were linked with endometriosis without infertility.	('I-II endometriosis', 'Disease', 'MESH:D004715', (200, 218))	('rs2234693', 'Mutation', 'rs2234693', (30, 39))	('dinucleotide', 'Chemical', 'MESH:D015226', (49, 61))	('endometriosis', 'Phenotype', 'HP:0030127', (205, 218))	('rs2234693-T/C', 'Var', (30, 43))	('endometriosis', 'Disease', 'MESH:D004715', (272, 285))	('I-II endometriosis', 'Disease', (200, 218))	('endometriosis', 'Disease', (272, 285))	('infertility', 'Disease', 'MESH:D007247', (294, 305))	('dinucleotide', 'Chemical', 'MESH:D015226', (91, 103))	('endometriosis', 'Phenotype', 'HP:0030127', (272, 285))	('endometriosis', 'Disease', 'MESH:D004715', (205, 218))	('infertility', 'Phenotype', 'HP:0000789', (294, 305))	('correlated with susceptibility', 'Reg', (160, 190))	('infertility', 'Disease', (294, 305))	('endometriosis', 'Disease', (205, 218))
4586	22648069	Two independent studies have confirmed that the ERalpha gene-397 (T/C) PvuII polymorphism predisposes women to approximately 2.6-fold increase in endometriosis.	('endometriosis', 'Phenotype', 'HP:0030127', (146, 159))	('women', 'Species', '9606', (102, 107))	('ERalpha', 'Gene', (48, 55))	('endometriosis', 'Disease', 'MESH:D004715', (146, 159))	('endometriosis', 'Disease', (146, 159))	('increase', 'PosReg', (134, 142))	('polymorphism', 'Var', (77, 89))	('-397 (T/C)', 'Mutation', 'rs2234693', (60, 70))
4587	22648069	Evaluation of intron 1 and exon 1 ERalpha gene polymorphisms was not associated with increased risk for endometriosis.	('polymorphisms', 'Var', (47, 60))	('ERalpha', 'Gene', (34, 41))	('endometriosis', 'Disease', 'MESH:D004715', (104, 117))	('endometriosis', 'Disease', (104, 117))	('endometriosis', 'Phenotype', 'HP:0030127', (104, 117))
4588	22648069	Together, these data suggest that ER SNPs, specifically SNPs for ERbeta, are associated with increased susceptibility for endometriosis.	('endometriosis', 'Disease', 'MESH:D004715', (122, 135))	('endometriosis', 'Disease', (122, 135))	('ER', 'Gene', '2099', (65, 67))	('endometriosis', 'Phenotype', 'HP:0030127', (122, 135))	('ER', 'Gene', '2099', (34, 36))	('SNPs', 'Var', (56, 60))
4590	22648069	The same group demonstrates increased ERbeta levels concomitant with lower ERalpha levels in endometriosis and experimentally demonstrates that knockdown of ERbeta increases ERalpha while overexpression of ERbeta decreases ERalpha levels.	('increased', 'PosReg', (28, 37))	('increases', 'PosReg', (164, 173))	('ERalpha', 'MPA', (174, 181))	('ERalpha levels', 'MPA', (75, 89))	('ERbeta levels', 'MPA', (38, 51))	('men', 'Species', '9606', (117, 120))	('increased ERbeta levels', 'Phenotype', 'HP:0003141', (28, 51))	('lower', 'NegReg', (69, 74))	('endometriosis', 'Disease', 'MESH:D004715', (93, 106))	('knockdown', 'Var', (144, 153))	('endometriosis', 'Disease', (93, 106))	('endometriosis', 'Phenotype', 'HP:0030127', (93, 106))	('ERbeta', 'Gene', (157, 163))
4602	22648069	ERalpha SNPs (rs9322331 and rs17847075) analyzed in Brazilian women do not differ in women with fibroids compared to controls.	('rs17847075', 'Mutation', 'rs17847075', (28, 38))	('rs9322331', 'Mutation', 'rs9322331', (14, 23))	('rs9322331', 'Var', (14, 23))	('women', 'Species', '9606', (85, 90))	('rs17847075', 'Var', (28, 38))	('women', 'Species', '9606', (62, 67))
4603	22648069	In contrast, a study of Asian Indian women examining a T/C SNP in intron 1 and exon 2 boundary of ERalpha indicated a significant association of the C allele with endometriosis (OR = 2.66) and fibroids (OR = 2.08).	('C allele', 'Var', (149, 157))	('fibroids', 'Disease', (193, 201))	('women', 'Species', '9606', (37, 42))	('endometriosis', 'Phenotype', 'HP:0030127', (163, 176))	('T/C SNP', 'Var', (55, 62))	('endometriosis', 'Disease', 'MESH:D004715', (163, 176))	('endometriosis', 'Disease', (163, 176))
4606	22648069	investigated the DNA methylation status of ERalpha promoter region (-1188 to +229 bp) and indicate hypomethylation of the CpG sites in leiomyomas coincides with increased ERalpha mRNA levels.	('hypomethylation', 'Var', (99, 114))	('leiomyomas', 'Disease', 'MESH:D007889', (135, 145))	('ERalpha mRNA levels', 'MPA', (171, 190))	('leiomyomas', 'Disease', (135, 145))	('increased', 'PosReg', (161, 170))
4611	22648069	examined whether the ERalpha IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and the risk of cardiovascular disease, cancer of reproductive organs, and hip fracture.	('polymorphism', 'Var', (41, 53))	('hip fracture', 'Disease', (214, 226))	('men', 'Species', '9606', (126, 129))	('IVS1-397T/C polymorphism', 'Var', (29, 53))	('ERalpha', 'Gene', (21, 28))	('affects', 'Reg', (54, 61))	('hip fracture', 'Disease', 'MESH:D006620', (214, 226))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cardiovascular disease', 'Disease', (155, 177))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (155, 177))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cardiovascular disease', 'Disease', 'MESH:D002318', (155, 177))	('IVS1-397T/C', 'Mutation', 'c.IVS1-397T>C', (29, 40))	('cancer', 'Disease', (179, 185))	('cholesterol', 'Chemical', 'MESH:D002784', (87, 98))
4620	22648069	Selectively, knocking out ERalpha reduces estrogen's protection by increasing atherosclerotic plaques and serum cholesterol levels in ApoE mice (reviewed in).	('ApoE', 'Gene', (134, 138))	('ApoE', 'Gene', '11816', (134, 138))	('cholesterol', 'Chemical', 'MESH:D002784', (112, 123))	('reduces', 'NegReg', (34, 41))	('atherosclerotic', 'Disease', 'MESH:D050197', (78, 93))	('knocking out', 'Var', (13, 25))	('estrogen', 'MPA', (42, 50))	('increasing atherosclerotic plaques', 'Phenotype', 'HP:0004943', (67, 101))	('mice', 'Species', '10090', (139, 143))	('atherosclerotic', 'Disease', (78, 93))	('ERalpha', 'Gene', (26, 33))	('serum cholesterol levels', 'MPA', (106, 130))	('increasing', 'PosReg', (67, 77))
4621	22648069	Loss of ERalpha specifically in coronary endothelial cells abolishes the protective action of estrogen to limit infarct size and coronary endothelial function.	('protective action', 'CPA', (73, 90))	('limit', 'NegReg', (106, 111))	('infarct', 'Disease', 'MESH:D007238', (112, 119))	('infarct', 'Disease', (112, 119))	('abolishes', 'NegReg', (59, 68))	('ERalpha', 'Gene', (8, 15))	('coronary endothelial function', 'CPA', (129, 158))	('Loss', 'Var', (0, 4))
4627	22648069	The ERbeta knockout mice have elevated blood pressure, and 8beta-VE2, an ERbeta selective ligand that does not promote uterine growth, lowers blood pressure in these mice superior to estradiol or the ERalpha selective agonist 16alpha-LE2.	('16alpha-LE2', 'Chemical', '-', (226, 237))	('elevated blood pressure', 'Phenotype', 'HP:0032263', (30, 53))	('mice', 'Species', '10090', (20, 24))	('lowers', 'NegReg', (135, 141))	('lowers blood pressure', 'Phenotype', 'HP:0002615', (135, 156))	('elevated', 'PosReg', (30, 38))	('mice', 'Species', '10090', (166, 170))	('estradiol', 'Chemical', 'MESH:D004958', (183, 192))	('8beta-VE2', 'Var', (59, 68))	('blood pressure', 'MPA', (39, 53))	('blood pressure', 'MPA', (142, 156))
4719	24899394	This was eliminated by CA 125, AB-PAS and CDX-2 IHC marker negativity within the endometrium while p63 and high molecular weight cytokeratin CK5/6 positivity in the cervix and metastatic ovarian deposits.	('ovarian deposits', 'Disease', 'MESH:D010049', (187, 203))	('p63', 'Gene', '8626', (99, 102))	('CDX-2', 'Gene', '1045', (42, 47))	('CDX-2', 'Gene', (42, 47))	('CK5/6', 'Gene', (141, 146))	('ovarian deposits', 'Disease', (187, 203))	('negativity', 'Var', (59, 69))	('CK5/6', 'Gene', '3852', (141, 146))	('p63', 'Gene', (99, 102))
4792	22209775	High expression of TUBB3 is associated with sensitivity to patupilone in primary CS cell lines and may act as a genetic marker to predict chemotherapy efficacy.	('High expression', 'Var', (0, 15))	('associated', 'Reg', (28, 38))	('TUBB3', 'Gene', (19, 24))	('TUBB3', 'Gene', '10381', (19, 24))	('patupilone', 'Chemical', 'MESH:C093788', (59, 69))
4851	22209775	As demonstrated in the lower panel of Figure 3, TUBB3 copy numbers where again found to be significantly over-expressed in uterine versus ovarian fresh frozen CS specimens (mean +- SEM = 1014 +- 188.5 in uterine vs 363.4 +- 78.57 in ovarian CS, P=0.04).	('over-expressed', 'PosReg', (105, 119))	('copy numbers', 'Var', (54, 66))	('TUBB3', 'Gene', (48, 53))	('TUBB3', 'Gene', '10381', (48, 53))
4876	22209775	We found primary uterine CS to be significantly more sensitive to patupilone when compared to paclitaxel.	('patupilone', 'Var', (66, 76))	('sensitive', 'MPA', (53, 62))	('paclitaxel', 'Chemical', 'MESH:D017239', (94, 104))	('patupilone', 'Chemical', 'MESH:C093788', (66, 76))	('primary uterine CS', 'Disease', (9, 27))
4974	21860733	Both neoplasms are associated with obesity, nulliparity, and exogenous estrogen use.	('associated', 'Reg', (19, 29))	('nulliparity', 'Var', (44, 55))	('neoplasms', 'Phenotype', 'HP:0002664', (5, 14))	('obesity', 'Phenotype', 'HP:0001513', (35, 42))	('neoplasms', 'Disease', 'MESH:D009369', (5, 14))	('neoplasms', 'Disease', (5, 14))	('obesity', 'Disease', 'MESH:D009765', (35, 42))	('obesity', 'Disease', (35, 42))
4983	20368795	The molecular changes in type I endometrial carcinomas include mutations in PTEN, PIK3CA, KRAS, and beta-catenin, along with microsatellite instability, whereas type II endometrial carcinomas are characterized by genetic alterations in p53, HER2/neu, p16, and E-cadherin.	('E-cadherin', 'Gene', (260, 270))	('type II endometrial carcinomas', 'Disease', 'MESH:D016889', (161, 191))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (169, 191))	('PIK3CA', 'Gene', '5290', (82, 88))	('E-cadherin', 'Gene', '999', (260, 270))	('HER2/neu', 'Gene', '2064', (241, 249))	('type I endometrial carcinomas', 'Disease', 'MESH:D016889', (25, 54))	('mutations', 'Var', (63, 72))	('type II endometrial carcinomas', 'Disease', (161, 191))	('PTEN', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (90, 94))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (32, 54))	('p53', 'Gene', '7157', (236, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('type I endometrial carcinomas', 'Disease', (25, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('beta-catenin', 'Gene', (100, 112))	('PIK3CA', 'Gene', (82, 88))	('beta-catenin', 'Gene', '1499', (100, 112))	('KRAS', 'Gene', (90, 94))	('p53', 'Gene', (236, 239))	('PTEN', 'Gene', '5728', (76, 80))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (32, 53))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (169, 190))	('HER2/neu', 'Gene', (241, 249))	('p16', 'Gene', (251, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('p16', 'Gene', '1029', (251, 254))
4984	20368795	For endometrial neoplasms with a malignant mesenchymal component, C-MYC mutations and loss of heterozygosity are frequently seen in carcinosarcomas, and a fusion gene, JAZF1/JJAZ1, is distinctive for endometrial stromal sarcoma.	('seen', 'Reg', (124, 128))	('endometrial stromal sarcoma', 'Disease', (200, 227))	('C-MYC', 'Gene', '4609', (66, 71))	('mutations', 'Var', (72, 81))	('C-MYC', 'Gene', (66, 71))	('JJAZ1', 'Gene', '23512', (174, 179))	('JAZF1', 'Gene', '221895', (168, 173))	('JJAZ1', 'Gene', (174, 179))	('carcinosarcomas', 'Disease', 'MESH:D002296', (132, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('JAZF1', 'Gene', (168, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('endometrial neoplasms', 'Disease', 'MESH:D016889', (4, 25))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (200, 227))	('carcinosarcomas', 'Disease', (132, 147))	('endometrial neoplasms', 'Disease', (4, 25))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (16, 24))
4985	20368795	In addition, p53 mutations may play an important role in tumorigenesis of undifferentiated endometrial sarcoma.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (91, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('endometrial sarcoma', 'Disease', (91, 110))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p53', 'Gene', (13, 16))	('tumor', 'Disease', (57, 62))	('play', 'Reg', (31, 35))	('mutations', 'Var', (17, 26))	('p53', 'Gene', '7157', (13, 16))
5015	20368795	The two distinct histological types of carcinomas are associated with genetic alterations of independent sets of genes.	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('carcinomas', 'Disease', (39, 49))	('carcinomas', 'Disease', 'MESH:D002277', (39, 49))	('genetic alterations', 'Var', (70, 89))
5018	20368795	According to this model, normal endometrial cells would transform into endometrioid endometrial carcinoma through 5 different molecular changes, including, mutations of PTEN, PIK3CA, KRAS, and CTNNB1 (beta-catenin) genes and microsatellite instability (MSI) while non-endometrioid endometrial carcinoma is frequently related to alterations of p53 and chromosomal instability.	('MSI', 'Disease', (253, 256))	('CTNNB1', 'Gene', '1499', (193, 199))	('PIK3CA', 'Gene', '5290', (175, 181))	('p53', 'Gene', (343, 346))	('transform', 'Reg', (56, 65))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (84, 105))	('microsatellite', 'MPA', (225, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('KRAS', 'Gene', '3845', (183, 187))	('CTNNB1', 'Gene', (193, 199))	('PIK3CA', 'Gene', (175, 181))	('endometrioid endometrial carcinoma', 'Disease', (71, 105))	('KRAS', 'Gene', (183, 187))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (281, 302))	('mutations', 'Var', (156, 165))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (71, 105))	('PTEN', 'Gene', (169, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('endometrioid endometrial carcinoma', 'Disease', (268, 302))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (268, 302))	('beta-catenin', 'Gene', (201, 213))	('PTEN', 'Gene', '5728', (169, 173))	('chromosomal instability', 'Phenotype', 'HP:0040012', (351, 374))	('p53', 'Gene', '7157', (343, 346))	('beta-catenin', 'Gene', '1499', (201, 213))	('MSI', 'Disease', 'None', (253, 256))
5020	20368795	Furthermore, none of the five main alterations of endometrioid endometrial carcinoma (mutations of PTEN, PIK3CA, KRAS, and CTNNB1 genes and MSI) plays a major role in non-endometrioid endometrial carcinoma.	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (50, 84))	('endometrioid endometrial carcinoma', 'Disease', (50, 84))	('PIK3CA', 'Gene', '5290', (105, 111))	('KRAS', 'Gene', '3845', (113, 117))	('MSI', 'Disease', 'None', (140, 143))	('CTNNB1', 'Gene', (123, 129))	('MSI', 'Disease', (140, 143))	('KRAS', 'Gene', (113, 117))	('PTEN', 'Gene', (99, 103))	('PIK3CA', 'Gene', (105, 111))	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (184, 205))	('PTEN', 'Gene', '5728', (99, 103))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (171, 205))	('endometrioid endometrial carcinoma', 'Disease', (171, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (63, 84))	('CTNNB1', 'Gene', '1499', (123, 129))
5022	20368795	described the development of non-endometrioid endometrial carcinoma through these possible pathways: (i) de novo, through p53 mutations, loss of heterozygosity (LOH) at several loci, and some other still unknown gene alterations; or (ii) through dedifferentiation of a pre-existing endometrioid carcinoma.	('endometrioid endometrial carcinoma', 'Disease', (33, 67))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (33, 67))	('loss of heterozygosity', 'Var', (137, 159))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (282, 304))	('p53', 'Gene', '7157', (122, 125))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (282, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('endometrioid carcinoma', 'Disease', (282, 304))	('mutations', 'Var', (126, 135))	('alterations', 'Var', (217, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (46, 67))	('p53', 'Gene', (122, 125))
5031	20368795	PTEN may be inactivated by several mechanisms such as mutation, LOH, and promoter hypermethylation.	('promoter hypermethylation', 'Var', (73, 98))	('LOH', 'Var', (64, 67))	('mutation', 'Var', (54, 62))	('inactivated', 'NegReg', (12, 23))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
5032	20368795	Somatic PTEN mutations are common in endometrial carcinoma, and they are almost exclusively restricted to endometrioid endometrial carcinomas, occurring up to 83% of them.	('endometrial carcinoma', 'Disease', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (119, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('endometrioid endometrial carcinomas', 'Disease', (106, 141))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (119, 140))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (119, 141))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (37, 58))	('mutations', 'Var', (13, 22))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (106, 141))	('common', 'Reg', (27, 33))
5033	20368795	Germline mutations of PTEN are responsible for Cowden syndrome.	('Germline mutations', 'Var', (0, 18))	('Cowden syndrome', 'Disease', 'MESH:D006223', (47, 62))	('Cowden syndrome', 'Disease', (47, 62))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('responsible', 'Reg', (31, 42))
5034	20368795	PTEN may be also inactivated by deletion, as shown by LOH in 40% of endometrial carcinomas.	('deletion', 'Var', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (68, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('endometrial carcinomas', 'Disease', (68, 90))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (68, 90))
5035	20368795	Promoter hypermethylation leading to PTEN inactivation, is found in about 20% of tumors, most of which are high-stage.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('inactivation', 'NegReg', (42, 54))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('Promoter hypermethylation', 'Var', (0, 25))
5036	20368795	PTEN mutations have been detected in 15-55% of endometrial hyperplasias with and without atypia.	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (47, 70))	('mutations', 'Var', (5, 14))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (47, 71))	('endometrial hyperplasias', 'Disease', (47, 71))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (47, 71))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('detected', 'Reg', (25, 33))
5038	20368795	This suggests that PTEN could be a target for mutations in the context of DNA repair deficiency.	('PTEN', 'Gene', (19, 23))	('mutations', 'Var', (46, 55))	('PTEN', 'Gene', '5728', (19, 23))
5039	20368795	In addition, identical PTEN mutations have been also identified in hyperplasias coexisting with MSI-positive endometrioid endometrial carcinoma, which suggests that PTEN mutations are early events in their development.	('MSI-positive endometrioid endometrial carcinoma', 'Disease', (96, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (122, 143))	('PTEN', 'Gene', (165, 169))	('PTEN', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('hyperplasias', 'Disease', (67, 79))	('identified', 'Reg', (53, 63))	('PTEN', 'Gene', '5728', (23, 27))	('MSI-positive endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 143))	('mutations', 'Var', (28, 37))	('hyperplasias', 'Disease', 'MESH:D006965', (67, 79))	('PTEN', 'Gene', '5728', (165, 169))
5040	20368795	On the other hand, identical PTEN mutations have been detected in MSI-negative endometrial hyperplasia with coexisting MSI-positive endometrioid endometrial carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('MSI', 'Disease', 'None', (66, 69))	('MSI-positive endometrioid endometrial carcinomas', 'Disease', (119, 167))	('MSI', 'Disease', (119, 122))	('PTEN', 'Gene', (29, 33))	('endometrial hyperplasia', 'Disease', (79, 102))	('MSI-positive endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (119, 167))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (79, 102))	('PTEN', 'Gene', '5728', (29, 33))	('MSI', 'Disease', (66, 69))	('detected', 'Reg', (54, 62))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (145, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (79, 102))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (145, 166))	('mutations', 'Var', (34, 43))	('MSI', 'Disease', 'None', (119, 122))
5041	20368795	Thus, some PTEN mutations may precede MSI, and coexistence of both alterations does not necessarily mean a cause-effect relationship.	('PTEN', 'Gene', (11, 15))	('PTEN', 'Gene', '5728', (11, 15))	('MSI', 'Disease', 'None', (38, 41))	('mutations', 'Var', (16, 25))	('MSI', 'Disease', (38, 41))
5045	20368795	In addition, recent data suggest that only PTEN mutations outside exons 5-7 may predict favorable survival, independent of the clinical and pathological features of the tumors.	('favorable survival', 'CPA', (88, 106))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('predict', 'Reg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('mutations', 'Var', (48, 57))
5049	20368795	Activation of PI3K produces the second messenger PIP3 which subsequently activates various down-stream pathways such as AKT.	('AKT', 'Gene', (120, 123))	('PI3K', 'Var', (14, 18))	('down-stream pathways', 'Pathway', (91, 111))	('AKT', 'Gene', '207', (120, 123))	('activates', 'PosReg', (73, 82))
5051	20368795	Mutations in AKT family members and their correlation with other gene alterations are found in endometrial carcinoma, including AKT2 (D399N), AKT2 (D32H) and AKT3 (E438D) mutations.	('AKT3', 'Gene', '10000', (158, 162))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (95, 116))	('D399N', 'Mutation', 'rs1319165364', (134, 139))	('AKT', 'Gene', (142, 145))	('AKT', 'Gene', '207', (128, 131))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (95, 116))	('AKT3', 'Gene', (158, 162))	('AKT', 'Gene', (13, 16))	('AKT2', 'Gene', '208', (128, 132))	('D32H', 'Mutation', 'p.D32H', (148, 152))	('AKT', 'Gene', '207', (158, 161))	('AKT', 'Gene', '207', (142, 145))	('E438D', 'Mutation', 'p.E438D', (164, 169))	('AKT2', 'Gene', (128, 132))	('D32H', 'Var', (148, 152))	('AKT2', 'Gene', '208', (142, 146))	('AKT', 'Gene', '207', (13, 16))	('E438D) mutations', 'Var', (164, 180))	('AKT2', 'Gene', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('endometrial carcinoma', 'Disease', (95, 116))	('AKT', 'Gene', (128, 131))	('AKT', 'Gene', (158, 161))
5052	20368795	Mutations of AKT3 (E438D) also have amplification of and a mutation in PIK3CA .	('E438D', 'Var', (19, 24))	('amplification', 'MPA', (36, 49))	('PIK3CA', 'Gene', '5290', (71, 77))	('E438D', 'Mutation', 'p.E438D', (19, 24))	('AKT3', 'Gene', (13, 17))	('AKT3', 'Gene', '10000', (13, 17))	('PIK3CA', 'Gene', (71, 77))
5053	20368795	AKT1 E17K mutation is not associated with either PTEN or PIK3CA genomic alteration.	('PTEN', 'Gene', '5728', (49, 53))	('AKT1', 'Gene', '207', (0, 4))	('PIK3CA', 'Gene', '5290', (57, 63))	('AKT1', 'Gene', (0, 4))	('E17K', 'Mutation', 'rs121434592', (5, 9))	('E17K', 'Var', (5, 9))	('PTEN', 'Gene', (49, 53))	('PIK3CA', 'Gene', (57, 63))
5054	20368795	In vitro studies showed that activating mutations of PIK3CA in combination with PTEN mutations led to an additional increase in phosphorylated AKT when compared with cells with only inactivated PTEN.	('PTEN', 'Gene', (80, 84))	('PIK3CA', 'Gene', '5290', (53, 59))	('PTEN', 'Gene', '5728', (80, 84))	('PTEN', 'Gene', (194, 198))	('PIK3CA', 'Gene', (53, 59))	('phosphorylated', 'MPA', (128, 142))	('PTEN', 'Gene', '5728', (194, 198))	('AKT', 'Gene', '207', (143, 146))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (85, 94))	('increase', 'PosReg', (116, 124))	('activating', 'PosReg', (29, 39))	('AKT', 'Gene', (143, 146))
5055	20368795	Some investigators have claimed that PIK3CA mutations are mutually exclusive of PTEN mutations, suggesting that tumorigenic signaling through this pathway can occur either through activation of PIK3CA or inactivation of PTEN.	('PIK3CA', 'Gene', '5290', (194, 200))	('PIK3CA', 'Gene', (37, 43))	('PIK3CA', 'Gene', '5290', (37, 43))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PIK3CA', 'Gene', (194, 200))	('inactivation', 'Var', (204, 216))	('tumor', 'Disease', (112, 117))	('PTEN', 'Gene', (220, 224))	('PTEN', 'Gene', '5728', (220, 224))	('activation', 'PosReg', (180, 190))
5056	20368795	Recently, interactions between the PI3K/AKT and p53 signaling pathways have been described in which activation of the PI3K/AKT pathway through PTEN or PIK3CA mutations, together with p53 inactivation, results in malignant transformation.	('activation', 'PosReg', (100, 110))	('p53', 'Gene', (48, 51))	('results in', 'Reg', (201, 211))	('p53', 'Gene', '7157', (48, 51))	('interactions', 'Interaction', (10, 22))	('PIK3CA', 'Gene', (151, 157))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('AKT', 'Gene', '207', (40, 43))	('PTEN', 'Gene', '5728', (143, 147))	('AKT', 'Gene', '207', (123, 126))	('PIK3CA', 'Gene', '5290', (151, 157))	('AKT', 'Gene', (40, 43))	('PTEN', 'Gene', (143, 147))	('AKT', 'Gene', (123, 126))	('mutations', 'Var', (158, 167))	('malignant transformation', 'CPA', (212, 236))
5057	20368795	Moreover, patients with dysregulation of PI3K/AKT signaling pathway and p53 alterations had shorter survival than patients with only p53 alterations.	('survival', 'MPA', (100, 108))	('alterations', 'Var', (76, 87))	('AKT', 'Gene', '207', (46, 49))	('p53', 'Gene', '7157', (133, 136))	('dysregulation', 'Var', (24, 37))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('AKT', 'Gene', (46, 49))	('patients', 'Species', '9606', (10, 18))	('p53', 'Gene', (133, 136))	('patients', 'Species', '9606', (114, 122))	('shorter', 'NegReg', (92, 99))
5058	20368795	Mutations were more common in mixed endometrioid-nonendometrioid adenocarcinomas (44%) than in pure endometrioid adenocarcinomas (28%) or pure nonendometrioid adenocarcinomas (21%).	('endometrioid adenocarcinomas', 'Disease', (146, 174))	('endometrioid adenocarcinomas', 'Disease', (52, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('Mutations', 'Var', (0, 9))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (100, 128))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (52, 80))	('common', 'Reg', (20, 26))	('endometrioid adenocarcinomas', 'Disease', (100, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
5059	20368795	In fact, PIK3CA mutations are usually missense and cluster in exons 9 (helical domain) and 20 (kinase domain).	('PIK3CA', 'Gene', '5290', (9, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))
5060	20368795	The tumors carrying exon 9 PIK3CA mutations are more likely to be low-grade carcinomas; in contrast, carcinomas with exon 20 mutations or PIK3CA mRNA overexpression are often high-grade carcinomas associated with myometrial invasion and tended to have lymphovascular invasion.	('myometrial invasion', 'Disease', (213, 232))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('carcinomas', 'Disease', (76, 86))	('PIK3CA', 'Gene', (27, 33))	('PIK3CA', 'Gene', (138, 144))	('carcinomas', 'Disease', (186, 196))	('carcinomas', 'Disease', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('associated', 'Reg', (197, 207))	('mutations', 'Var', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('lymphovascular invasion', 'CPA', (252, 275))	('exon 9', 'Var', (20, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('tumors', 'Disease', (4, 10))	('carcinomas', 'Disease', 'MESH:D002277', (76, 86))	('overexpression', 'PosReg', (150, 164))	('carcinomas', 'Disease', 'MESH:D002277', (186, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('carcinomas', 'Disease', 'MESH:D002277', (101, 111))	('PIK3CA', 'Gene', '5290', (27, 33))	('PIK3CA', 'Gene', '5290', (138, 144))
5061	20368795	Furthermore, in high-grade endometrioid adenocarcinomas and mixed carcinomas, PIK3CA mutations in exon 20 coexist with p53 alterations more frequently than in nonendometrioid adenocarcinomas.	('PIK3CA', 'Gene', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (66, 76))	('carcinomas', 'Disease', (180, 190))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (27, 55))	('p53', 'Gene', '7157', (119, 122))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (162, 190))	('alterations', 'Var', (123, 134))	('carcinomas', 'Disease', (45, 55))	('mutations in', 'Var', (85, 97))	('mixed', 'Disease', (60, 65))	('p53', 'Gene', (119, 122))	('carcinomas', 'Disease', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('PIK3CA', 'Gene', '5290', (78, 84))	('endometrioid adenocarcinomas', 'Disease', (27, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrioid adenocarcinomas', 'Disease', (162, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('carcinomas', 'Disease', 'MESH:D002277', (45, 55))
5063	20368795	PIK3CA mutations did not correlate with MSI or beta-catenin/CTNNB1 mutations.	('beta-catenin', 'Gene', '1499', (47, 59))	('CTNNB1', 'Gene', (60, 66))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (67, 76))	('PIK3CA', 'Gene', '5290', (0, 6))	('beta-catenin', 'Gene', (47, 59))	('MSI', 'Disease', 'None', (40, 43))	('CTNNB1', 'Gene', '1499', (60, 66))	('MSI', 'Disease', (40, 43))	('mutations', 'Var', (7, 16))
5064	20368795	PIK3CA mutations, particularly exon 20 mutations or PIK3CA mRNA overexpression, are frequent in endometrioid endometrial carcinoma in association with invasion and adverse prognostic factors such as blood vessel invasion.	('blood vessel invasion', 'CPA', (199, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('exon 20 mutations', 'Var', (31, 48))	('frequent', 'Reg', (84, 92))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (109, 130))	('PIK3CA', 'Gene', (52, 58))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 130))	('endometrioid endometrial carcinoma', 'Disease', (96, 130))	('PIK3CA', 'Gene', '5290', (52, 58))	('mRNA', 'MPA', (59, 63))	('mutations', 'Var', (7, 16))
5066	20368795	KRAS mutations have been identified in 10-30% of endometrioid endometrial carcinomas while some investigators have reported an almost complete absence of KRAS mutations in serous and clear cell carcinomas of endometrium.	('KRAS', 'Gene', '3845', (154, 158))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (62, 84))	('clear cell carcinomas', 'Disease', (183, 204))	('identified', 'Reg', (25, 35))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (49, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (62, 83))	('endometrioid endometrial carcinomas', 'Disease', (49, 84))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (183, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', (154, 158))	('KRAS', 'Gene', '3845', (0, 4))
5067	20368795	Some studies found a higher frequency of KRAS mutations in MSI-positive carcinomas than in MSI-negative tumors suggesting that both events may occur simultaneously before clonal expansion.	('MSI', 'Disease', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('KRAS', 'Gene', '3845', (41, 45))	('mutations', 'Var', (46, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MSI', 'Disease', 'None', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MSI-positive carcinomas', 'Disease', 'MESH:D002277', (59, 82))	('MSI-positive carcinomas', 'Disease', (59, 82))	('tumors', 'Disease', (104, 110))	('MSI', 'Disease', (59, 62))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('MSI', 'Disease', 'None', (91, 94))	('KRAS', 'Gene', (41, 45))
5068	20368795	KRAS mutations were detected in endometrial hyperplasias at a similar rate to that observed in endometrioid endometrial carcinomas, suggesting that KRAS mutations are early events in endometrial carcinogensis.	('KRAS', 'Gene', (148, 152))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (32, 55))	('endometrial hyperplasias', 'Disease', (32, 56))	('endometrioid endometrial carcinomas', 'Disease', (95, 130))	('mutations', 'Var', (153, 162))	('endometrial carcinogensis', 'Disease', (183, 208))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (32, 56))	('endometrial carcinogensis', 'Disease', 'MESH:D014591', (183, 208))	('endometrial carcinogensis', 'Phenotype', 'HP:0012114', (183, 208))	('KRAS', 'Gene', '3845', (148, 152))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (108, 130))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (32, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (95, 130))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (108, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
5069	20368795	No relationship has been found between KRAS mutations and tumor stage, histologic grade, depth of myometrial invasion, age, or clinical outcome in endometrioid endometrial carcinomas.	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (147, 182))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('endometrioid endometrial carcinomas', 'Disease', (147, 182))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (160, 182))	('KRAS', 'Gene', '3845', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (160, 181))
5073	20368795	Mutations in exon 3 of CTNNB1 result in stabilization of a protein that resists degradation, leading to nuclear accumulation of beta-catenin, have been described in endometrioid endometrial carcinoma.	('CTNNB1', 'Gene', (23, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('described', 'Reg', (152, 161))	('beta-catenin', 'Gene', (128, 140))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (178, 199))	('stabilization', 'MPA', (40, 53))	('beta-catenin', 'Gene', '1499', (128, 140))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (165, 199))	('endometrioid endometrial carcinoma', 'Disease', (165, 199))	('Mutations in', 'Var', (0, 12))	('CTNNB1', 'Gene', '1499', (23, 29))
5076	20368795	By comparison in colonic adenocarcinomas, elevated beta-catenin levels caused by mutations in CTNNB1 or APC result in activation of the Wnt/beta-catenin/LEF1 pathway through a LEF1 binding site in the cyclin D1 promotor, triggering cyclin D1 gene expression, and subsequently, uncontrolled progression of tumor cells into the cell cycle.	('cyclin D1', 'Gene', '595', (201, 210))	('colonic adenocarcinomas', 'Disease', (17, 40))	('binding', 'Interaction', (181, 188))	('cyclin D1', 'Gene', (232, 241))	('mutations', 'Var', (81, 90))	('tumor', 'Disease', (305, 310))	('triggering', 'Reg', (221, 231))	('expression', 'MPA', (247, 257))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('cyclin D1', 'Gene', '595', (232, 241))	('elevated', 'PosReg', (42, 50))	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (17, 40))	('LEF1', 'Gene', (176, 180))	('LEF1', 'Gene', (153, 157))	('CTNNB1', 'Gene', '1499', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('beta-catenin', 'Gene', (51, 63))	('beta-catenin', 'Gene', (140, 152))	('activation', 'PosReg', (118, 128))	('beta-catenin', 'Gene', '1499', (140, 152))	('cyclin D1', 'Gene', (201, 210))	('beta-catenin', 'Gene', '1499', (51, 63))	('APC', 'Disease', 'MESH:D011125', (104, 107))	('APC', 'Disease', (104, 107))	('LEF1', 'Gene', '51176', (153, 157))	('CTNNB1', 'Gene', (94, 100))	('LEF1', 'Gene', '51176', (176, 180))
5078	20368795	The reported frequency of CTNNB1 mutations in endometrioid endometrial carcinoma ranges from 14-44%.	('CTNNB1', 'Gene', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutations', 'Var', (33, 42))	('CTNNB1', 'Gene', '1499', (26, 32))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (59, 80))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (46, 80))	('endometrioid endometrial carcinoma', 'Disease', (46, 80))
5080	20368795	In all cases, the mutations were homogeneously distributed in different areas of the tumors suggesting that they play a role in early steps of endometrial tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('play', 'Reg', (113, 117))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('role', 'Reg', (120, 124))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (18, 27))
5081	20368795	Alterations in beta-catenin have been reported in endometrial hyperplasias with squamous metaplasia.	('squamous metaplasia', 'Phenotype', 'HP:0002860', (80, 99))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (50, 73))	('reported', 'Reg', (38, 46))	('endometrial hyperplasias', 'Disease', (50, 74))	('Alterations', 'Var', (0, 11))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (50, 74))	('beta-catenin', 'Gene', (15, 27))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (50, 74))	('beta-catenin', 'Gene', '1499', (15, 27))	('squamous metaplasia', 'Disease', (80, 99))	('squamous metaplasia', 'Disease', 'MESH:D008679', (80, 99))
5082	20368795	Although there was a good correlation between CTNNB1 mutations and beta-catenin nuclear immunostaining, the presence of cytoplasmic and nuclear beta-catenin immunoreactivity in some endometrial carcinomas without CTNNB mutation suggests that the changes of other genes in the Wnt/beta-catenin/LEF-1 pathway may be responsible for the stabilization and putative transcription activator role of beta-catenin.	('CTNNB', 'Gene', '1499', (213, 218))	('endometrial carcinomas', 'Disease', (182, 204))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (182, 203))	('CTNNB', 'Gene', (213, 218))	('beta-catenin', 'Gene', (144, 156))	('LEF-1', 'Gene', '51176', (293, 298))	('beta-catenin', 'Gene', '1499', (144, 156))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (182, 204))	('LEF-1', 'Gene', (293, 298))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (182, 204))	('CTNNB', 'Gene', (46, 51))	('beta-catenin', 'Gene', (393, 405))	('mutations', 'Var', (53, 62))	('CTNNB1', 'Gene', '1499', (46, 52))	('beta-catenin', 'Gene', '1499', (393, 405))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('beta-catenin', 'Gene', (280, 292))	('CTNNB', 'Gene', '1499', (46, 51))	('beta-catenin', 'Gene', (67, 79))	('beta-catenin', 'Gene', '1499', (280, 292))	('beta-catenin', 'Gene', '1499', (67, 79))	('CTNNB1', 'Gene', (46, 52))
5083	20368795	Endometrioid endometrial carcinomas with CTNNB1 mutations are characteristically early stage tumors associated with favorable prognosis.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (13, 34))	('stage tumors', 'Disease', 'MESH:D062706', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (13, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('CTNNB1', 'Gene', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('endometrial carcinomas', 'Disease', (13, 35))	('stage tumors', 'Disease', (87, 99))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (13, 35))	('mutations', 'Var', (48, 57))	('CTNNB1', 'Gene', '1499', (41, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))
5092	20368795	In sporadic endometrial carcinoma, epigenetic cause of MSI is more common involving MLH1 promotor hypermethylation which is the main cause of MMR deficiency.	('MMR deficiency', 'Disease', (142, 156))	('epigenetic', 'Var', (35, 45))	('MLH1', 'Gene', '4292', (84, 88))	('MLH1', 'Gene', (84, 88))	('MMR deficiency', 'Disease', 'MESH:C536143', (142, 156))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (12, 33))	('MSI', 'Disease', 'None', (55, 58))	('common', 'Reg', (67, 73))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (12, 33))	('MSI', 'Disease', (55, 58))	('cause', 'Reg', (46, 51))	('endometrial carcinoma', 'Disease', (12, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('hypermethylation', 'Var', (98, 114))
5093	20368795	This epigenetic inactivation usually occurs in atypical hyperplasia, most of which coexists with carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (47, 67))	('atypical hyperplasia', 'Disease', (47, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('carcinomas', 'Disease', (97, 107))	('carcinomas', 'Disease', 'MESH:D002277', (97, 107))	('occurs', 'Reg', (37, 43))	('epigenetic inactivation', 'Var', (5, 28))
5094	20368795	Thus, MLH1 hypermethylation is an early event in the pathogenesis of endometrioid endometrial carcinoma, which precedes the development of MSI.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('MSI', 'Disease', (139, 142))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (82, 103))	('hypermethylation', 'Var', (11, 27))	('MLH1', 'Gene', '4292', (6, 10))	('MLH1', 'Gene', (6, 10))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (69, 103))	('endometrioid endometrial carcinoma', 'Disease', (69, 103))	('MSI', 'Disease', 'None', (139, 142))
5095	20368795	The remaining unmethylated MLH1 cases reveal MSH2 mutations (15%) and MSH6 mutations (60%), of which almost half are germline mutations.	('mutations', 'Var', (50, 59))	('MSH2', 'Gene', (45, 49))	('MSH6', 'Gene', (70, 74))	('MLH1', 'Gene', '4292', (27, 31))	('MSH2', 'Gene', '4436', (45, 49))	('MLH1', 'Gene', (27, 31))	('MSH6', 'Gene', '2956', (70, 74))	('mutations', 'Var', (75, 84))
5096	20368795	Thus, MSH6 mutations seem to be a frequent cause of MSI.	('mutations', 'Var', (11, 20))	('cause', 'Reg', (43, 48))	('MSI', 'Disease', 'None', (52, 55))	('MSH6', 'Gene', '2956', (6, 10))	('MSI', 'Disease', (52, 55))	('MSH6', 'Gene', (6, 10))
5097	20368795	Tumors with MSI of CpG island methylation in the promoter region have been identified in some other genes, for example, p16, PTEN, and E-cadherin (CDH1), suggesting altered methylation may be a coexisting independent early change.	('methylation', 'Var', (30, 41))	('PTEN', 'Gene', (125, 129))	('CDH1', 'Gene', '999', (147, 151))	('PTEN', 'Gene', '5728', (125, 129))	('p16', 'Gene', (120, 123))	('E-cadherin', 'Gene', '999', (135, 145))	('MSI', 'Disease', 'None', (12, 15))	('methylation', 'MPA', (173, 184))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p16', 'Gene', '1029', (120, 123))	('CDH1', 'Gene', (147, 151))	('E-cadherin', 'Gene', (135, 145))	('MSI', 'Disease', (12, 15))
5098	20368795	The presentation of some small short-tandem repeats such as mononucleotide repeats located within the coding sequence of important genes for example, transforming growth factor beta receptor type II (TGF-betaRII), BAX, insulin-like growth factor II receptor (IGFIIR), MSH3, MSH6, caspase-5, and PTEN may promote MSI-positive endometrial carcinoma.	('mononucleotide', 'Chemical', '-', (60, 74))	('promote', 'PosReg', (304, 311))	('caspase-5', 'Gene', '838', (280, 289))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (325, 346))	('short-tandem repeats', 'Var', (31, 51))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (325, 346))	('MSH3', 'Gene', (268, 272))	('insulin-like growth factor II receptor', 'Gene', '3482', (219, 257))	('MSH3', 'Gene', '4437', (268, 272))	('MSH6', 'Gene', (274, 278))	('TGF-betaRII', 'Gene', '7048', (200, 211))	('MSI', 'Disease', 'None', (312, 315))	('BAX', 'Gene', (214, 217))	('MSH6', 'Gene', '2956', (274, 278))	('insulin-like growth factor II receptor', 'Gene', (219, 257))	('BAX', 'Gene', '581', (214, 217))	('MSI', 'Disease', (312, 315))	('caspase-5', 'Gene', (280, 289))	('PTEN', 'Gene', (295, 299))	('transforming growth factor beta receptor type II', 'Gene', '7048', (150, 198))	('TGF-betaRII', 'Gene', (200, 211))	('endometrial carcinoma', 'Disease', (325, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (337, 346))	('mononucleotide repeats', 'Var', (60, 82))	('transforming growth factor beta receptor type II', 'Gene', (150, 198))	('IGFIIR', 'Gene', '3482', (259, 265))	('PTEN', 'Gene', '5728', (295, 299))	('IGFIIR', 'Gene', (259, 265))
5103	20368795	While p53 mutations occur in 90% of non-endometrioid endometrial carcinoma, they are only present in 10-20% of endometrioid endometrial carcinoma, which are mostly high-grade.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (111, 145))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (53, 74))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (40, 74))	('endometrioid endometrial carcinoma', 'Disease', (40, 74))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (124, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('mutations', 'Var', (10, 19))	('endometrioid endometrial carcinoma', 'Disease', (111, 145))
5104	20368795	The abnormal p53 expression has been found in 11% of grade 1 endometrioid endometrial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (74, 95))	('abnormal', 'Var', (4, 12))	('endometrioid endometrial carcinoma', 'Disease', (61, 95))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 95))	('found', 'Reg', (37, 42))	('expression', 'MPA', (17, 27))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))
5105	20368795	This finding supports that p53 mutations may influence progression of endometrioid endometrial carcinomas to non-endometrioid endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('mutations', 'Var', (31, 40))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (70, 105))	('p53', 'Gene', '7157', (27, 30))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (83, 105))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (126, 147))	('endometrioid endometrial carcinomas', 'Disease', (113, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (83, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('influence', 'Reg', (45, 54))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (113, 148))	('endometrioid endometrial carcinomas', 'Disease', (70, 105))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (126, 148))	('p53', 'Gene', (27, 30))
5106	20368795	In fact, p53 mutation is the most characteristic genetic alteration of non-endometrioid endometrial carcinomas and may be useful in their distinction from endometrioid endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (88, 109))	('endometrioid endometrial carcinomas', 'Disease', (75, 110))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (155, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('mutation', 'Var', (13, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (168, 189))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (88, 110))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (75, 110))	('endometrioid endometrial carcinomas', 'Disease', (155, 190))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (168, 190))
5111	20368795	p53 mutations produce a non-functional protein that resists degradation and can be visualized by immunostaining.	('p53', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('p53', 'Gene', '7157', (0, 3))	('non-functional protein', 'MPA', (24, 46))
5112	20368795	However, loss of function of p53 resulting from LOH may not correlate with protein overexpression.	('LOH', 'Var', (48, 51))	('loss of function', 'NegReg', (9, 25))	('p53', 'Gene', '7157', (29, 32))	('p53', 'Gene', (29, 32))
5113	20368795	In addition, frameshift mutations and stop codons lead to a truncated protein, which is not detected by antibodies and leads to negative immunohistochemistry After DNA damage, nuclear p53 accumulates and causes cell cycle arrest by inhibiting cyclin D1 phosphorylation of the Rb gene and thereby promoting apoptosis.	('phosphorylation', 'MPA', (253, 268))	('lead to', 'Reg', (50, 57))	('truncated', 'MPA', (60, 69))	('promoting', 'PosReg', (296, 305))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (211, 228))	('p53', 'Gene', (184, 187))	('cyclin D1', 'Gene', '595', (243, 252))	('p53', 'Gene', '7157', (184, 187))	('accumulates', 'PosReg', (188, 199))	('cyclin D1', 'Gene', (243, 252))	('cell cycle arrest', 'CPA', (211, 228))	('frameshift mutations', 'Var', (13, 33))	('causes', 'Reg', (204, 210))	('apoptosis', 'CPA', (306, 315))	('inhibiting', 'NegReg', (232, 242))
5114	20368795	Overexpression of p53 is associated with high histological grade and advanced stage as well as unfavorable prognosis.	('p53', 'Gene', '7157', (18, 21))	('advanced stage', 'CPA', (69, 83))	('Overexpression', 'Var', (0, 14))	('p53', 'Gene', (18, 21))
5117	20368795	Mutations of p53 are also found in 75-80% of EIC.	('p53', 'Gene', (13, 16))	('found', 'Reg', (26, 31))	('Mutations', 'Var', (0, 9))	('EIC', 'Disease', (45, 48))	('p53', 'Gene', '7157', (13, 16))
5118	20368795	It is postulated that mutation in one allele occurs early during the development of serous carcinoma, and loss of the second normal allele occurs late in the progression to carcinoma.	('mutation', 'Var', (22, 30))	('serous carcinoma', 'Disease', (84, 100))	('carcinoma', 'Disease', 'MESH:D002277', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('serous carcinoma', 'Disease', 'MESH:D018284', (84, 100))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Disease', (173, 182))	('carcinoma', 'Disease', (91, 100))
5119	20368795	p53 mutations are almost always associated with aneuploidy and do not seem to occur with PTEN mutations in the same tumor.	('p53', 'Gene', (0, 3))	('aneuploidy', 'Disease', (48, 58))	('p53', 'Gene', '7157', (0, 3))	('aneuploidy', 'Disease', 'MESH:D000782', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('associated with', 'Reg', (32, 47))	('mutations', 'Var', (4, 13))	('PTEN', 'Gene', (89, 93))	('tumor', 'Disease', (116, 121))	('PTEN', 'Gene', '5728', (89, 93))
5121	20368795	HER2/neu overexpression or amplification is more frequently found in non-endometrioid endometrial carcinoma (18-80%) than in grade 2 and 3 endometrioid carcinoma (10-30%) and has been associated with adverse prognostic parameters including advanced stage, high histologic grade, and low overall survival.	('endometrioid carcinoma', 'Disease', (139, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('overexpression', 'PosReg', (9, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (139, 161))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (73, 107))	('endometrioid endometrial carcinoma', 'Disease', (73, 107))	('HER2/neu', 'Gene', '2064', (0, 8))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (139, 161))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (86, 107))	('amplification', 'Var', (27, 40))	('HER2/neu', 'Gene', (0, 8))
5124	20368795	p16 inactivation can lead to uncontrolled cell growth.	('inactivation', 'Var', (4, 16))	('uncontrolled cell growth', 'CPA', (29, 53))	('p16', 'Gene', (0, 3))	('lead to', 'Reg', (21, 28))	('p16', 'Gene', '1029', (0, 3))
5125	20368795	Inactivation of p16 is more frequent in non-endometrioid endometrial carcinoma (40-45%) than in endometrioid endometrial carcinoma (10%).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (109, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (57, 78))	('p16', 'Gene', '1029', (16, 19))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (44, 78))	('endometrioid endometrial carcinoma', 'Disease', (44, 78))	('frequent', 'Reg', (28, 36))	('endometrioid endometrial carcinoma', 'Disease', (96, 130))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 130))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))
5126	20368795	Loss of p16 expression is correlated with KRAS and p53 mutations and is associated with high stage, high grade, and poor survival.	('high stage', 'CPA', (88, 98))	('KRAS', 'Gene', (42, 46))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('p16', 'Gene', '1029', (8, 11))	('KRAS', 'Gene', '3845', (42, 46))	('mutations', 'Var', (55, 64))	('associated', 'Reg', (72, 82))	('Loss', 'NegReg', (0, 4))	('p16', 'Gene', (8, 11))	('expression', 'MPA', (12, 22))	('high grade', 'CPA', (100, 110))
5128	20368795	It is thought to be a tumor suppressor gene, the loss of which has been demonstrated to promote tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss', 'Var', (49, 53))	('metastasis', 'CPA', (115, 125))	('promote', 'PosReg', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
5133	20368795	p53 mutations are only present in about 30-40% of clear cell carcinomas compared to 90% of serous carcinomas.	('serous carcinomas', 'Disease', (91, 108))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('clear cell carcinomas', 'Disease', (50, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (50, 71))	('mutations', 'Var', (4, 13))	('serous carcinomas', 'Disease', 'MESH:D018284', (91, 108))
5134	20368795	However, the frequency of MSI and PTEN alterations in clear cell carcinoma is higher than in serous carcinoma (15% versus <5 for MSI and 30% versus 10% for PTEN) but lower compared with endometrioid carcinoma (20-40% and 35-50%, resp.).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('PTEN', 'Gene', (156, 160))	('serous carcinoma', 'Disease', 'MESH:D018284', (93, 109))	('endometrioid carcinoma', 'Disease', (186, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('PTEN', 'Gene', '5728', (156, 160))	('MSI', 'Disease', 'None', (26, 29))	('PTEN', 'Gene', (34, 38))	('MSI', 'Disease', 'None', (129, 132))	('MSI', 'Disease', (129, 132))	('MSI', 'Disease', (26, 29))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (186, 208))	('lower', 'NegReg', (166, 171))	('PTEN', 'Gene', '5728', (34, 38))	('clear cell carcinoma', 'Disease', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('serous carcinoma', 'Disease', (93, 109))	('alterations', 'Var', (39, 50))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (186, 208))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (54, 74))
5135	20368795	A recent molecular study demonstrated that the majority of pure clear cell carcinomas do not show mutations in either PTEN or p53, the most commonly altered genes in type I and type II tumors, respectively.	('type II tumors', 'Disease', (177, 191))	('p53', 'Gene', '7157', (126, 129))	('type II tumors', 'Disease', 'MESH:D009369', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('PTEN', 'Gene', '5728', (118, 122))	('clear cell carcinomas', 'Disease', (64, 85))	('PTEN', 'Gene', (118, 122))	('mutations', 'Var', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('p53', 'Gene', (126, 129))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (64, 85))
5151	20368795	One study found STK15 amplification in 9 of 15 (60%) non-endometrioid endometrial carcinomas but in none of endometrioid endometrial carcinomas.	('STK15', 'Gene', (16, 21))	('STK15', 'Gene', '6790', (16, 21))	('endometrioid endometrial carcinomas', 'Disease', (57, 92))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (121, 143))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (108, 143))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (70, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('amplification', 'Var', (22, 35))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (57, 92))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (121, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (70, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('endometrioid endometrial carcinomas', 'Disease', (108, 143))
5162	20368795	In addition, the number of chromosomal aberrations in complex hyperplasia is significantly higher than simple hyperplasia and close to the number found in atypical hyperplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (164, 175))	('hyperplasia', 'Disease', (110, 121))	('chromosomal aberrations', 'Var', (27, 50))	('higher', 'PosReg', (91, 97))	('hyperplasia', 'Disease', 'MESH:D006965', (62, 73))	('hyperplasia', 'Disease', 'MESH:D006965', (110, 121))	('atypical hyperplasia', 'Disease', (155, 175))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 50))	('hyperplasia', 'Disease', (164, 175))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (155, 175))	('hyperplasia', 'Disease', (62, 73))
5165	20368795	However, PTEN and KRAS mutations seem to occur earlier, since they were found in simple hyperplasia, partially associated with monoclonality.	('hyperplasia', 'Disease', 'MESH:D006965', (88, 99))	('found', 'Reg', (72, 77))	('KRAS', 'Gene', (18, 22))	('PTEN', 'Gene', (9, 13))	('KRAS', 'Gene', '3845', (18, 22))	('PTEN', 'Gene', '5728', (9, 13))	('hyperplasia', 'Disease', (88, 99))	('mutations', 'Var', (23, 32))
5167	20368795	The inactivation of E-cadherin gene by methylation seems to play a role during progression of endometrioid carcinoma, since it is most frequently found in grade 3 and least frequently in grade 1 tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('methylation', 'Var', (39, 50))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (94, 116))	('E-cadherin', 'Gene', (20, 30))	('E-cadherin', 'Gene', '999', (20, 30))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (94, 116))	('endometrioid carcinoma', 'Disease', (94, 116))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('inactivation', 'NegReg', (4, 16))
5168	20368795	Furthermore, p53 mutations, HER2/neu overexpression or amplification, and p16 inactivation are considered in late events during carcinogenesis of endometrioid carcinoma, since they are predominantly identified in grade 3 tumors, but rarely in grade 1 tumors, and are absent in atypical hyperplastic lesions.	('overexpression', 'PosReg', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('mutations', 'Var', (17, 26))	('p16', 'Gene', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinogenesis of endometrioid carcinoma', 'Disease', (128, 168))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('p16', 'Gene', '1029', (74, 77))	('tumors', 'Disease', (221, 227))	('p53', 'Gene', '7157', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('HER2/neu', 'Gene', (28, 36))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('p53', 'Gene', (13, 16))	('inactivation', 'NegReg', (78, 90))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (146, 168))	('carcinogenesis of endometrioid carcinoma', 'Disease', 'MESH:D016889', (128, 168))	('HER2/neu', 'Gene', '2064', (28, 36))
5169	20368795	Hypothetically, p53 mutations and HER2/neu amplification might also be early events in de novo poorly differentiated endometrioid carcinomas (Figure 2).	('HER2/neu', 'Gene', (34, 42))	('endometrioid carcinomas', 'Disease', (117, 140))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (117, 139))	('p53', 'Gene', (16, 19))	('amplification', 'Var', (43, 56))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (117, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('p53', 'Gene', '7157', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (117, 140))	('HER2/neu', 'Gene', '2064', (34, 42))	('mutations', 'Var', (20, 29))
5170	20368795	Endometrial pre-cancers (e.g., EIC) have been postulated to share common genetic alterations with endometrioid endometrial carcinoma, including PTEN mutations and MSI.	('cancers', 'Disease', (16, 23))	('mutations', 'Var', (149, 158))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (98, 132))	('endometrioid endometrial carcinoma', 'Disease', (98, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('MSI', 'Disease', 'None', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('PTEN', 'Gene', (144, 148))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (111, 132))	('MSI', 'Disease', (163, 166))	('PTEN', 'Gene', '5728', (144, 148))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
5171	20368795	Mutations of p53 were found in approximately 80% of EIC, but in contrast to most serous carcinomas, there is no LOH at the locus TP53.	('EIC', 'Disease', (52, 55))	('serous carcinomas', 'Disease', (81, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('TP53', 'Gene', '7157', (129, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('TP53', 'Gene', (129, 133))	('p53', 'Gene', '7157', (13, 16))	('serous carcinomas', 'Disease', 'MESH:D018284', (81, 98))
5172	20368795	Thus, it is hypothesized that p53 mutation of one allele occurs early, whereas loss of the normal second allele accompanies progression into serous carcinoma.	('serous carcinoma', 'Disease', (141, 157))	('serous carcinoma', 'Disease', 'MESH:D018284', (141, 157))	('mutation', 'Var', (34, 42))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
5173	20368795	The alterations of E-cadherin, p16, and HER2/neu seem to affect the progression from EIC to serous carcinoma.	('p16', 'Gene', '1029', (31, 34))	('alterations', 'Var', (4, 15))	('HER2/neu', 'Gene', '2064', (40, 48))	('E-cadherin', 'Gene', (19, 29))	('EIC', 'Disease', (85, 88))	('HER2/neu', 'Gene', (40, 48))	('affect', 'Reg', (57, 63))	('serous carcinoma', 'Disease', (92, 108))	('p16', 'Gene', (31, 34))	('E-cadherin', 'Gene', '999', (19, 29))	('serous carcinoma', 'Disease', 'MESH:D018284', (92, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))
5174	20368795	Another group hypothesized that serous carcinoma may develop from endometrioid carcinoma through p53 mutation based on findings in mixed endometrioid and serous carcinomas.	('serous carcinomas', 'Disease', 'MESH:D018284', (154, 171))	('serous carcinoma', 'Disease', 'MESH:D018284', (154, 170))	('serous carcinomas', 'Disease', (154, 171))	('serous carcinoma', 'Disease', (32, 48))	('p53', 'Gene', (97, 100))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (66, 88))	('p53', 'Gene', '7157', (97, 100))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (66, 88))	('serous carcinoma', 'Disease', 'MESH:D018284', (32, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('develop', 'Reg', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('endometrioid carcinoma', 'Disease', (66, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('mutation', 'Var', (101, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))
5178	20368795	It is an autosomal dominant syndrome that predisposes its carriers to multiple malignancies particularly colorectal, and endometrial carcinomas, caused by a germline mutation in one of the DNA MMR genes occurring in 30-60% of cases.	('DNA MMR', 'Gene', (189, 196))	('caused by', 'Reg', (145, 154))	('malignancies particularly colorectal', 'Disease', 'MESH:D009369', (79, 115))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (121, 143))	('autosomal dominant syndrome', 'Disease', (9, 36))	('germline mutation', 'Var', (157, 174))	('malignancies particularly colorectal', 'Disease', (79, 115))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (121, 143))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (9, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (121, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('endometrial carcinomas', 'Disease', (121, 143))
5181	20368795	The frequency of germline DNA MMR gene mutations among unselected patients with endometrial carcinoma has been found to be 1.8-2.1%, which is similar to the frequency of HNPCC in colorectal carcinoma.	('HNPCC in colorectal carcinoma', 'Disease', 'MESH:D015179', (170, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('HNPCC', 'Phenotype', 'HP:0006716', (170, 175))	('HNPCC in colorectal carcinoma', 'Disease', (170, 199))	('DNA MMR', 'Gene', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (80, 101))	('mutations', 'Var', (39, 48))	('endometrial carcinoma', 'Disease', (80, 101))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('patients', 'Species', '9606', (66, 74))
5182	20368795	Patients with endometrial carcinoma in the HNPCC population have an inherited germline mutation in MLH1, MSH2, MSH6, or PMS2 (first hit) but endometrial carcinoma develops only after the initiation of a deletion or mutation in the contralateral MLH1, MSH2, MSH6, or PMS2 allele (second hit) in endometrial cells.	('MLH1', 'Gene', (245, 249))	('MSH2', 'Gene', '4436', (105, 109))	('MSH6', 'Gene', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (14, 35))	('PMS2', 'Gene', (266, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (141, 162))	('HNPCC', 'Disease', 'None', (43, 48))	('MSH6', 'Gene', '2956', (111, 115))	('HNPCC', 'Disease', (43, 48))	('MLH1', 'Gene', '4292', (245, 249))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (14, 35))	('MSH2', 'Gene', (251, 255))	('PMS2', 'Gene', '5395', (120, 124))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (141, 162))	('Patients', 'Species', '9606', (0, 8))	('MSH6', 'Gene', (257, 261))	('mutation', 'Var', (215, 223))	('MSH6', 'Gene', '2956', (257, 261))	('MSH2', 'Gene', '4436', (251, 255))	('MLH1', 'Gene', (99, 103))	('HNPCC', 'Phenotype', 'HP:0006716', (43, 48))	('PMS2', 'Gene', '5395', (266, 270))	('deletion', 'Var', (203, 211))	('mutation', 'Var', (87, 95))	('PMS2', 'Gene', (120, 124))	('MSH2', 'Gene', (105, 109))	('MLH1', 'Gene', '4292', (99, 103))	('endometrial carcinoma', 'Disease', (14, 35))	('endometrial carcinoma', 'Disease', (141, 162))
5184	20368795	Unlike HNPCC associated colorectal carcinoma, which appears to frequently have MLH1 and MSH2 mutations, endometrial carcinomas have a higher probability of MSH2 and MSH6 mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (24, 44))	('MLH1', 'Gene', '4292', (79, 83))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (104, 126))	('HNPCC', 'Phenotype', 'HP:0006716', (7, 12))	('MSH6', 'Gene', (165, 169))	('MSH2', 'Gene', '4436', (88, 92))	('MSH6', 'Gene', '2956', (165, 169))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (104, 126))	('MSH2', 'Gene', (156, 160))	('mutations', 'Var', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('endometrial carcinomas', 'Disease', (104, 126))	('MSH2', 'Gene', '4436', (156, 160))	('HNPCC', 'Disease', (7, 12))	('HNPCC', 'Disease', 'None', (7, 12))	('mutations', 'Var', (170, 179))	('MLH1', 'Gene', (79, 83))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (104, 125))	('colorectal carcinoma', 'Disease', (24, 44))	('MSH2', 'Gene', (88, 92))
5185	20368795	Women with HNPCC who carry MSH2 and MSH6 mutations have a higher chance to present initially with endometrial rather than colorectal cancer.	('mutations', 'Var', (41, 50))	('HNPCC', 'Disease', 'None', (11, 16))	('HNPCC', 'Phenotype', 'HP:0006716', (11, 16))	('HNPCC', 'Disease', (11, 16))	('Women', 'Species', '9606', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('colorectal cancer', 'Disease', (122, 139))	('MSH2', 'Gene', (27, 31))	('MSH6', 'Gene', (36, 40))	('MSH2', 'Gene', '4436', (27, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('MSH6', 'Gene', '2956', (36, 40))	('endometrial', 'Disease', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
5194	20368795	PTEN inactivation by mutation seems to also be involved in tumorigenesis, since it occurs in about 90% of type I carcinomas.	('type I carcinomas', 'Disease', 'MESH:D017827', (106, 123))	('tumor', 'Disease', (59, 64))	('involved', 'Reg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutation', 'Var', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('inactivation', 'NegReg', (5, 17))	('type I carcinomas', 'Disease', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
5197	20368795	studied serial endometrial biopsy samples taken during a 10-year followup of HPNCC mutation carriers and found abnormal MMR protein expression, MSI, or tumor suppressor promotor hypermethylation in various endometrial histologies, including normal and hyperplastic endometria.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('MSI', 'Disease', 'None', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('hyperplastic endometria', 'Phenotype', 'HP:0040298', (252, 275))	('HPNCC', 'Gene', (77, 82))	('tumor', 'Disease', (152, 157))	('MSI', 'Disease', (144, 147))	('mutation', 'Var', (83, 91))	('MMR protein', 'Protein', (120, 131))	('abnormal', 'Reg', (111, 119))	('hypermethylation', 'Var', (178, 194))
5198	20368795	The most frequently methylated genes were CDH13, RASSF1A, and GSTP1.	('CDH13', 'Gene', '1012', (42, 47))	('methylated', 'Var', (20, 30))	('RASSF1A', 'Gene', (49, 56))	('GSTP1', 'Gene', (62, 67))	('RASSF1A', 'Gene', '11186', (49, 56))	('CDH13', 'Gene', (42, 47))	('GSTP1', 'Gene', '2950', (62, 67))
5200	20368795	PTEN hamartoma tumor syndrome, caused by a germline mutation in PTEN gene on chromosome 10q, comprises a group of disorders including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, Proteus-like syndrome, and autism spectrum disorder with macrocephaly.	('Cowden syndrome', 'Disease', (134, 149))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('autism', 'Phenotype', 'HP:0000717', (231, 237))	('hamartoma', 'Phenotype', 'HP:0010566', (5, 14))	('macrocephaly', 'Disease', (261, 273))	('Proteus-like syndrome', 'Disease', 'MESH:D016715', (204, 225))	('autism spectrum disorder', 'Disease', 'MESH:D000067877', (231, 255))	('macrocephaly', 'Disease', 'MESH:D058627', (261, 273))	('Proteus syndrome', 'Disease', (186, 202))	('hamartoma tumor syndrome', 'Disease', (5, 29))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', 'MESH:D006223', (151, 184))	('autism spectrum disorder', 'Disease', (231, 255))	('Proteus-like syndrome', 'Disease', (204, 225))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (231, 255))	('PTEN', 'Gene', (64, 68))	('Proteus syndrome', 'Disease', 'MESH:D016715', (186, 202))	('PTEN', 'Gene', (0, 4))	('caused by', 'Reg', (31, 40))	('macrocephaly', 'Phenotype', 'HP:0000256', (261, 273))	('Cowden syndrome', 'Disease', 'MESH:D006223', (134, 149))	('hamartoma tumor syndrome', 'Disease', 'MESH:D006222', (5, 29))	('germline mutation', 'Var', (43, 60))	('PTEN', 'Gene', '5728', (64, 68))	('PTEN', 'Gene', '5728', (0, 4))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', (151, 184))
5204	20368795	PTEN mutations in exon 5, coding for the active site and flanking amino acids, is a common site for mutations in patients with Cowden syndrome, and missense mutations are only found in this active area.	('mutations', 'Var', (100, 109))	('Cowden syndrome', 'Disease', 'MESH:D006223', (127, 142))	('patients', 'Species', '9606', (113, 121))	('Cowden syndrome', 'Disease', (127, 142))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
5205	20368795	However, germline PTEN mutation has been detected in approximately 80% of Cowden syndrome patients.	('Cowden syndrome', 'Disease', 'MESH:D006223', (74, 89))	('PTEN', 'Gene', (18, 22))	('PTEN', 'Gene', '5728', (18, 22))	('mutation', 'Var', (23, 31))	('Cowden syndrome', 'Disease', (74, 89))	('patients', 'Species', '9606', (90, 98))	('detected', 'Reg', (41, 49))
5219	20368795	Many carcinosarcomas contained aberrations on chromosome 8 and 20 detected by FISH.	('aberrations', 'Var', (31, 42))	('carcinosarcomas', 'Disease', 'MESH:D002296', (5, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('carcinosarcomas', 'Disease', (5, 20))
5221	20368795	Gains or amplifications of 8q are the most common genetic aberration in carcinosarcomas.	('Gains', 'Var', (0, 5))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('carcinosarcomas', 'Disease', 'MESH:D002296', (72, 87))	('carcinosarcomas', 'Disease', (72, 87))
5225	20368795	p53 mutations and LOH for TP53 occur frequently in both carcinosarcoma components which are associated with frequent protein overexpression.	('p53', 'Gene', '7157', (0, 3))	('TP53', 'Gene', (26, 30))	('p53', 'Gene', (0, 3))	('carcinosarcoma', 'Disease', 'MESH:D002296', (56, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('carcinosarcoma', 'Disease', (56, 70))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (4, 13))
5258	20368795	In contrast to epithelial endometrial carcinoma, endometrial stromal tumors are characterized by distinct cytogenetic abnormalities, particularly translocations leading to gene fusion.	('epithelial endometrial carcinoma', 'Disease', 'MESH:D016889', (15, 47))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (49, 75))	('translocations', 'Var', (146, 160))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (26, 47))	('epithelial endometrial carcinoma', 'Disease', (15, 47))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('gene', 'MPA', (172, 176))	('endometrial stromal tumors', 'Disease', (49, 75))	('genetic abnormalities', 'Disease', 'MESH:D030342', (110, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('genetic abnormalities', 'Disease', (110, 131))
5259	20368795	Cytogenetic studies reported to-date are primarily for low grade endometrial stromal sarcomas, mostly showing rearrangement of chromosomes 6, 7, and 17.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (65, 93))	('rearrangement', 'Var', (110, 123))	('endometrial stromal sarcomas', 'Disease', (65, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
5260	20368795	Loss of chromosome arm 7p (55.6% of the cases) is the most frequent aberration and may play a role in tumor development and progression.	('tumor', 'Disease', (102, 107))	('role', 'Reg', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Loss', 'Var', (0, 4))	('play', 'Reg', (87, 91))
5272	20368795	A major subgroup of endometrial stromal sarcomas has been found to have translocations involving short arm of chromosome 6, particularly band 6p21.	('p21', 'Gene', (143, 146))	('p21', 'Gene', '644914', (143, 146))	('translocations', 'Var', (72, 86))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (20, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('endometrial stromal sarcomas', 'Disease', (20, 48))	('short arm', 'Phenotype', 'HP:0009824', (97, 106))
5274	20368795	introduced that a low-grade endometrial stromal sarcoma cell line carrying a der(7)t(6;7)(p21;p22) also harbors a JAZF1/PHF1 fusion.	('PHF1', 'Gene', (120, 124))	('der(7)t(6;7)(p21;p22', 'Var', (77, 97))	('JAZF1', 'Gene', '221895', (114, 119))	('PHF1', 'Gene', '5252', (120, 124))	('endometrial stromal sarcoma', 'Disease', (28, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('der(7)t(6;7)(p21;p22)', 'STRUCTURAL_ABNORMALITY', 'None', (77, 98))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (28, 55))	('JAZF1', 'Gene', (114, 119))
5276	20368795	Additionally, few endometrial stromal sarcoma cases were reported with a t(X;17)(p11.2;q23) and a t(10;17)(q22;p13).	('t(10;17)(q22;p13', 'Var', (98, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('endometrial stromal sarcoma', 'Disease', (18, 45))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (98, 115))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (18, 45))	('t(X;17)(p11.2;q23', 'Var', (73, 90))	('t(X;17)(p11.2;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (73, 91))
5292	20368795	The importance of p53 mutations for the development of undifferentiated endometrial sarcomas is not evident, but p53 overexpression was detected in three of four high-grade stromal sarcomas.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('undifferentiated endometrial sarcomas', 'Disease', (55, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('p53', 'Gene', '7157', (113, 116))	('overexpression', 'PosReg', (117, 131))	('mutations', 'Var', (22, 31))	('stromal sarcomas', 'Disease', (173, 189))	('p53', 'Gene', (113, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('stromal sarcomas', 'Disease', 'MESH:D046152', (173, 189))	('undifferentiated endometrial sarcomas', 'Disease', 'MESH:D018203', (55, 92))
5293	20368795	have recently found frequent nuclear accumulation of p53 and TP53 gene missense mutations in undifferentiated endometrial sarcoma with nuclear pleomorphism, 3 (50%) of 6 cases.	('missense mutations', 'Var', (71, 89))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (110, 129))	('endometrial sarcoma', 'Disease', (110, 129))	('nuclear accumulation', 'MPA', (29, 49))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
5295	20368795	p53 alteration may be one different pathway that contributes the tumorigenesis of undifferentiated endometrial sarcoma.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('alteration', 'Var', (4, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (99, 118))	('endometrial sarcoma', 'Disease', (99, 118))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
5302	20368795	Dysregulation of these pathways allows beta-catenin to accumulate and translocate to the nucleus, where it forms complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) leading to uncontrolled cell growth and carcinogenesis.	('TCF/LEF', 'Gene', '3172', (169, 176))	('complexes', 'Interaction', (113, 122))	('Dysregulation', 'Var', (0, 13))	('accumulate', 'PosReg', (55, 65))	('carcinogenesis', 'Disease', (218, 232))	('uncontrolled cell growth', 'CPA', (189, 213))	('carcinogenesis', 'Disease', 'MESH:D063646', (218, 232))	('beta-catenin', 'Gene', (39, 51))	('beta-catenin', 'Gene', '1499', (39, 51))	('TCF/LEF', 'Gene', (169, 176))
5306	20368795	Therefore, we can exploit our knowledge of the dualistic model and their typical gene mutations and use the immunoprofile as a diagnostic tool, in concert with the histomorphologic features to specify the tumor type, particularly in difficult cases such as in the differentiation between high-grade endometrioid carcinoma and serous carcinoma (Table 3).	('mutations', 'Var', (86, 95))	('endometrioid carcinoma and serous carcinoma', 'Disease', 'MESH:D016889', (299, 342))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (299, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))
5307	20368795	The distinct molecular alteration described in the majority of endometrial stromal sarcomas is the t(7;17)(p15;q21) leading to the formation of fusion gene JAZF1/JJAZ1, which can be detected by RT-PCR or FISH assays.	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('JAZF1', 'Gene', (156, 161))	('JJAZ1', 'Gene', '23512', (162, 167))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (63, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('t(7;17)(p15;q21', 'Var', (99, 114))	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('JJAZ1', 'Gene', (162, 167))	('JAZF1', 'Gene', '221895', (156, 161))	('endometrial stromal sarcomas', 'Disease', (63, 91))
5316	20368795	By CGH, leiomyosarcomas have the most frequent losses including 10q, 11q, 13q, and 2p while the most common gains are Xp, 1q, 5p, 8q, 12q, 17p and 19p.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (8, 22))	('leiomyosarcomas', 'Disease', (8, 23))	('10q', 'Var', (64, 67))	('losses', 'NegReg', (47, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (8, 23))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (8, 23))
5317	20368795	There are a variety of genetic changes and mutations inclusive of TP53 and MDM2 expression associated with progression of leiomyosarcomas.	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (122, 137))	('MDM2', 'Gene', '4193', (75, 79))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (122, 137))	('MDM2', 'Gene', (75, 79))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (122, 136))	('mutations', 'Var', (43, 52))	('leiomyosarcomas', 'Disease', (122, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('associated', 'Reg', (91, 101))
5318	20368795	LOH of 10q is found in more than half of leiomyosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (41, 56))	('LOH of 10q', 'Var', (0, 10))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (41, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('leiomyosarcomas', 'Disease', (41, 56))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (41, 55))
5321	20368795	Drug targets may focus on genes that affect apoptosis, signal transduction, epigenetic modification, drug resistance, protein folding and degradation, cell cycle progression, hormone receptor activity, and angiogenesis.	('hormone receptor', 'Gene', (175, 191))	('degradation', 'MPA', (138, 149))	('drug resistance', 'MPA', (101, 116))	('hormone receptor', 'Gene', '3164', (175, 191))	('cell cycle', 'CPA', (151, 161))	('apoptosis', 'CPA', (44, 53))	('affect', 'Reg', (37, 43))	('epigenetic modification', 'Var', (76, 99))	('drug resistance', 'Phenotype', 'HP:0020174', (101, 116))	('angiogenesis', 'CPA', (206, 218))	('protein folding', 'MPA', (118, 133))
5325	20368795	In in vitro studies, cells with PTEN inactivation in endometrioid carcinoma are sensitive to mTOR inhibitors, since the loss of PTEN leads to constitutive activation of downstream components, which in turn up-regulates mTOR activity.	('mTOR', 'Gene', (219, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('up-regulates', 'PosReg', (206, 218))	('PTEN', 'Gene', (128, 132))	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (93, 97))	('PTEN', 'Gene', (32, 36))	('constitutive', 'MPA', (142, 154))	('PTEN', 'Gene', '5728', (128, 132))	('PTEN', 'Gene', '5728', (32, 36))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (53, 75))	('mTOR', 'Gene', '2475', (219, 223))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (53, 75))	('loss', 'Var', (120, 124))	('activation', 'PosReg', (155, 165))	('endometrioid carcinoma', 'Disease', (53, 75))
5352	20368795	They are associated with a number of well-described genetic alterations including mutations of PTEN, KRAS, beta-catenin, PIK3CA, and inactivation of DNA mismatch repair.	('beta-catenin', 'Gene', (107, 119))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('associated', 'Reg', (9, 19))	('beta-catenin', 'Gene', '1499', (107, 119))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', (121, 127))	('PTEN', 'Gene', (95, 99))	('PIK3CA', 'Gene', '5290', (121, 127))	('PTEN', 'Gene', '5728', (95, 99))	('DNA mismatch repair', 'Protein', (149, 168))	('inactivation', 'Var', (133, 145))
5355	20368795	Mutations of p53 are present in approximately 90% of this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('p53', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('p53', 'Gene', '7157', (13, 16))
5356	20368795	Carcinosarcoma is considered to be a high-grade carcinoma with sarcomatous differentiation and a high frequency of C-MYC mutations and LOH of p53.	('Carcinosarcoma', 'Disease', 'MESH:D002296', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('C-MYC', 'Gene', '4609', (115, 120))	('sarcomatous', 'Disease', (63, 74))	('p53', 'Gene', (142, 145))	('carcinoma', 'Disease', (48, 57))	('p53', 'Gene', '7157', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Carcinosarcoma', 'Disease', (0, 14))	('LOH', 'Var', (135, 138))	('sarcomatous', 'Disease', 'MESH:D018316', (63, 74))	('C-MYC', 'Gene', (115, 120))	('carcinoma', 'Disease', 'MESH:D002277', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
5360	18603495	Tamoxifen results in a spectrum of abnormalities involving the genital tract, the most significant being an increased incidence of endometrial cancer and uterine sarcoma.	('results in', 'Reg', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('Tamoxifen', 'Var', (0, 9))	('endometrial cancer', 'Disease', (131, 149))	('sarcoma', 'Disease', (162, 169))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (154, 169))	('abnormalities involving the genital tract', 'Phenotype', 'HP:0000078', (35, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('endometrial cancer', 'Phenotype', 'HP:0012114', (131, 149))	('endometrial cancer', 'Disease', 'MESH:D016889', (131, 149))
5374	18603495	Tamoxifen results in a spectrum of uterine abnormalities including benign alterations such as endometrial polyps, endometrial hyperplasia, endometrial cystic atrophy, adenomyosis, and uterine fibroid growth as well as malignant transformation into endometrial carcinoma and uterine sarcoma.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (274, 289))	('adenomyosis', 'Disease', (167, 178))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('endometrial carcinoma', 'Disease', (248, 269))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (114, 137))	('uterine abnormalities', 'Phenotype', 'HP:0000130', (35, 56))	('endometrial polyps', 'Disease', (94, 112))	('malignant transformation', 'CPA', (218, 242))	('sarcoma', 'Disease', 'MESH:D012509', (282, 289))	('results in', 'Reg', (10, 20))	('sarcoma', 'Disease', (282, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('endometrial hyperplasia', 'Disease', (114, 137))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (248, 269))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (114, 137))	('endometrial cystic atrophy', 'Disease', (139, 165))	('Tamoxifen', 'Var', (0, 9))	('uterine fibroid', 'Phenotype', 'HP:0000131', (184, 199))	('uterine', 'Disease', (184, 191))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (248, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('endometrial polyps', 'Disease', 'MESH:D011127', (94, 112))	('adenomyosis', 'Disease', 'MESH:D062788', (167, 178))	('endometrial cystic atrophy', 'Disease', 'MESH:D016889', (139, 165))
5408	18603495	Asymptomatic unilocular cysts in these patients should be followed conservatively and discontinuation of tamoxifen usually leads to the reduction and disappearance of these cysts.	('unilocular cysts', 'Disease', (13, 29))	('tamoxifen', 'Chemical', 'MESH:D013629', (105, 114))	('discontinuation', 'Var', (86, 101))	('patients', 'Species', '9606', (39, 47))
5410	18603495	Of particular concern is the negative effect of tamoxifen-induced ovulation and the risk of ovarian carcinoma in patients with BRCA1 and BRCA2 gene mutations.	('BRCA2', 'Gene', '675', (137, 142))	('mutations', 'Var', (148, 157))	('BRCA1', 'Gene', '672', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (92, 109))	('patients', 'Species', '9606', (113, 121))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (92, 109))	('BRCA1', 'Gene', (127, 132))	('ovarian carcinoma', 'Disease', (92, 109))	('tamoxifen', 'Chemical', 'MESH:D013629', (48, 57))	('BRCA2', 'Gene', (137, 142))
5501	33842328	APOBEC3B, a member of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like) enzymes with cytidine deaminase activity, can induce prevalent mutagen of genomic DNA in multiple cancers.	('cytidine deaminase', 'Gene', (109, 127))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('APOBEC3B', 'Gene', (0, 8))	('mutagen', 'Var', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('induce', 'Reg', (142, 148))	('cytidine deaminase', 'Gene', '978', (109, 127))
5503	33842328	High expression of APOBEC3B is associated with immune evasion of cancer.	('High', 'Var', (0, 4))	('APOBEC3B', 'Gene', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (31, 41))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
5504	33842328	Notably, high expression of APOBEC3B also enhances the sensitivity to immune checkpoint blockade in melanoma.	('APOBEC3B', 'Gene', (28, 36))	('sensitivity to immune checkpoint blockade', 'MPA', (55, 96))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('enhances', 'PosReg', (42, 50))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('high', 'Var', (9, 13))
5525	33842328	To figure out the relationship between APOBEC3B and molecular subtypes, we further investigated the expression level of APOBEC3B among subtypes: increased expression level of APBOEC3B was found in CL and ME compared to PN and NE (P <.05, respectively;  Figure 1C ).	('APBOEC3B', 'Var', (175, 183))	('ME', 'Chemical', '-', (204, 206))	('CL', 'Disease', 'None', (197, 199))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (155, 165))
5528	33842328	Glioma patients with codeletion of 1p and 19q derived more benefits in several clinical trials.	('codeletion', 'Var', (21, 31))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('benefits', 'PosReg', (59, 67))	('patients', 'Species', '9606', (7, 15))
5529	33842328	We observed that the expression of APOBEC3B was decreased in the 1p19q codeletion cluster in pan-glioma analysis (P <.05, respectively;  Figure 1D ).	('glioma', 'Disease', (97, 103))	('1p19q', 'Var', (65, 70))	('expression', 'MPA', (21, 31))	('decreased', 'NegReg', (48, 57))	('APOBEC3B', 'Gene', (35, 43))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
5544	33842328	We revealed that APOBEC3Bhigh patients showed shorter overall survival (OS) than APOBEC3Blow patients in pan-glioma, LGG, and GBM (P <.05, respectively;  Figures 3A, B ).	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('APOBEC3Bhigh', 'Var', (17, 29))	('overall survival', 'MPA', (54, 70))	('glioma', 'Disease', (109, 115))	('patients', 'Species', '9606', (30, 38))	('shorter', 'NegReg', (46, 53))	('patients', 'Species', '9606', (93, 101))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
5547	33842328	High APOBEC3B expression was significantly correlated to worse prognosis in nine cancer types, including ACC, CHOL, ESCA, LIHC, LUAD, PAAD, UCEC, UCS, and KICH (P <.0001, respectively;  Figure 3C ).	('CHOL', 'Disease', 'None', (110, 114))	('LUAD', 'Phenotype', 'HP:0030078', (128, 132))	('cancer', 'Disease', (81, 87))	('ACC', 'Phenotype', 'HP:0006744', (105, 108))	('ACC', 'Disease', (105, 108))	('LIHC', 'Disease', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ESCA', 'Phenotype', 'HP:0011459', (116, 120))	('KICH', 'Disease', 'None', (155, 159))	('High', 'Var', (0, 4))	('LUAD', 'Disease', (128, 132))	('CHOL', 'Disease', (110, 114))	('UCEC', 'Disease', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('CHOL', 'Phenotype', 'HP:0030153', (110, 114))	('PAAD', 'Phenotype', 'HP:0006725', (134, 138))	('KICH', 'Disease', (155, 159))	('APOBEC3B', 'Gene', (5, 13))	('ESCA', 'Disease', (116, 120))	('PAAD', 'Disease', (134, 138))	('expression', 'MPA', (14, 24))	('UCS', 'Disease', (146, 149))
5550	33842328	Besides the variation of chr1 and chr19, amplification of chr7 and deletion of chr10 most frequently occurred in glioma patients ( Figure 4A ).	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('occurred', 'Reg', (101, 109))	('deletion', 'Var', (67, 75))	('chr7', 'Gene', (58, 62))	('glioma', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('amplification', 'Var', (41, 54))	('chr10', 'Gene', (79, 84))
5551	33842328	As a genomic symbol of oligodendroglioma, deletion of 1p and 19q tended to appear in APOBEC3Blow cluster ( Figure 4B ).	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('APOBEC3Blow', 'Gene', (85, 96))	('oligodendroglioma', 'Disease', (23, 40))	('oligodendroglioma', 'Disease', 'MESH:D009837', (23, 40))	('deletion', 'Var', (42, 50))	('appear', 'Reg', (75, 81))
5557	33842328	Common carcinogenic pathways were found to be more active in APOBEC3Bhigh group ( Figures 5E, G ).	('carcinogenic', 'Disease', (7, 19))	('carcinogenic', 'Disease', 'MESH:D063646', (7, 19))	('APOBEC3Bhigh', 'Var', (61, 73))	('more active', 'PosReg', (46, 57))
5558	33842328	The strongest co-occurrent pairs of gene alteration in the APOBEC3Bhigh group were ATRX-TP53, and in the APOBEC3Blow groups were ATRX-TP53 as well as ATRX-IDH1, which was in line with previous studies> Meanwhile, the most mutually exclusive pairs in APOBEC3Bhigh and APOBEC3Blow groups were CIC-TP53 and EGFR-IDH1, respectively ( Figures 5F, H ).	('TP53', 'Gene', (134, 138))	('ATRX', 'Gene', (150, 154))	('IDH1', 'Gene', '3417', (155, 159))	('TP53', 'Gene', '7157', (88, 92))	('ATRX', 'Gene', '546', (150, 154))	('IDH1', 'Gene', (309, 313))	('EGFR', 'Gene', (304, 308))	('TP53', 'Gene', '7157', (295, 299))	('ATRX', 'Gene', (83, 87))	('ATRX', 'Gene', '546', (83, 87))	('TP53', 'Gene', '7157', (134, 138))	('ATRX', 'Gene', (129, 133))	('rat', 'Species', '10116', (45, 48))	('IDH1', 'Gene', '3417', (309, 313))	('ATRX', 'Gene', '546', (129, 133))	('EGFR', 'Gene', '1956', (304, 308))	('alteration', 'Var', (41, 51))	('TP53', 'Gene', (88, 92))	('TP53', 'Gene', (295, 299))	('IDH1', 'Gene', (155, 159))
5583	33842328	Generally, somatic mutation has been considered as a therapy evasion promoter of cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('somatic mutation', 'Var', (11, 27))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
5584	33842328	Correspondingly, mutation can also promote antitumor T-cell response.	('mutation', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('promote', 'PosReg', (35, 42))	('tumor', 'Disease', (47, 52))
5587	33842328	For example, highly expressed APOBEC3B is regarded as an unfavorable prognostic factors in myeloma, ovarian cancer, and clear cell renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('APOBEC3B', 'Gene', (30, 38))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 151))	('clear cell renal cell carcinoma', 'Disease', (120, 151))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (120, 151))	('myeloma, ovarian cancer', 'Disease', 'MESH:D009101', (91, 114))	('highly expressed', 'Var', (13, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
5590	33842328	Most recently, the duality of APOBEC3B in immunotherapy has been demonstrated, in which APOBEC3B not only acts as the general driving force of therapy escape but also significantly activates the immune system in melanoma.	('rat', 'Species', '10116', (72, 75))	('APOBEC3B', 'Var', (88, 96))	('immune system', 'CPA', (195, 208))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('activates', 'PosReg', (181, 190))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))
5594	33842328	But the activation of tumor-infiltrating immune cells also mediates APOBEC3B deletion in breast cancer in Asian patients.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('APOBEC3B', 'Gene', (68, 76))	('breast cancer', 'Disease', (89, 102))	('patients', 'Species', '9606', (112, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('deletion', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('rat', 'Species', '10116', (34, 37))
5602	33842328	Several immune infiltrating cell types possess the features of immunosuppression: It is well documented that MDSC is able to inhibit innate and adaptive immunity, and macrophages have been indicated to promote cancer cell proliferation, immunosuppression, and angiogenesis in cancers.	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('inhibit', 'NegReg', (125, 132))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('rat', 'Species', '10116', (229, 232))	('cancers', 'Disease', (276, 283))	('promote', 'PosReg', (202, 209))	('immunosuppression', 'CPA', (237, 254))	('angiogenesis', 'CPA', (260, 272))	('rat', 'Species', '10116', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('MDSC', 'Var', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
5605	33842328	Cell type enrichment analysis further revealed that APOBEC3B was significantly correlated with MDSC, macrophage, regulatory T cells, and Th2 cells in glioma, KICH, PAAD, and UCS, providing evidence to the statement that APOBEC3B was an immunotherapy escape driver in LGG.	('KICH', 'Disease', (158, 162))	('PAAD', 'Phenotype', 'HP:0006725', (164, 168))	('APOBEC3B', 'Var', (220, 228))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Disease', (150, 156))	('KICH', 'Disease', 'None', (158, 162))	('UCS', 'Phenotype', 'HP:0002891', (174, 177))	('APOBEC3B', 'Gene', (52, 60))	('correlated', 'Reg', (79, 89))	('Th2', 'Chemical', '-', (137, 140))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
5613	33842328	CD276 has become a novel Cart-T target for GBM while inhibition of PD-1/PD-L1 pathway can be a latent treatment strategy for glioma.	('glioma', 'Disease', (125, 131))	('inhibition', 'Var', (53, 63))	('PD-1', 'Gene', (67, 71))	('rat', 'Species', '10116', (114, 117))	('PD-1', 'Gene', '5133', (67, 71))	('PD-L1', 'Gene', '29126', (72, 77))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('CD276', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('CD276', 'Gene', '80381', (0, 5))	('PD-L1', 'Gene', (72, 77))
5652	31833974	HER2 amplification/overexpression is an effective therapeutic target in select gynecologic malignancies, and especially in the rare endometrial cancer subtype, uterine serous carcinoma.	('malignancies', 'Disease', (91, 103))	('amplification/overexpression', 'PosReg', (5, 33))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('amplification/overexpression', 'Var', (5, 33))	('endometrial cancer', 'Disease', (132, 150))	('endometrial cancer', 'Phenotype', 'HP:0012114', (132, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('endometrial cancer', 'Disease', 'MESH:D016889', (132, 150))	('serous carcinoma', 'Disease', 'MESH:D018297', (168, 184))	('HER2', 'Protein', (0, 4))	('serous carcinoma', 'Disease', (168, 184))
5655	31833974	Overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast, gastric, and uterine cancers, .	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gastric', 'Disease', (147, 154))	('breast', 'Disease', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('uterine cancer', 'Phenotype', 'HP:0010784', (160, 174))	('cancers', 'Disease', (168, 175))	('Overexpression', 'Var', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('uterine cancers', 'Phenotype', 'HP:0010784', (160, 175))
5659	31833974	HER2 amplification in human breast cancers was first noted in 1985, and since then a large body of evidence has supported the role of HER2 as a predictive biomarker and therapeutic target in human cancer.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('amplification', 'Var', (5, 18))	('breast cancers', 'Disease', 'MESH:D001943', (28, 42))	('cancer', 'Disease', (197, 203))	('breast cancers', 'Disease', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('HER2', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('human', 'Species', '9606', (191, 196))	('human', 'Species', '9606', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancer', 'Disease', (35, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (28, 42))
5665	31833974	HER2 dimerization then activates various signaling pathways inside the cell, including the PI3K/AKT pathway, the RAS/MAPK pathway, and the JAK-STAT pathway.	('AKT', 'Gene', (96, 99))	('dimerization', 'Var', (5, 17))	('JAK-STAT pathway', 'Pathway', (139, 155))	('activates', 'PosReg', (23, 32))	('RAS/MAPK pathway', 'Pathway', (113, 129))	('signaling pathways', 'Pathway', (41, 59))	('AKT', 'Gene', '207', (96, 99))	('HER2', 'Protein', (0, 4))
5668	31833974	Amplification of the ERBB2 gene is the most common way that HER2 is overexpressed in cancer.	('overexpressed', 'PosReg', (68, 81))	('Amplification', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('ERBB2', 'Gene', '2064', (21, 26))	('HER2', 'Protein', (60, 64))	('ERBB2', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
5700	31833974	Single institution reports have evaluated consecutive series of women with USC and HER2 overexpression has ranged from 18 to 42% of cases and gene amplification range from 16 to 47%.	('gene amplification', 'Var', (142, 160))	('HER2', 'Protein', (83, 87))	('overexpression', 'PosReg', (88, 102))	('women', 'Species', '9606', (64, 69))
5706	31833974	HER2 expression and amplification have been noted in other histologic subtypes of endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (82, 100))	('endometrial cancer', 'Disease', 'MESH:D016889', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('amplification', 'Var', (20, 33))	('endometrial cancer', 'Disease', (82, 100))	('HER2', 'Protein', (0, 4))
5719	31833974	evaluated 61 patients with advanced or recurrent uterine serous carcinoma overexpressing HER2 .	('patients', 'Species', '9606', (13, 21))	('serous carcinoma', 'Disease', 'MESH:D018297', (57, 73))	('serous carcinoma', 'Disease', (57, 73))	('overexpressing', 'Var', (74, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('HER2', 'Protein', (89, 93))
5728	31833974	In a recent metaanalysis of 34 studies that included over 5180 ovarian cancer patients, of women with ovarian cancer, HER2 expression was associated with worse progression-free and overall survival .	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('HER2', 'Protein', (118, 122))	('patients', 'Species', '9606', (78, 86))	('expression', 'Var', (123, 133))	('women', 'Species', '9606', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('ovarian cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('worse', 'NegReg', (154, 159))	('overall survival', 'CPA', (181, 197))	('ovarian cancer', 'Disease', (63, 77))
5729	31833974	Thirty-four studies that included 5180 ovarian cancer patients were collected for analysis, and expression of HER2 was negatively correlated with clinical prognosis of overall survival (HR = 1.57, 95% CI 1.31-1.89, P < 0.001) and progression-free survival (HR = 1.26, 95% CI 1.06-1.49) in ovarian cancers.	('HER2', 'Protein', (110, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (39, 53))	('ovarian cancers', 'Disease', 'MESH:D010051', (289, 304))	('progression-free survival', 'CPA', (230, 255))	('negatively', 'NegReg', (119, 129))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('ovarian cancer', 'Disease', (39, 53))	('patients', 'Species', '9606', (54, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (289, 303))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (289, 303))	('ovarian cancers', 'Phenotype', 'HP:0100615', (289, 304))	('ovarian cancers', 'Disease', (289, 304))	('expression', 'Var', (96, 106))
5736	31833974	Although much of the focus of HER2 in gynecologic malignancies has focused on type II endometrial cancers, ERBB/HER2 mutations and amplifications are found frequently in cervical carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (117, 126))	('cervical carcinoma', 'Disease', 'MESH:D002583', (170, 188))	('malignancies', 'Disease', (50, 62))	('II endometrial cancers', 'Disease', (83, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('ERBB', 'Gene', '1956', (107, 111))	('II endometrial cancers', 'Disease', 'MESH:D016889', (83, 105))	('endometrial cancer', 'Phenotype', 'HP:0012114', (86, 104))	('found', 'Reg', (150, 155))	('amplifications', 'Var', (131, 145))	('cervical carcinoma', 'Disease', (170, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('malignancies', 'Disease', 'MESH:D009369', (50, 62))	('ERBB', 'Gene', (107, 111))
5737	31833974	In the cancer genome atlas report of 228 cases, the rate of HER2 amplification was 17% and more common in adenocarcinoma compared with squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('common', 'Reg', (96, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('adenocarcinoma', 'Disease', (106, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (106, 120))	('squamous cell carcinoma', 'Disease', (135, 158))	('HER2', 'Protein', (60, 64))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('amplification', 'Var', (65, 78))
5738	31833974	In a more recent study that performed whole-exome sequencing on 69 cervical cancer specimens, 5.8% of tumors had mutations in the extracellular domain of ERBB2 and cell lines with these ERBB2 mutations showed sensitivity to the HER inhibitors afatinib and neratinib .	('sensitivity', 'MPA', (209, 220))	('tumors', 'Disease', (102, 108))	('ERBB2', 'Gene', (154, 159))	('neratinib', 'Chemical', 'MESH:C487932', (256, 265))	('ERBB2', 'Gene', '2064', (154, 159))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('mutations in', 'Var', (113, 125))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('ERBB2', 'Gene', '2064', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mutations', 'Var', (192, 201))	('afatinib', 'Chemical', 'MESH:D000077716', (243, 251))	('ERBB2', 'Gene', (186, 191))
5742	31833974	In a genomically targeted basket trial, neratinib monotherapy was studied in patients with a variety of tumor types all harboring ERBB2 mutations.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ERBB2', 'Gene', '2064', (130, 135))	('ERBB2', 'Gene', (130, 135))	('neratinib', 'Chemical', 'MESH:C487932', (40, 49))	('tumor', 'Disease', (104, 109))	('patients', 'Species', '9606', (77, 85))	('mutations', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
5743	31833974	Of five patients with ERBB2 mutated cervical cancer, three had a clinical benefit (including one partial response) and therefore enrollment of this cohort is ongoing .	('ERBB2', 'Gene', '2064', (22, 27))	('mutated', 'Var', (28, 35))	('ERBB2', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('benefit', 'PosReg', (74, 81))	('patients', 'Species', '9606', (8, 16))
5745	31833974	Among the four groups listed above, heterogeneity of HER2 expression is the leading cause of resistance to HER2-targeted therapies in uterine serous carcinoma, leading to over-growth of HER2-negative cells.	('serous carcinoma', 'Disease', 'MESH:D018297', (142, 158))	('serous carcinoma', 'Disease', (142, 158))	('heterogeneity', 'Var', (36, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('over-growth', 'PosReg', (171, 182))	('HER2', 'Protein', (53, 57))	('cause', 'Reg', (84, 89))
5760	31833974	Alterations in HER2 signaling through overexpression, gene amplification, and gene mutations represent a promising target for the development of new therapeutic options for patients with gynecologic malignancies.	('malignancies', 'Disease', 'MESH:D009369', (199, 211))	('patients', 'Species', '9606', (173, 181))	('HER2', 'Protein', (15, 19))	('malignancies', 'Disease', (199, 211))	('overexpression', 'PosReg', (38, 52))	('gene amplification', 'Var', (54, 72))	('gene mutations', 'Var', (78, 92))	('Alterations', 'Reg', (0, 11))
5773	32443727	Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer.	('IGF-IR', 'Gene', '3480', (160, 166))	('IGFBPs', 'Gene', (24, 30))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('IGFBPs', 'Gene', '3485;3486;16009;24484', (24, 30))	('IGF-I receptor', 'Gene', '3480', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('IGFBP-3', 'Var', (61, 68))	('IGF-I receptor', 'Gene', (144, 158))	('IGF-IR', 'Gene', (160, 166))
5774	32443727	Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer.	('prostate', 'Disease', (166, 174))	('implicated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('IGFBP-3', 'Gene', (14, 21))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('breast', 'Disease', (158, 164))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', (141, 147))	('Disruption', 'Var', (0, 10))
5780	32443727	Dysregulation of the IGF system attributes to pathophysiology of a variety of human diseases such as cancer, diabetes, chronic inflammatory disease, and malnutrition.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('malnutrition', 'Phenotype', 'HP:0004395', (153, 165))	('cancer', 'Disease', (101, 107))	('Dysregulation', 'Var', (0, 13))	('inflammatory disease', 'Disease', (127, 147))	('inflammatory disease', 'Disease', 'MESH:D007249', (127, 147))	('diabetes', 'Disease', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('diabetes', 'Disease', 'MESH:D003920', (109, 117))	('human', 'Species', '9606', (78, 83))	('malnutrition', 'Disease', (153, 165))
5809	32443727	Further studies using p53 mutants have revealed a link between p53's activation of IGFBP-3 transcription and its induction of apoptosis by showing that the mutants that lost the ability to activate IGFBP-3 could not induce apoptosis.	('transcription', 'MPA', (91, 104))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('IGFBP-3', 'Gene', (83, 90))	('p53', 'Gene', (22, 25))	('mutants', 'Var', (156, 163))	('apoptosis', 'CPA', (223, 232))	('mutants', 'Var', (26, 33))	('p53', 'Gene', '7157', (22, 25))	('activation', 'PosReg', (69, 79))
5810	32443727	Further research also demonstrated that the transfection of doxycycline-inducible p53 plasmids resulted in increased expression of p53 and IGFBP-3 and, subsequently, induced apoptosis in p53-negative PC-3 prostate cancer cells.	('induced', 'Reg', (166, 173))	('transfection', 'Var', (44, 56))	('prostate cancer', 'Disease', (205, 220))	('PC-3', 'CellLine', 'CVCL:0035', (200, 204))	('p53', 'Gene', (187, 190))	('increased', 'PosReg', (107, 116))	('expression', 'MPA', (117, 127))	('p53', 'Gene', (131, 134))	('apoptosis', 'CPA', (174, 183))	('p53', 'Gene', '7157', (187, 190))	('doxycycline', 'Chemical', 'MESH:D004318', (60, 71))	('p53', 'Gene', '7157', (131, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('IGFBP-3', 'Gene', (139, 146))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))
5811	32443727	This p53-depedent induction of apoptosis was inhibited by treating with IGF-I, IGFBP-3 blocking antibodies, and IGFBP-3 antisense oligonucleotides, which demonstrated p53-dependent IGFBP-3's proapoptotic function.	('inhibited', 'NegReg', (45, 54))	('IGFBP-3', 'Gene', (79, 86))	('oligonucleotides', 'Chemical', 'MESH:D009841', (130, 146))	('IGF-I', 'Gene', '3479', (72, 77))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (167, 170))	('p53', 'Gene', '7157', (5, 8))	('antisense oligonucleotides', 'Var', (120, 146))	('p53', 'Gene', (167, 170))	('IGF-I', 'Gene', (72, 77))	('IGFBP-3', 'Gene', (112, 119))	('apoptosis', 'CPA', (31, 40))
5813	32443727	It appears that DeltaNp63alpha binds the p53 binding sites, Box A and Box B, in the IGFBP-3 gene, and, thereby, inhibits p53-dependent IGFBP-3 expression and presumably suppresses IGFBP-3-induced apoptosis.	('suppresses', 'NegReg', (169, 179))	('p53', 'Gene', '7157', (41, 44))	('DeltaNp63alpha', 'Var', (16, 30))	('expression', 'MPA', (143, 153))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('IGFBP-3', 'Gene', (135, 142))	('IGFBP-3', 'Gene', (84, 91))	('inhibits', 'NegReg', (112, 120))	('p53', 'Gene', (41, 44))
5842	32443727	Humanin is a mitochondrial-derived peptide that inhibits neuronal cell death induced by mutant genes in Alzheimer's disease.	('Human', 'Species', '9606', (0, 5))	('death', 'Disease', 'MESH:D003643', (71, 76))	('death', 'Disease', (71, 76))	('inhibits', 'NegReg', (48, 56))	('mutant genes', 'Var', (88, 100))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (104, 123))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (104, 123))	("Alzheimer's disease", 'Disease', (104, 123))
5864	32443727	However, recent studies also showed that IGFBP-3 mutants that failed to translocate to the nucleus and lost binding ability to RXR-alpha, still induced apoptosis in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('IGFBP-3', 'Gene', (41, 48))	('breast cancer', 'Disease', (165, 178))	('mutants', 'Var', (49, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('binding', 'Interaction', (108, 115))	('RXR-alpha', 'Gene', '6256', (127, 136))	('induced', 'Reg', (144, 151))	('apoptosis', 'CPA', (152, 161))	('RXR-alpha', 'Gene', (127, 136))
5878	32443727	Additionally, IGFBP-3R activates caspase-8-induced apoptosis in unconventional ways: (1) IGFBP-3R and inactive procaspase-8 is pre-complexed at the resting stage, and IGFBP-3 binding to IGFBP-3R releases procaspase-8, and, thereby, activates caspase-8-dependent apoptosis, and (2) IGFBP-3R complexes with procasepase-8 without involvement of a typical death domain (DD) sequence.	('releases', 'PosReg', (195, 203))	('binding', 'Interaction', (175, 182))	('death', 'Disease', 'MESH:D003643', (352, 357))	('caspase-8', 'Gene', (33, 42))	('caspase-8', 'Gene', (114, 123))	('activates', 'PosReg', (232, 241))	('caspase-8', 'Gene', (207, 216))	('caspase-8', 'Gene', '841', (207, 216))	('IGFBP-3', 'Var', (167, 174))	('caspase-8', 'Gene', '841', (242, 251))	('caspase-8', 'Gene', (242, 251))	('caspase-8', 'Gene', '841', (33, 42))	('caspase-8', 'Gene', '841', (114, 123))	('death', 'Disease', (352, 357))
5889	32443727	This inhibitory action of IGFBP-3 was IGF/IGF-IR-independent since the IGFBP-3 mutant devoid of IGF binding affinity had a similar inhibitory effect.	('IGF-IR', 'Gene', (42, 48))	('IGFBP-3', 'Gene', (71, 78))	('mutant', 'Var', (79, 85))	('IGF-IR', 'Gene', '3480', (42, 48))
5920	32443727	Survival in pan-kidney cohort (KICH+KIRC+KIRP), lower grade glioma, mesothelioma, colorectal adenocarcinoma was similarly affected by IGFBP-3 to a lesser extent (FDR = 1.74 10-6 (HR = 2.73), 1.25 10-5 (HR = 2.36), 1.22 10-3 (HR = 2.98), 3.87 10-3 (HR = 2.20), respectively) (Figure 6B,C).	('mesothelioma', 'Disease', (68, 80))	('colorectal adenocarcinoma', 'Disease', (82, 107))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (82, 107))	('KICH+KIRC+KIRP', 'Disease', 'None', (31, 45))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('affected', 'Reg', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('IGFBP-3', 'Var', (134, 141))	('glioma', 'Disease', (60, 66))	('KICH+KIRC+KIRP', 'Disease', (31, 45))
5923	32443727	Of note, the observed dichotomy of IGFBP-3 expression and patients' survival in various cancers may be attributed to other factors such as IGF-1/IGF-2 expression, IGFBP-3 polymorphism status, tumor suppressor p53 family status, tumor metabolic characteristics, and others.	('IGFBP-3', 'Gene', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('polymorphism', 'Var', (171, 183))	('IGF-1', 'Gene', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('cancers', 'Disease', (88, 95))	('IGF-1', 'Gene', '3479', (139, 144))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patients', 'Species', '9606', (58, 66))	('p53', 'Gene', '7157', (209, 212))	('IGF-2', 'Gene', (145, 150))	('IGFBP-3', 'Gene', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('IGF-2', 'Gene', '3481', (145, 150))	('tumor', 'Disease', (228, 233))	('p53', 'Gene', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
5938	32443727	Similar results were observed for clinical subgroups in mesothelioma, the pan-kidney cohort, rectum adenocarcinoma, colorectal adenocarcinoma, and colon adenocarcinoma cancers, where low expression of IGFBP-3 was similarly associated with better survival outcome.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colon adenocarcinoma cancers', 'Disease', 'MESH:D015179', (147, 175))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('rectum adenocarcinoma', 'Disease', (93, 114))	('associated', 'Reg', (223, 233))	('colon adenocarcinoma cancers', 'Disease', (147, 175))	('IGFBP-3', 'Gene', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (93, 114))	('mesothelioma', 'Disease', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('low expression', 'Var', (183, 197))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
5939	32443727	These results confirm previous observations that the expression of IGFBP-3 may affect survival in glioma, mesothelioma, kidney, and colorectal cancers.	('affect', 'Reg', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mesothelioma', 'Disease', (106, 118))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('expression', 'Var', (53, 63))	('kidney', 'Disease', (120, 126))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('colorectal cancers', 'Disease', 'MESH:D015179', (132, 150))	('survival', 'CPA', (86, 94))	('IGFBP-3', 'Gene', (67, 74))	('glioma', 'Disease', (98, 104))	('colorectal cancers', 'Disease', (132, 150))
5940	32443727	Further analyses of the effect of IGFBP-3 and TMEM219 expression in specific clinical subgroups revealed that kidney renal papillary cell carcinoma is the only cancer where the expression of both IGFBP-3 and TMEM219 is marginally associated with survival in "race-black or the African-American" subgroup.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (110, 147))	('cancer', 'Disease', (160, 166))	('associated', 'Reg', (230, 240))	('expression', 'Var', (177, 187))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (117, 147))	('TMEM219', 'Gene', '124446', (46, 53))	('TMEM219', 'Gene', '124446', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', (110, 147))	('IGFBP-3', 'Gene', (196, 203))	('TMEM219', 'Gene', (46, 53))	('TMEM219', 'Gene', (208, 215))
5947	32443727	Of note were race-specific survival effects with high expression of IGFBP-3 being beneficial in the "race-black or African-American" subgroup (FDR = 2.01 10-1 (HR = 0.42), Figure 10E) and TMEM219 high expression being beneficial in the "race-Asian" subgroup (FDR = 1.16 10-1 (HR = 0.00), Figure 10D).	('TMEM219', 'Gene', (188, 195))	('high expression', 'Var', (49, 64))	('TMEM219', 'Gene', '124446', (188, 195))	('beneficial', 'PosReg', (82, 92))	('IGFBP-3', 'Gene', (68, 75))
5948	32443727	Confirming our previous observations, the survival benefits of IGFBP-3 expression in breast cancer were consistently associated with high IGFBP-3 expression, while the effect of TMEM219 was more diverse and subgroup-specific.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('IGFBP-3', 'Gene', (63, 70))	('TMEM219', 'Gene', (178, 185))	('breast cancer', 'Disease', (85, 98))	('high', 'Var', (133, 137))	('IGFBP-3', 'Gene', (138, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TMEM219', 'Gene', '124446', (178, 185))	('expression', 'MPA', (146, 156))	('benefits', 'PosReg', (51, 59))	('high IGFBP', 'Phenotype', 'HP:0030269', (133, 143))
5954	32443727	Given the fact that IGFBP-3/IGFBP-3R (TMEM219) axis is impaired and shown to have great impact on the survival outcome in specific cancers, IGFBP-3 and TMEM219 may serve as new diagnostic and prognostic biomarkers in specific cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('impact', 'Reg', (88, 94))	('TMEM219', 'Gene', '124446', (38, 45))	('cancers', 'Disease', (131, 138))	('TMEM219', 'Gene', '124446', (152, 159))	('TMEM219', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('IGFBP-3/IGFBP-3R', 'Gene', (20, 36))	('IGFBP-3', 'Var', (140, 147))	('TMEM219', 'Gene', (152, 159))	('impaired', 'NegReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
6000	32256668	While the Pap smear remains an insensitive tool for detecting carcinosarcoma, the presence of a positive Pap smear correlates with cervical involvement and stage-independent decreased survival.	('decreased', 'NegReg', (174, 183))	('cervical involvement', 'Disease', (131, 151))	('carcinosarcoma', 'Disease', 'MESH:D002296', (62, 76))	('Pap', 'Gene', (105, 108))	('presence', 'Var', (82, 90))	('carcinosarcoma', 'Disease', (62, 76))	('survival', 'CPA', (184, 192))
6019	31835584	When GPR15 controls the homing of FOXP3+ regulatory T cells (Tregs) to the large intestine lamina propria, it alleviates colonic inflammation.	('alleviates', 'NegReg', (110, 120))	('colonic inflammation', 'Disease', 'MESH:D007249', (121, 141))	('colonic inflammation', 'Disease', (121, 141))	('FOXP3', 'Gene', (34, 39))	('homing', 'CPA', (24, 30))	('FOXP3', 'Gene', '50943', (34, 39))	('GPR15', 'Var', (5, 10))
6034	31835584	It is most frequently mutated in uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS), lung squamous carcinoma (LUSC), rectal adenocarcinoma (READ), and colon adenocarcinoma (COAD) (Figure 1A).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (48, 69))	('READ', 'Disease', (163, 167))	('carcinosarcoma', 'Disease', 'MESH:D002296', (86, 100))	('mutated', 'Var', (22, 29))	('colon adenocarcinoma', 'Disease', (174, 194))	('LUSC', 'Disease', (133, 137))	('UCS', 'Phenotype', 'HP:0002891', (102, 105))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (78, 100))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (140, 161))	('READ', 'Disease', 'MESH:D012004', (163, 167))	('LUSC', 'Disease', 'MESH:D002294', (133, 137))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (174, 194))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('COAD', 'Disease', (196, 200))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (108, 131))	('endometrial carcinoma', 'Disease', (48, 69))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (113, 131))	('rectal adenocarcinoma', 'Disease', (140, 161))	('lung squamous carcinoma', 'Disease', (108, 131))	('COAD', 'Disease', 'MESH:D015179', (196, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (48, 69))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinosarcoma', 'Disease', (86, 100))
6036	31835584	Most mutations in GPR15 are missense mutations while the minority mutational pattern is heterogenous, and the variant classification varies from frameshift deletion (COAD), frameshift insertion (LUSC), and nonsense mutation (LUSC, READ) to missense mutation (Figure 2).	('LUSC', 'Phenotype', 'HP:0030359', (195, 199))	('missense mutation', 'Var', (240, 257))	('READ', 'Disease', (231, 235))	('COAD', 'Disease', 'MESH:D015179', (166, 170))	('mutations', 'Var', (5, 14))	('LUSC', 'Disease', 'MESH:D002294', (225, 229))	('LUSC', 'Disease', (195, 199))	('LUSC', 'Disease', (225, 229))	('missense mutations', 'Var', (28, 46))	('frameshift insertion', 'Var', (173, 193))	('COAD', 'Disease', (166, 170))	('nonsense mutation', 'Var', (206, 223))	('GPR15', 'Gene', (18, 23))	('READ', 'Disease', 'MESH:D012004', (231, 235))	('LUSC', 'Phenotype', 'HP:0030359', (225, 229))	('LUSC', 'Disease', 'MESH:D002294', (195, 199))	('frameshift deletion', 'Var', (145, 164))
6037	31835584	Moreover, it is worth noting that GPR15 in COAD is both hypermutated and significantly downregulated compared to that in normal tissues.	('COAD', 'Disease', (43, 47))	('GPR15', 'Var', (34, 39))	('downregulated', 'NegReg', (87, 100))	('COAD', 'Disease', 'MESH:D015179', (43, 47))
6038	31835584	This pattern implies that alterations in GPR15-meditor T-cell homing may have undiscovered effects on the pathophysiology of COAD.	('COAD', 'Disease', 'MESH:D015179', (125, 129))	('COAD', 'Disease', (125, 129))	('alterations', 'Var', (26, 37))	('effects', 'Reg', (91, 98))	('GPR15-meditor', 'Gene', (41, 54))
6041	31835584	Integrated network analysis revealed that, apart from immunity control, GPR15 may have effects on cell growth, thereby affecting carcinogenesis.	('GPR15', 'Var', (72, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('effects', 'Reg', (87, 94))	('affecting', 'Reg', (119, 128))	('carcinogenesis', 'Disease', (129, 143))	('cell growth', 'CPA', (98, 109))
6050	31835584	GPR15 can reduce the inflammation level in the large intestine by controlling T-cell homing.	('T-cell homing', 'CPA', (78, 91))	('inflammation', 'Disease', 'MESH:D007249', (21, 33))	('inflammation', 'Disease', (21, 33))	('GPR15', 'Var', (0, 5))	('reduce', 'NegReg', (10, 16))
6069	31835584	We found that TRP89, SER109, ARG172, LYS180, CYS183, TRP195, PHE257, and LYS261 residues were located in the active region in GPR15.	('LYS261', 'CellLine', 'CVCL:2490', (73, 79))	('PHE257', 'Var', (61, 67))	('CYS183', 'Var', (45, 51))	('TRP89', 'Var', (14, 19))	('GPR15', 'Gene', (126, 131))	('SER109', 'Var', (21, 27))	('ARG172', 'Var', (29, 35))	('TRP195', 'Var', (53, 59))	('ARG172', 'Chemical', 'MESH:C545206', (29, 35))	('CYS183', 'Chemical', 'MESH:C082474', (45, 51))	('LYS261 residues', 'Var', (73, 88))	('PHE257', 'Chemical', 'MESH:C040798', (61, 67))	('LYS180', 'Var', (37, 43))
6071	31835584	Compound 5 showed more than 90% salt bridge interaction with Lys261 (Figure S9) in the MD trajectories.	('Lys261', 'Var', (61, 67))	('Lys261', 'Chemical', 'MESH:C046598', (61, 67))	('salt bridge interaction', 'MPA', (32, 55))
6072	31835584	The fluctuation in RMSD was further supported by the MM/PBSA results (Table S4), which showed that compound 5 (C34H47O6N3) had a stronger binding affinity (lowest binding free energy) among the hits with consistently lower RMSD values.	('C34H47O6N3', 'Chemical', 'MESH:C010808', (111, 121))	('stronger', 'PosReg', (129, 137))	('binding', 'Interaction', (163, 170))	('C34H47O6N3', 'Var', (111, 121))	('binding affinity', 'Interaction', (138, 154))
6081	31835584	GPR15 was proven to mediate regulatory T cells (Tregs) to migrate to the large intestine and reduce inflammation in the mouse model, but it is preferentially expressed on human effector T cells.	('inflammation', 'Disease', (100, 112))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('GPR15', 'Var', (0, 5))	('reduce', 'NegReg', (93, 99))	('human', 'Species', '9606', (171, 176))	('mouse', 'Species', '10090', (120, 125))
6082	31835584	Further research supported that GPR15-dependent human CD8+ T cells can migrate into the inflamed gut, and GPR15 can also help dendritic epidermal T cells migrate to the skin.	('CD8', 'Gene', '925', (54, 57))	('help', 'PosReg', (121, 125))	('dendritic epidermal T', 'Disease', 'MESH:D007635', (126, 147))	('human', 'Species', '9606', (48, 53))	('dendritic epidermal T', 'Disease', (126, 147))	('inflamed gut', 'Phenotype', 'HP:0002037', (88, 100))	('GPR15', 'Var', (106, 111))	('CD8', 'Gene', (54, 57))
6091	31835584	MD simulation and free energy calculation conducted on the top eight compounds led to the discovery of the best compound, compund 5 (C34H47O6N3), which could be a hit for novel drugs targeting STAD.	('STAD', 'Disease', 'MESH:D013274', (193, 197))	('C34H47O6N3', 'Var', (133, 143))	('C34H47O6N3', 'Chemical', 'MESH:C010808', (133, 143))	('STAD', 'Disease', (193, 197))
6112	31744257	We aimed to evaluate the expression profile of let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, and let-7i and to assess their value as prognostic markers in uterine leiomyosarcoma (LMS) patients.	('let-7c', 'Gene', (63, 69))	('LMS', 'Phenotype', 'HP:0100243', (189, 192))	('let-7d', 'Gene', '406886', (71, 77))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('leiomyosarcoma', 'Disease', (173, 187))	('let-7i', 'Gene', '406891', (107, 113))	('let-7d', 'Gene', (71, 77))	('let-7c', 'Gene', '406885', (63, 69))	('let-7g', 'Gene', '406890', (95, 101))	('let-7g', 'Gene', (95, 101))	('patients', 'Species', '9606', (194, 202))	('let-7e', 'Gene', (79, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('let-7b', 'Gene', '406884', (55, 61))	('let-7f', 'Var', (87, 93))	('let-7i', 'Gene', (107, 113))	('let-7a', 'Gene', (47, 53))	('let-7e', 'Gene', '406887', (79, 85))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (173, 187))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (173, 187))	('let-7b', 'Gene', (55, 61))
6117	31744257	Patients' ages were associated with let-7d, let-7e and let-7f (p = 0.0160) downregulation.	('downregulation', 'NegReg', (75, 89))	('let-7d', 'Gene', '406886', (36, 42))	('let-7d', 'Gene', (36, 42))	('Patients', 'Species', '9606', (0, 8))	('let-7f', 'Var', (55, 61))	('let-7e', 'Gene', '406887', (44, 50))	('let-7e', 'Gene', (44, 50))
6119	31744257	Let-7e expression might influence the OS, while let-7b and le-7d might influence the DFS.	('le-7d', 'Var', (59, 64))	('influence', 'Reg', (71, 80))	('Let-7e', 'Gene', '406887', (0, 6))	('DFS', 'MPA', (85, 88))	('let-7b', 'Gene', '406884', (48, 54))	('let-7b', 'Gene', (48, 54))	('influence', 'Reg', (24, 33))	('Let-7e', 'Gene', (0, 6))
6120	31744257	The lowest expression levels of let-7d, let-7e, and let-7f were associated with the oldest patients.	('patients', 'Species', '9606', (91, 99))	('let-7d', 'Gene', '406886', (32, 38))	('let-7d', 'Gene', (32, 38))	('expression levels', 'MPA', (11, 28))	('let-7f', 'Var', (52, 58))	('let-7e', 'Gene', '406887', (40, 46))	('lowest', 'NegReg', (4, 10))	('let-7e', 'Gene', (40, 46))
6122	31744257	Several neoplasms have been related to the deregulated expression of miRNAs, including gynecological cancers such as ovary, endometrium, cervical, and uterine sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('neoplasms', 'Disease', 'MESH:D009369', (8, 17))	('cervical', 'Disease', (137, 145))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('deregulated', 'Var', (43, 54))	('neoplasms', 'Disease', (8, 17))	('ovary', 'Disease', (117, 122))	('expression', 'MPA', (55, 65))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (151, 166))	('ovary', 'Disease', 'MESH:D010051', (117, 122))	('sarcomas', 'Disease', 'MESH:D012509', (159, 167))	('neoplasms', 'Phenotype', 'HP:0002664', (8, 17))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('cancers', 'Disease', (101, 108))	('endometrium', 'Disease', (124, 135))	('sarcomas', 'Disease', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miRNAs', 'Gene', (69, 75))
6126	31744257	The let-7 family is the largest miRNA family and is composed of 10 mature subtypes, including let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, let-7i, miR-98, and miR-202.	('let-7e', 'Gene', (126, 132))	('let-7d', 'Gene', '406886', (118, 124))	('let-7f', 'Var', (134, 140))	('let-7d', 'Gene', (118, 124))	('let-7c', 'Gene', (110, 116))	('let-7a', 'Var', (94, 100))	('let-7g', 'Gene', '406890', (142, 148))	('let-7b', 'Gene', '406884', (102, 108))	('let-7b', 'Gene', (102, 108))	('miR-98', 'Gene', '407054', (158, 164))	('let-7i', 'Gene', (150, 156))	('let-7c', 'Gene', '406885', (110, 116))	('miR-98', 'Gene', (158, 164))	('miR-202', 'Gene', (170, 177))	('let-7e', 'Gene', '406887', (126, 132))	('miR-202', 'Gene', '574448', (170, 177))	('let-7g', 'Gene', (142, 148))	('let-7i', 'Gene', '406891', (150, 156))
6128	31744257	Many genes, proteins and factors are involved in this process, such as Lin28 and Lin28B, nuclear factor (NF) 90 and NF45 interactions, certain complete regulatory loops that involved NFkappaB, IL6, IMP1 and c-Myc genes, and DNA methylation.	('Lin28B', 'Gene', (81, 87))	('NF45', 'Gene', '3608', (116, 120))	('IMP1', 'Gene', '10642', (198, 202))	('IL6', 'Gene', (193, 196))	('Lin28', 'Gene', (71, 76))	('Lin28', 'Gene', '79727', (71, 76))	('IMP1', 'Gene', (198, 202))	('Lin28B', 'Gene', '389421', (81, 87))	('interactions', 'Var', (121, 133))	('nuclear factor (NF) 90', 'Gene', '3609', (89, 111))	('c-Myc', 'Gene', (207, 212))	('NFkappaB', 'Gene', '4790', (183, 191))	('NF45', 'Gene', (116, 120))	('c-Myc', 'Gene', '4609', (207, 212))	('nuclear factor (NF) 90', 'Gene', (89, 111))	('NFkappaB', 'Gene', (183, 191))	('IL6', 'Gene', '3569', (193, 196))	('Lin28', 'Gene', (81, 86))	('Lin28', 'Gene', '79727', (81, 86))
6135	31744257	Signaling pathways and their molecular mechanisms are responsible for malignant LMS transformation processes are still unknown, but some evidence suggests that tumor instability is a result of multiple genetic and epigenetic errors.	('malignant LMS transformation', 'Disease', 'MESH:C537878', (70, 98))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('LMS', 'Phenotype', 'HP:0100243', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('epigenetic errors', 'Var', (214, 231))	('malignant LMS transformation', 'Disease', (70, 98))	('tumor', 'Disease', (160, 165))
6139	31744257	Eight members of the let-7 family were selected (let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, let-7e-5p, let-7f-5p, let-7g-5p and let-7i-5p), and the quantitative real time-polymerase chain reaction (qRT-PCR) was carried out using a miScript SYBR  Green PCR-kit (Qiagen, Hilden, Germany) with MIHS-109ZA-Qiagen 96 wells plate (Qiagen, Hilden, Germany).	('let-7g', 'Gene', '406890', (115, 121))	('let-7b', 'Gene', '406884', (60, 66))	('let-7b', 'Gene', (60, 66))	('let-7e', 'Gene', '406887', (93, 99))	('let-7c', 'Gene', (71, 77))	('let-7i', 'Gene', (129, 135))	('let-7e', 'Gene', (93, 99))	('let-7d', 'Gene', '406886', (82, 88))	('let-7g', 'Gene', (115, 121))	('let-7d', 'Gene', (82, 88))	('let-7c', 'Gene', '406885', (71, 77))	('let-7i', 'Gene', '406891', (129, 135))	('let-7f-5p', 'Var', (104, 113))
6146	31744257	Initially, to explore the potential regulatory role of let-7 miRNAs in LMS, we performed a non-supervised hierarchical clustering analysis of eight members of the let-7 family (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, and let-7i) in the GeneGlobe Data Analysis Center software.	('let-7e', 'Gene', (209, 215))	('let-7d', 'Gene', '406886', (201, 207))	('let-7f', 'Var', (217, 223))	('let-7d', 'Gene', (201, 207))	('let-7i', 'Gene', '406891', (237, 243))	('let-7c', 'Gene', (193, 199))	('let-7a', 'Var', (177, 183))	('let-7g', 'Gene', '406890', (225, 231))	('let-7b', 'Gene', '406884', (185, 191))	('LMS', 'Phenotype', 'HP:0100243', (71, 74))	('let-7c', 'Gene', '406885', (193, 199))	('let-7e', 'Gene', '406887', (209, 215))	('let-7i', 'Gene', (237, 243))	('let-7b', 'Gene', (185, 191))	('let-7g', 'Gene', (225, 231))
6150	31744257	We also analyzed the expression profile of let-7b (p = 0.0482), let-7c (p = 0.0280), let-7d (p = 0.0221), let-7e (p = 0.0114), let-7f (p = 0.0097), let-7g (p = 0.1367), and let-7i (p = 0.005) in LMS compared to MM.	('let-7b', 'Gene', (43, 49))	('LMS', 'Phenotype', 'HP:0100243', (195, 198))	('let-7f', 'Var', (127, 133))	('let-7e', 'Gene', (106, 112))	('let-7i', 'Gene', (173, 179))	('let-7g', 'Gene', '406890', (148, 154))	('let-7d', 'Gene', '406886', (85, 91))	('let-7d', 'Gene', (85, 91))	('let-7i', 'Gene', '406891', (173, 179))	('let-7e', 'Gene', '406887', (106, 112))	('let-7c', 'Gene', (64, 70))	('let-7g', 'Gene', (148, 154))	('let-7b', 'Gene', '406884', (43, 49))	('let-7c', 'Gene', '406885', (64, 70))
6175	31744257	Deregulation at the expression level of these molecules has also been observed in pancreatic cancers, as well as prostate cancer, primary pigmented nodular adrenocortical disease (PPNAD), head and neck malignancies, and ovary, breast, bladder, kidney and retinoblastomas.	('retinoblastomas', 'Phenotype', 'HP:0009919', (255, 270))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (138, 178))	('pancreatic cancers', 'Disease', 'MESH:D010190', (82, 100))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (138, 178))	('pigmented nodular adrenocortical disease', 'Disease', (138, 178))	('breast', 'Disease', (227, 233))	('bladder', 'Disease', (235, 242))	('prostate cancer', 'Disease', (113, 128))	('neck malignancies', 'Disease', 'MESH:D006258', (197, 214))	('observed', 'Reg', (70, 78))	('retinoblastomas', 'Disease', 'MESH:D012175', (255, 270))	('neck malignancies', 'Disease', (197, 214))	('kidney', 'Disease', (244, 250))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('head and neck malignancies', 'Phenotype', 'HP:0012288', (188, 214))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (82, 100))	('Deregulation', 'Var', (0, 12))	('ovary', 'Disease', (220, 225))	('retinoblastoma', 'Phenotype', 'HP:0009919', (255, 269))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pancreatic cancers', 'Disease', (82, 100))	('ovary', 'Disease', 'MESH:D010051', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('retinoblastomas', 'Disease', (255, 270))
6189	31744257	Gene amplification or deletion, abnormalities in the transcriptional control of miRNAs, epigenetic changes, and disorders of the mechanism of biogenesis are the factors responsible for the alteration in miRNA levels in human cancers.	('alteration', 'Reg', (189, 199))	('human', 'Species', '9606', (219, 224))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('deletion', 'Var', (22, 30))	('cancers', 'Disease', (225, 232))	('abnormalities', 'Var', (32, 45))	('Gene amplification', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
6191	31744257	Two highly conserved binding proteins, LIN28A and LIN28B, may be involved in this process because of their ability to inhibit let-7 biogenesis in mammals by directly binding to the pre-let-7 processed by Dicer and/or pri-let-7 processed by Drosha.	('inhibit', 'NegReg', (118, 125))	('Dicer', 'Gene', '23405', (204, 209))	('LIN28B', 'Gene', (50, 56))	('Dicer', 'Gene', (204, 209))	('binding', 'Interaction', (166, 173))	('LIN28B', 'Gene', '389421', (50, 56))	('LIN28A', 'Gene', '79727', (39, 45))	('let-7 biogenesis', 'MPA', (126, 142))	('LIN28A', 'Gene', (39, 45))	('pre-let-7', 'Var', (181, 190))
6202	31744257	The let-7a-3 was identified as a miRNA gene that is epigenetically regulated, suggesting that aberrant methylation might contribute to the human cancer epigenome.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('methylation', 'MPA', (103, 114))	('human', 'Species', '9606', (139, 144))	('contribute', 'Reg', (121, 131))	('let-7a-3', 'Gene', '406883', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('let-7a-3', 'Gene', (4, 12))	('aberrant', 'Var', (94, 102))
6205	31744257	Notably, our results show that downregulation was also a worse prognostic factor in patients with LMS.	('patients', 'Species', '9606', (84, 92))	('LMS', 'Phenotype', 'HP:0100243', (98, 101))	('downregulation', 'Var', (31, 45))	('LMS', 'Disease', (98, 101))
6213	31744257	Curiously, we also verified an association between older patients and the downregulation of let-7d, let-7e and let-7f miRNAs.	('let-7e', 'Gene', '406887', (100, 106))	('downregulation', 'NegReg', (74, 88))	('patients', 'Species', '9606', (57, 65))	('let-7e', 'Gene', (100, 106))	('let-7d', 'Gene', '406886', (92, 98))	('let-7f', 'Var', (111, 117))	('let-7d', 'Gene', (92, 98))
6231	31744257	In addition, the downregulation of let-7d, let-7e, and let-7f was associated with the oldest patients.	('let-7e', 'Gene', '406887', (43, 49))	('let-7d', 'Gene', '406886', (35, 41))	('downregulation', 'NegReg', (17, 31))	('let-7f', 'Var', (55, 61))	('let-7e', 'Gene', (43, 49))	('patients', 'Species', '9606', (93, 101))	('let-7d', 'Gene', (35, 41))
6251	31173648	Conversely, nulliparity is associated with an elevated endometrial cancer risk.	('endometrial cancer', 'Disease', (55, 73))	('endometrial cancer', 'Phenotype', 'HP:0012114', (55, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('endometrial cancer', 'Disease', 'MESH:D016889', (55, 73))	('nulliparity', 'Var', (12, 23))
6286	31173648	Compared with having one recorded birth, increased parity progressively decreased risk of endometrial cancer [e.g., four or more births: OR=0.64 (0.59-0.69)] (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('parity', 'Var', (51, 57))	('endometrial cancer', 'Disease', (90, 108))	('decreased', 'NegReg', (72, 81))	('endometrial cancer', 'Phenotype', 'HP:0012114', (90, 108))	('endometrial cancer', 'Disease', 'MESH:D016889', (90, 108))
6289	31173648	However, the risk reductions for time since first and last birth among multiparous women were greater than among the uniparous women [e.g., time since first birth <10 vs. >=30 years: uniparous OR=0.43 (0.30-0.61); multiparous OR=0.24 (0.15-0.38)].	('reductions', 'NegReg', (18, 28))	('women', 'Species', '9606', (127, 132))	('multiparous', 'Var', (71, 82))	('women', 'Species', '9606', (83, 88))
6300	31173648	The association between birthweight and endometrial cancer risk appeared heterogenous by subtype, with elevated risks with high birthweights (4000+ grams) for Type I tumors, and with very low birthweights (<1000 grams) for Type II tumors.	('endometrial cancer', 'Disease', 'MESH:D016889', (40, 58))	('Type II tumors', 'Disease', 'MESH:D009369', (223, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('endometrial cancer', 'Phenotype', 'HP:0012114', (40, 58))	('Type I tumors', 'Disease', (159, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('endometrial cancer', 'Disease', (40, 58))	('high birthweights', 'Phenotype', 'HP:0001520', (123, 140))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('low birthweights', 'Phenotype', 'HP:0001518', (188, 204))	('4000+ grams', 'Var', (142, 153))	('Type I tumors', 'Disease', 'MESH:D018761', (159, 172))	('Type II tumors', 'Disease', (223, 237))
6313	31173648	Thus the mechanisms by which all births, but specifically births later in life, may reduce endometrial cancer risk in the mother include: 1) exposures to higher levels of progesterone (relative to estrogen) throughout pregnancy which possibly facilitate removal/apoptosis of premalignant lesions (e.g., reduction in endometrial hyperplasia with progesterone treatment in the PEPI trial ; 2) mechanical removal/sloughing of premalignant cells during parturition and/or uterine involution; 3) immune-mediation during pregnancy.	('reduce', 'NegReg', (84, 90))	('endometrial cancer', 'Disease', 'MESH:D016889', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('progesterone', 'Chemical', 'MESH:D011374', (345, 357))	('endometrial hyperplasia', 'Disease', (316, 339))	('uterine involution', 'Phenotype', 'HP:0000139', (468, 486))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (316, 339))	('higher levels of progesterone', 'Phenotype', 'HP:0031216', (154, 183))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('endometrial cancer', 'Disease', (91, 109))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (316, 339))	('progesterone', 'Chemical', 'MESH:D011374', (171, 183))	('reduction', 'NegReg', (303, 312))	('births', 'Var', (33, 39))
6409	31581718	It has been shown that:similar to human beings, dogs and cats :myoepithelial cells in rabbits express the pancytokeratin marker AE1/AE3, vimentin, p63, SMA and calponin.	('human', 'Species', '9606', (34, 39))	('cats', 'Species', '9685', (57, 61))	('AE3', 'Gene', '100008675', (132, 135))	('dogs', 'Species', '9615', (48, 52))	('AE3', 'Gene', (132, 135))	('rabbits', 'Species', '9986', (86, 93))	('p63', 'Var', (147, 150))	('vimentin', 'Gene', (137, 145))	('vimentin', 'Gene', '100008924', (137, 145))
6416	31581718	In contrast, 63% of the invasive carcinomas are immunonegative for both receptors.	('invasive carcinomas', 'Disease', (24, 43))	('invasive carcinomas', 'Disease', 'MESH:D009361', (24, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('immunonegative', 'Var', (48, 62))
6428	31581718	The mammary gland changes were interpreted to be caused by the cyclosporine treatment, since the cyclosporine application was associated with increased serum prolactin, and the termination of the treatment resulted in a decrease in serum prolactin and a complete regression of the mammary lesions within 14 days.	('cyclosporine', 'Chemical', 'MESH:D016572', (63, 75))	('increased', 'PosReg', (142, 151))	('cyclosporine', 'Var', (97, 109))	('cyclosporine', 'Chemical', 'MESH:D016572', (97, 109))	('decrease', 'NegReg', (220, 228))	('serum prolactin', 'MPA', (232, 247))	('serum prolactin', 'MPA', (152, 167))	('increased serum prolactin', 'Phenotype', 'HP:0000870', (142, 167))	('decrease in serum prolactin', 'Phenotype', 'HP:0008202', (220, 247))
6435	31581718	In the mammary gland tissue, which is also equipped with prolactin receptors, prolactin has not only endocrine functions, but can also evoke paracrine and autocrine effects.	('prolactin receptor', 'Gene', (57, 75))	('prolactin receptor', 'Gene', '5618', (57, 75))	('endocrine', 'MPA', (101, 110))	('prolactin', 'Var', (78, 87))	('evoke', 'Reg', (135, 140))
6479	31514752	Both high- and low-grade ESS demonstrated T2 hypointense bands, marginal nodules, intratumoral nodules, and worm-like intra-myometrial nodules, and their tumor apparent diffusion coefficient (ADC) values were significantly lower than those of T2-hyperintense leiomyomas (P < .001).	('leiomyomas', 'Disease', 'MESH:D007889', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('lower', 'NegReg', (223, 228))	('tumor', 'Disease', (87, 92))	('leiomyomas', 'Disease', (259, 269))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumoral', 'Disease', 'MESH:D009369', (87, 94))	('tumoral', 'Disease', (87, 94))	('T2 hypointense', 'Var', (42, 56))	('tumor', 'Disease', (154, 159))
6585	30835723	Nowadays, with the advent of computational methods and the use of genomic features such as somatic mutations, DNA methylation, and somatic copy-number variation (CNV), it is feasible to estimate tumor purity.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (195, 200))
6659	30541518	In-frame deletions at exon 19 in the EGFR gene in both the carcinomatous component and the sarcomatous component have been detected in resected PCS specimens, indicating the potential to identify oncogenic driver mutations for targeting in PCS tumors.	('PCS tumors', 'Disease', (240, 250))	('In-frame deletions', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('PCS', 'Phenotype', 'HP:0030445', (144, 147))	('EGFR', 'Gene', '1956', (37, 41))	('carcinomatous component and the sarcomatous component', 'Disease', 'MESH:D018316', (59, 112))	('PCS', 'Chemical', '-', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('PCS', 'Phenotype', 'HP:0030445', (240, 243))	('PCS', 'Chemical', '-', (240, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('EGFR', 'Gene', (37, 41))	('PCS tumors', 'Disease', 'OMIM:176430', (240, 250))
6689	28355107	The NOD background is characterized by a loss of function mutation in the C5 hemolytic complement gene, decreased (but not completely absent) natural killer (NK) cell activity, defects in antigen-presenting activity, and impaired macrophage function.	('NOD', 'Gene', (4, 7))	('C5 hemolytic', 'Disease', 'MESH:C537005', (74, 86))	('impaired', 'NegReg', (221, 229))	('defects', 'NegReg', (177, 184))	('decreased', 'NegReg', (104, 113))	('C5 hemolytic', 'Disease', (74, 86))	('antigen-presenting activity', 'MPA', (188, 215))	('mutation', 'Var', (58, 66))	('macrophage function', 'CPA', (230, 249))	('NOD', 'Gene', '1822', (4, 7))
6690	28355107	A defective somatic recombination at the level of T cell receptor and immunoglobulin chains loci derives from homozygosity for the Prkdcscid mutation, with consequent defective development and maturation of T and B cell clones, leading to an absence of functional lymphocytes and hypogammaglobulinemia.	('hypogammaglobulinemia', 'Phenotype', 'HP:0004313', (280, 301))	('Prkdcscid', 'Gene', (131, 140))	('maturation', 'CPA', (193, 203))	('defective', 'NegReg', (167, 176))	('hypogammaglobulinemia', 'Disease', (280, 301))	('functional lymphocytes', 'CPA', (253, 275))	('mutation', 'Var', (141, 149))	('absence', 'NegReg', (242, 249))	('hypogammaglobulinemia', 'Disease', 'MESH:D000361', (280, 301))
6751	28355107	Given the nature of the experiment, skin abnormalities were most commonly detected in animals enrolled in groups G1, G2, G3, and G5; 1 G4 mouse had evidence of marked necrosuppurative dermatitis.	('mouse', 'Species', '10090', (138, 143))	('skin abnormalities', 'Disease', 'MESH:D012868', (36, 54))	('dermatitis', 'Disease', 'MESH:D003872', (184, 194))	('dermatitis', 'Disease', (184, 194))	('skin abnormalities', 'Phenotype', 'HP:0000951', (36, 54))	('detected', 'Reg', (74, 82))	('dermatitis', 'Phenotype', 'HP:0011123', (184, 194))	('skin abnormalities', 'Disease', (36, 54))	('G5; 1 G4', 'Var', (129, 137))
6787	28355107	Specifically, AMP was found in association with pulmonary adenomas or carcinomas in 3 cases, and with metastases of mammary carcinomas in 2 cases, while it was the only pulmonary finding in the remaining 4 cases.	('AMP', 'Var', (14, 17))	('metastases of mammary carcinomas', 'Disease', (102, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('metastases of mammary carcinomas', 'Disease', 'MESH:D009362', (102, 134))	('AMP', 'Chemical', '-', (14, 17))	('pulmonary adenomas or carcinomas', 'Disease', (48, 80))	('association', 'Reg', (31, 42))	('pulmonary adenomas or carcinomas', 'Disease', 'MESH:D000236', (48, 80))
6861	28355107	This finding contrasts with the higher incidence of hematopoietic neoplasms in the strain that contributed to the NSG genetic background, including NOD, NOD scid and BALB/c mice, B6;129, and FVB (another Swiss-derived strain).	('NOD', 'Gene', '1822', (148, 151))	('NOD', 'Gene', '1822', (153, 156))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (52, 75))	('hematopoietic neoplasms', 'Disease', (52, 75))	('neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('NOD', 'Gene', (148, 151))	('NOD', 'Gene', (153, 156))	('B6;129', 'Var', (179, 185))	('neoplasms', 'Phenotype', 'HP:0002664', (66, 75))	('hematopoietic neoplasms', 'Disease', 'MESH:D019337', (52, 75))	('mice', 'Species', '10090', (173, 177))
6868	28355107	P. pneumotropica was the only bacterium isolated from pulmonary lesions, and it may have been the underlying cause of other commonly encountered lesions including otitis media, pericarditis, endometritis and myocarditis, although microbiology was not performed on these lesions.	('myocarditis', 'Disease', (208, 219))	('myocarditis', 'Phenotype', 'HP:0012819', (208, 219))	('otitis media', 'Phenotype', 'HP:0000388', (163, 175))	('otitis', 'Disease', (163, 169))	('cause', 'Reg', (109, 114))	('pulmonary lesions', 'Disease', 'MESH:D008171', (54, 71))	('endometritis', 'Phenotype', 'HP:0025636', (191, 203))	('pulmonary lesions', 'Disease', (54, 71))	('endometritis', 'Disease', (191, 203))	('otitis', 'Disease', 'MESH:D010031', (163, 169))	('endometritis', 'Disease', 'MESH:D004716', (191, 203))	('myocarditis', 'Disease', 'MESH:D009205', (208, 219))	('pericarditis', 'Disease', 'MESH:D010493', (177, 189))	('pericarditis', 'Disease', (177, 189))	('P. pneumotropica', 'Species', '758', (0, 16))	('pericarditis', 'Phenotype', 'HP:0001701', (177, 189))	('P. pneumotropica', 'Var', (0, 16))
6869	28355107	Also, in those mice exhibiting suppurative pulmonary lesions in which no culture was performed, P. pneumotropica was suspected to be the cause due to similarities on HE and Gram stains.	('P. pneumotropica', 'Var', (96, 112))	('HE', 'Chemical', '-', (166, 168))	('pulmonary lesions', 'Disease', 'MESH:D008171', (43, 60))	('pulmonary lesions', 'Disease', (43, 60))	('mice', 'Species', '10090', (15, 19))	('P. pneumotropica', 'Species', '758', (96, 112))
6878	28355107	AMP has been originally described in Swiss mice, and in mice with a Swiss background; it has been reported as a major cause of disease and death in 129S4/SvJae and 129S6/SvEvTac mice, while it has been less commonly observed in B6;129 mice, and in C57BL/6J.	('mice', 'Species', '10090', (43, 47))	('death', 'Disease', (139, 144))	('AMP', 'Var', (0, 3))	('mice', 'Species', '10090', (178, 182))	('mice', 'Species', '10090', (56, 60))	('AMP', 'Chemical', '-', (0, 3))	('death', 'Disease', 'MESH:D003643', (139, 144))	('mice', 'Species', '10090', (235, 239))	('disease', 'Disease', (127, 134))	('cause', 'Reg', (118, 123))
6893	28355107	C. bovis is a gram-positive coryneform that has been associated with skin disease in mice carrying deficits for T-cell (Foxn1-nu athymic nude mice) and T- and B-cells (Pkrdcscid).	('mice', 'Species', '10090', (85, 89))	('T-cell', 'CPA', (112, 118))	('nude mice', 'Species', '10090', (137, 146))	('Foxn1', 'Gene', '15218', (120, 125))	('skin disease', 'Phenotype', 'HP:0000951', (69, 81))	('mice', 'Species', '10090', (142, 146))	('Foxn1', 'Gene', (120, 125))	('skin disease', 'Disease', (69, 81))	('associated', 'Reg', (53, 63))	('C. bovis', 'Var', (0, 8))	('skin disease', 'Disease', 'MESH:D012871', (69, 81))	('C. bovis', 'Species', '36808', (0, 8))
6894	28355107	The underlying mechanism responsible for the epidermal proliferation is unknown; however, mice deficient in host defense components are likely to have increased disease.	('increased', 'PosReg', (151, 160))	('mice', 'Species', '10090', (90, 94))	('disease', 'Disease', (161, 168))	('deficient', 'Var', (95, 104))
6938	26537303	In contrary to other uterine sarcomas, such as carcinosarcoma, leiomyosarcoma, and high-grade ESS, low-grade ESS generally involves a slowly growing malignancy with an indolent clinical course and late recurrence.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (63, 77))	('malignancy', 'Disease', 'MESH:D009369', (149, 159))	('carcinosarcoma', 'Disease', (47, 61))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (63, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (21, 36))	('malignancy', 'Disease', (149, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('carcinosarcoma', 'Disease', 'MESH:D002296', (47, 61))	('sarcomas', 'Disease', (29, 37))	('leiomyosarcoma', 'Disease', (63, 77))	('low-grade', 'Var', (99, 108))
6939	26537303	Low-grade ESS patients tend to be younger than typical patients with other uterine sarcomas, with a mean age of 52 years.	('Low-grade', 'Var', (0, 9))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (75, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcomas', 'Disease', (83, 91))	('ESS', 'Disease', (10, 13))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (14, 22))	('sarcomas', 'Disease', 'MESH:D012509', (83, 91))
6941	26537303	However, the preoperative diagnosis of low-grade ESS is important because the current standard treatment for early-stage (stage I or II) low-grade ESS is hysterectomy and bilateral salpingo-oophorectomy for hormonally sensitive tumors, which is different from the treatment of the more common condition of benign leiomyoma.	('benign leiomyoma', 'Disease', (306, 322))	('benign leiomyoma', 'Disease', 'MESH:D007889', (306, 322))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('low-grade', 'Var', (137, 146))	('tumors', 'Disease', 'MESH:D009369', (228, 234))
6959	26537303	The ten patients with low-grade ESS were presented with symptoms including menorrhagia (n=4), abdominal pain (n=2), and postmenopausal vaginal bleeding (n=1).	('menorrhagia', 'Disease', (75, 86))	('vaginal bleeding', 'Disease', (135, 151))	('vaginal bleeding', 'Disease', 'MESH:D014592', (135, 151))	('abdominal pain', 'Phenotype', 'HP:0002027', (94, 108))	('menorrhagia', 'Phenotype', 'HP:0000132', (75, 86))	('abdominal pain', 'Disease', (94, 108))	('menorrhagia', 'Disease', 'MESH:D008595', (75, 86))	('pain', 'Phenotype', 'HP:0012531', (104, 108))	('low-grade', 'Var', (22, 31))	('abdominal pain', 'Disease', 'MESH:D015746', (94, 108))	('patients', 'Species', '9606', (8, 16))
6996	26537303	Subsequently, a subset of ESS with a unique YWHAE-FAM22 gene rearrangement was discovered, and the high-grade ESS category was re-established as a subset of ESS with a prognosis intermediate between low-grade ESS and UUS.	('YWHAE', 'Gene', (44, 49))	('rearrangement', 'Var', (61, 74))	('YWHAE', 'Gene', '7531', (44, 49))	('UUS', 'Disease', (217, 220))	('UUS', 'Chemical', '-', (217, 220))
7038	26745314	Immunohistochemical study with antibodies against p16, p53 and Ki-67 were performed and 64% of cells were positive for Ki-67 (Fig.	('Ki-67', 'Var', (119, 124))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('positive', 'Reg', (106, 114))	('p16', 'Gene', '1029', (50, 53))	('p16', 'Gene', (50, 53))
7066	23529353	HER2 overexpressed and/or gene amplified tumors are generally regarded as biologically aggressive neoplasms.	('aggressive neoplasms', 'Disease', (87, 107))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('gene amplified', 'Var', (26, 40))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('aggressive neoplasms', 'Disease', 'MESH:D001523', (87, 107))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('overexpressed', 'PosReg', (5, 18))	('HER2', 'Protein', (0, 4))
7067	23529353	In breast, cervical, endometrial and ovarian cancer, there have been several studies linking the amplification of the c-erbB2 gene with chemo-resistance and overall poor survival.	('amplification', 'Var', (97, 110))	('breast', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('c-erbB2', 'Gene', '2064', (118, 125))	('cervical', 'Disease', (11, 19))	('c-erbB2', 'Gene', (118, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (37, 51))	('endometrial and ovarian cancer', 'Disease', 'MESH:D016889', (21, 51))
7070	23529353	Exome-wide analyses have recently greatly contributed to a better understanding of the biology of human neoplasms through the identification of mutations and copy number variations in genes crucial for the development of human tumors.	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('neoplasms', 'Disease', 'MESH:D009369', (104, 113))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('neoplasms', 'Disease', (104, 113))	('human', 'Species', '9606', (221, 226))	('copy number variations', 'Var', (158, 180))	('human', 'Species', '9606', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('mutations', 'Var', (144, 153))
7120	23529353	Amplification was detected in 7% and low copy number increase (three-five fold) detected in 14% of these carcinomas.	('Amplification', 'Var', (0, 13))	('low copy', 'MPA', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('carcinomas', 'Disease', (105, 115))	('carcinomas', 'Disease', 'MESH:D002277', (105, 115))
7130	23529353	In a more recent study by the same research group, the presence of HER2 amplification/overexpression or KRAS mutation in mucinous carcinomas was associated with a decreased likelihood of disease recurrence or death.	('amplification/overexpression', 'PosReg', (72, 100))	('presence', 'Var', (55, 63))	('death', 'Disease', 'MESH:D003643', (209, 214))	('mucinous carcinomas', 'Disease', (121, 140))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (121, 140))	('KRAS', 'Gene', '3845', (104, 108))	('death', 'Disease', (209, 214))	('HER2', 'Protein', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('decreased', 'NegReg', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('disease recurrence', 'CPA', (187, 205))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (121, 139))	('amplification/overexpression', 'Var', (72, 100))	('KRAS', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
7148	23529353	As mentioned previously, some research in ovarian carcinoma has found HER2 expression to be an independent risk factor for decreased survival.	('decreased', 'NegReg', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('HER2', 'Protein', (70, 74))	('expression', 'Var', (75, 85))	('survival', 'MPA', (133, 141))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (42, 59))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (42, 59))	('ovarian carcinoma', 'Disease', (42, 59))
7149	23529353	Conversely patients with negative HER2 have been noted to have better chemotherapy responses, higher rates of negative second-look laparotomy and also improved survival.	('survival', 'CPA', (160, 168))	('improved', 'PosReg', (151, 159))	('better', 'PosReg', (63, 69))	('HER2', 'Protein', (34, 38))	('patients', 'Species', '9606', (11, 19))	('chemotherapy responses', 'CPA', (70, 92))	('negative', 'Var', (25, 33))
7160	23529353	Rates of HER2 overexpression and amplification range from 4% to 69% in endometrial adenocarcinoma.	('amplification', 'Var', (33, 46))	('HER2', 'Protein', (9, 13))	('endometrial adenocarcinoma', 'Disease', (71, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (71, 97))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (71, 97))	('overexpression', 'PosReg', (14, 28))
7161	23529353	Generally, HER2 expression and amplification is more common in higher grade and stage endometrial tumors.	('HER2', 'Protein', (11, 15))	('endometrial tumors', 'Disease', (86, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('common', 'Reg', (53, 59))	('endometrial tumors', 'Disease', 'MESH:D016889', (86, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('expression', 'MPA', (16, 26))	('amplification', 'Var', (31, 44))
7163	23529353	HER2 expression/amplification in these tumors was associated with shorter overall survival.	('expression/amplification', 'Var', (5, 29))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('shorter', 'NegReg', (66, 73))	('overall survival', 'MPA', (74, 90))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('HER2', 'Protein', (0, 4))
7165	23529353	Several studies on endometrial adenocarcinoma have also demonstrated that HER2 gene amplification is of prognostic value and associated with a worse prognosis in histological types such as clear cell carcinoma and serous carcinoma.	('gene amplification', 'Var', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('endometrial adenocarcinoma', 'Disease', (19, 45))	('clear cell carcinoma', 'Disease', (189, 209))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (19, 45))	('serous carcinoma', 'Disease', (214, 230))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (189, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('serous carcinoma', 'Disease', 'MESH:D018284', (214, 230))	('associated with', 'Reg', (125, 140))	('HER2', 'Protein', (74, 78))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (19, 45))
7166	23529353	Amplification of HER2 has been documented in as many as 38% of clear cell endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Amplification', 'Var', (0, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('endometrial carcinomas', 'Disease', (74, 96))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (74, 95))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (74, 96))	('HER2', 'Protein', (17, 21))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (74, 96))
7178	23529353	Studies supporting the monoclonal origin of this tumor have found identical patterns of chromosomal inactivation as well as identical mutations of K-ras and p53 in the two components.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('p53', 'Gene', '7157', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (134, 143))	('K-ras', 'Gene', (147, 152))	('p53', 'Gene', (157, 160))	('K-ras', 'Gene', '3845', (147, 152))
7192	23529353	Squamous and adenosquamous carcinomas however had the association of positive HER2 staining with poor prognosis most apparent in those patients without lymph node metastases.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('lymph node metastases', 'Disease', (152, 173))	('patients', 'Species', '9606', (135, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('HER2', 'Protein', (78, 82))	('positive', 'Var', (69, 77))	('adenosquamous carcinomas', 'Disease', 'MESH:D018196', (13, 37))	('adenosquamous carcinomas', 'Disease', (13, 37))	('Squamous', 'Disease', (0, 8))	('lymph node metastases', 'Disease', 'MESH:D009362', (152, 173))
7206	23529353	In a recent study of metastatic breast cancer patients treated with trastuzumab and paclitaxel, Jung and colleagues found that high HER2 amplification index and high class III beta-tubulin expression were predictive of a good response to therapy.	('breast cancer', 'Disease', (32, 45))	('trastuzumab', 'Chemical', 'MESH:D000068878', (68, 79))	('patients', 'Species', '9606', (46, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('HER2', 'Protein', (132, 136))	('high', 'Var', (127, 131))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('paclitaxel', 'Chemical', 'MESH:D017239', (84, 94))	('expression', 'MPA', (189, 199))	('high', 'Var', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('class III beta-tubulin', 'Gene', '10381', (166, 188))	('class III beta-tubulin', 'Gene', (166, 188))
7218	23529353	Clinical results have also shown that there is a improved response to trastuzumab in patients with a particular Fc polymorphism resulting in a higher NK affinity to IgG1, again lending support that ADCC inclusive of its mediators is critical for the in vivo efficacy of trastuzumab.	('improved', 'PosReg', (49, 57))	('trastuzumab', 'Chemical', 'MESH:D000068878', (70, 81))	('patients', 'Species', '9606', (85, 93))	('polymorphism', 'Var', (115, 127))	('NK affinity', 'MPA', (150, 161))	('higher', 'PosReg', (143, 149))	('response', 'MPA', (58, 66))	('IgG1', 'Protein', (165, 169))	('trastuzumab', 'Chemical', 'MESH:D000068878', (270, 281))
7256	23529353	Inhibition of mCRPs on type II endometrial cancers harboring c-erbB2 gene amplification may prove to be a useful strategy to improve the response of these aggressive tumors to trastuzumab-mediated CDC and ADCC.	('c-erbB2', 'Gene', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('aggressive tumors', 'Disease', (155, 172))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('type II endometrial cancers', 'Disease', 'MESH:D016889', (23, 50))	('endometrial cancer', 'Phenotype', 'HP:0012114', (31, 49))	('response', 'MPA', (137, 145))	('gene amplification', 'Var', (69, 87))	('type II endometrial cancers', 'Disease', (23, 50))	('trastuzumab', 'Chemical', 'MESH:D000068878', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('c-erbB2', 'Gene', '2064', (61, 68))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('improve', 'PosReg', (125, 132))	('aggressive tumors', 'Disease', 'MESH:D001523', (155, 172))
7281	23529353	This study also showed that a single intravenous dose of cyclophosphamide (300mg/m2) has no effect on the number of circulating Tregs despite previous evidence reported of cyclophosphamide enhancing tumor immunotherapy by eliminating Tregs.	('tumor', 'Disease', (199, 204))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (172, 188))	('Tregs', 'Chemical', '-', (128, 133))	('cyclophosphamide', 'Var', (172, 188))	('Tregs', 'CPA', (234, 239))	('enhancing', 'PosReg', (189, 198))	('Tregs', 'Chemical', '-', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (57, 73))	('eliminating', 'NegReg', (222, 233))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
7286	23529353	The elucidation of genetic mutations which may modify tumor response to targeted agents and the correlation with HER2 expression is expected to provide important information for future cancer treatment.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('modify', 'Reg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('HER2', 'Protein', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (54, 59))	('cancer', 'Disease', (185, 191))
7371	21559205	This theory was supported by molecular studies of giant cell tumors of pancreas and liver showing the same K-ras mutations in the tumor cells and their precursor lesions.	('K-ras', 'Gene', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors of pancreas', 'Phenotype', 'HP:0002894', (61, 79))	('giant cell tumor', 'Phenotype', 'HP:0011847', (50, 66))	('mutations', 'Var', (113, 122))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('giant cell tumors of pancreas', 'Disease', 'MESH:D005870', (50, 79))	('K-ras', 'Gene', '16653', (107, 112))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (61, 66))	('giant cell tumors', 'Phenotype', 'HP:0011847', (50, 67))	('giant cell tumors of pancreas', 'Disease', (50, 79))
7387	21559205	The negativity of CD117 (c-kit) also ruled out the possibility of malignant gastrointestinal stromal tumor with osteoclast-like giant cells.	('CD117', 'Gene', (18, 23))	('malignant gastrointestinal stromal tumor', 'Disease', (66, 106))	('c-kit', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('c-kit', 'Gene', '16590', (25, 30))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (76, 106))	('negativity', 'Var', (4, 14))	('malignant gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (66, 106))	('CD117', 'Gene', '16590', (18, 23))
7392	21559205	To the best of our knowledge, this is the first report of a case showing an undifferentiated endometrial sarcoma with nuclear pleomorphism associated with presence of osteoclast-like giant cells and no true osteochondromatous differentiation, which further expands the spectrum of this rare uterine neoplasms.	('endometrial sarcoma', 'Disease', 'MESH:D018203', (93, 112))	('neoplasm', 'Phenotype', 'HP:0002664', (299, 307))	('neoplasms', 'Disease', 'MESH:D009369', (299, 308))	('osteochondromatous differentiation', 'Disease', (207, 241))	('endometrial sarcoma', 'Disease', (93, 112))	('neoplasms', 'Disease', (299, 308))	('nuclear pleomorphism', 'Var', (118, 138))	('associated', 'Reg', (139, 149))	('uterine neoplasm', 'Phenotype', 'HP:0010784', (291, 307))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('uterine neoplasms', 'Phenotype', 'HP:0010784', (291, 308))	('osteochondromatous differentiation', 'Phenotype', 'HP:0030431', (207, 241))	('neoplasms', 'Phenotype', 'HP:0002664', (299, 308))	('osteochondromatous differentiation', 'Disease', 'MESH:D012734', (207, 241))	('osteoclast-like giant cells', 'CPA', (167, 194))
7395	21412130	Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas.	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (210, 241))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('ARID1A', 'Gene', (35, 41))	('mutated', 'Var', (148, 155))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (63, 85))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('ARID1A', 'Gene', '8289', (35, 41))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (218, 241))	('ovarian clear cell', 'Disease', (180, 198))	('ARID1A', 'Gene', (86, 92))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (63, 85))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (218, 240))	('ovarian endometrioid carcinomas', 'Disease', (210, 241))	('loss of expression', 'NegReg', (13, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ARID1A', 'Gene', '8289', (86, 92))	('tumor', 'Disease', (118, 123))	('endometrioid carcinoma', 'Disease', (63, 85))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (218, 240))
7397	21412130	Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutation', 'Var', (68, 76))	('inactivation', 'Var', (52, 64))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ARID1A', 'Gene', (80, 86))
7401	21412130	All mutations in endometrioid carcinomas were nonsense or insertion/deletion mutations and tumors with ARID1A mutations demonstrated complete loss or clonal loss of ARID1A expression.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (17, 39))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (17, 40))	('ARID1A', 'Gene', (103, 109))	('insertion/deletion', 'Var', (58, 76))	('endometrioid carcinomas', 'Disease', (17, 40))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('mutations', 'Var', (4, 13))	('tumors', 'Disease', (91, 97))	('nonsense', 'Var', (46, 54))	('loss', 'NegReg', (142, 146))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (17, 40))	('ARID1A', 'Gene', (165, 171))	('expression', 'MPA', (172, 182))	('loss', 'NegReg', (157, 161))
7402	21412130	In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression.	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (123, 145))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (123, 145))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('endometrioid carcinoma', 'Disease', (123, 145))	('ARID1A', 'Gene', (224, 230))	('mutations', 'Var', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('loss', 'NegReg', (216, 220))	('carcinomas', 'Disease', 'MESH:D002277', (81, 91))	('ARID1A', 'Gene', (186, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Disease', (81, 91))	('expression', 'MPA', (231, 241))	('tumor', 'Disease', (165, 170))
7403	21412130	These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high frequency of loss of expression and mutation of ARID1A.	('expression', 'MPA', (253, 263))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (76, 98))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (76, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('mutation', 'Var', (268, 276))	('endometrioid carcinoma', 'Disease', (76, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('clear cell carcinoma', 'Disease', (156, 176))	('ARID1A', 'Gene', (280, 286))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (156, 176))	('loss of', 'NegReg', (245, 252))
7405	21412130	Sequence mutations that are acquired during tumor evolution can lead to activation of oncogenes and inactivation of tumor suppressors and DNA repair genes, thereby propelling tumor development and progression.	('activation', 'PosReg', (72, 82))	('inactivation', 'NegReg', (100, 112))	('tumor', 'Disease', (175, 180))	('oncogenes', 'Protein', (86, 95))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('DNA repair genes', 'Gene', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('propelling', 'PosReg', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (44, 49))	('progression', 'CPA', (197, 208))
7407	21412130	With the use of whole exome sequencing and transcriptome sequencing, two independent studies recently reported ARID1A (also known as BAF250A) mutations in 43-56% of ovarian clear cell carcinomas and 30% of ovarian low-grade endometrioid carcinomas but not in matched controls, confirming the somatic nature of the mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('mutations', 'Var', (142, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('endometrioid carcinomas', 'Disease', (224, 247))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (165, 194))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (224, 246))	('BAF250A', 'Gene', (133, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('ovarian clear cell carcinomas', 'Disease', (165, 194))	('ARID1A', 'Gene', (111, 117))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (224, 247))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (224, 247))	('BAF250A', 'Gene', '8289', (133, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
7408	21412130	Since both of these tumor types are believed to be derived from endometriosis and because one of these studies also found ARID1A mutations in adjacent atypical endometriosis it is conceivable that ARID1A loss is a relatively specific molecular event in the genesis of these tumors.	('endometriosis', 'Disease', (64, 77))	('endometriosis', 'Phenotype', 'HP:0030127', (64, 77))	('ARID1A', 'Gene', (122, 128))	('tumors', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('endometriosis', 'Phenotype', 'HP:0030127', (160, 173))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('found', 'Reg', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('endometriosis', 'Disease', 'MESH:D004715', (160, 173))	('tumor', 'Disease', (274, 279))	('endometriosis', 'Disease', 'MESH:D004715', (64, 77))	('endometriosis', 'Disease', (160, 173))	('tumor', 'Disease', (20, 25))
7413	21412130	Inactivation of ARID1A is thought to enhance cell cycle progression by potentially involving c-myc, thereby contributing to uncontrolled cellular proliferation in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cell cycle progression', 'CPA', (45, 67))	('c-myc', 'Gene', '4609', (93, 98))	('uncontrolled', 'MPA', (124, 136))	('c-myc', 'Gene', (93, 98))	('involving', 'Reg', (83, 92))	('contributing', 'Reg', (108, 120))	('ARID1A', 'Gene', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Inactivation', 'Var', (0, 12))	('cancer', 'Disease', (163, 169))	('enhance', 'PosReg', (37, 44))
7414	21412130	Although ARID1A has emerged as a new cancer-associated gene which is frequently mutated in endometriosis-related ovarian neoplasms, it is not known whether its mutation, like FOXL2 and APC, is detected only in specific types of cancer or, like in TP53 and KRAS, occurs in a variety of neoplastic diseases.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('ovarian neoplasms', 'Phenotype', 'HP:0100615', (113, 130))	('neoplastic diseases', 'Disease', 'MESH:D009386', (285, 304))	('mutated', 'Var', (80, 87))	('ARID1A', 'Gene', (9, 15))	('KRAS', 'Gene', '3845', (256, 260))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('endometriosis', 'Disease', 'MESH:D004715', (91, 104))	('TP53', 'Gene', (247, 251))	('endometriosis', 'Disease', (91, 104))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', (37, 43))	('FOXL2', 'Gene', '668', (175, 180))	('ovarian neoplasms', 'Disease', 'MESH:D010051', (113, 130))	('neoplastic diseases', 'Disease', (285, 304))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('KRAS', 'Gene', (256, 260))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('FOXL2', 'Gene', (175, 180))	('ovarian neoplasms', 'Disease', (113, 130))	('endometriosis', 'Phenotype', 'HP:0030127', (91, 104))	('APC', 'Disease', 'MESH:D011125', (185, 188))	('APC', 'Disease', (185, 188))	('TP53', 'Gene', '7157', (247, 251))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
7415	21412130	Because ARID1A mutations are randomly distributed in 20 exons and are insertion/deletion type of mutations that lead to truncated proteins, we used loss of ARID1A immunoreactivity as a surrogate marker for a mutation to screen a variety of carcinomas.	('truncated', 'MPA', (120, 129))	('loss', 'NegReg', (148, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (240, 250))	('carcinomas', 'Disease', (240, 250))	('lead', 'Reg', (112, 116))	('mutations', 'Var', (15, 24))	('carcinomas', 'Disease', 'MESH:D002277', (240, 250))	('ARID1A', 'Gene', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('proteins', 'Protein', (130, 138))	('ARID1A', 'Gene', (156, 162))
7420	21412130	Since the ARID1A mutation status has been previously reported in ovarian clear cell and ovarian low-grade endometrioid carcinomas, these carcinomas were not included in the current study.	('carcinomas', 'Disease', (119, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('carcinomas', 'Disease', (137, 147))	('carcinomas', 'Disease', 'MESH:D002277', (137, 147))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (106, 129))	('mutation', 'Var', (17, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('ARID1A', 'Gene', (10, 16))	('ovarian clear cell and ovarian low-grade endometrioid carcinomas', 'Disease', 'MESH:D010051', (65, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('reported', 'Reg', (53, 61))	('carcinomas', 'Disease', 'MESH:D002277', (119, 129))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (106, 128))
7426	21412130	A total of 93 tumor samples were analyzed for somatic ARID1A mutations.	('ARID1A', 'Gene', (54, 60))	('tumor', 'Disease', (14, 19))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
7435	21412130	Western blot analysis demonstrated a significant decrease of ARID1A protein in HeLa cells after transfection with ARID1A specific shRNAs, especially the shRNA-2 and shRNA-3, as compared to control shRNA, indicating the specificity of the ARID1A antibody (Fig.	('ARID1A', 'Gene', (61, 67))	('specific', 'Var', (121, 129))	('decrease', 'NegReg', (49, 57))	('ARID1A', 'Gene', (114, 120))	('HeLa', 'CellLine', 'CVCL:0030', (79, 83))	('protein', 'Protein', (68, 75))
7437	21412130	Since the ARID1A mutation status has been previously reported in ovarian clear cell and ovarian endometrioid carcinomas, these carcinomas were not included in the current study.	('carcinomas', 'Disease', 'MESH:D002277', (127, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('carcinomas', 'Disease', (127, 137))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (96, 119))	('mutation', 'Var', (17, 25))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (96, 118))	('ARID1A', 'Gene', (10, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ovarian clear cell and ovarian endometrioid carcinomas', 'Disease', 'MESH:D010051', (65, 119))	('reported', 'Reg', (53, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Disease', (109, 119))	('carcinomas', 'Disease', 'MESH:D002277', (109, 119))
7448	21412130	As shown in Table 2, somatic ARID1A mutation was detected in 10 (40%) of 25 uterine low-grade endometrioid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('detected', 'Reg', (49, 57))	('endometrioid carcinomas', 'Disease', (94, 117))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (94, 116))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (94, 117))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (94, 117))	('ARID1A', 'Gene', (29, 35))	('mutation', 'Var', (36, 44))
7449	21412130	As in ovarian clear cell and ovarian endometrioid carcinomas, the mutations were either insertion/deletion mutations or nonsense mutations which were widely distributed in the ARID1A gene (Table 3).	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('ovarian clear cell and ovarian endometrioid carcinomas', 'Disease', 'MESH:D010051', (6, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (37, 59))	('insertion/deletion mutations', 'Var', (88, 116))	('nonsense mutations', 'Var', (120, 138))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (37, 60))
7451	21412130	We found that 5 (50%) of 10 tumors with ARID1A mutations did not demonstrate any detectable level of ARID1A immunoreactivity.	('ARID1A', 'Gene', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
7452	21412130	Interestingly, four ARID1A positive cases with ARID1A mutations exhibited a pattern of immunoreactivity in which areas of negative cells were present adjacent to positive areas suggesting that mutations arose in clones within the tumor (Fig.	('tumor', 'Disease', (230, 235))	('ARID1A', 'Gene', (47, 53))	('ARID1A', 'Gene', (20, 26))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
7456	21412130	One of the main findings has been the identification of somatic mutations of several chromatin remodeling genes in certain types of human cancer.	('cancer', 'Disease', (138, 144))	('chromatin remodeling genes', 'Gene', (85, 111))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (64, 73))	('human', 'Species', '9606', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
7458	21412130	The findings in the present study extend previous observations and provide cogent evidence that epigenetic changes, like genetic alteration, is a "driver" rather than a "passenger" that is directly involved in tumor development of uterine low-grade endometrioid carcinoma.	('endometrioid carcinoma', 'Disease', (249, 271))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (249, 271))	('epigenetic changes', 'Var', (96, 114))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (249, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
7460	21412130	The main findings were the loss of ARID1A immunoreactivity and mutation of ARDIA in low-grade uterine endometrioid carcinoma as compared to other types of carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('immunoreactivity', 'MPA', (42, 58))	('endometrioid carcinoma', 'Disease', (102, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('ARDIA', 'Gene', (75, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('carcinomas', 'Disease', (155, 165))	('carcinomas', 'Disease', 'MESH:D002277', (155, 165))	('mutation', 'Var', (63, 71))	('ARID1A', 'Gene', (35, 41))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (102, 124))	('loss', 'NegReg', (27, 31))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (102, 124))
7461	21412130	Although loss of ARID1A expression also occurs in other tumor types, the frequency of loss of expression is low, indicating that ARID1A mutations are associated with specific types of carcinoma.	('associated', 'Reg', (150, 160))	('carcinoma', 'Disease', 'MESH:D002277', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ARID1A', 'Gene', (129, 135))	('tumor', 'Disease', (56, 61))	('ARID1A', 'Gene', (17, 23))	('carcinoma', 'Disease', (184, 193))	('mutations', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
7462	21412130	Mutational analysis demonstrated somatic ARID1A mutations in 40% of uterine endometrioid carcinoma, a finding that has not been previously reported.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (76, 98))	('ARID1A', 'Gene', (41, 47))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (76, 98))	('endometrioid carcinoma', 'Disease', (76, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('mutations', 'Var', (48, 57))
7464	21412130	Type I tumors are composed of endometrioid carcinomas which frequently harbor sequence mutations in CCNB1, PTEN and PIK3CA while type II tumors are largely serous carcinomas that contain TP53 mutations in the majority of cases.	('PIK3CA', 'Gene', (116, 122))	('harbor', 'Reg', (71, 77))	('type II tumors', 'Disease', 'MESH:D009369', (129, 143))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('TP53', 'Gene', (187, 191))	('mutations', 'Var', (87, 96))	('CCNB1', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (30, 53))	('PTEN', 'Gene', (107, 111))	('serous carcinomas', 'Disease', (156, 173))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (30, 52))	('type II tumors', 'Disease', (129, 143))	('PTEN', 'Gene', '5728', (107, 111))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (30, 53))	('TP53', 'Gene', '7157', (187, 191))	('PIK3CA', 'Gene', '5290', (116, 122))	('Type I tumors', 'Disease', (0, 13))	('CCNB1', 'Gene', '891', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('serous carcinomas', 'Disease', 'MESH:D018284', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('endometrioid carcinomas', 'Disease', (30, 53))
7467	21412130	Thus the relatively frequent loss of ARID1A expression and ARID1A mutations in uterine endometrioid carcinoma but not in uterine serous carcinoma further supports their distinct pathogenesis.	('mutations', 'Var', (66, 75))	('expression', 'MPA', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (87, 109))	('serous carcinoma', 'Disease', (129, 145))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (87, 109))	('loss', 'NegReg', (29, 33))	('ARID1A', 'Gene', (59, 65))	('endometrioid carcinoma', 'Disease', (87, 109))	('serous carcinoma', 'Disease', 'MESH:D018284', (129, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('ARID1A', 'Gene', (37, 43))
7468	21412130	Given the well established roles of Pten-AKT pathway and Wnt pathway in the development of low-grade uterine endometrioid carcinoma (type I tumor), it will be important to determine if the ARID1A pathway cross-talks with those signaling pathways and to assess how inactivation of ARID1A contributes to tumor initiation and progression in this type of carcinoma.	('Pten', 'Gene', '5728', (36, 40))	('Pten', 'Gene', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('endometrioid carcinoma', 'Disease', (109, 131))	('carcinoma', 'Disease', (351, 360))	('AKT', 'Gene', '207', (41, 44))	('contributes', 'Reg', (287, 298))	('ARID1A', 'Gene', (280, 286))	('type I tumor', 'Disease', (133, 145))	('carcinoma', 'Disease', 'MESH:D002277', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinoma', 'Disease', 'MESH:D002277', (351, 360))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (109, 131))	('inactivation', 'Var', (264, 276))	('cross-talks', 'Reg', (204, 215))	('AKT', 'Gene', (41, 44))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (109, 131))	('type I tumor', 'Disease', 'MESH:D005776', (133, 145))	('tumor initiation', 'Disease', 'MESH:D009369', (302, 318))	('tumor initiation', 'Disease', (302, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Disease', (122, 131))
7469	21412130	Although ARID1A mutations were most often associated with complete loss of its protein expression in low-grade uterine endometrioid carcinoma, we observed several uterine endometrioid carcinomas with ARID1A mutations that showed a heterogeneous staining pattern.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (119, 141))	('endometrioid carcinomas', 'Disease', (171, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (119, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('protein expression', 'MPA', (79, 97))	('endometrioid carcinoma', 'Disease', (119, 141))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (171, 194))	('mutations', 'Var', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('mutations', 'Var', (207, 216))	('loss', 'NegReg', (67, 71))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (171, 194))	('ARID1A', 'Gene', (200, 206))	('ARID1A', 'Gene', (9, 15))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (171, 193))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (171, 193))
7471	21412130	This type of clonal loss of ARID1A immunoreactivity was only detected in uterine endometrioid carcinomas with ARID1A mutations but not in those without mutations or in ovarian clear cell carcinomas.	('mutations', 'Var', (117, 126))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (81, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (81, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('ARID1A', 'Gene', (28, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('ovarian clear cell carcinomas', 'Disease', (168, 197))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (168, 197))	('ARID1A', 'Gene', (110, 116))	('endometrioid carcinomas', 'Disease', (81, 104))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (81, 103))
7472	21412130	It is likely that ARID1A mutations occur after tumor initiation in endometrioid carcinoma, creating tumor subclones during evolution of the carcinoma.	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('carcinoma', 'Disease', 'MESH:D002277', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('endometrioid carcinoma', 'Disease', (67, 89))	('mutations', 'Var', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Disease', (80, 89))	('ARID1A', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (67, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('creating', 'Reg', (91, 99))	('tumor', 'Disease', (47, 52))	('carcinoma', 'Disease', (140, 149))	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor initiation', 'Disease', 'MESH:D009369', (47, 63))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (67, 89))	('tumor initiation', 'Disease', (47, 63))
7476	21412130	The results from this study along with our previous reports strongly suggest that loss of ARID1A expression and/or its mutations are confined to ovarian clear cell and ovarian endometrioid carcinomas, because the high-grade and low-grade serous carcinomas as well as mucinous carcinomas did not show ARID1A mutations or loss of expression.	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (267, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('ovarian clear cell and ovarian endometrioid carcinomas', 'Disease', 'MESH:D010051', (145, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (176, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (176, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (276, 286))	('ARID1A', 'Gene', (90, 96))	('loss', 'NegReg', (82, 86))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (267, 286))	('mutations', 'Var', (119, 128))	('serous carcinomas', 'Disease', 'MESH:D018284', (238, 255))	('expression', 'MPA', (97, 107))	('mucinous carcinomas', 'Disease', (267, 286))	('serous carcinomas', 'Disease', (238, 255))
7477	21412130	It is, therefore, conceivable that ARID1A mutation plays an important role in the development of ovarian tumors derived from endometriosis.	('endometriosis', 'Phenotype', 'HP:0030127', (125, 138))	('ovarian tumors', 'Disease', (97, 111))	('ovarian tumors', 'Phenotype', 'HP:0100615', (97, 111))	('mutation', 'Var', (42, 50))	('ovarian tumors', 'Disease', 'MESH:D010051', (97, 111))	('endometriosis', 'Disease', 'MESH:D004715', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('ARID1A', 'Gene', (35, 41))	('endometriosis', 'Disease', (125, 138))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
7478	21412130	Since it is generally thought that endometriosis develops from retrograde menstruation, the underlying critical molecular event for the development of uterine low-grade endometrioid, ovarian endometrioid, and clear cell carcinomas in some cases is mutation of ARIDIA in endometrial tissue.	('clear cell carcinomas', 'Disease', 'MESH:C538614', (209, 230))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('ovarian endometrioid', 'Disease', 'MESH:D016889', (183, 203))	('endometriosis', 'Phenotype', 'HP:0030127', (35, 48))	('mutation', 'Var', (248, 256))	('endometriosis', 'Disease', 'MESH:D004715', (35, 48))	('clear cell carcinomas', 'Disease', (209, 230))	('ovarian endometrioid', 'Disease', (183, 203))	('endometriosis', 'Disease', (35, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))
7480	21412130	In conclusion, based on ARID1A immunohistochemistry and mutational analysis, we found that ARID1A inactivation, either by somatic mutations or by loss of expression, frequently occurs in uterine low-grade endometrioid carcinomas in addition to ovarian low-grade endometrioid and ovarian clear cell carcinomas.	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (205, 228))	('ARID1A', 'Gene', (91, 97))	('ovarian low-grade endometrioid', 'Disease', (244, 274))	('carcinomas', 'Phenotype', 'HP:0030731', (298, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('ovarian clear cell carcinomas', 'Disease', (279, 308))	('loss of expression', 'NegReg', (146, 164))	('endometrioid carcinomas', 'Disease', (205, 228))	('mutations', 'Var', (130, 139))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (279, 308))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (205, 228))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (205, 227))	('inactivation', 'NegReg', (98, 110))
7538	29971677	In contrast, in the LVSI-sarcoma group, ifosfamide (HR 0.48, 95% CI 0.20-1.11, p = 0.09) and anthracycline (HR 0.35, 95% CI 0.11-1.12, p = 0.08) were suggestive for improved PFS, although this did not reach statistical significance.	('improved', 'PosReg', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('LVSI-sarcoma', 'Disease', (20, 32))	('anthracycline', 'Chemical', 'MESH:D018943', (93, 106))	('LVSI-sarcoma', 'Disease', 'MESH:D012509', (20, 32))	('anthracycline', 'Var', (93, 106))	('PFS', 'Disease', (174, 177))	('ifosfamide', 'Chemical', 'MESH:D007069', (40, 50))
7549	29971677	While intriguing to speculate that low-grade carcinoma is associated with increased LVSI-sarcoma, this association is most likely skewed by the impact of sarcoma dominance.	('carcinoma', 'Disease', 'MESH:D009369', (45, 54))	('low-grade', 'Var', (35, 44))	('carcinoma', 'Disease', (45, 54))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('LVSI-sarcoma', 'Disease', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('LVSI-sarcoma', 'Disease', 'MESH:D012509', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
7588	31388127	Such studies have shown that PTEN mutation, the most frequent somatic mutation among EECs (Table 1), is an early but insufficient event in the initiation of tumorigenesis.	('tumor', 'Disease', (157, 162))	('EEC', 'Chemical', '-', (85, 88))	('PTEN', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('mutation', 'Var', (34, 42))	('EC', 'Phenotype', 'HP:0012114', (86, 88))	('ECs', 'Phenotype', 'HP:0012114', (86, 89))	('EEC', 'Phenotype', 'HP:0012114', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
7589	31388127	This observation is corroborated and complemented by genetically engineered mouse models of EC, which have demonstrated that biallelic Pten loss leads to development of CAH, whereas biallelic Pten loss together with mutational activation of Pik3ca results in progression of CAH to EC.	('EC', 'Phenotype', 'HP:0012114', (92, 94))	('Pik3ca', 'Gene', (241, 247))	('CAH', 'Disease', (169, 172))	('Pten', 'Gene', (135, 139))	('EC', 'Phenotype', 'HP:0012114', (281, 283))	('CAH', 'Disease', (274, 277))	('Pten', 'Gene', '19211', (135, 139))	('mouse', 'Species', '10090', (76, 81))	('Pik3ca', 'Gene', '18706', (241, 247))	('Pten', 'Gene', (192, 196))	('loss', 'NegReg', (197, 201))	('Pten', 'Gene', '19211', (192, 196))	('leads to', 'Reg', (145, 153))	('biallelic', 'Var', (182, 191))	('loss', 'NegReg', (140, 144))	('mutational', 'Var', (216, 226))	('biallelic', 'Var', (125, 134))
7590	31388127	These findings add context to the fact that PTEN mutations commonly co-occur with PIK3CA and PIK3R1 mutations in human EECs.	('mutations', 'Var', (100, 109))	('EC', 'Phenotype', 'HP:0012114', (120, 122))	('PIK3CA', 'Gene', (82, 88))	('mutations', 'Var', (49, 58))	('EEC', 'Chemical', '-', (119, 122))	('ECs', 'Phenotype', 'HP:0012114', (120, 123))	('EEC', 'Phenotype', 'HP:0012114', (119, 122))	('PIK3CA', 'Gene', '5290', (82, 88))	('PIK3R1', 'Gene', '5295', (93, 99))	('PTEN', 'Gene', (44, 48))	('PIK3R1', 'Gene', (93, 99))	('human', 'Species', '9606', (113, 118))
7591	31388127	Genetically-engineered mouse models have also inferred co-operativity between Pten loss and Ctnnb1 (which encodes beta-CATENIN) mutation (exon 3 deletion, resulting in beta-catenin stabilization) or Mlh1 inactivation.	('beta-CATENIN', 'Gene', '12387', (114, 126))	('Ctnnb1', 'Gene', '12387', (92, 98))	('mutation', 'Var', (128, 136))	('Pten', 'Gene', (78, 82))	('Pten', 'Gene', '19211', (78, 82))	('Mlh1', 'Gene', (199, 203))	('inactivation', 'NegReg', (204, 216))	('beta-CATENIN', 'Gene', (114, 126))	('mouse', 'Species', '10090', (23, 28))	('Mlh1', 'Gene', '17350', (199, 203))	('beta-catenin stabilization', 'MPA', (168, 194))	('Ctnnb1', 'Gene', (92, 98))	('loss', 'NegReg', (83, 87))	('deletion', 'Var', (145, 153))
7592	31388127	Specifically, Ctnnb1 exon 3 deletion synergizes with biallelic Pten loss and Pik3ca activation to promote EC and myometrial invasion in the setting of ovarian insufficiency [G], and endometrial tumorigenesis is accelerated in Pten+/-/Mlh1-/- mice as compared to Pten+/- mice.	('promote', 'PosReg', (98, 105))	('Pik3ca', 'Gene', (77, 83))	('Pten', 'Gene', (226, 230))	('Pten', 'Gene', '19211', (226, 230))	('loss', 'NegReg', (68, 72))	('endometrial tumorigenesis', 'Disease', (182, 207))	('ovarian insufficiency', 'Disease', 'MESH:D016649', (151, 172))	('myometrial invasion', 'CPA', (113, 132))	('endometrial tumorigenesis', 'Disease', 'MESH:D016889', (182, 207))	('Mlh1', 'Gene', '17350', (234, 238))	('Ctnnb1', 'Gene', '12387', (14, 20))	('mice', 'Species', '10090', (242, 246))	('accelerated', 'PosReg', (211, 222))	('Mlh1', 'Gene', (234, 238))	('Ctnnb1', 'Gene', (14, 20))	('Pik3ca', 'Gene', '18706', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('mice', 'Species', '10090', (270, 274))	('deletion', 'Var', (28, 36))	('Pten', 'Gene', (63, 67))	('Pten', 'Gene', (262, 266))	('Pten', 'Gene', '19211', (63, 67))	('Pten', 'Gene', '19211', (262, 266))	('ovarian insufficiency', 'Phenotype', 'HP:0008209', (151, 172))	('ovarian insufficiency', 'Disease', (151, 172))	('activation', 'PosReg', (84, 94))	('EC', 'Phenotype', 'HP:0012114', (106, 108))
7593	31388127	In the context of human EC, gain-of-function missense mutations in CTNNB1 exon 3, resulting in beta-catenin stabilization, and epigenetic silencing of MLH1, leading to mismatch repair [G] deficiency (MMR-D), are frequent aberrations in EEC that often independently co-occur with PTEN inactivating mutations (Table 1).	('epigenetic silencing', 'Var', (127, 147))	('EC', 'Phenotype', 'HP:0012114', (237, 239))	('EEC', 'Phenotype', 'HP:0012114', (236, 239))	('human', 'Species', '9606', (18, 23))	('EC', 'Phenotype', 'HP:0012114', (24, 26))	('CTNNB1', 'Gene', '1499', (67, 73))	('MLH1', 'Gene', '4292', (151, 155))	('beta-catenin stabilization', 'MPA', (95, 121))	('mismatch repair [G]', 'MPA', (168, 187))	('missense mutations', 'Var', (45, 63))	('MLH1', 'Gene', (151, 155))	('gain-of-function', 'PosReg', (28, 44))	('CTNNB1', 'Gene', (67, 73))	('EEC', 'Chemical', '-', (236, 239))
7594	31388127	The pathogenicity of MMR-D in EC is further underscored by the inherited predisposition to EC in MMR gene mutation carriers in Lynch Syndrome families (Box 1).	('EC', 'Phenotype', 'HP:0012114', (30, 32))	('Lynch Syndrome', 'Disease', (127, 141))	('mutation', 'Var', (106, 114))	('MMR gene', 'Gene', (97, 105))	('EC', 'Phenotype', 'HP:0012114', (91, 93))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (127, 141))
7595	31388127	Another common aberration among EECs is mutational inactivation of the ARID1A tumor suppressor gene [G] (Table 1).	('EEC', 'Phenotype', 'HP:0012114', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutational inactivation', 'Var', (40, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('EC', 'Phenotype', 'HP:0012114', (33, 35))	('tumor', 'Disease', (78, 83))	('ARID1A', 'Gene', '8289', (71, 77))	('ARID1A', 'Gene', (71, 77))	('EEC', 'Chemical', '-', (32, 35))	('ECs', 'Phenotype', 'HP:0012114', (33, 36))
7599	31388127	The occurrence of TP53 mutations and/or p53 stabilization in SEIC, is evidence for this aberration being an early event in SEC pathogenesis.	('SEIC', 'Disease', (61, 65))	('SEC', 'Disease', (123, 126))	('TP53', 'Gene', (18, 22))	('p53', 'Gene', (40, 43))	('mutations', 'Var', (23, 32))	('EC', 'Phenotype', 'HP:0012114', (124, 126))	('SEC', 'Phenotype', 'HP:0012887', (123, 126))	('p53', 'Gene', '7157', (40, 43))	('stabilization', 'NegReg', (44, 57))
7601	31388127	However, this phenotype is in contrast to the lack of endometrial tumors in mice with endometrial-specific deletion of Trp53.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Trp53', 'Gene', '22059', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mice', 'Species', '10090', (76, 80))	('endometrial tumors', 'Disease', (54, 72))	('deletion', 'Var', (107, 115))	('Trp53', 'Gene', (119, 124))	('endometrial tumors', 'Disease', 'MESH:D016889', (54, 72))
7604	31388127	The functional impairment of SEC-associated recurrent mutations in FBXW7, PIK3CA, and PPP2R1A has been established experimentally, and the pathogenicity of cyclin E dysregulation in cancer is well-recognized.	('EC', 'Phenotype', 'HP:0012114', (30, 32))	('PPP2R1A', 'Gene', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('PPP2R1A', 'Gene', '5518', (86, 93))	('FBXW7', 'Gene', (67, 72))	('PIK3CA', 'Gene', '5290', (74, 80))	('mutations', 'Var', (54, 63))	('SEC-associated', 'Disease', (29, 43))	('SEC', 'Phenotype', 'HP:0012887', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('FBXW7', 'Gene', '55294', (67, 72))	('PIK3CA', 'Gene', (74, 80))
7607	31388127	However, unlike most other subtypes of EC (except grade 3 EEC) where PTEN and TP53 mutations tend to be mutually exclusive, a majority of UCSs with PTEN mutations also have TP53 mutations.	('PTEN', 'Gene', (148, 152))	('mutations', 'Var', (153, 162))	('EEC', 'Chemical', '-', (58, 61))	('EC', 'Phenotype', 'HP:0012114', (59, 61))	('EC', 'Phenotype', 'HP:0012114', (39, 41))	('EEC', 'Phenotype', 'HP:0012114', (58, 61))	('TP53', 'Gene', (173, 177))
7608	31388127	The co-occurrence of PTEN and TP53 mutations is not likely due to the biphasic nature of UCSs since the carcinoma [G] and sarcoma [G] components of most UCSs share mutations.	('TP53', 'Gene', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Disease', 'MESH:D009369', (104, 113))	('carcinoma', 'Disease', (104, 113))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('PTEN', 'Gene', (21, 25))	('sarcoma', 'Disease', (122, 129))	('mutations', 'Var', (164, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
7615	31388127	While UCSs were characterized by TCGA independently, TCGA assimilated EECs and SECs into four distinct molecular subgroups with prognostic significance: The first subgroup is formed by POLE-mutated (ultramutated) tumors, which were characterized by POLE exonuclease domain (ED) mutations, predominantly recurrent POLEP286R or POLEV411L, and an excess of G:C>T:A transversions.	('mutations', 'Var', (278, 287))	('EEC', 'Phenotype', 'HP:0012114', (70, 73))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('G:C>T:A transversions', 'Var', (354, 375))	('POLEV411L', 'Var', (326, 335))	('EC', 'Phenotype', 'HP:0012114', (80, 82))	('ED', 'Gene', (274, 276))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('EC', 'Phenotype', 'HP:0012114', (71, 73))	('ECs', 'Phenotype', 'HP:0012114', (80, 83))	('SEC', 'Phenotype', 'HP:0012887', (79, 82))	('EEC', 'Chemical', '-', (70, 73))	('POLEP286R', 'Var', (313, 322))	('ECs', 'Phenotype', 'HP:0012114', (71, 74))
7617	31388127	The second subgroup is formed by hypermutated tumors, which were characterized by microsatellite instability [G] (MSI) and hypermethylation of the MLH1 promoter.	('microsatellite', 'MPA', (82, 96))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MLH1', 'Gene', '4292', (147, 151))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('MLH1', 'Gene', (147, 151))	('hypermethylation', 'Var', (123, 139))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
7618	31388127	Forming the third subgroup, copy number low/microsatellite stable (MSS) tumors were characterized by low copy number aberrations, MSS, and exhibited frequent CTNNB1 (beta-catenin) mutation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CTNNB1', 'Gene', (158, 164))	('copy number low/microsatellite stable', 'Var', (28, 65))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('CTNNB1', 'Gene', '1499', (158, 164))	('mutation', 'Var', (180, 188))	('low', 'NegReg', (101, 104))
7619	31388127	Tumours in the fourth subgroup were copy number high (serous-like) tumors and were characterized by frequent TP53 mutation and high-level somatic copy number alterations.	('copy number', 'Var', (36, 47))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TP53', 'Gene', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutation', 'Var', (114, 122))	('tumors', 'Disease', (67, 73))
7622	31388127	Paradoxically, the POLE-mutated subgroup exhibited the best PFS but was enriched for high-grade EECs.	('PFS', 'MPA', (60, 63))	('POLE-mutated', 'Var', (19, 31))	('EEC', 'Chemical', '-', (96, 99))	('ECs', 'Phenotype', 'HP:0012114', (97, 100))	('EEC', 'Phenotype', 'HP:0012114', (96, 99))	('EC', 'Phenotype', 'HP:0012114', (97, 99))
7623	31388127	Several subsequent studies confirmed significant associations between POLE-ED mutations and favorable clinical outcomes for high-grade EEC.	('EC', 'Phenotype', 'HP:0012114', (136, 138))	('EEC', 'Phenotype', 'HP:0012114', (135, 138))	('mutations', 'Var', (78, 87))	('high-grade EEC', 'Disease', (124, 138))	('EEC', 'Chemical', '-', (135, 138))
7625	31388127	However, recent studies indicate that the favorable prognosis for POLE-mutant ECs is not likely due to differential treatment response or tumor immunogenic phenotype.	('ECs', 'Phenotype', 'HP:0012114', (78, 81))	('EC', 'Phenotype', 'HP:0012114', (78, 80))	('ECs', 'Gene', (78, 81))	('tumor', 'Disease', (138, 143))	('POLE-mutant', 'Var', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
7630	31388127	In 2018, this test was advanced closer to commercial availability under the name of the "PapSEEK" test, which detects mutations in targeted regions of 18 genes as well as aneuploidy; a test is positive for cancer if a mutation or abnormal chromosome arm number is detected (Fig.	('aneuploidy', 'Disease', 'MESH:D000782', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mutation', 'Var', (218, 226))	('mutations', 'Var', (118, 127))	('aneuploidy', 'Disease', (171, 181))	('abnormal chromosome arm', 'Phenotype', 'HP:0031411', (230, 253))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
7635	31388127	The PapSEEK test has shown increased specificity over the use of next generation sequencing [G] (NGS) on uterine lavage [G] samples (FIG.2), but it is possible that a "false positive" may reflect the detection of somatic driver aberrations in non-cancerous endometrium, a phenomenon reported by several groups, or actually may be accurate early identification of EC.	('EC', 'Phenotype', 'HP:0012114', (363, 365))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancerous', 'Disease', 'MESH:D009369', (247, 256))	('aberrations', 'Var', (228, 239))	('cancerous', 'Disease', (247, 256))
7636	31388127	For example, PTEN mutations were detected in the uterine lavage of an asymptomatic woman with no clinical evidence of cancer 10 months prior to the identification of a single microscopic focus of EC.	('cancer', 'Disease', (118, 124))	('EC', 'Phenotype', 'HP:0012114', (196, 198))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('detected', 'Reg', (33, 41))	('woman', 'Species', '9606', (83, 88))	('PTEN', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (18, 27))
7645	31388127	When TransPORTEC was used to classify 116 EC patients deemed high-risk based on clinicopathological features, only patients in the p53 mutant (n=39) and NSMP (n=44) groups were shown to be truly high-risk; they exhibited significantly higher rates of distant metastases and lower 5-year RFS compared to those in the POLE-mutant (n=14) and MSI (n=19) groups (who had favorable prognoses) (FIG.	('patients', 'Species', '9606', (115, 123))	('higher', 'PosReg', (235, 241))	('metastases', 'Disease', (259, 269))	('EC', 'Phenotype', 'HP:0012114', (42, 44))	('mutant', 'Var', (135, 141))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('EC', 'Phenotype', 'HP:0012114', (14, 16))	('patients', 'Species', '9606', (45, 53))	('metastases', 'Disease', 'MESH:D009362', (259, 269))	('RFS', 'MPA', (287, 290))	('lower', 'NegReg', (274, 279))
7656	31388127	The inclusion of CTNNB1 sequencing reflects findings that CTNNB1 exon 3 mutations have emerged as a prognostic marker for increased risk of disease recurrence among patients with low-grade and early-stage EEC.	('mutations', 'Var', (72, 81))	('EC', 'Phenotype', 'HP:0012114', (206, 208))	('CTNNB1', 'Gene', (17, 23))	('EEC', 'Phenotype', 'HP:0012114', (205, 208))	('EEC', 'Disease', (205, 208))	('CTNNB1', 'Gene', (58, 64))	('patients', 'Species', '9606', (165, 173))	('CTNNB1', 'Gene', '1499', (17, 23))	('EEC', 'Chemical', '-', (205, 208))	('CTNNB1', 'Gene', '1499', (58, 64))
7657	31388127	However, substantive intratumor heterogeneity for CTNNB1 mutations observed in the molecular evolution of low-grade EECs from precursor lesions has been noted, prompting caution on the choice of clinical tissue sampling approaches for this marker.	('CTNNB1', 'Gene', (50, 56))	('EC', 'Phenotype', 'HP:0012114', (117, 119))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('CTNNB1', 'Gene', '1499', (50, 56))	('EEC', 'Chemical', '-', (116, 119))	('mutations', 'Var', (57, 66))	('ECs', 'Phenotype', 'HP:0012114', (117, 120))	('EEC', 'Phenotype', 'HP:0012114', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
7662	31388127	Further complicating the interpretation and translation of genomic results is the fact that therapies targeting identical aberrations in different tumor types have shown differing efficacy; likewise, different aberrations within the same gene have been shown to produce distinctive functional consequences.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('aberrations', 'Var', (210, 221))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
7663	31388127	Despite the challenges associated with molecularly guiding therapies, three quarters of 1,281 US physician survey respondents in 2017 reported using NGS tests to guide treatment decisions, and treatment of solid tumors based on matching actionable mutations to targeted therapies has resulted in improved outcomes of patients with advanced cancers.	('mutations', 'Var', (248, 257))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('cancers', 'Phenotype', 'HP:0002664', (340, 347))	('improved', 'PosReg', (296, 304))	('cancers', 'Disease', (340, 347))	('cancers', 'Disease', 'MESH:D009369', (340, 347))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('patients', 'Species', '9606', (317, 325))
7664	31388127	Counter to this optimistic data, clinical trials targeting aberrations in the PI3K pathway or ERBB2 (also known as HER2), which are some of the most common clinically actionable aberrations in advanced ECs, have yielded modest results.	('aberrations', 'Var', (59, 70))	('HER2', 'Gene', (115, 119))	('HER2', 'Gene', '2064', (115, 119))	('ECs', 'Phenotype', 'HP:0012114', (202, 205))	('EC', 'Phenotype', 'HP:0012114', (202, 204))	('PI3K pathway', 'Pathway', (78, 90))	('ERBB2', 'Gene', '2064', (94, 99))	('ERBB2', 'Gene', (94, 99))
7665	31388127	Lack of response could be due in part to initial or acquired drug resistance; in this respect it is noteworthy that a majority (70%; 14/20) of ERBB2 amplified ECs also harbor PI3K pathway aberrations, raising the potential for combination therapies.	('aberrations', 'Var', (188, 199))	('amplified', 'Var', (149, 158))	('ERBB2', 'Gene', (143, 148))	('ECs', 'Phenotype', 'HP:0012114', (159, 162))	('ERBB2', 'Gene', '2064', (143, 148))	('EC', 'Phenotype', 'HP:0012114', (159, 161))	('ECs', 'Disease', (159, 162))	('drug resistance', 'Phenotype', 'HP:0020174', (61, 76))	('harbor', 'Reg', (168, 174))	('PI3K pathway', 'Pathway', (175, 187))
7673	31388127	In this regard, it is noteworthy that in a recent prospective analysis, 47% (16/34) of EC patients who matched to a therapy after NGS panel tumor profiling experienced clinical benefit, including 40% (2/5) of MSI-H patients treated with immune checkpoint inhibitors and 42% (8/19) of patients matched based on PIK3CA and PTEN mutations.	('patients', 'Species', '9606', (215, 223))	('patients', 'Species', '9606', (284, 292))	('mutations', 'Var', (326, 335))	('EC', 'Phenotype', 'HP:0012114', (87, 89))	('benefit', 'PosReg', (177, 184))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('PTEN', 'Gene', (321, 325))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('PIK3CA', 'Gene', (310, 316))	('patients', 'Species', '9606', (90, 98))	('PIK3CA', 'Gene', '5290', (310, 316))	('tumor', 'Disease', (140, 145))
7675	31388127	The most common clinically actionable aberrations among the entire cohort were PIK3CA or PTEN mutation, MSI, and ERBB2 amplification.	('ERBB2', 'Gene', (113, 118))	('ERBB2', 'Gene', '2064', (113, 118))	('PIK3CA', 'Gene', (79, 85))	('MSI', 'Disease', (104, 107))	('PTEN', 'Gene', (89, 93))	('PIK3CA', 'Gene', '5290', (79, 85))	('mutation', 'Var', (94, 102))
7676	31388127	Importantly, of 4 patients with matched primary and metastatic samples within this study, the mutational profiles differed between primary and metastatic sites; in 2 cases, metastases acquired potentially actionable mutations in MTOR and PIK3R1.	('MTOR', 'Gene', (229, 233))	('metastases', 'Disease', (173, 183))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('PIK3R1', 'Gene', '5295', (238, 244))	('MTOR', 'Gene', '2475', (229, 233))	('PIK3R1', 'Gene', (238, 244))	('patients', 'Species', '9606', (18, 26))	('mutations', 'Var', (216, 225))
7681	31388127	Encouragingly, a recent mutational analysis of metastases from 20 untreated cancer patients (including 4 ECs lacking POLE mutation) indicated that all metastases within a patient share functional driver mutations.	('patient', 'Species', '9606', (171, 178))	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('metastases', 'Disease', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('patient', 'Species', '9606', (83, 90))	('patients', 'Species', '9606', (83, 91))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('mutations', 'Var', (203, 212))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('metastases', 'Disease', (151, 161))	('ECs', 'Phenotype', 'HP:0012114', (105, 108))	('EC', 'Phenotype', 'HP:0012114', (105, 107))
7686	31388127	Importantly, and relevant to the next section of this review, EC patients that are MMR-D that enroll in the MATCH trial and those in the TAPUR trial that harbor POLE/POLD1 mutations, have a high mutational load, or are MSI-H have the potential to match to immunotherapies.	('POLD1', 'Gene', (166, 171))	('POLD1', 'Gene', '5424', (166, 171))	('mutations', 'Var', (172, 181))	('EC', 'Phenotype', 'HP:0012114', (62, 64))	('mutational load', 'MPA', (195, 210))	('patients', 'Species', '9606', (65, 73))
7694	31388127	The combined results of these cohorts may indicate that hypermutation or high TILs combined with PD-L1 positivity may predict response to PD-1 blockade: of patients responding to atezolizumab, one exhibited 70% TIL, while the other was hypermutated and a patient that exhibited a prolonged (>14 month) partial response to pembrolizumab harbored POLE mutations; all three patients were PD-L1 positive (Table 2).	('patients', 'Species', '9606', (156, 164))	('PD-L1', 'Gene', '29126', (385, 390))	('patient', 'Species', '9606', (371, 378))	('atezolizumab', 'Chemical', 'MESH:C000594389', (179, 191))	('PD-L1', 'Gene', '29126', (97, 102))	('PD-1 blockade', 'Disease', 'MESH:D010300', (138, 151))	('patients', 'Species', '9606', (371, 379))	('patient', 'Species', '9606', (255, 262))	('pembrolizumab', 'Chemical', 'MESH:C582435', (322, 335))	('mutations', 'Var', (350, 359))	('PD-L1', 'Gene', (385, 390))	('PD-L1', 'Gene', (97, 102))	('patient', 'Species', '9606', (156, 163))	('PD-1 blockade', 'Disease', (138, 151))
7697	31388127	It was further speculated that tumors within two other clusters encompassing 32.5% and 36.9% of SEC-like EECs, SECs, and UCSs might respond to HER2 targeted therapy (discussed above as a potential promising treatment strategy for ERBB2 amplified SECs) or therapies targeting the DNA damage response.	('ECs', 'Phenotype', 'HP:0012114', (112, 115))	('SEC', 'Phenotype', 'HP:0012887', (111, 114))	('ERBB2', 'Gene', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('SECs', 'Disease', (111, 115))	('SEC-like', 'Disease', (96, 104))	('HER2', 'Gene', '2064', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('targeted therapy', 'Var', (148, 164))	('tumors', 'Disease', (31, 37))	('ERBB2', 'Gene', '2064', (230, 235))	('respond', 'Reg', (132, 139))	('HER2', 'Gene', (143, 147))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('SEC', 'Phenotype', 'HP:0012887', (96, 99))	('EC', 'Phenotype', 'HP:0012114', (112, 114))	('ECs', 'Phenotype', 'HP:0012114', (247, 250))	('EC', 'Phenotype', 'HP:0012114', (247, 249))	('SEC', 'Phenotype', 'HP:0012887', (246, 249))	('ECs', 'Phenotype', 'HP:0012114', (106, 109))	('EC', 'Phenotype', 'HP:0012114', (106, 108))	('EEC', 'Phenotype', 'HP:0012114', (105, 108))	('EC', 'Phenotype', 'HP:0012114', (97, 99))	('EEC', 'Chemical', '-', (105, 108))
7701	31388127	Future challenges in the field include: overcoming difficulties associated with incorporation of molecular subtyping in the clinic; more extensive genomic characterization of CCECs and of EC metastases; functional characterization of mutations in novel driver genes; proteomic studies to provide a global view of the net impact of genomic, transcriptomic and translational perturbations in ECs; and high throughput screens for druggable targets and synthetic lethal interactions in this disease.	('EC', 'Phenotype', 'HP:0012114', (188, 190))	('EC metastases', 'Disease', (188, 201))	('CCECs', 'Disease', (175, 180))	('EC metastases', 'Disease', 'MESH:D009362', (188, 201))	('ECs', 'Phenotype', 'HP:0012114', (177, 180))	('EC', 'Phenotype', 'HP:0012114', (177, 179))	('ECs', 'Phenotype', 'HP:0012114', (390, 393))	('EC', 'Phenotype', 'HP:0012114', (390, 392))	('mutations', 'Var', (234, 243))
7709	31388127	driver genes Pathogenic aberrations of these genes contribute to the initiation and/or progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Pathogenic aberrations', 'Var', (13, 35))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('contribute', 'Reg', (51, 61))
7724	31388127	Increased risk for developing endometrioid endometrial cancer (EC), an estrogen dependent tumor type, is associated with obesity, diabetes, unopposed estrogen use, nulliparity, early menarche, and late menopause.	('obesity', 'Disease', (121, 128))	('nulliparity', 'Var', (164, 175))	('diabetes', 'Disease', 'MESH:D003920', (130, 138))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (30, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('endometrial cancer', 'Phenotype', 'HP:0012114', (43, 61))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('EC', 'Phenotype', 'HP:0012114', (63, 65))	('obesity', 'Phenotype', 'HP:0001513', (121, 128))	('endometrioid endometrial cancer', 'Disease', (30, 61))	('late menopause', 'Phenotype', 'HP:0008209', (197, 211))	('obesity', 'Disease', 'MESH:D009765', (121, 128))	('diabetes', 'Disease', (130, 138))
7727	31388127	Lynch Syndrome is a highly penetrant, autosomal dominant cancer predisposition syndrome caused by monoallelic germline mutation in a mismatch repair gene, specifically MLH1, MSH2, MSH6 or PMS2, or by germline deletion within EPCAM that leads to epigenetic silencing of the adjacent MSH2 gene.	('Lynch Syndrome', 'Disease', (0, 14))	('EPCAM', 'Gene', '4072', (225, 230))	('MLH1', 'Gene', '4292', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('caused by', 'Reg', (88, 97))	('MSH2', 'Gene', (174, 178))	('MSH6', 'Gene', (180, 184))	('MSH6', 'Gene', '2956', (180, 184))	('EPCAM', 'Gene', (225, 230))	('PMS2', 'Gene', '5395', (188, 192))	('MSH2', 'Gene', '4436', (174, 178))	('MSH2', 'Gene', (282, 286))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (0, 14))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (38, 63))	('autosomal dominant cancer', 'Disease', (38, 63))	('epigenetic silencing', 'MPA', (245, 265))	('MLH1', 'Gene', (168, 172))	('MSH2', 'Gene', '4436', (282, 286))	('germline deletion', 'Var', (200, 217))	('PMS2', 'Gene', (188, 192))
7728	31388127	Mutation carriers are at increased risk of developing colorectal cancer and ECs, the two major component tumors of Lynch Syndrome, as well as cancers of the ovary, stomach, kidney, urinary tract, biliary tract, small intestine and skin.	('cancers of the ovary', 'Disease', (142, 162))	('component tumors of Lynch Syndrome', 'Disease', 'MESH:D003123', (95, 129))	('component tumors of Lynch Syndrome', 'Disease', (95, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers of the ovary', 'Disease', 'MESH:D010051', (142, 162))	('EC', 'Phenotype', 'HP:0012114', (76, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('ECs', 'Phenotype', 'HP:0012114', (76, 79))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('colorectal cancer', 'Disease', (54, 71))	('ECs', 'Disease', (76, 79))
7730	31388127	Polymerase Proofreading Associated Polyposis is an autosomal dominant cancer susceptibility syndrome attributed to germline mutations in the exonuclease domain of POLD1 or POLE.	('attributed', 'Reg', (101, 111))	('germline mutations in', 'Var', (115, 136))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (51, 76))	('Polyposis', 'Disease', (35, 44))	('POLD1', 'Gene', (163, 168))	('POLD1', 'Gene', '5424', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('autosomal dominant cancer', 'Disease', (51, 76))	('Polyposis', 'Disease', 'MESH:D044483', (35, 44))
7731	31388127	POLD1 mutation carriers are at increased risk of developing attenuated adenomatous polyposis of the colorectum and cancers of the colorectum, endometrium, breast, and brain.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('mutation', 'Var', (6, 14))	('breast', 'Disease', (155, 161))	('endometrium', 'Disease', (142, 153))	('attenuated adenomatous polyposis of the colorectum', 'Disease', 'MESH:C538265', (60, 110))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('POLD1', 'Gene', '5424', (0, 5))	('POLD1', 'Gene', (0, 5))	('attenuated adenomatous polyposis', 'Phenotype', 'HP:0005227', (60, 92))	('attenuated adenomatous polyposis of the colorectum', 'Disease', (60, 110))
7732	31388127	POLE mutation carriers are at increased risk of developing colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal cancer', 'Disease', (59, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('mutation', 'Var', (5, 13))
7733	31388127	Cowden syndrome is a condition in which PTEN mutation carriers have an increased predisposition for developing multiple hamartomas, and cancers of the breast, thyroid, endometrium, colorectum, kidney, and skin.	('hamartomas', 'Phenotype', 'HP:0010566', (120, 130))	('colorectum', 'Disease', (181, 191))	('breast', 'Disease', (151, 157))	('multiple hamartomas', 'Disease', (111, 130))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PTEN', 'Gene', (40, 44))	('Cowden syndrome', 'Disease', 'MESH:D006223', (0, 15))	('cancers', 'Disease', (136, 143))	('thyroid', 'Disease', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('mutation', 'Var', (45, 53))	('multiple hamartomas', 'Disease', 'MESH:D006223', (111, 130))	('Cowden syndrome', 'Disease', (0, 15))	('kidney', 'Disease', (193, 199))	('endometrium', 'Disease', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
7756	32429325	Class II is commonly subdivided into two sub-classes (Table 1) based on sequence analysis: IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb (HDAC6 and HDAC10).	('HDAC10', 'Gene', '83933', (147, 153))	('HDAC5', 'Gene', '10014', (103, 108))	('IIb', 'Gene', (132, 135))	('HDAC5', 'Gene', (103, 108))	('HDAC7', 'Gene', '51564', (110, 115))	('HDAC6', 'Gene', '10013', (137, 142))	('HDAC6', 'Gene', (137, 142))	('IIb', 'Gene', '5658173', (132, 135))	('HDAC7', 'Gene', (110, 115))	('HDAC4', 'Var', (96, 101))	('HDAC10', 'Gene', (147, 153))	('HDAC9', 'Gene', '9734', (121, 126))	('HDAC9', 'Gene', (121, 126))
7774	32429325	Drosophila melanogaster (fruit fly) carries a total of 5 HDAC genes, translated in the following protein products: NP_001259507.1 located in Class IIa, NP_001259569.1 in Class IIb, NP_733048.1 in Class IV and two Class I HDACs: NP_647918.2 and NP_651978.2.	('NP_651978.2', 'Var', (244, 255))	('IIb', 'Gene', (176, 179))	('NP_733048.1', 'Var', (181, 192))	('IIb', 'Gene', '5658173', (176, 179))	('Drosophila melanogaster', 'Species', '7227', (0, 23))	('fruit fly', 'Species', '7227', (25, 34))	('HDAC genes', 'Gene', (57, 67))	('NP_001259569.1', 'Var', (152, 166))	('NP_001259507.1', 'Var', (115, 129))
7779	32429325	Arabidopsis in particular carries the largest number of HDAC genes in all species investigated (14, Table 2); this is the result of recent HDAC expansion, as this plant carries a cluster of three recently duplicated Class I HDAC loci, which are located in succession on its genome: NP_190052.1 (encoded by gene At3g44660), NP_190054.2 (At3g44680), and NP_190035.1 (At3g44490).	('At3', 'Species', '1239833', (311, 314))	('At3g44660', 'Var', (311, 320))	('Arabidopsis', 'Species', '3702', (0, 11))	('At3', 'Species', '1239833', (336, 339))	('At3g44680', 'Var', (336, 345))	('At3g44490', 'Var', (365, 374))	('At3', 'Species', '1239833', (365, 368))
7780	32429325	Two more highly homologous Arabidopsis Class I HDAC loci, represented by protein NP_198410.1 (gene At5g35600) and NP_201116.1 (gene At5g63110) are separated instead by more than 10 million nucleotides on the plant chromosome 5.	('At5', 'Species', '1239833', (99, 102))	('Arabidopsis', 'Species', '3702', (27, 38))	('gene At5g35600', 'Var', (94, 108))	('At5', 'Species', '1239833', (132, 135))	('gene At5g63110', 'Var', (127, 141))
7782	32429325	Sequences NP_563817.1 (Arabidopsis) and XP_015638622.1 (rice), dubbed HDAC8 by the NCBI annotation and in our tree (Figure 1, between Class IV and Class IIb) are even more separated from the rest of the organisms, and appear as a completely unique class of plant-specific HDACs.	('NP_563817.1', 'Var', (10, 21))	('HDAC8', 'Gene', (70, 75))	('Arabidopsis', 'Species', '3702', (23, 34))	('IIb', 'Gene', (153, 156))	('IIb', 'Gene', '5658173', (153, 156))	('HDAC8', 'Gene', '55869', (70, 75))	('XP_015638622.1', 'Var', (40, 54))	('rice', 'Species', '4530', (56, 60))	('S', 'Chemical', 'MESH:D012694', (0, 1))
7784	32429325	Schizosaccharomyces pombe (fission yeast) HDACs appear very similar to S.cerevisiae, with clear orthologs of Rpd3 (NP_595333.1), Hos2 (NP_594079.1) and Hda1 (NP_595104.1).	('Hda1', 'Gene', (152, 156))	('fission yeast', 'Species', '4896', (27, 40))	('Hos2', 'Gene', '852681', (129, 133))	('Hos2', 'Gene', (129, 133))	('NP_595333.1', 'Var', (115, 126))	('NP_594079.1', 'Var', (135, 146))	('Hda1', 'Gene', '855710', (152, 156))	('Schizosaccharomyces pombe', 'Species', '4896', (0, 25))	('S.cerevisiae', 'Species', '4932', (71, 83))
7818	32429325	These methodologies were applied for the identification of HDAC8 candidate substrates using, respectively, the specific HDAC8 inhibitor PCI-34051 and a recombinant HDAC8 protein in which tyrosine 100 is replaced with a p-benzoyl-L-phenylalanine (Bpa).	('tyrosine', 'Chemical', 'MESH:D014443', (187, 195))	('HDAC8', 'Gene', '55869', (59, 64))	('Bpa', 'Chemical', 'MESH:C488060', (246, 249))	('HDAC8', 'Gene', '55869', (120, 125))	('HDAC8', 'Gene', '55869', (164, 169))	('HDAC8', 'Gene', (120, 125))	('tyrosine 100', 'Var', (187, 199))	('HDAC8', 'Gene', (164, 169))	('HDAC8', 'Gene', (59, 64))	('p-benzoyl-L-phenylalanine', 'Chemical', 'MESH:C488060', (219, 244))
7826	32429325	HDAC8 has been shown to deacetylate ERRalpha, which results in an enhancement of the transcription factor function, and SMC3, one of the components of the cohesin complex, the deacetylation of which facilitates renewal of cohesin following its removal from chromatin during prophase or anaphase.	('acetyl', 'Chemical', '-', (26, 32))	('ERRalpha', 'Gene', '2101', (36, 44))	('HDAC8', 'Gene', '55869', (0, 5))	('deacetylate', 'Var', (24, 35))	('transcription factor function', 'MPA', (85, 114))	('facilitates', 'PosReg', (199, 210))	('acetyl', 'Chemical', '-', (178, 184))	('SMC3', 'Gene', '9126', (120, 124))	('deacetylation', 'Var', (176, 189))	('renewal', 'MPA', (211, 218))	('SMC3', 'Gene', (120, 124))	('cohesin', 'Protein', (222, 229))	('HDAC8', 'Gene', (0, 5))	('ERRalpha', 'Gene', (36, 44))	('enhancement', 'PosReg', (66, 77))
7830	32429325	For example, HDAC1 decrotonylates H3K4cr, H3K9cr, H3K23cr, H4K8cr, and H4K12cr in vitro; H3K8cr can be also decrotonylated by HDAC2 and HDAC8.	('HDAC2', 'Gene', (126, 131))	('HDAC2', 'Gene', '3066', (126, 131))	('HDAC8', 'Gene', '55869', (136, 141))	('H3K23cr', 'Var', (50, 57))	('H3K9cr', 'Var', (42, 48))	('H4K8cr', 'Var', (59, 65))	('HDAC8', 'Gene', (136, 141))	('H4K12cr', 'Var', (71, 78))	('H3K8cr', 'Var', (89, 95))	('H3K4cr', 'Var', (34, 40))
7833	32429325	About the catalytic activity, for vertebrate Class IIa HDACs, the catalytic Tyrosine 345 residue is replaced by a histidine side chain, which is too short to reach into the active site (Figure 3A).	('histidine', 'Chemical', 'MESH:D006639', (114, 123))	('Tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('catalytic', 'MPA', (66, 75))	('Tyrosine 345', 'Var', (76, 88))
7834	32429325	Due to the Y-H substitution, the catalytic activity of those enzymes on acetylated lysines of histone tail peptides is very low when compared to that of Class I HDACs.	('lysines', 'Chemical', 'MESH:D008239', (83, 90))	('catalytic activity', 'MPA', (33, 51))	('peptides', 'Chemical', 'MESH:D010455', (107, 115))	('Y-H substitution', 'Var', (11, 27))	('low', 'NegReg', (124, 127))	('acetyl', 'Chemical', '-', (72, 78))
7835	32429325	This property is independent from the Y-H catalytic residue as replacement of H with a Y in Class IIa HDACs promotes deacetylation of acetylated histone tail peptides, but it does not impact on transcriptional repression.	('peptides', 'Chemical', 'MESH:D010455', (158, 166))	('acetyl', 'Chemical', '-', (134, 140))	('replacement', 'Var', (63, 74))	('acetyl', 'Chemical', '-', (119, 125))	('promotes', 'PosReg', (108, 116))	('deacetylation of acetylated histone tail peptides', 'MPA', (117, 166))
7864	32429325	Since simultaneous deletion of HDAC1 and 2 genes results in early embryonic lethality conditional mutants were produced to investigate their role during development.	('results in', 'Reg', (49, 59))	('deletion', 'Var', (19, 27))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('embryonic lethality', 'Disease', (66, 85))	('HDAC1', 'Gene', (31, 36))	('S', 'Chemical', 'MESH:D012694', (0, 1))
7870	32429325	In adult individuals, deletion of HDAC3 in hepatocytes causes an increase of adipogenesis leading to hepatosteatosis whereas its loss in the heart cause interstitial fibrosis.	('increase', 'PosReg', (65, 73))	('HDAC3', 'Gene', '8841', (34, 39))	('hepatosteatosis', 'Disease', 'None', (101, 116))	('leading to', 'Reg', (90, 100))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (153, 174))	('HDAC3', 'Gene', (34, 39))	('deletion', 'Var', (22, 30))	('loss', 'NegReg', (129, 133))	('fibrosis', 'Disease', (166, 174))	('hepatosteatosis', 'Disease', (101, 116))	('fibrosis', 'Disease', 'MESH:D005355', (166, 174))	('adipogenesis', 'MPA', (77, 89))
7880	32429325	Its deletions in mouse knockout models has been linked to cardiac defects, mainly depending on deregulation of one of its targets, transcription factor MEF2.	('cardiac defects', 'Disease', 'MESH:D006331', (58, 73))	('mouse', 'Species', '10090', (17, 22))	('deletions', 'Var', (4, 13))	('cardiac defects', 'Disease', (58, 73))	('deregulation', 'MPA', (95, 107))	('MEF2', 'Gene', (152, 156))	('linked', 'Reg', (48, 54))
7886	32429325	However, deletion of HDAC6 led to no evident defects in animal models, possibly due to redundancy of functions shared with HDAC10.	('deletion', 'Var', (9, 17))	('HDAC6', 'Gene', '10013', (21, 26))	('HDAC10', 'Gene', (123, 129))	('HDAC6', 'Gene', (21, 26))	('HDAC10', 'Gene', '83933', (123, 129))
7890	32429325	It is thought to have a role in immune cells development, and it has been recently shown that HDAC10 deletion improves Foxp3+ Treg cells suppressive function in vivo.	('deletion', 'Var', (101, 109))	('Foxp3', 'Gene', (119, 124))	('HDAC10', 'Gene', '83933', (94, 100))	('improves', 'PosReg', (110, 118))	('Foxp3', 'Gene', '50943', (119, 124))	('HDAC10', 'Gene', (94, 100))
7902	32429325	The interaction of SIN3A/HDAC1 complex with cell cycle regulators such as Rb and the Mxd1 family suggests that loss of SIN3A would cause an uncontrollably cell cycle progression.	('interaction', 'Interaction', (4, 15))	('SIN3A', 'Gene', (119, 124))	('loss', 'Var', (111, 115))	('Mxd1', 'Gene', (85, 89))	('cause', 'Reg', (131, 136))	('uncontrollably', 'MPA', (140, 154))	('Mxd1', 'Gene', '4084', (85, 89))
7939	32429325	After that, LSD1 demethylates H3-K4Me1-2 causing the reversibly transcriptional repression of the gene locus.	('H3-K4Me1-2', 'Var', (30, 40))	('demethylates H3-K4Me1-2', 'Var', (17, 40))	('LSD1', 'Gene', (12, 16))	('LSD1', 'Gene', '23028', (12, 16))	('reversibly transcriptional repression', 'MPA', (53, 90))
7940	32429325	Finally, the recruitment of histone methyltransferase such as G9a or SUV39H1 and methylation of "repressive" sites like H3-K9 induces a stable long-term silencing of targets through the binding to K9-methyl residues of the heterochromatin protein 1 (HP1) that generate the heterochromatinization of the locus.	('SUV39H1', 'Gene', (69, 76))	('methylation', 'Var', (81, 92))	('H3-K9', 'Gene', (120, 125))	('HP1', 'Gene', '23468', (250, 253))	('silencing', 'NegReg', (153, 162))	('HP1', 'Gene', (250, 253))	('SUV39H1', 'Gene', '6839', (69, 76))	('G9a', 'Gene', '10919', (62, 65))	('heterochromatin protein 1', 'Gene', '23468', (223, 248))	('G9a', 'Gene', (62, 65))	('binding', 'Interaction', (186, 193))	('heterochromatin protein 1', 'Gene', (223, 248))
7947	32429325	An aberrant protein levels of ZNF217 has been reported in many cancer cell lines and may cause unregulated targeting by the CoREST-LSD1 complex, with a profound effect on cancer progression.	('unregulated targeting', 'MPA', (95, 116))	('cause', 'Reg', (89, 94))	('aberrant', 'Var', (3, 11))	('protein levels', 'MPA', (12, 26))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('LSD1', 'Gene', '23028', (131, 135))	('CoREST', 'Gene', '23186', (124, 130))	('LSD1', 'Gene', (131, 135))	('cancer', 'Disease', (171, 177))	('CoREST', 'Gene', (124, 130))	('reported', 'Reg', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ZNF217', 'Gene', (30, 36))	('ZNF217', 'Gene', '7764', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (63, 69))	('effect', 'Reg', (161, 167))
7956	32429325	In particular, it has been demonstrated that NuRD complex binds methylated DNA in correspondence to the pericentric heterochromatin containing MBD2 proteins.	('methylated', 'Var', (64, 74))	('MBD2', 'Gene', (143, 147))	('rice', 'Species', '4530', (106, 110))	('MBD2', 'Gene', '8932', (143, 147))
7959	32429325	PWWP2A was correlated to H3K36me3 marked genes and PWWP2B to active promoters and enhancers.	('H3K36me3 marked', 'Var', (25, 40))	('PWWP2A', 'Gene', '70802', (0, 6))	('PWWP2B', 'Gene', (51, 57))	('PWWP2B', 'Gene', '101631', (51, 57))	('PWWP2A', 'Gene', (0, 6))
7961	32429325	Specifically, MBD2 and MBD3 mediates NuRD recruitment to methylated or hemi-methylated DNA, respectively.	('MBD3', 'Gene', (23, 27))	('mediates', 'Reg', (28, 36))	('MBD2', 'Gene', '8932', (14, 18))	('MBD3', 'Gene', '53615', (23, 27))	('hemi-methylated', 'Var', (71, 86))	('MBD2', 'Gene', (14, 18))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('methylated', 'Var', (57, 67))
7963	32429325	Furthermore, WDR529 and UpSET30 recruits the complex to promoter regions.	('S', 'Chemical', 'MESH:D012694', (26, 27))	('UpSET30', 'Var', (24, 31))	('complex', 'MPA', (45, 52))	('WDR529', 'Var', (13, 19))
7965	32429325	For instance, in mESCs, it has been reported that after H3K36me3 deposition by SET2 on specific promoters of active genes, NuRD/HDAC complex are recruited to the action of PWWP2A/B and the deacetylation of H3K9ac by HDAC2 facilitates RNA Pol II transcriptional elongation.	('recruited', 'PosReg', (145, 154))	('facilitates', 'PosReg', (222, 233))	('SET2', 'Gene', (79, 83))	('deacetylation', 'Var', (189, 202))	('PWWP2A', 'Gene', '70802', (172, 178))	('HDAC2', 'Gene', (216, 221))	('HDAC2', 'Gene', '3066', (216, 221))	('S', 'Chemical', 'MESH:D012694', (19, 20))	('acetyl', 'Chemical', '-', (191, 197))	('RNA Pol II transcriptional', 'Enzyme', (234, 260))	('H3K36me3', 'Var', (56, 64))	('SET2', 'Gene', '29072', (79, 83))	('PWWP2A', 'Gene', (172, 178))	('S', 'Chemical', 'MESH:D012694', (79, 80))
7973	32429325	Specifically, the knockdown of CHD4, an ATPase subunit of NuRD complex (Figure 5), dramatically upregulates C4B expression, a critical component of the complement system, and this can trigger proliferation and tumor progression.	('C4B', 'Gene', '721', (108, 111))	('knockdown', 'Var', (18, 27))	('CHD4', 'Gene', (31, 35))	('expression', 'MPA', (112, 122))	('trigger', 'Reg', (184, 191))	('proliferation', 'CPA', (192, 205))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('CHD4', 'Gene', '1108', (31, 35))	('upregulates', 'PosReg', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('C4B', 'Gene', (108, 111))
8003	32429325	Although, the production of the aberrant PML-RARalpha protein causes an increase in the binding affinity between RARalpha and NCoR/SMRT complex.	('SMRT', 'Gene', (131, 135))	('PML-RAR', 'Gene', (41, 48))	('increase', 'PosReg', (72, 80))	('RARalpha', 'Gene', '5914', (45, 53))	('NCoR', 'Gene', (126, 130))	('binding affinity', 'Interaction', (88, 104))	('RARalpha', 'Gene', (45, 53))	('RARalpha', 'Gene', '5914', (113, 121))	('PML-RAR', 'Gene', '84106', (41, 48))	('aberrant', 'Var', (32, 40))	('SMRT', 'Gene', '9612', (131, 135))	('RARalpha', 'Gene', (113, 121))	('NCoR', 'Gene', '9611', (126, 130))
8016	32429325	In mice, deletion of HDAC4 in the forebrain resulted in the impairment of memory, behavioral learning, and long-term synaptic plasticity.	('impairment of memory', 'Disease', 'MESH:D008569', (60, 80))	('impairment of memory', 'Disease', (60, 80))	('long-term synaptic plasticity', 'CPA', (107, 136))	('deletion', 'Var', (9, 17))	('mice', 'Species', '10090', (3, 7))	('HDAC4', 'Gene', (21, 26))	('impairment of memory', 'Phenotype', 'HP:0002354', (60, 80))	('behavioral learning', 'CPA', (82, 101))
8017	32429325	In human, the HDAC4 locus is deleted or mutated in patients with brachydactyly mental retardation (BDMR) syndrome, which is characterized by intellectual disabilities, developmental delays, behavioral abnormalities, and skeletal abnormalities.	('developmental delays', 'Disease', 'MESH:D002658', (168, 188))	('behavioral abnormalities', 'Disease', 'MESH:D001523', (190, 214))	('behavioral abnormalities', 'Phenotype', 'HP:0000708', (190, 214))	('human', 'Species', '9606', (3, 8))	('skeletal abnormalities', 'Disease', (220, 242))	('developmental delays', 'Disease', (168, 188))	('developmental delays', 'Phenotype', 'HP:0001263', (168, 188))	('brachydactyly', 'Phenotype', 'HP:0001156', (65, 78))	('behavioral abnormalities', 'Disease', (190, 214))	('brachydactyly mental retardation (BDMR) syndrome', 'Disease', 'MESH:C538317', (65, 113))	('intellectual disabilities', 'Phenotype', 'HP:0001249', (141, 166))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (220, 242))	('mutated', 'Var', (40, 47))	('patients', 'Species', '9606', (51, 59))	('mental retardation', 'Phenotype', 'HP:0001249', (79, 97))	('HDAC4', 'Gene', (14, 19))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (220, 242))
8033	32429325	HDAC11 was shown to de-acetylate Lys24 and Lys49 at the N-terminus of the chromatin licensing and DNA replication factor 1 (Cdt1) and affect its proteasomal degradation.	('de-acetylate', 'NegReg', (20, 32))	('Lys49', 'Chemical', '-', (43, 48))	('Cdt1', 'Gene', '81620', (124, 128))	('acetyl', 'Chemical', '-', (23, 29))	('proteasomal degradation', 'MPA', (145, 168))	('Cdt1', 'Gene', (124, 128))	('affect', 'Reg', (134, 140))	('Lys24', 'Var', (33, 38))	('Lys49', 'Var', (43, 48))	('HDAC11', 'Gene', (0, 6))	('Lys24', 'Chemical', '-', (33, 38))
8037	32429325	However, deregulation of HDACs has been reported a role in the development and progression of several cancer types.	('role', 'Reg', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('deregulation', 'Var', (9, 21))	('HDACs', 'Protein', (25, 30))
8044	32429325	Silencing or inhibition of HDAC1 was proven to be effective in reducing acquired chemoresistance and aggressiveness in cellular models of ovarian and lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('reducing', 'NegReg', (63, 71))	('inhibition', 'Var', (13, 23))	('ovarian and lung cancers', 'Disease', 'MESH:D055370', (138, 162))	('lung cancers', 'Phenotype', 'HP:0100526', (150, 162))	('acquired chemoresistance', 'CPA', (72, 96))	('HDAC1', 'Gene', (27, 32))	('aggressiveness', 'Disease', 'MESH:D001523', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('Silencing', 'Var', (0, 9))	('aggressiveness', 'Disease', (101, 115))	('S', 'Chemical', 'MESH:D012694', (0, 1))
8065	32429325	Overexpression of HDAC8 and 3 was associated with an improved survival in stage IV metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('HDAC8', 'Gene', '55869', (18, 23))	('Overexpression', 'Var', (0, 14))	('improved', 'PosReg', (53, 61))	('HDAC8', 'Gene', (18, 23))
8081	32429325	Survival analysis reported several significant associations in different tumor subtypes: high transcript levels are associated with a reduced OS in CESC, GBM, LGG, and KIRP, while it is a good prognostic factor in BLCA, DLBC, KICH, NBL, and THYM (Figure 6B).	('KICH', 'Disease', (226, 230))	('DLBC', 'Disease', (220, 224))	('KIRP', 'Disease', (168, 172))	('NBL', 'Gene', (232, 235))	('CESC', 'Disease', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('NBL', 'Gene', '9253', (232, 235))	('BLCA', 'Disease', (214, 218))	('LGG', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('KICH', 'Disease', 'None', (226, 230))	('high', 'Var', (89, 93))	('tumor', 'Disease', (73, 78))	('GBM', 'Disease', (154, 157))	('reduced', 'NegReg', (134, 141))	('S', 'Chemical', 'MESH:D012694', (150, 151))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('S', 'Chemical', 'MESH:D012694', (143, 144))
8084	32429325	Overexpression of HDAC7 is frequently reported in several hematologic malignancies like ALL and CLL, often correlated with poor outcomes.	('CLL', 'Phenotype', 'HP:0005550', (96, 99))	('CLL', 'Disease', (96, 99))	('ALL', 'Phenotype', 'HP:0006721', (88, 91))	('reported', 'Reg', (38, 46))	('HDAC7', 'Gene', (18, 23))	('hematologic malignancies', 'Disease', 'MESH:D019337', (58, 82))	('Overexpression', 'Var', (0, 14))	('hematologic malignancies', 'Disease', (58, 82))	('ALL', 'Disease', (88, 91))	('HDAC7', 'Gene', '51564', (18, 23))
8087	32429325	Low expression is associated with a significantly poorer OS in ACC and CHOL.	('ACC', 'Disease', (63, 66))	('S', 'Chemical', 'MESH:D012694', (58, 59))	('CHOL', 'Disease', (71, 75))	('Low expression', 'Var', (0, 14))	('CHOL', 'Disease', 'None', (71, 75))	('poorer', 'NegReg', (50, 56))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))
8101	32429325	It has been found in cervical cancers as metastasis suppressor, and low expression is associated to a bad prognosis in lung and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('expression', 'MPA', (72, 82))	('low', 'Var', (68, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('gastric cancers', 'Disease', 'MESH:D013274', (128, 143))	('gastric cancers', 'Phenotype', 'HP:0012126', (128, 143))	('gastric cancers', 'Disease', (128, 143))	('lung', 'Disease', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
8102	32429325	In the TCGA cohort, low expression is associated with a bad OS in BLCA and PCPG, while better outcomes are expected in HDAC10 low-expressing KIRC and THCA patients (Figure 6B).	('PCPG', 'Disease', (75, 79))	('THCA', 'Chemical', '-', (150, 154))	('low expression', 'Var', (20, 34))	('HDAC10', 'Gene', '83933', (119, 125))	('HDAC10', 'Gene', (119, 125))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('patients', 'Species', '9606', (155, 163))	('BLCA', 'Disease', (66, 70))
8107	32429325	Low-expressing LUAD, NBL, and UVM patients experience worse OS (Figure 6B).	('Low-expressing', 'Var', (0, 14))	('LUAD', 'Disease', (15, 19))	('patients', 'Species', '9606', (34, 42))	('NBL', 'Gene', '9253', (21, 24))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('NBL', 'Gene', (21, 24))
8120	32429325	Cell cycle blocks is mainly caused by the mis-regulation of key genes such as CDKN1A and AKT and by the hyperacetylation/activation of the tumor suppressor p53.	('caused', 'Reg', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mis-regulation', 'Var', (42, 56))	('acetyl', 'Chemical', '-', (109, 115))	('CDKN1A', 'Gene', (78, 84))	('hyperacetylation/activation', 'PosReg', (104, 131))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('AKT', 'Gene', '207', (89, 92))	('tumor', 'Disease', (139, 144))	('CDKN1A', 'Gene', '1026', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AKT', 'Gene', (89, 92))	('Cell cycle blocks', 'CPA', (0, 17))
8126	32429325	In vitro and in vivo studies have revealed an important link between ARID1A mutation status and SAHA sensitivity in ovarian cancer.	('SAHA sensitivity in ovarian cancer', 'Disease', 'MESH:D003807', (96, 130))	('ARID1A', 'Gene', '8289', (69, 75))	('SAHA sensitivity in ovarian cancer', 'Disease', (96, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ARID1A', 'Gene', (69, 75))	('mutation', 'Var', (76, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))
8131	32429325	The loss of Crebbp leads to reduced H3K27Ac and transcriptional downregulation of CDH1 which, in turn, promotes cell transformation.	('reduced', 'NegReg', (28, 35))	('downregulation', 'NegReg', (64, 78))	('Crebbp', 'Gene', (12, 18))	('CDH1', 'Gene', '999', (82, 86))	('cell transformation', 'CPA', (112, 131))	('promotes', 'PosReg', (103, 111))	('CDH1', 'Gene', (82, 86))	('H3K27Ac', 'Protein', (36, 43))	('loss', 'Var', (4, 8))
8132	32429325	Pracinostat treatment of DMS53 (human SCLC cells with CRISPR-generated CREBBP deletion) resulted in a widely increase in H3K27Ac, H3K18Ac, and increased CDH1 RNA and protein expression.	('Pracinostat', 'Chemical', 'MESH:C557525', (0, 11))	('CREBBP', 'Gene', (71, 77))	('increased', 'PosReg', (143, 152))	('S', 'Chemical', 'MESH:D012694', (27, 28))	('DMS53', 'Chemical', '-', (25, 30))	('S', 'Chemical', 'MESH:D012694', (38, 39))	('increase', 'PosReg', (109, 117))	('CREBBP', 'Gene', '1387', (71, 77))	('CDH1', 'Gene', (153, 157))	('S', 'Chemical', 'MESH:D012694', (57, 58))	('human', 'Species', '9606', (32, 37))	('CDH1', 'Gene', '999', (153, 157))	('DMS53', 'Var', (25, 30))	('H3K27Ac', 'Protein', (121, 128))	('H3K18Ac', 'Protein', (130, 137))
8136	32429325	Specifically, LBH589 treatment seems to induce a depletion of histone H2B ubiquitination via misregulation of the RNF20/RNF40/WAC E3 ligase complex axis.	('RNF40', 'Gene', (120, 125))	('depletion', 'MPA', (49, 58))	('ubiquitination', 'MPA', (74, 88))	('RNF40', 'Gene', '9810', (120, 125))	('RNF20', 'Gene', (114, 119))	('LBH589', 'Chemical', 'MESH:D000077767', (14, 20))	('histone H2B', 'Protein', (62, 73))	('misregulation', 'Var', (93, 106))	('LBH589', 'Var', (14, 20))	('RNF20', 'Gene', '56254', (114, 119))	('S', 'Chemical', 'MESH:D012694', (0, 1))
8158	32429325	Mocetinostat (MGCD0103), Entinostat (MS275), Chidamide (HBI-8000), K560, and K560(1a) are the best characterized HDACi benzamide compounds able to interfere in tumor cell growth of many types of tumor.	('tumor', 'Disease', (195, 200))	('benzamide', 'Chemical', 'MESH:C037689', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('K560', 'Var', (77, 81))	('K560', 'Chemical', '-', (67, 71))	('K560', 'Chemical', '-', (77, 81))	('Entinostat', 'Chemical', 'MESH:C118739', (25, 35))	('Mocetinostat', 'Chemical', 'MESH:C523184', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Chidamide', 'Chemical', 'MESH:C547816', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('HBI-8000', 'Chemical', 'MESH:C000613826', (56, 64))	('interfere', 'NegReg', (147, 156))	('tumor', 'Disease', (160, 165))	('MGCD0103', 'Chemical', 'MESH:C523184', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('MS275', 'Chemical', 'MESH:C118739', (37, 42))
8165	32429325	Interestingly, Entinostat stimulate MHCII pathway only in the immunocompetent C57BL/6 mouse model, suggesting a strong coordination between the epigenetic modulation exerted by MS275 treatment and the consequent stimulation of adaptive immunity.	('Entinostat', 'Chemical', 'MESH:C118739', (15, 25))	('MHCII', 'Gene', '111364', (36, 41))	('adaptive immunity', 'CPA', (227, 244))	('stimulation', 'PosReg', (212, 223))	('mouse', 'Species', '10090', (86, 91))	('MS275', 'Var', (177, 182))	('epigenetic modulation', 'MPA', (144, 165))	('MHCII', 'Gene', (36, 41))	('MS275', 'Chemical', 'MESH:C118739', (177, 182))
8168	32429325	Specifically, cytofluorimetric and biochemical assays have revealed that MS275 and 5-fluorouracil co-treatment exert a synergistic effect triggering apoptosis via deregulation of key cell cycle related genes such as p53, CDKN1A, and cyclin A.	('CDKN1A', 'Gene', (221, 227))	('apoptosis', 'CPA', (149, 158))	('MS275', 'Var', (73, 78))	('CDKN1A', 'Gene', '1026', (221, 227))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('cyclin A', 'Gene', (233, 241))	('deregulation', 'PosReg', (163, 175))	('S', 'Chemical', 'MESH:D012694', (74, 75))	('p53', 'Gene', '7157', (216, 219))	('triggering', 'Reg', (138, 148))	('MS275', 'Chemical', 'MESH:C118739', (73, 78))	('cyclin A', 'Gene', '890', (233, 241))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (83, 97))	('p53', 'Gene', (216, 219))
8172	32429325	In two recent studies, two putative HDAC1,2 benzamide specific inhibitors, K560 and K560(1a), were developed and tested for their neuroprotective abilities.	('neuroprotective abilities', 'CPA', (130, 155))	('K560', 'Chemical', '-', (84, 88))	('benzamide', 'Chemical', 'MESH:C037689', (44, 53))	('K560', 'Var', (84, 88))	('K560', 'Chemical', '-', (75, 79))	('K560', 'Var', (75, 79))
8173	32429325	Authors have shown how K560 benzamide drugs can exert neuroprotective abilities in MPP+ induced toxicity on in vitro SH-SY5Y retinoic acid differentiated cells.	('neuroprotective abilities', 'CPA', (54, 79))	('toxicity', 'Disease', 'MESH:D064420', (96, 104))	('benzamide', 'Chemical', 'MESH:C037689', (28, 37))	('toxicity', 'Disease', (96, 104))	('K560', 'Chemical', '-', (23, 27))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (117, 124))	('K560', 'Var', (23, 27))	('retinoic acid', 'Chemical', 'MESH:D014212', (125, 138))	('MPP+', 'Chemical', 'MESH:C044202', (83, 87))
8174	32429325	Specifically, K560 treatment stimulates HDAC1,2 protein expression and abrogates the cell death effect of MPP+ by modulating key apoptosis-related factors such as claspin, XIAP, and livin, and observed an increased p53 activation through phosphorylation.	('claspin', 'Gene', (163, 170))	('cell death effect', 'CPA', (85, 102))	('K560', 'Var', (14, 18))	('livin', 'Gene', (182, 187))	('XIAP', 'Gene', (172, 176))	('XIAP', 'Gene', '331', (172, 176))	('abrogates', 'NegReg', (71, 80))	('MPP+', 'Chemical', 'MESH:C044202', (106, 110))	('p53', 'Gene', (215, 218))	('livin', 'Gene', '79444', (182, 187))	('p53', 'Gene', '7157', (215, 218))	('activation', 'PosReg', (219, 229))	('modulating', 'Reg', (114, 124))	('K560', 'Chemical', '-', (14, 18))	('phosphorylation', 'MPA', (238, 253))	('claspin', 'Gene', '63967', (163, 170))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('stimulates', 'PosReg', (29, 39))
8192	32429325	Among these, FR901375 chromopeptide A, FR901375, largazole, spiruchostatin A, HC-toxin, trapoxin, and azumamide are currently investigated for their anti-tumorigenic potential.	('FR901375', 'Chemical', 'MESH:C482963', (39, 47))	('azumamide', 'Chemical', '-', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('FR901375', 'Chemical', 'MESH:C482963', (13, 21))	('HC-toxin', 'Disease', (78, 86))	('largazole', 'Chemical', 'MESH:C527895', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('trapoxin', 'Chemical', 'MESH:C067070', (88, 96))	('HC-toxin', 'Disease', 'MESH:D065766', (78, 86))	('FR901375', 'Var', (39, 47))	('FR901375 chromopeptide A', 'Chemical', '-', (13, 37))	('FR901375', 'Var', (13, 21))	('tumor', 'Disease', (154, 159))
8202	32429325	For example, inhibition of HDACs could modulate their action in genomic instability, often observed in cancer in the form of amplifications/deletions, chromosomic rearrangements, and chromothripsis.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('genomic instability', 'MPA', (64, 83))	('inhibition', 'Var', (13, 23))	('chromothripsis', 'Disease', (183, 197))	('modulate', 'Reg', (39, 47))	('chromothripsis', 'Disease', 'MESH:D000072837', (183, 197))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('HDACs', 'Protein', (27, 32))
8224	31535077	A number of studies have suggested that, even when controlling for a more complex patient population, the quality of surgical care at SNH remains inferior to the care rendered at non-SNH.	('SNH', 'Var', (134, 137))	('inferior', 'NegReg', (146, 154))	('patient', 'Species', '9606', (82, 89))
8231	31535077	The objective of our study was to examine the quality of care, readmission rates, and survival of women with uterine, ovarian, or cervical cancer treated at SNH compared with those treated at non-SNH.	('SNH', 'Var', (157, 160))	('cervical cancer', 'Disease', (130, 145))	('uterine', 'Disease', (109, 116))	('cervical cancer', 'Disease', 'MESH:D002583', (130, 145))	('women', 'Species', '9606', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ovarian', 'Disease', (118, 125))	('ovarian', 'Disease', 'MESH:D010051', (118, 125))
8237	31535077	Each hospital was classified into the following quartiles based on the proportion of patients who were uninsured or Medicaid recipients: lowest Medicaid payer mix, low Medicaid payer mix, high Medicaid payer mix, and highest Medicaid payer mix.	('patients', 'Species', '9606', (85, 93))	('low', 'NegReg', (164, 167))	('lowest', 'NegReg', (137, 143))	('high', 'Var', (188, 192))
8240	31535077	Patient characteristics included cancer type (uterine, ovarian, cervical), patient's age (<40, 40-49, 50-59, 60-69, 70-79, and >=80 years), race or ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and others), insurance status (private, Medicare, Medicaid, uninsured, and other government), zip code-level median household income (<$30 000, $30 000-$35 999, $36 000-$45 999, and >=$46 000), zip-code level education (>=29%, 20%-28.9%, 14%-19.9%, and <14% of adults without a high school diploma), and patients' residential location (metropolitan, urban, rural, and unknown).	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('patient', 'Species', '9606', (75, 82))	('diploma', 'Disease', (499, 506))	('<$30 000', 'Var', (343, 351))	('ovarian', 'Disease', (55, 62))	('zip', 'Gene', '1613', (403, 406))	('zip', 'Gene', '1613', (303, 306))	('>=29', 'Var', (429, 433))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('patient', 'Species', '9606', (513, 520))	('patients', 'Species', '9606', (513, 521))	('ovarian', 'Disease', 'MESH:D010051', (55, 62))	('zip', 'Gene', (403, 406))	('zip', 'Gene', (303, 306))	('diploma', 'Disease', 'None', (499, 506))	('Patient', 'Species', '9606', (0, 7))
8264	31535077	Patients at SNH were younger (11.4% vs 6.7% were age <40 years), more frequently black (16.1% vs 6.8%) or Hispanic (13.6% vs 3.6%), and lived in metropolitan zip codes with lower income and lower educational attainment (P < .0001 for all).	('zip', 'Gene', (158, 161))	('Patients', 'Species', '9606', (0, 8))	('Hispanic', 'Var', (106, 114))	('lower educational attainment', 'Phenotype', 'HP:0001249', (190, 218))	('zip', 'Gene', '1613', (158, 161))
8284	31535077	Interestingly, for gynecological cancers, we found that although the quality of surgical care at SNH was lower than at non-SNH, receipt of evidence-based chemotherapy was higher at SNH for uterine and ovarian cancer patients.	('lower', 'NegReg', (105, 110))	('SNH', 'Var', (181, 184))	('quality', 'MPA', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('ovarian cancer', 'Disease', (201, 215))	('cancers', 'Disease', (33, 40))	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('higher', 'PosReg', (171, 177))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('patients', 'Species', '9606', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('SNH', 'Var', (97, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('uterine', 'Disease', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
8311	31423217	Cell proliferative, migratory and invasive activities were suppressed by CBR1 overexpression, accompanied by increases in the expressions of epithelial markers (E-cadherin and cytokeratin) and decreases in the expressions of mesenchymal markers (N-cadherin and fibronectin), suggesting that CBR1 overexpression inhibits malignant behaviors and EMT in uLMS cells.	('CBR1', 'Gene', '873', (291, 295))	('CBR1', 'Gene', (291, 295))	('uLMS', 'Phenotype', 'HP:0002891', (351, 355))	('fibronectin', 'Gene', (261, 272))	('Cell proliferative', 'CPA', (0, 18))	('expressions', 'MPA', (126, 137))	('malignant behaviors', 'CPA', (320, 339))	('CBR1', 'Gene', '873', (73, 77))	('CBR1', 'Gene', (73, 77))	('expressions', 'MPA', (210, 221))	('fibronectin', 'Gene', '2335', (261, 272))	('E-cadherin', 'Gene', (161, 171))	('E-cadherin', 'Gene', '999', (161, 171))	('decreases', 'NegReg', (193, 202))	('N-cadherin', 'Gene', (246, 256))	('N-cadherin', 'Gene', '1000', (246, 256))	('suppressed', 'NegReg', (59, 69))	('increases', 'PosReg', (109, 118))	('overexpression', 'Var', (78, 92))	('inhibits', 'NegReg', (311, 319))
8325	31423217	Furthermore, low-expression of CBR1 is closely associated with lymph node metastasis and a poor prognosis in ovarian, uterine cervical, or endometrial cancers.	('ovarian', 'Disease', (109, 116))	('low-expression', 'Var', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lymph node metastasis', 'Disease', (63, 84))	('lymph node metastasis', 'Disease', 'MESH:D009362', (63, 84))	('endometrial cancers', 'Disease', 'MESH:D016889', (139, 158))	('CBR1', 'Gene', '873', (31, 35))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('uterine cervical', 'Disease', (118, 134))	('associated', 'Reg', (47, 57))	('CBR1', 'Gene', (31, 35))	('endometrial cancers', 'Disease', (139, 158))
8384	31423217	2), suggesting that CBR1 overexpression decreased cell proliferation.	('overexpression', 'Var', (25, 39))	('CBR1', 'Gene', '873', (20, 24))	('CBR1', 'Gene', (20, 24))	('decreased', 'NegReg', (40, 49))	('cell proliferation', 'CPA', (50, 68))
8404	31423217	We further investigated whether CBR1 overexpression suppresses TGFbeta/Smad signaling.	('CBR1', 'Gene', (32, 36))	('Smad', 'Gene', '4089;4089', (71, 75))	('TGFbeta', 'Gene', '7040', (63, 70))	('TGFbeta', 'Gene', (63, 70))	('Smad', 'Gene', (71, 75))	('overexpression', 'Var', (37, 51))	('CBR1', 'Gene', '873', (32, 36))	('suppresses', 'NegReg', (52, 62))
8408	31423217	The expression levels of P-Smad2 and P-Smad3 proteins were confirmed to be decreased by SB431542 (Fig.	('expression levels', 'MPA', (4, 21))	('SB431542', 'Chemical', 'MESH:C459179', (88, 96))	('Smad3', 'Gene', (39, 44))	('SB431542', 'Var', (88, 96))	('Smad2', 'Gene', '4087', (27, 32))	('Smad3', 'Gene', '4088', (39, 44))	('Smad2', 'Gene', (27, 32))	('decreased', 'NegReg', (75, 84))
8409	31423217	The protein and mRNA levels of E-cadherin (CDH1) expression were increased while those of Snail (SNAI1) were decreased by SB431542 treatment (Fig.	('decreased', 'NegReg', (109, 118))	('E-cadherin', 'Gene', '999', (31, 41))	('increased', 'PosReg', (65, 74))	('mRNA levels', 'MPA', (16, 27))	('expression', 'MPA', (49, 59))	('SB431542', 'Var', (122, 130))	('protein', 'MPA', (4, 11))	('Snail', 'Gene', (90, 95))	('CDH1', 'Gene', (43, 47))	('SB431542', 'Chemical', 'MESH:C459179', (122, 130))	('Snail', 'Gene', '6615', (90, 95))	('E-cadherin', 'Gene', (31, 41))	('SNAI1', 'Gene', '6615', (97, 102))	('SNAI1', 'Gene', (97, 102))	('CDH1', 'Gene', '999', (43, 47))
8431	31423217	Dwivedi et al showed that TGF-beta promotes cell migration by phosphorylating Smad2 and Smad3 in uterine carcinosarcomas.	('Smad2', 'Gene', '4087', (78, 83))	('Smad3', 'Gene', (88, 93))	('carcinosarcomas', 'Disease', 'MESH:D002296', (105, 120))	('Smad2', 'Gene', (78, 83))	('promotes', 'PosReg', (35, 43))	('phosphorylating', 'Var', (62, 77))	('TGF-beta', 'Gene', '7040', (26, 34))	('carcinosarcomas', 'Disease', (105, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('TGF-beta', 'Gene', (26, 34))	('cell migration', 'CPA', (44, 58))	('Smad3', 'Gene', '4088', (88, 93))
8433	31423217	Our results clearly show that TGF-beta treatment activates EMT, that the blockage of TGF-beta signaling inhibits EMT in uLMS cells (Fig.	('uLMS', 'Disease', (120, 124))	('EMT', 'CPA', (59, 62))	('blockage', 'Var', (73, 81))	('TGF-beta', 'Gene', (85, 93))	('activates', 'PosReg', (49, 58))	('inhibits', 'NegReg', (104, 112))	('uLMS', 'Phenotype', 'HP:0002891', (120, 124))	('TGF-beta', 'Gene', '7040', (30, 38))	('EMT', 'CPA', (113, 116))	('TGF-beta', 'Gene', '7040', (85, 93))	('TGF-beta', 'Gene', (30, 38))
8458	31423217	In summary, the present study shows that increased CBR1 expression inhibits malignant behaviors and EMT by suppressing TGF-beta signaling in uLMS cells.	('increased', 'PosReg', (41, 50))	('malignant behaviors', 'CPA', (76, 95))	('TGF-beta', 'Gene', '7040', (119, 127))	('CBR1', 'Gene', '873', (51, 55))	('CBR1', 'Gene', (51, 55))	('TGF-beta', 'Gene', (119, 127))	('suppressing', 'NegReg', (107, 118))	('inhibits', 'NegReg', (67, 75))	('uLMS', 'Phenotype', 'HP:0002891', (141, 145))	('expression', 'Var', (56, 66))	('EMT', 'CPA', (100, 103))
8482	30935419	More aggressive treatment strategies are adopted because under-interpretation of uterine sarcomas might delay necessary treatment and, hence, worsen the prognosis.	('sarcomas', 'Disease', (89, 97))	('uterine', 'Disease', (81, 88))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (81, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('worsen', 'Reg', (142, 148))	('prognosis', 'MPA', (153, 162))	('delay', 'NegReg', (104, 109))	('under-interpretation', 'Var', (57, 77))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
8585	30521505	During 1999-2015, uterine cancer incidence rates increased 12%, about 0.7% per year on average, with larger increases observed among AI/AN (53%; AAPC = 2.7%), black (46%; 2.4%), API (38%; 2.0%), and Hispanic (32%; 1.8%) women than among white women (9%; 0.5%) (Figure 1).	('uterine cancer', 'Phenotype', 'HP:0010784', (18, 32))	('AAPC', 'Disease', (145, 149))	('cancer', 'Disease', (26, 32))	('increases', 'PosReg', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('women', 'Species', '9606', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('AI/AN', 'Var', (133, 138))	('women', 'Species', '9606', (220, 225))	('AAPC', 'Disease', 'MESH:D011125', (145, 149))
8636	30022854	Garg et al compared OCS survival rates with those of uterine carcinosarcoma (UCS) by analyzing the SEER database and showed that LND was significantly associated with an improved OCS and UCS survival.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (53, 75))	('carcinosarcoma', 'Disease', (61, 75))	('LND', 'Var', (129, 132))	('improved', 'PosReg', (170, 178))	('carcinosarcoma', 'Disease', 'MESH:D002296', (61, 75))	('UCS survival', 'CPA', (187, 199))	('OCS', 'Disease', (179, 182))
8650	30022854	AJCC T1: tumor limited to one or both ovaries; AJCC T2: tumor involves one or both ovaries with pelvic extension; AJCC N0: no regional LNM; AJCC N1: regional LNM; AJCC M0: no distant metastasis; AJCC M1: distant metastasis; AJCC T1N0M0: FIGO stage I; AJCC T1aN0M0, T1bN0M0, T1cN0M0: FIGO Ia, Ib, Ic; AJCC T2N0M0: FIGO II; AJCC T2aN0M0, T2bN0M0, T2cN0M0: FIGO stage IIa, IIb, IIc; AJCC T1/2N1M0: FIGO IIIa.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('T2bN0M0', 'Var', (336, 343))	('T2aN0M0', 'Var', (327, 334))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (56, 61))	('tumor limited to one or both ovaries', 'Phenotype', 'HP:0100615', (9, 45))	('tumor', 'Disease', (9, 14))	('T2cN0M0', 'Var', (345, 352))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
8660	30022854	Contrastingly, 16.3% patients had LNM in AJCC T2 (Table 2).	('LNM', 'Var', (34, 37))	('patients', 'Species', '9606', (21, 29))	('AJCC T2', 'Gene', (41, 48))
8667	30022854	In LND (+) group, the subgroup analysis by AJCC T categories revealed that patients with LNM had lower CSS (p = 0.004; Figure 3C) and OS (p = 0.003; Figure 3D) rate than patients without LNM in AJCC T2.	('patients', 'Species', '9606', (170, 178))	('LNM', 'Var', (89, 92))	('CSS', 'Chemical', '-', (103, 106))	('patients', 'Species', '9606', (75, 83))	('lower', 'NegReg', (97, 102))	('OS', 'Chemical', '-', (134, 136))
8669	30022854	Any two comparisons of four groups by Log-rank method showed that patients with AJCC T2N1M0 had a poorer survival outcome than patients with AJCC T2N0M0 (p = 0.006 for CSS, p = 0.005 for OS), T1N1M0 (p = 0.034 for CSS, p =0.043 for OS) and T1N0M0 (p < 0.001 for CSS, p < 0.001 for OS).	('CSS', 'Chemical', '-', (262, 265))	('poorer', 'NegReg', (98, 104))	('AJCC T2N1M0', 'Var', (80, 91))	('OS', 'Chemical', '-', (187, 189))	('OS', 'Chemical', '-', (232, 234))	('T2N1M0', 'Var', (85, 91))	('CSS', 'Chemical', '-', (214, 217))	('patients', 'Species', '9606', (127, 135))	('CSS', 'Chemical', '-', (168, 171))	('survival outcome', 'CPA', (105, 121))	('OS', 'Chemical', '-', (281, 283))	('patients', 'Species', '9606', (66, 74))
8670	30022854	However, there was no statistically significant survival difference between patients with AJCC T1N1M0 and patients with AJCC T1N0M0 (p = 0.377 for CSS, p = 0.257 for OS; Table S1).	('T1N1M0', 'Var', (95, 101))	('patients', 'Species', '9606', (76, 84))	('OS', 'Chemical', '-', (166, 168))	('AJCC T1N1M0', 'Var', (90, 101))	('patients', 'Species', '9606', (106, 114))	('CSS', 'Chemical', '-', (147, 150))
8673	30022854	Garg et al used the SEER database to make a comparison of prognostic factors between 924 women with OCS and 2,759 women with UCS and found that LND significantly improved survival outcomes of OCS and UCS.	('women', 'Species', '9606', (114, 119))	('improved', 'PosReg', (162, 170))	('women', 'Species', '9606', (89, 94))	('survival outcomes', 'CPA', (171, 188))	('LND', 'Var', (144, 147))	('OCS', 'Disease', (192, 195))
8686	30022854	LND significantly improved the survival of patients with AJCC T2 (CSS, HR = 0.61, 95% CI = 0.43-0.87; OS, HR = 0.59, 95% CI = 0.42-0.83).	('OS', 'Chemical', '-', (102, 104))	('AJCC T2', 'Var', (57, 64))	('patients', 'Species', '9606', (43, 51))	('survival', 'CPA', (31, 39))	('improved', 'PosReg', (18, 26))	('CSS', 'Chemical', '-', (66, 69))
8697	30022854	Meanwhile, there was no significant difference seen between the survival of patients with AJCC T1N1M0 and AJCC T1N0M0, while a worse survival trend was observed in AJCC T1N1M0 when compared to AJCC T1N0M0.	('patients', 'Species', '9606', (76, 84))	('T1N1M0', 'Var', (95, 101))	('AJCC T1N1M0', 'Var', (90, 101))
8701	30022854	Patients with LNM in AJCC T2 were shown to have poor survival outcomes and LND improved the prognosis of patients with AJCC T2.	('patients', 'Species', '9606', (105, 113))	('improved', 'PosReg', (79, 87))	('LND', 'Var', (75, 78))	('LNM', 'Var', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('AJCC', 'Disease', (21, 25))	('prognosis', 'MPA', (92, 101))
8703	28679774	SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression.	('HER2/neu', 'Gene', '2064', (304, 312))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('Neu', 'Gene', (147, 150))	('Neu', 'Gene', '2064', (147, 150))	('malignancies', 'Disease', (217, 229))	('Ovarian Carcinosarcoma', 'Phenotype', 'HP:0025318', (114, 136))	('SYD985', 'Var', (0, 6))	('HER2', 'Gene', '2064', (142, 146))	('HER2', 'Gene', (304, 308))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (246, 275))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('HER2', 'Gene', (34, 38))	('Carcinosarcomas', 'Disease', 'MESH:D002296', (162, 177))	('Ovarian Carcinosarcoma', 'Disease', (114, 136))	('Carcinosarcomas', 'Disease', (162, 177))	('HER2/neu', 'Gene', (304, 312))	('Ovarian Carcinosarcoma', 'Disease', 'MESH:D002296', (114, 136))	('Duocarmycin', 'Chemical', '-', (16, 27))	('HER2', 'Gene', (142, 146))	('Uterine', 'Disease', (102, 109))	('HER2', 'Gene', '2064', (304, 308))	('HER2', 'Gene', '2064', (34, 38))
8727	28679774	Because of the reported overexpression and/or gene amplification of HER2 in over one third of uterine serous carcinoma which represents the high grade epithelial component of a large number of gynecologic CS, HER2 may represent an attractive target for anticancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('HER2', 'Gene', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('overexpression', 'PosReg', (24, 38))	('serous carcinoma', 'Disease', (102, 118))	('gene amplification', 'Var', (46, 64))	('serous carcinoma', 'Disease', 'MESH:D018284', (102, 118))
8780	28679774	On the basis of the HER2/neu results, we selected a total of 4 primary CS cell lines with similar growth rate and different HER2 expression and OM(M)98 (ie CS-PDX1) for the additional in vitro and in vivo experiments described below.	('HER2/neu', 'Gene', (20, 28))	('OM(M)98', 'Var', (144, 151))	('HER2/neu', 'Gene', '2064', (20, 28))	('HER2', 'Protein', (124, 128))
8816	28679774	In this comprehensive report, in agreement with previously published clinical data, we demonstrated at molecular level that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas.	('mutations', 'Var', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('carcinomas', 'Disease', 'MESH:D002277', (222, 232))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (124, 153))	('carcinomas', 'Disease', (222, 232))
8836	28679774	The cleavage of duocarmycine from its linker, unlike the cleavage of DM1, may take place in CS not only within HER2/neu overexpressing tumor cells after antibody internalization but also extracellularly within the tumor microenvironment, inducing a potent bystander effect.	('cleavage', 'Var', (4, 12))	('HER2/neu', 'Gene', '2064', (111, 119))	('HER2/neu', 'Gene', (111, 119))	('DM1', 'Gene', '28509', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('duocarmycine', 'Chemical', 'MESH:C058289', (16, 28))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('bystander effect', 'CPA', (256, 272))	('DM1', 'Gene', (69, 72))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
8837	28679774	Consistent with this view, we found SYD985 to be signifcantly more potent than T-DM1 in its ability to induce bystander killing of low/negative HER2/neu expressing tumor cells admixed with HER2/neu positive tumor cells.	('DM1', 'Gene', (81, 84))	('SYD', 'Gene', (36, 39))	('tumor', 'Disease', (164, 169))	('bystander killing', 'CPA', (110, 127))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('SYD', 'Gene', '23162', (36, 39))	('low/negative', 'Var', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('HER2/neu', 'Gene', '2064', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('HER2/neu', 'Gene', '2064', (189, 197))	('DM1', 'Gene', '28509', (81, 84))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('HER2/neu', 'Gene', (144, 152))	('HER2/neu', 'Gene', (189, 197))
8920	24300913	They found that using G-CSF in conjunction with paclitaxel could prevent neutropenia in most patients while still achieving tumor response rates in the 30-40% range; however, it now appeared that shortening the infusion time would decrease the rate of neutropenia and decrease the need for G-CSF.	('G-CSF', 'Gene', '1440', (22, 27))	('shortening', 'Var', (196, 206))	('neutropenia', 'Disease', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('G-CSF', 'Gene', (22, 27))	('G-CSF', 'Gene', (290, 295))	('G-CSF', 'Gene', '1440', (290, 295))	('neutropenia', 'Phenotype', 'HP:0001875', (252, 263))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('neutropenia', 'Disease', 'MESH:D009503', (252, 263))	('neutropenia', 'Disease', (252, 263))	('neutropenia', 'Phenotype', 'HP:0001875', (73, 84))	('decrease', 'NegReg', (268, 276))	('neutropenia', 'Disease', 'MESH:D009503', (73, 84))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))	('patients', 'Species', '9606', (93, 101))	('decrease', 'NegReg', (231, 239))
8959	24300913	However, studies have shown improved overall survival (from 47 to 84 months) in patients treated with paclitaxel IV followed by cisplatin and paclitaxel IP compared to IV cisplatin and paclitaxel in patients with BRCA 1 mutations and ovarian cancer.	('paclitaxel', 'Chemical', 'MESH:D017239', (102, 112))	('patients', 'Species', '9606', (80, 88))	('improved', 'PosReg', (28, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('paclitaxel', 'Chemical', 'MESH:D017239', (142, 152))	('ovarian cancer', 'Phenotype', 'HP:0100615', (234, 248))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('overall survival', 'MPA', (37, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (234, 248))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('paclitaxel', 'Chemical', 'MESH:D017239', (185, 195))	('ovarian cancer', 'Disease', (234, 248))	('mutations', 'Var', (220, 229))	('BRCA 1', 'Gene', '672', (213, 219))	('BRCA 1', 'Gene', (213, 219))
8982	24300913	Grade 3 and 4 neutropenia were noted more frequently with Docetaxel while neuropathy was more common with paclitaxel.	('neuropathy', 'Phenotype', 'HP:0009830', (74, 84))	('neutropenia', 'Disease', (14, 25))	('Docetaxel', 'Var', (58, 67))	('neuropathy', 'Disease', (74, 84))	('neutropenia', 'Disease', 'MESH:D009503', (14, 25))	('Grade 3', 'Disease', (0, 7))	('neutropenia', 'Phenotype', 'HP:0001875', (14, 25))	('Docetaxel', 'Chemical', 'MESH:D000077143', (58, 67))	('neuropathy', 'Disease', 'MESH:D009422', (74, 84))	('paclitaxel', 'Chemical', 'MESH:D017239', (106, 116))
9056	24300913	In normal cells, the PIK3/AKT/mTOR pathway is tightly controlled, but a large number of cancers harbor genetic mutations that result in the dysregulation and activation of this pathway.	('mutations', 'Var', (111, 120))	('AKT', 'Gene', '207', (26, 29))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('PIK3', 'Gene', '5294', (21, 25))	('cancers', 'Disease', (88, 95))	('dysregulation', 'MPA', (140, 153))	('activation', 'PosReg', (158, 168))	('AKT', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (30, 34))	('PIK3', 'Gene', (21, 25))
9058	24300913	These alterations allow them to grow despite conditions where nutrients and oxygen are scarce.	('alterations', 'Var', (6, 17))	('allow', 'Reg', (18, 23))	('oxygen', 'Chemical', 'MESH:D010100', (76, 82))
9078	24300913	In another Cochrane review of six trials including 1072 women comparing neoadjuvant chemotherapy followed by surgery versus radical surgery alone for early-stage disease, progression-free survival was significantly improved with neoadjuvant chemotherapy (HR = 0.76, 95% CI = 0.62 to 0.94, p = 0.01), but no overall survival benefit was observed (HR = 0.85, 95% CI = 0.67 to 1.07, p = 0.17).	('women', 'Species', '9606', (56, 61))	('progression-free survival', 'CPA', (171, 196))	('neoadjuvant chemotherapy', 'Var', (229, 253))	('improved', 'PosReg', (215, 223))
9125	24300913	Data from GOG-169 suggested the combination of cisplatin 50 mg/m2 with paclitaxel 135 mg/m2 day 1 every 3 weeks improved response rate (35% versus 19%) and progression free survival (4.8 versus 2.8) but not overall survival (9.7 versus 8.8 months) relative to cisplatin alone.	('cisplatin', 'Var', (47, 56))	('GOG', 'Chemical', '-', (10, 13))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('progression free survival', 'CPA', (156, 181))	('improved', 'PosReg', (112, 120))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('response rate', 'CPA', (121, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (260, 269))
9214	24716055	MMMTs have also been associated with other primary tumors such as ovarian thecoma and serous adenocarcinoma.	('MMMTs', 'Var', (0, 5))	('primary tumors', 'Disease', 'MESH:D009369', (43, 57))	('ovarian thecoma', 'Disease', 'MESH:D013798', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ovarian thecoma', 'Disease', (66, 81))	('associated', 'Reg', (21, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('ovarian thecoma', 'Phenotype', 'HP:0030983', (66, 81))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('serous adenocarcinoma', 'Disease', 'MESH:D000230', (86, 107))	('primary tumors', 'Disease', (43, 57))	('serous adenocarcinoma', 'Disease', (86, 107))
9221	24716055	MMMTs have also been associated with autoimmune manifestations such as myasthenia gravis and thrombocytopenic purpura.	('myasthenia', 'Phenotype', 'HP:0003473', (71, 81))	('MMMTs', 'Var', (0, 5))	('autoimmune manifestations', 'Phenotype', 'HP:0002960', (37, 62))	('thrombocytopenic purpura', 'Phenotype', 'HP:0001973', (93, 117))	('thrombocytopenic purpura', 'Disease', 'MESH:D011696', (93, 117))	('purpura', 'Phenotype', 'HP:0000979', (110, 117))	('associated', 'Reg', (21, 31))	('myasthenia gravis', 'Disease', (71, 88))	('thrombocytopenic purpura', 'Disease', (93, 117))	('myasthenia gravis', 'Disease', 'MESH:D009157', (71, 88))
9231	24716055	However, some microsatellite instability high colorectal adenocarcinomas can be CK7+/CK20- negative.	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (46, 72))	('microsatellite instability', 'Var', (14, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('CK7', 'Gene', (80, 83))	('CK7', 'Gene', '3855', (80, 83))	('colorectal adenocarcinomas', 'Disease', (46, 72))	('high', 'PosReg', (41, 45))	('CK20', 'Gene', '54474', (85, 89))	('CK20', 'Gene', (85, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
9255	24649216	Genetic profiling efforts have identified amplification, overexpression and mutation, while the molecular mechanisms of tumorigenesis driven by these genomic and genetic aberrations have yet to be fully elucidated yet.	('overexpression', 'PosReg', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('amplification', 'Var', (42, 55))	('mutation', 'Var', (76, 84))	('tumor', 'Disease', (120, 125))
9257	24649216	In conclusion, aberrations of cell cycle control would be a critical step in the development of uterine sarcoma.	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('aberrations', 'Var', (15, 26))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (96, 111))	('aberrations of cell cycle', 'Phenotype', 'HP:0011018', (15, 40))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))
9277	24649216	In general, amplification of c-myc correlates with distant metastases and is a factor of poor prognosis.	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('amplification', 'Var', (12, 25))	('c-myc', 'Gene', '4609', (29, 34))	('c-myc', 'Gene', (29, 34))	('metastases', 'Disease', (59, 69))
9282	24649216	Overexpression of specific genes, including transforming growth factor (TGF)-beta, retinoblastoma (Rb), p53, HER-2 (also known as ERBB2, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2), vascular endothelial growth factor (VEGF), estrogen receptor (ER), progesterone receptor (PR), cancer-testis-associated antigens (CATs), beta-catenin, B-cell CLL/lymphoma 2 (BCL-2), cyclooxygenase (COX)-2, p16INK4a (CDKN2A, cyclin-dependent kinase inhibitor 2A), phosphatase and tensin homolog (PTEN) and vimentin, has been detected in several cases (Table I).	('beta-catenin', 'Gene', (334, 346))	('cyclooxygenase (COX)-2', 'Gene', '807936', (379, 401))	('p53', 'Gene', '7157', (104, 107))	('Rb', 'Gene', '5925', (99, 101))	('cancer-testis-associated antigens (CATs)', 'Gene', '54478', (292, 332))	('beta-catenin', 'Gene', '1499', (334, 346))	('TGF', 'Gene', (72, 75))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (348, 367))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '101089220', (421, 457))	('lymphoma', 'Phenotype', 'HP:0002665', (359, 367))	('p53', 'Gene', (104, 107))	('vascular endothelial growth factor', 'Gene', '493845', (197, 231))	('vimentin', 'Gene', '101091951', (502, 510))	('Rb', 'Phenotype', 'HP:0009919', (99, 101))	('vimentin', 'Gene', (502, 510))	('TGF', 'Gene', '7040;7043', (72, 75))	('retinoblastoma', 'Phenotype', 'HP:0009919', (83, 97))	('p16INK4a', 'Var', (403, 411))	('cancer-testis-associated antigens (CATs', 'Gene', (292, 331))	('retinoblastoma', 'Disease', (83, 97))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (421, 457))	('vascular endothelial growth factor', 'Gene', (197, 231))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('estrogen receptor', 'Gene', (240, 257))	('ERBB2', 'Gene', '751824', (130, 135))	('B-cell CLL/lymphoma 2', 'Gene', (348, 369))	('estrogen receptor', 'Gene', '552888', (240, 257))	('erb', 'Gene', (139, 142))	('erb', 'Gene', '2100', (139, 142))	('leukemia', 'Phenotype', 'HP:0001909', (161, 169))	('ERBB2', 'Gene', (130, 135))	('cyclooxygenase (COX)-2', 'Gene', (379, 401))	('erythroblastic leukemia viral', 'Disease', (146, 175))	('B-cell CLL/lymphoma 2', 'Gene', '493934', (348, 369))	('b2 erythroblastic leukemia', 'Phenotype', 'HP:0004812', (143, 169))	('erythroblastic leukemia viral', 'Disease', 'MESH:D004915', (146, 175))	('retinoblastoma', 'Disease', 'MESH:D012175', (83, 97))
9297	24649216	Mutations of these genes have been identified as biomarkers against the treatment of certain carcinomas with small molecule inhibitors or monoclonal antibodies to the specific growth factor receptor.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('carcinomas', 'Disease', (93, 103))	('carcinomas', 'Disease', 'MESH:D002277', (93, 103))	('Mutations', 'Var', (0, 9))
9328	24649216	Loss of heterozygosity (LOH), amplification, overexpression and mutations may contribute to the risk of leiomyosarcoma development (Tables I and II).	('leiomyosarcoma development', 'Disease', (104, 130))	('Loss of heterozygosity', 'Var', (0, 22))	('amplification', 'Var', (30, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('mutations', 'Var', (64, 73))	('overexpression', 'PosReg', (45, 59))	('leiomyosarcoma development', 'Disease', 'MESH:D007890', (104, 130))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (104, 118))
9329	24649216	LOH on chromosome 10 occurred more frequently in leiomyosarcoma compared to leiomyoma and may contribute to sarcomagenesis.	('leiomyoma', 'Disease', (76, 85))	('sarcoma', 'Disease', (108, 115))	('sarcoma', 'Disease', (56, 63))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (49, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('LOH on chromosome', 'Var', (0, 17))	('leiomyoma', 'Disease', 'MESH:D007889', (76, 85))	('leiomyosarcoma', 'Disease', (49, 63))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (49, 63))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('contribute', 'Reg', (94, 104))
9332	24649216	Mutation of p53 was observed in 24% of leiomyosarcoma cases.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (39, 53))	('Mutation', 'Var', (0, 8))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('observed', 'Reg', (20, 28))	('leiomyosarcoma', 'Disease', (39, 53))
9350	24649216	Since BRCA1, a well-known tumor suppressor gene, plays a role in maintaining genomic stability, loss of BRCA1 function potentially is involved in the progression of leiomyosarcoma.	('BRCA1', 'Gene', (6, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('loss', 'Var', (96, 100))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (165, 179))	('BRCA1', 'Gene', '672', (104, 109))	('involved', 'Reg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('function', 'MPA', (110, 118))	('BRCA1', 'Gene', (104, 109))	('leiomyosarcoma', 'Disease', (165, 179))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (165, 179))	('tumor', 'Disease', (26, 31))	('BRCA1', 'Gene', '672', (6, 11))
9351	24649216	Frequent mutations of the MED12 gene were identified in 70% of leiomyosarcoma.	('identified', 'Reg', (42, 52))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (63, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('MED12', 'Gene', (26, 31))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (63, 77))	('mutations', 'Var', (9, 18))	('MED12', 'Gene', '9968', (26, 31))	('leiomyosarcoma', 'Disease', (63, 77))
9355	24649216	Mice with homozygous LMP2 deletion spontaneously developed uterine leiomyosarcoma.	('leiomyosarcoma', 'Disease', (67, 81))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (67, 81))	('LMP2', 'Gene', (21, 25))	('deletion', 'Var', (26, 34))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (67, 81))	('developed', 'Reg', (49, 58))	('Mice', 'Species', '10090', (0, 4))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
9380	24649216	Immunohistochemical study using a well-characterized panel of antibodies to p16, p53 and Ki-67 could pose a challenge, while it may be helpful in distinguishing STUMP from usual leiomyoma and leiomyosarcoma cases (Tables I and III).	('Ki-67', 'Gene', (89, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('leiomyoma and leiomyosarcoma', 'Disease', 'MESH:D007890', (178, 206))	('p16', 'Var', (76, 79))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('usual leiomyoma', 'Phenotype', 'HP:0007620', (172, 187))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (192, 206))
9384	24649216	A subset of STUMP characterized by strong, diffuse p16 positivity contains the morphological changes of coagulative tumor cell necrosis.	('coagulative tumor cell necrosis', 'Disease', (104, 135))	('p16 positivity', 'Var', (51, 65))	('positivity', 'Var', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('coagulative tumor cell necrosis', 'Disease', 'MESH:D025861', (104, 135))
9386	24649216	It may be possible to discern meaningful subsets of the STUMP patients with a malignant potential by using p16, p21 and p53 immunostaining.	('p53', 'Gene', '7157', (120, 123))	('p16', 'Var', (107, 110))	('p21', 'Gene', '1026', (112, 115))	('p53', 'Gene', (120, 123))	('patients', 'Species', '9606', (62, 70))	('p21', 'Gene', (112, 115))
9387	24649216	p16 is a cyclin-dependent kinase inhibitor (CDKI) that reduces cell cycle progression.	('p16', 'Var', (0, 3))	('CDKI', 'Gene', '1033', (44, 48))	('cyclin-dependent kinase inhibitor', 'Gene', (9, 42))	('CDKI', 'Gene', (44, 48))	('cell cycle progression', 'CPA', (63, 85))	('reduces', 'NegReg', (55, 62))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (9, 42))
9389	24649216	Although limited, p16, p21 and p53 may serve as useful markers in the assessment of problematic uterine smooth muscle tumors.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('p16', 'Var', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('muscle tumors', 'Disease', 'MESH:D009217', (111, 124))	('problematic uterine smooth muscle tumors', 'Phenotype', 'HP:0000131', (84, 124))	('muscle tumors', 'Disease', (111, 124))	('p21', 'Gene', '1026', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('p21', 'Gene', (23, 26))
9409	24649216	Recent genome-wide studies have identified complex chromosomal rearrangements as a sarcomagenic mechanism (Table I).	('complex chromosomal rearrangements', 'Var', (43, 77))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma', 'Disease', (83, 90))
9412	24649216	In addition, the 14-3-3 fusion oncogene rearrangements resulting from t(10;17) fusion transcripts were specific for undifferentiated endometrial stroma.	('endometrial stroma', 'Disease', (133, 151))	('t(10;17', 'Gene', (70, 77))	('endometrial stroma', 'Disease', 'MESH:D014591', (133, 151))	('fusion transcripts', 'Var', (79, 97))
9426	24649216	By contrast, adenosarcoma with sarcomatous overgrowth had a WT1 (+), Ki-67 (+) and p53 (+) immunophenotype.	('WT1', 'Gene', (60, 63))	('overgrowth', 'Phenotype', 'HP:0001548', (43, 53))	('sarcomatous overgrowth', 'Disease', 'MESH:D018316', (31, 53))	('p53', 'Gene', (83, 86))	('adenosarcoma', 'Disease', (13, 25))	('Ki-67', 'Var', (69, 74))	('adenosarcoma', 'Disease', 'MESH:D018195', (13, 25))	('p53', 'Gene', '7157', (83, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('sarcomatous overgrowth', 'Disease', (31, 53))	('WT1', 'Gene', '7490', (60, 63))
9431	24649216	In addition, HMGA1a transgenic mice developed aggressive uterine tumors resembling human uterine adenosarcoma.	('aggressive uterine tumors', 'Disease', 'MESH:D014594', (46, 71))	('aggressive uterine tumors', 'Disease', (46, 71))	('transgenic mice', 'Species', '10090', (20, 35))	('human', 'Species', '9606', (83, 88))	('uterine tumors', 'Phenotype', 'HP:0010784', (57, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('developed', 'PosReg', (36, 45))	('HMGA1a', 'Gene', (13, 19))	('transgenic', 'Var', (20, 30))	('adenosarcoma', 'Disease', (97, 109))	('adenosarcoma', 'Disease', 'MESH:D018195', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
9443	24649216	In addition, p16 and p53 may have an oncogenic function due to the promotion of cell cycle regulation.	('promotion', 'PosReg', (67, 76))	('p53', 'Gene', (21, 24))	('p16', 'Var', (13, 16))	('p53', 'Gene', '7157', (21, 24))	('cell cycle regulation', 'CPA', (80, 101))
9444	24649216	These findings suggest that changes in the TGF-beta pathway as well as alterations in cell cycle regulation may be essential for the establishment and maintenance of the phenotypic characteristics of uterine carcinosarcoma.	('carcinosarcoma', 'Disease', (208, 222))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (200, 222))	('alterations', 'Reg', (71, 82))	('TGF-beta pathway', 'Pathway', (43, 59))	('carcinosarcoma', 'Disease', 'MESH:D002296', (208, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('changes', 'Var', (28, 35))	('cell', 'MPA', (86, 90))
9445	24649216	A diagnosis of uterine leiomyosarcoma is performed when 2/3 morphological criteria are met, such as coagulative tumor cell necrosis, diffuse cytological atypia, and mitotic index >10 MFs/10 HPFs.	('coagulative tumor cell necrosis', 'Disease', (100, 131))	('leiomyosarcoma', 'Disease', (23, 37))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (15, 37))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (23, 37))	('>10 MFs/10', 'Var', (179, 189))	('mitotic index', 'CPA', (165, 178))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (23, 37))	('coagulative tumor cell necrosis', 'Disease', 'MESH:D025861', (100, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
9447	24649216	Ki-67, p53, p16 and p21 were strongly expressed in leiomyosarcoma and a moderate expression of PTEN, FSCN1, ER, PR and MIB1 was also present (Tables I-III).	('MIB1', 'Gene', '57534', (119, 123))	('p21', 'Gene', (20, 23))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (51, 65))	('p21', 'Gene', '1026', (20, 23))	('p53', 'Gene', '7157', (7, 10))	('MIB1', 'Gene', (119, 123))	('FSCN1', 'Gene', (101, 106))	('p16', 'Var', (12, 15))	('PTEN', 'Gene', (95, 99))	('FSCN1', 'Gene', '6624', (101, 106))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (51, 65))	('leiomyosarcoma', 'Disease', (51, 65))	('p53', 'Gene', (7, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
9448	24649216	In experimental knockout models, the deficiency or germline mutation in the target genes such as LMP2 caused alterations in the expression of various genes associated with leiomyosarcomagenesis.	('germline mutation', 'Var', (51, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('deficiency', 'Disease', (37, 47))	('alterations', 'Reg', (109, 120))	('leiomyosarcomagenesis', 'Disease', 'None', (172, 193))	('leiomyosarcomagenesis', 'Disease', (172, 193))	('LMP2', 'Gene', (97, 101))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (172, 186))	('expression', 'MPA', (128, 138))	('deficiency', 'Disease', 'MESH:D007153', (37, 47))
9449	24649216	p16 and p53 pathway abnormalities were associated with cell cycle regulation.	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (8, 11))	('cell cycle regulation', 'CPA', (55, 76))	('associated', 'Reg', (39, 49))	('abnormalities', 'Var', (20, 33))
9453	24649216	Limited data are available regarding whether there was a significant difference in the expression and localization of p16, p21, p53 and Ki-67 between leiomyosarcoma and STUMP, as well as STUMP and usual leiomyoma (Tables I and III).	('Ki-67', 'Gene', (136, 141))	('usual leiomyoma', 'Phenotype', 'HP:0007620', (197, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('leiomyoma', 'Disease', 'MESH:D007889', (203, 212))	('leiomyosarcoma', 'Disease', (150, 164))	('p16', 'Var', (118, 121))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (150, 164))	('p21', 'Gene', '1026', (123, 126))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (150, 164))	('leiomyoma', 'Disease', (203, 212))	('p21', 'Gene', (123, 126))
9457	24649216	Chromosomal rearrangements that encode a tumor-specific chimeric oncogenic fusion protein appear to be critical events in the carcinogenesis of certain leukemias and solid carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('leukemias', 'Disease', (152, 161))	('tumor', 'Disease', (41, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('solid carcinomas', 'Disease', 'MESH:D018250', (166, 182))	('carcinogenesis', 'Disease', (126, 140))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('leukemias', 'Disease', 'MESH:D007938', (152, 161))	('solid carcinomas', 'Disease', (166, 182))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('leukemias', 'Phenotype', 'HP:0001909', (152, 161))	('Chromosomal rearrangements', 'Var', (0, 26))
9458	24649216	Previous genome-wide studies have identified complex chromosomal rearrangements in ESS, including JAZF1 (low-grade morphology) and 14-3-3 (YWHAE, undifferentiated morphology), as an oncogenic mechanism.	('JAZF1', 'Gene', (98, 103))	('ESS', 'Gene', (83, 86))	('YWHAE', 'Gene', '7531', (139, 144))	('JAZF1', 'Gene', '221895', (98, 103))	('chromosomal rearrangements', 'Var', (53, 79))	('YWHAE', 'Gene', (139, 144))
9461	24649216	Clinicopathological features including morphological criteria and clinical outcome appeared to correlate with immunohistochemical profiles, including Ki-67, p53, WT1 and CD10.	('Ki-67', 'Var', (150, 155))	('p53', 'Gene', '7157', (157, 160))	('CD10', 'Gene', (170, 174))	('CD10', 'Gene', '4311', (170, 174))	('WT1', 'Gene', '7490', (162, 165))	('WT1', 'Gene', (162, 165))	('p53', 'Gene', (157, 160))
9544	23533863	However, complete duplication of the uterus and cervix may prevent descent of the fetal head in late pregnancy or obstruct labor by the nonpregnant horn, something that was mentioned in our patient's medical history.	('obstruct labor', 'Disease', (114, 128))	('descent of the fetal head', 'CPA', (67, 92))	('prevent', 'NegReg', (59, 66))	('late pregnancy', 'Phenotype', 'HP:0001622', (96, 110))	('complete duplication', 'Var', (9, 29))	('obstruct labor', 'Disease', 'MESH:D048949', (114, 128))
9564	20605134	These observations support a potential role of dysregulated estrogen signaling in the development of this tumor.	('dysregulated', 'Var', (47, 59))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
9573	20605134	In contrast, ERbeta expression was significantly elevated in uterine carcinosarcoma, compared with normal endometrium, and high ERbeta expression was significantly associated with advanced stage disease.	('elevated', 'PosReg', (49, 57))	('expression', 'MPA', (20, 30))	('associated', 'Reg', (164, 174))	('ERbeta', 'Gene', (128, 134))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (61, 83))	('ERbeta', 'Gene', '2100', (13, 19))	('advanced stage disease', 'Disease', (180, 202))	('high', 'Var', (123, 127))	('carcinosarcoma', 'Disease', 'MESH:D002296', (69, 83))	('ERbeta', 'Gene', (13, 19))	('ERbeta', 'Gene', '2100', (128, 134))	('carcinosarcoma', 'Disease', (69, 83))
9613	20605134	It is also plausible that both GPR30 and ERbeta are coordinately upregulated due to the underlying genomic alterations that have been observed in carcinosarcoma, such as amplification of c-myc and ZNF217, observed in 78% and 87% of these tumors.	('upregulated', 'PosReg', (65, 76))	('amplification', 'Var', (170, 183))	('GPR30', 'Gene', (31, 36))	('GPR30', 'Gene', '2852', (31, 36))	('tumors', 'Disease', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('carcinosarcoma', 'Disease', 'MESH:D002296', (146, 160))	('c-myc', 'Gene', (187, 192))	('ERbeta', 'Gene', '2100', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('c-myc', 'Gene', '4609', (187, 192))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('ZNF217', 'Gene', (197, 203))	('ZNF217', 'Gene', '7764', (197, 203))	('carcinosarcoma', 'Disease', (146, 160))	('ERbeta', 'Gene', (41, 47))
9617	20605134	Consistent with the previously reported studies of GPR30 expression in ovarian, endometrial, and breast cancer, high GPR30 expression was found to be significantly correlated with advanced stage disease in this study of carcinosarcomas.	('carcinosarcomas', 'Disease', (220, 235))	('expression', 'MPA', (123, 133))	('GPR30', 'Gene', (51, 56))	('GPR30', 'Gene', '2852', (117, 122))	('GPR30', 'Gene', '2852', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('correlated with', 'Reg', (164, 179))	('advanced stage disease', 'Disease', (180, 202))	('high', 'Var', (112, 116))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('carcinosarcomas', 'Disease', 'MESH:D002296', (220, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('GPR30', 'Gene', (117, 122))
9622	20605134	The ability of GPR30 knockdown by RNA interference to abrogate cellular migration supports the validity of targeting this pathway therapeutically.	('cellular migration', 'CPA', (63, 81))	('abrogate', 'NegReg', (54, 62))	('GPR30', 'Gene', (15, 20))	('GPR30', 'Gene', '2852', (15, 20))	('RNA interference', 'MPA', (34, 50))	('knockdown', 'Var', (21, 30))
9625	20605134	These results support undertaking further investigation and validation of these hormone receptor alterations in an additional, independent group of carcinosarcoma patients.	('patients', 'Species', '9606', (163, 171))	('alterations', 'Var', (97, 108))	('hormone receptor', 'Gene', '3164', (80, 96))	('carcinosarcoma', 'Disease', 'MESH:D002296', (148, 162))	('hormone receptor', 'Gene', (80, 96))	('carcinosarcoma', 'Disease', (148, 162))
9637	33125840	All six patients with POLE-mutated tumors, including one with stage IV SWI/SNF-deficient tumor were alive with no evidence of disease.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('POLE-mutated', 'Var', (22, 34))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('SNF-deficient tumor', 'Disease', 'MESH:D009369', (75, 94))	('SNF-deficient tumor', 'Disease', (75, 94))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('patients', 'Species', '9606', (8, 16))
9645	33125840	In the case of DDEC, the inactivating mutation and consequent protein loss was only observed in the undifferentiated carcinoma and not in the corresponding clonally related differentiated endometrioid carcinoma component [2, 3].	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (188, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('loss', 'NegReg', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('undifferentiated carcinoma', 'Disease', (100, 126))	('endometrioid carcinoma', 'Disease', (188, 210))	('inactivating mutation', 'Var', (25, 46))	('protein', 'MPA', (62, 69))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (100, 126))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (188, 210))
9646	33125840	While additional functional studies are needed to confirm a causal relationship between core SWI/SNF protein inactivation and the development of DDEC/UEC, there are several examples linking core SWI/SNF protein inactivation and the development of histologically and immunophenotypically undifferentiated malignancy.	('core SWI/SNF', 'Gene', (190, 202))	('undifferentiated malignancy', 'Disease', 'MESH:D008228', (287, 314))	('inactivation', 'NegReg', (211, 223))	('undifferentiated malignancy', 'Disease', (287, 314))	('DDEC/UEC', 'Disease', (145, 153))	('inactivation', 'Var', (109, 121))
9647	33125840	These include SMARCB1 (protein also known as INI1) inactivation in malignant rhabdoid tumor, atypical rhabdoid/teratoid tumor, epithelioid sarcoma and undifferentiated sinonasal carcinoma, and SMARCA4 (protein also known as BRG1) inactivation in small cell carcinoma hypercalcemic-type of the ovary, SMARCA4-deficient uterine sarcoma/malignant rhabdoid tumor of the uterus, rhabdoid undifferentiated lung carcinoma and gastrointestinal tract carcinoma [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26].	('SMARCB1', 'Gene', (14, 21))	('small cell carcinoma hypercalcemic-type of the ovary', 'Disease', 'MESH:D010051', (246, 298))	('SMARCB1', 'Gene', '6598', (14, 21))	('gastrointestinal tract carcinoma', 'Phenotype', 'HP:0002672', (419, 451))	('carcinoma', 'Phenotype', 'HP:0030731', (405, 414))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (334, 358))	('malignant rhabdoid tumor', 'Disease', (334, 358))	('rhabdoid', 'Disease', (374, 382))	('sarcoma', 'Phenotype', 'HP:0100242', (326, 333))	('teratoid tumor', 'Disease', 'MESH:D013724', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('BRG1', 'Gene', '6597', (224, 228))	('teratoid tumor', 'Phenotype', 'HP:0009792', (111, 125))	('inactivation', 'Var', (51, 63))	('SMARCA4', 'Gene', (300, 307))	('rhabdoid', 'Disease', (102, 110))	('BRG1', 'Gene', (224, 228))	('rhabdoid', 'Disease', 'MESH:D018335', (374, 382))	('SMARCA4', 'Gene', '6597', (193, 200))	('rhabdoid', 'Disease', 'MESH:D018335', (344, 352))	('rhabdoid', 'Disease', 'MESH:D018335', (102, 110))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (318, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (442, 451))	('rhabdoid undifferentiated lung carcinoma and gastrointestinal tract carcinoma', 'Disease', 'MESH:D012142', (374, 451))	('rhabdoid', 'Disease', (77, 85))	('sarcoma', 'Disease', (139, 146))	('SMARCA4-deficient uterine sarcoma/malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (300, 358))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (67, 91))	('rhabdoid', 'Disease', (344, 352))	('tumor of the uterus', 'Phenotype', 'HP:0010784', (353, 372))	('inactivation', 'Var', (230, 242))	('malignant rhabdoid tumor', 'Disease', (67, 91))	('deficient uterine', 'Phenotype', 'HP:0000013', (308, 325))	('rhabdoid', 'Disease', 'MESH:D018335', (77, 85))	('teratoid tumor', 'Disease', (111, 125))	('sarcoma', 'Disease', 'MESH:D012509', (326, 333))	('INI1', 'Gene', (45, 49))	('undifferentiated sinonasal carcinoma', 'Disease', (151, 187))	('SMARCA4', 'Gene', '6597', (300, 307))	('undifferentiated sinonasal carcinoma', 'Disease', 'MESH:C537344', (151, 187))	('INI1', 'Gene', '6598', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SMARCA4', 'Gene', (193, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (246, 266))	('sarcoma', 'Disease', (326, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
9671	33125840	Two SWI/SNF-deficient DDEC/UEC harbored POLE exonuclease domain mutation (both POLE V411L hotspot) - a SMARCB1-deficient DDEC (FIGO IA) and an ARID1A/1B-deficient DDEC (FIGO IVB).	('SMARCB1', 'Gene', (103, 110))	('mutation', 'Var', (64, 72))	('1B-deficient DDEC', 'Disease', 'MESH:C536016', (150, 167))	('ARID1A/1B', 'Gene', (143, 152))	('SNF-deficient DDEC/UEC', 'Disease', (8, 30))	('SWI/SNF-deficient DDEC', 'Disease', (4, 26))	('ARID1A/1B', 'Gene', '8289;57492', (143, 152))	('1B-deficient DDEC', 'Disease', (150, 167))	('SNF-deficient DDEC/UEC', 'Disease', 'MESH:D007153', (8, 30))	('SWI/SNF-deficient DDEC', 'Disease', 'MESH:D007153', (4, 26))	('SMARCB1', 'Gene', '6598', (103, 110))	('V411L', 'Mutation', 'rs1196350669', (84, 89))
9673	33125840	Three SWI/SNF-intact DDEC harbored POLE mutations (two P286R and one V411L) (all with stage I disease - pT1 and N0) and one SWI/SNF-intact UEC harbored a POLE mutation (P286R) (FIGO IVB with mesenteric tumor metastasis).	('P286R', 'Mutation', 'p.P286R', (55, 60))	('tumor metastasis', 'Disease', 'MESH:D009362', (202, 218))	('tumor metastasis', 'Disease', (202, 218))	('P286R', 'Mutation', 'p.P286R', (169, 174))	('V411L', 'Mutation', 'rs1196350669', (69, 74))	('P286R', 'Var', (55, 60))	('P286R', 'Var', (169, 174))	('V411L', 'Var', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
9676	33125840	Two the 4 SWI/SNF-intact tumors with POLE mutation were MMR-deficient, with one showing isolated PMS2 loss and the other showing isolated MSH6 loss.	('MMR-deficient', 'Disease', 'MESH:C536928', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('MSH6', 'Gene', (138, 142))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PMS2', 'Gene', (97, 101))	('MSH6', 'Gene', '2956', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutation', 'Var', (42, 50))	('loss', 'NegReg', (143, 147))	('MMR-deficient', 'Disease', (56, 69))	('loss', 'NegReg', (102, 106))	('PMS2', 'Gene', '5395', (97, 101))
9684	33125840	Nearly all of the patients (30 of 31) with stage III and IV SWI/SNF-deficient tumors died from their disease, except for one patient with stage IV ARID1A/1B-deficient tumor that also harbored a POLE V411L mutation.	('1B-deficient tumor', 'Disease', 'MESH:C536016', (154, 172))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('V411L', 'Mutation', 'rs1196350669', (199, 204))	('ARID1A/1B', 'Gene', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SNF-deficient tumors died', 'Disease', (64, 89))	('patient', 'Species', '9606', (18, 25))	('ARID1A/1B', 'Gene', '8289;57492', (147, 156))	('V411L', 'Var', (199, 204))	('patients', 'Species', '9606', (18, 26))	('1B-deficient tumor', 'Disease', (154, 172))	('patient', 'Species', '9606', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('SNF-deficient tumors died', 'Disease', 'MESH:D003643', (64, 89))
9709	33125840	The majority of DDEC/UEC harbor inactivating mutations involving core components of SWI/SNF complex with SMARCA4 and ARID1A/ARID1B being most commonly inactivated, resulting in absent expression of corresponding proteins in the undifferentiated tumor.	('SMARCA4', 'Gene', '6597', (105, 112))	('DDEC/UEC', 'Disease', (16, 24))	('ARID1B', 'Gene', (124, 130))	('ARID1A', 'Gene', '8289', (117, 123))	('absent', 'NegReg', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('ARID1A', 'Gene', (117, 123))	('inactivating mutations', 'Var', (32, 54))	('undifferentiated tumor', 'Disease', (228, 250))	('expression', 'MPA', (184, 194))	('undifferentiated tumor', 'Disease', 'MESH:D002277', (228, 250))	('proteins', 'Protein', (212, 220))	('ARID1B', 'Gene', '57492', (124, 130))	('SMARCA4', 'Gene', (105, 112))
9724	33125840	We however believe that these additional mechanism(s), if present, would only be involved in rare cases of DDEC/UEC, based on our prior studies that genetically screened 43 DDEC for mutations in all SWI/SNF complex proteins (implicated in human cancer development) which identified only genomic inactivation of SMARCA4, ARID1B, and SMARCB1 as recurrent events [2, 11].	('SMARCA4', 'Gene', '6597', (311, 318))	('ARID1B', 'Gene', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('inactivation', 'Var', (295, 307))	('cancer', 'Disease', (245, 251))	('SMARCB1', 'Gene', '6598', (332, 339))	('SMARCB1', 'Gene', (332, 339))	('ARID1B', 'Gene', '57492', (320, 326))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('SMARCA4', 'Gene', (311, 318))	('mutations', 'Var', (182, 191))	('human', 'Species', '9606', (239, 244))
9780	33402862	On the other hand, the deletion of Meis1 downregulates p21, p15, p16, and p19arf expression in cardiomyocytes and improves the cell cycle (Muralidhar and Sadek, 2016).	('p15', 'Gene', (60, 63))	('p16', 'Gene', '1029', (65, 68))	('cell cycle', 'CPA', (127, 137))	('p15', 'Gene', '1030', (60, 63))	('deletion', 'Var', (23, 31))	('p21', 'Gene', (55, 58))	('Meis1', 'Gene', (35, 40))	('downregulates', 'NegReg', (41, 54))	('p21', 'Gene', '644914', (55, 58))	('p19arf', 'Gene', (74, 80))	('p19arf', 'Gene', '1029', (74, 80))	('p16', 'Gene', (65, 68))	('improves', 'PosReg', (114, 122))	('expression', 'MPA', (81, 91))
9793	33402862	Meis1 is essential for normal hematopoiesis, as was indicated by Meis1 mutant mice having an internal hemorrhage, liver hypoplasia, and anemia (Azcoitia et al., 2005).	('Meis1', 'Gene', (65, 70))	('anemia', 'Phenotype', 'HP:0001903', (136, 142))	('liver hypoplasia', 'Disease', 'MESH:D017093', (114, 130))	('hemorrhage', 'Disease', 'MESH:D006470', (102, 112))	('liver hypoplasia', 'Disease', (114, 130))	('anemia', 'Disease', (136, 142))	('hematopoiesis', 'Disease', 'MESH:C536227', (30, 43))	('anemia', 'Disease', 'MESH:D000740', (136, 142))	('mutant', 'Var', (71, 77))	('Azcoitia', 'Disease', (144, 152))	('hemorrhage', 'Disease', (102, 112))	('hematopoiesis', 'Disease', (30, 43))	('mice', 'Species', '10090', (78, 82))	('Azcoitia', 'Disease', 'None', (144, 152))	('internal hemorrhage', 'Phenotype', 'HP:0011029', (93, 112))
9806	33402862	Under normal circumstances, 11 Hox paralogs in locus C are involved in healthy urogenital development; however, in the case of bladder cancer, these gene family variants are upregulated (Cantile et al., 2003).	('variants', 'Var', (161, 169))	('upregulated', 'PosReg', (174, 185))	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('men', 'Species', '9606', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('bladder cancer', 'Disease', (127, 141))
9807	33402862	Genetic and epigenetic modifications have an important function in carcinoma formation.	('carcinoma', 'Disease', 'MESH:D009369', (67, 76))	('Genetic', 'Var', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('epigenetic modifications', 'Var', (12, 36))	('carcinoma', 'Disease', (67, 76))
9808	33402862	DNA hypermethylation is among the most common and characterized epigenetic modification in human malignancies.	('human', 'Species', '9606', (91, 96))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('malignancies', 'Disease', (97, 109))	('hypermethylation', 'Var', (4, 20))
9815	33402862	Alternative splicing has a significant function in the posttranscriptional regulation of genes, as well as cancer development or progression.	('posttranscriptional regulation of genes', 'MPA', (55, 94))	('men', 'Species', '9606', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('progression', 'CPA', (129, 140))	('function', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Alternative splicing', 'Var', (0, 20))	('cancer', 'Disease', (107, 113))
9818	33402862	Moreover, Meis2 knockdown significantly inhibits the migration and invasion capacities of bladder cancer cells (Xie et al., 2019).	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('knockdown', 'Var', (16, 25))	('invasion capacities', 'CPA', (67, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('inhibits', 'NegReg', (40, 48))	('Meis2', 'Gene', (10, 15))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
9827	33402862	Mutations that affect HOX/PBX/MEIS interactions may also contribute to breast cancer (Dard et al., 2018).	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('interactions', 'Interaction', (35, 47))	('contribute', 'Reg', (57, 67))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
9831	33402862	Distant metastasis and associated mortality are closely related to Meis2 expression in colorectal cancer (Wan et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('expression', 'Var', (73, 83))	('Meis2', 'Gene', (67, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('mortality', 'Disease', 'MESH:D003643', (34, 43))	('colorectal cancer', 'Disease', (87, 104))	('Distant metastasis', 'CPA', (0, 18))	('mortality', 'Disease', (34, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))
9833	33402862	Moreover, high Meis2 expression may reduce the overall survival period of patients with colorectal cancer (Wan et al., 2019).	('colorectal cancer', 'Disease', (88, 105))	('reduce', 'NegReg', (36, 42))	('patients', 'Species', '9606', (74, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('expression', 'MPA', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('high', 'Var', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('overall survival period', 'CPA', (47, 70))	('Meis2', 'Protein', (15, 20))
9839	33402862	In addition, the knockdown of Hoxa9 and Hoxa4 in HT29 cells leads to a significant decrease in cell proliferation, and their overexpression causes an increase in the self-renewal ability of colorectal CSCs (Bhatlekar et al., 2018).	('cell proliferation', 'CPA', (95, 113))	('Hoxa4', 'Gene', (40, 45))	('HT29 cells', 'CellLine', 'CVCL:0320', (49, 59))	('Hoxa4', 'Gene', '3201', (40, 45))	('colorectal CSCs', 'Disease', (190, 205))	('colorectal CSCs', 'Disease', 'MESH:D015179', (190, 205))	('decrease', 'NegReg', (83, 91))	('Hoxa9', 'Gene', (30, 35))	('knockdown', 'Var', (17, 26))	('increase', 'PosReg', (150, 158))	('overexpression', 'PosReg', (125, 139))
9848	33402862	(2016) showed that the expression of Meis1 has a reverse association with lymph node involvement, metastasis, and tumor staging in ESCC (Rad et al., 2016).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('lymph node involvement', 'CPA', (74, 96))	('metastasis', 'CPA', (98, 108))	('expression', 'Var', (23, 33))	('tumor', 'Disease', (114, 119))	('Meis1', 'Gene', (37, 42))	('Rad', 'Gene', '6236', (137, 140))	('men', 'Species', '9606', (92, 95))	('Rad', 'Gene', (137, 140))	('ESCC', 'Disease', (131, 135))
9870	33402862	Nuclear receptor SET domain-containing protein-1 (NSD1) silencing by epigenetic modification leads to Sotos syndrome, as well as nonhereditary neuroblastoma and glioma development (Berdasco et al., 2009).	('Nuclear receptor SET domain-containing protein-1', 'Gene', (0, 48))	('NSD1', 'Gene', '64324', (50, 54))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('Sotos syndrome', 'Disease', 'MESH:D058495', (102, 116))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('leads', 'Reg', (93, 98))	('Nuclear receptor SET domain-containing protein-1', 'Gene', '64324', (0, 48))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('Sotos syndrome', 'Disease', (102, 116))	('neuroblastoma', 'Disease', (143, 156))	('epigenetic modification', 'Var', (69, 92))	('NSD1', 'Gene', (50, 54))	('glioma', 'Disease', (161, 167))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('silencing', 'NegReg', (56, 65))	('men', 'Species', '9606', (175, 178))
9871	33402862	Hypermethylation of Nsd1 causes the upregulation of Meis1 transcript and protein due to the absence of NSD1 binding to the Meis1 promoter in neuroblastoma cells (Berdasco et al., 2009).	('neuroblastoma', 'Disease', 'MESH:D009447', (141, 154))	('absence', 'NegReg', (92, 99))	('Meis1', 'Gene', (52, 57))	('Nsd1', 'Gene', (20, 24))	('neuroblastoma', 'Disease', (141, 154))	('protein', 'Protein', (73, 80))	('Hypermethylation', 'Var', (0, 16))	('binding', 'Interaction', (108, 115))	('NSD1', 'Gene', (103, 107))	('upregulation', 'PosReg', (36, 48))	('neuroblastoma', 'Phenotype', 'HP:0003006', (141, 154))	('transcript', 'MPA', (58, 68))	('Nsd1', 'Gene', '64324', (20, 24))	('NSD1', 'Gene', '64324', (103, 107))
9893	33402862	Intriguingly, stable transfection of the dominant-negative variant of MEIS1 has generated clones with altered cell proliferation, increased differentiated phenotype, and elevated contact inhibition and cell death.	('elevated', 'PosReg', (170, 178))	('death', 'Disease', 'MESH:D003643', (207, 212))	('death', 'Disease', (207, 212))	('differentiated phenotype', 'CPA', (140, 164))	('contact inhibition', 'CPA', (179, 197))	('MEIS1', 'Gene', (70, 75))	('cell proliferation', 'CPA', (110, 128))	('variant', 'Var', (59, 66))	('increased', 'PosReg', (130, 139))	('altered', 'Reg', (102, 109))
9911	33402862	Mutations in the MEIS-HOX signaling pathway and its downstream proteins have been found to cause MLL (Zhou et al., 2014).	('cause', 'Reg', (91, 96))	('MEIS-HOX signaling pathway', 'Pathway', (17, 43))	('Mutations', 'Var', (0, 9))	('MLL', 'Gene', (97, 100))	('MLL', 'Gene', '4297', (97, 100))
9913	33402862	In vivo studies have shown that PU.1 mutation contributes to MLL development by modulating MEIS-HOX downstream genes (Zhou et al., 2014).	('MLL', 'Gene', '4297', (61, 64))	('mutation', 'Var', (37, 45))	('MLL', 'Gene', (61, 64))	('men', 'Species', '9606', (72, 75))	('modulating', 'Reg', (80, 90))	('MEIS-HOX downstream genes', 'Gene', (91, 116))	('PU.1', 'Gene', '6688', (32, 36))	('PU.1', 'Gene', (32, 36))	('contributes', 'Reg', (46, 57))
9918	33402862	In cases with an inactivation mutation of Meis1 in fetal liver cells, myeloid transformation loses its capability for the differentiation and self-renewal of leukemia stem cells (Wong et al., 2007).	('Meis1', 'Gene', (42, 47))	('loses', 'NegReg', (93, 98))	('leukemia', 'Disease', (158, 166))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('leukemia', 'Disease', 'MESH:D007938', (158, 166))	('myeloid transformation', 'CPA', (70, 92))	('inactivation mutation', 'Var', (17, 38))
9928	33402862	Moreover, pre-B-cell ALL patients were observed to have E2A-PBX1 chimeric oncoprotein resulting from chromosomal translocation t(1;19), and translocation results in mutant oncoprotein (Carroll et al., 1984).	('t(1;19', 'Var', (127, 133))	('PBX1', 'Gene', (60, 64))	('translocation', 'Var', (140, 153))	('mutant', 'Var', (165, 171))	('E2A', 'Gene', '6929', (56, 59))	('oncoprotein', 'Protein', (74, 85))	('E2A', 'Gene', (56, 59))	('results in', 'Reg', (154, 164))	('pre-B', 'Gene', (10, 15))	('patients', 'Species', '9606', (25, 33))	('oncoprotein', 'Protein', (172, 183))	('PBX1', 'Gene', '5087', (60, 64))	('chimeric', 'Var', (65, 73))	('pre-B', 'Gene', '10113', (10, 15))
9930	33402862	MEIS1 and MEIS2 interact with HOX and PBX variants in leukemia (Garcia-Cuellar et al., 2015).	('PBX', 'Gene', (38, 41))	('Garcia-Cuellar', 'Disease', (64, 78))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('variants', 'Var', (42, 50))	('Garcia-Cuellar', 'Disease', 'MESH:C536767', (64, 78))	('leukemia', 'Disease', (54, 62))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))
9931	33402862	The presence of PBX3 and MEIS1 increases HOXA9-induced leukemia (Garcia-Cuellar et al., 2015).	('PBX3', 'Gene', '5090', (16, 20))	('Garcia-Cuellar', 'Disease', 'MESH:C536767', (65, 79))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('increases', 'PosReg', (31, 40))	('leukemia', 'Disease', 'MESH:D007938', (55, 63))	('HOXA9', 'Gene', '3205', (41, 46))	('Garcia-Cuellar', 'Disease', (65, 79))	('leukemia', 'Disease', (55, 63))	('MEIS1', 'Gene', (25, 30))	('HOXA9', 'Gene', (41, 46))	('presence', 'Var', (4, 12))	('PBX3', 'Gene', (16, 20))
9937	33402862	The deletion of Meis2 differentially modulates TAL1, and thereby impairs endothelial specification and endothelial to hematopoietic transition (Wang et al., 2018b).	('Meis2', 'Gene', (16, 21))	('TAL1', 'Gene', '6886', (47, 51))	('impairs', 'NegReg', (65, 72))	('endothelial specification', 'CPA', (73, 98))	('TAL1', 'Gene', (47, 51))	('deletion', 'Var', (4, 12))	('modulates', 'Reg', (37, 46))	('endothelial to hematopoietic transition', 'CPA', (103, 142))
9938	33402862	Aberrant expression of Tlx1/Hox11 also results in T-cell leukemogenesis via Meis1 and Meis2 (Milech et al., 2010).	('Aberrant expression', 'Var', (0, 19))	('Hox11', 'Gene', (28, 33))	('results in', 'Reg', (39, 49))	('T-cell leukemogenesis', 'Phenotype', 'HP:0005517', (50, 71))	('T-cell leukemogenesis', 'Disease', (50, 71))	('Hox11', 'Gene', '15404', (28, 33))
9939	33402862	It has been found that Meis1/Hoxa9 deregulation has an important function in the progression of leukemia (Collins and Hess, 2016).	('deregulation', 'Var', (35, 47))	('leukemia', 'Disease', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('leukemia', 'Disease', 'MESH:D007938', (96, 104))	('Meis1/Hoxa9', 'Gene', (23, 34))
9940	33402862	Meis1 mutations lead blood cells to develop the symptoms of leukemia, as well as gain the chemoresistance and proliferation of leukemia cells by triggering other MEIS-cofactors (summarized in Table 1).	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('leukemia', 'Disease', (127, 135))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('leukemia', 'Disease', 'MESH:D007938', (60, 68))	('proliferation', 'CPA', (110, 123))	('mutations', 'Var', (6, 15))	('develop', 'PosReg', (36, 43))	('chemoresistance', 'CPA', (90, 105))	('Meis1', 'Gene', (0, 5))	('leukemia', 'Disease', (60, 68))	('gain', 'PosReg', (81, 85))
9941	33402862	The ectopic expression of Meis1 has been shown to inhibit cell proliferation in nonsmall-cell lung cancer (NSCLC) (Li et al., 2014).	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (80, 105))	('NSCLC', 'Disease', (107, 112))	('inhibit', 'NegReg', (50, 57))	('cell proliferation', 'CPA', (58, 76))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('nonsmall-cell lung cancer', 'Disease', (80, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('Meis1', 'Gene', (26, 31))	('ectopic expression', 'Var', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
9949	33402862	Furthermore, the differentiation of methylated CpG of Hoxa7 and Hoxa9 genes when compared to healthy controls is a point that needs to be examined on a molecular level (Rauch et al., 2007).	('methylated', 'Var', (36, 46))	('Hoxa7', 'Gene', '3204', (54, 59))	('Hoxa7', 'Gene', (54, 59))	('Hoxa9 genes', 'Gene', (64, 75))
9954	33402862	Blocking of HIF-1alpha complexes has been shown to cause increased metastasis and angiogenesis and an increase in cancer cell proliferation (Lin et al., 2017; Yang et al., 2017).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Blocking', 'Var', (0, 8))	('metastasis', 'CPA', (67, 77))	('angiogenesis', 'CPA', (82, 94))	('HIF-1alpha', 'Gene', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('increase', 'PosReg', (102, 110))	('increased', 'PosReg', (57, 66))	('HIF-1alpha', 'Gene', '3091', (12, 22))	('cancer', 'Disease', (114, 120))
9956	33402862	Surprisingly, however, cells that have a high expression of HIF-2alpha are more aggressive against radiotherapy and FDG uptake (Sun et al., 2015; Higashi et al., 2016).	('more', 'PosReg', (75, 79))	('high expression', 'Var', (41, 56))	('HIF-2alpha', 'Gene', (60, 70))	('HIF-2alpha', 'Gene', '2034', (60, 70))	('FDG', 'Chemical', 'MESH:D019788', (116, 119))
9967	33402862	Moreover, it has been shown that miRNA-196a modulates the expression of target genes (cadherin-11, calponin-1, and osteopontin) by regulating Hoxc8 in melanocyte and melanoma cells (Mueller and Bosserhoff, 2011).	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('modulates', 'Reg', (44, 53))	('melanoma', 'Disease', (166, 174))	('calponin-1', 'Gene', '1264', (99, 109))	('Hoxc8', 'Gene', (142, 147))	('miRNA-196a', 'Var', (33, 43))	('expression', 'MPA', (58, 68))	('cadherin-11', 'Gene', '1009', (86, 97))	('osteopontin', 'Gene', '6696', (115, 126))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('Hoxc8', 'Gene', '3224', (142, 147))	('osteopontin', 'Gene', (115, 126))	('cadherin-11', 'Gene', (86, 97))	('regulating', 'Reg', (131, 141))	('calponin-1', 'Gene', (99, 109))
9969	33402862	Furthermore, the knockdown of Pbx1 by short interfering RNAs (siRNA) leads to the suppression of cell growth (Shiraishi et al., 2007).	('Pbx1', 'Gene', (30, 34))	('cell growth', 'CPA', (97, 108))	('knockdown', 'Var', (17, 26))	('Pbx1', 'Gene', '5087', (30, 34))	('suppression', 'NegReg', (82, 93))
9974	33402862	Moreover, a detailed DNA methylation analysis of all stages of human melanoma revealed that Hoxa9 DNA hypermethylation had a function in tumor development when compared to benign samples (Wouters et al., 2017).	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('tumor', 'Disease', (137, 142))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('Hoxa9', 'Var', (92, 97))	('men', 'Species', '9606', (150, 153))	('hypermethylation', 'Var', (102, 118))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('melanoma', 'Disease', (69, 77))
9978	33402862	Following the disruption of HOX-PBX interaction with double active peptide, c-Fos expression increases and apoptosis takes place (Platais et al., 2018).	('expression', 'MPA', (82, 92))	('c-Fos', 'Gene', '2353', (76, 81))	('increases', 'PosReg', (93, 102))	('interaction', 'Interaction', (36, 47))	('disruption', 'Var', (14, 24))	('apoptosis', 'CPA', (107, 116))	('c-Fos', 'Gene', (76, 81))
9980	33402862	The misregulated expression of Hoxc6 and Hoxa10 cluster proteins are involved in the proliferation, survival and migration of oral cell carcinoma.	('oral cell carcinoma', 'Disease', (126, 145))	('Hoxc6', 'Gene', '3223', (31, 36))	('Hoxa10', 'Gene', (41, 47))	('misregulated', 'Var', (4, 16))	('expression', 'MPA', (17, 27))	('involved', 'Reg', (69, 77))	('Hoxa10', 'Gene', '3206', (41, 47))	('survival', 'CPA', (100, 108))	('Hoxc6', 'Gene', (31, 36))	('migration', 'CPA', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('oral cell carcinoma', 'Disease', 'MESH:C538614', (126, 145))
9981	33402862	Disruption of Hoxc6 and Hoxa10 gene expression could enhance tumor progression (Carrera et al., 2015; Tang et al., 2019).	('Hoxa10', 'Gene', (24, 30))	('Hoxa10', 'Gene', '3206', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Hoxc6', 'Gene', (14, 19))	('enhance', 'PosReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Hoxc6', 'Gene', '3223', (14, 19))	('tumor', 'Disease', (61, 66))	('Disruption', 'Var', (0, 10))
9985	33402862	The hypermethylation of Meis1 has been identified in adenoid cystic carcinoma samples using the methylated CpG island amplification and microarray methods, but further validation studies are needed (Bell et al., 2011).	('adenoid cystic carcinoma', 'Disease', (53, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (53, 77))	('Meis1', 'Gene', (24, 29))	('hypermethylation', 'Var', (4, 20))
9986	33402862	Hoxa9 hypermethylation was also reported in the promoter methylation analysis of OSCC patient tissues (Guerrero-Preston et al., 2011) and salivary rinses (Schussel et al., 2013), which leads to the growth advantage of the tumor, and an increase in metastasis (Uchida et al., 2014).	('hypermethylation', 'Var', (6, 22))	('metastasis', 'CPA', (248, 258))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('growth advantage', 'CPA', (198, 214))	('OS', 'Phenotype', 'HP:0002669', (81, 83))	('patient', 'Species', '9606', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('increase', 'PosReg', (236, 244))
9987	33402862	Moreover, miR-139-5p inhibits cell proliferation, invasion, and migration by directly targeting Hoxa9 expression (Wang et al., 2017b).	('invasion', 'CPA', (50, 58))	('inhibits', 'NegReg', (21, 29))	('cell proliferation', 'CPA', (30, 48))	('expression', 'MPA', (102, 112))	('Hoxa9', 'Protein', (96, 101))	('targeting', 'Reg', (86, 95))	('migration', 'CPA', (64, 73))	('miR-139-5p', 'Var', (10, 20))	('miR-139-5p', 'Chemical', '-', (10, 20))
9989	33402862	Pbx2 and hypermethylation of Meis1 and HoxA9, however, may be considered prognostic markers of oral cancer.	('Pbx2', 'Gene', '5089', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('HoxA9', 'Gene', (39, 44))	('Meis1', 'Gene', (29, 34))	('hypermethylation', 'Var', (9, 25))	('HoxA9', 'Gene', '3205', (39, 44))	('Pbx2', 'Gene', (0, 4))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
9999	33402862	Similarly, lncRNA HOTAIR transcribed from the Hoxc locus of DNA in uterine cancers leads to cellular proliferation, metastasis, and radiotherapy resistance via the MAPK signaling pathway (Li et al., 2018).	('HOTAIR', 'Gene', (18, 24))	('Hoxc', 'Gene', (46, 50))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cellular proliferation', 'CPA', (92, 114))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('radiotherapy resistance', 'CPA', (132, 155))	('HOTAIR', 'Gene', '100124700', (18, 24))	('cancers', 'Disease', (75, 82))	('leads to', 'Reg', (83, 91))	('Hoxc', 'Gene', '3220', (46, 50))	('uterine cancer', 'Phenotype', 'HP:0010784', (67, 81))	('uterine cancers', 'Phenotype', 'HP:0010784', (67, 82))	('metastasis', 'CPA', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DNA', 'Gene', (60, 63))	('lncRNA', 'Var', (11, 17))
10011	33402862	In a case with retroperitoneal leiomyoma, it was reported that tumor cells had a t(9;22)(q33;q12) translocation, which resulted in a fusion of Ewsr1 and Pbx3 genes (Panagopoulos et al., 2015).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Pbx3', 'Gene', '5090', (153, 157))	('fusion', 'Var', (133, 139))	('Ewsr1', 'Gene', (143, 148))	('resulted in', 'Reg', (119, 130))	('t(9;22)(q33;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (81, 97))	('retroperitoneal leiomyoma', 'Disease', (15, 40))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Pbx3', 'Gene', (153, 157))	('Ewsr1', 'Gene', '2130', (143, 148))	('retroperitoneal leiomyoma', 'Disease', 'MESH:D007889', (15, 40))
10016	33402862	The aberrantly expressed Hoxa9 in patients with epithelial ovarian cancer has no significant predictive value during first-line platinum-taxane chemotherapy (Pontikakis et al., 2017).	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (48, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (59, 73))	('platinum-taxane', 'Chemical', '-', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (34, 42))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (48, 73))	('aberrantly expressed', 'Var', (4, 24))	('Hoxa9', 'Gene', (25, 30))	('epithelial ovarian cancer', 'Disease', (48, 73))
10018	33402862	Although, the methylation analyses of Hoxa9 with large cohorts has shown that Hoxa9 is hypermethylated in both high-grade serous ovarian cancer (Montavon et al., 2012) and primary ovarian cancer patients, (Wu et al., 2007) the association of hypermethylation with the stage, histological types, grade, and ascites could not be established (Xing et al., 2015).	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (122, 143))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('primary ovarian cancer', 'Disease', 'MESH:D016649', (172, 194))	('primary ovarian cancer', 'Disease', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ascites', 'Phenotype', 'HP:0001541', (306, 313))	('ovarian cancer', 'Phenotype', 'HP:0100615', (180, 194))	('Hoxa9', 'Gene', (78, 83))	('patients', 'Species', '9606', (195, 203))	('ascites', 'Disease', (306, 313))	('serous ovarian cancer', 'Disease', (122, 143))	('hypermethylated', 'Var', (87, 102))	('ascites', 'Disease', 'MESH:D001201', (306, 313))
10019	33402862	Interestingly, a study on ovarian cancer cell line and normal tissue showed that DNA methylation of some of the analyzed genes, including Hoxa9, Hoxa10, MiR-34b, Prom1, Cables1, Sparc, and Rsk4, had an inverse correlation with their expression level (Niskakoski et al., 2014).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Sparc', 'Gene', (178, 183))	('Cables1', 'Gene', '91768', (169, 176))	('Rsk4', 'Gene', (189, 193))	('Rsk4', 'Gene', '27330', (189, 193))	('methylation', 'Var', (85, 96))	('Prom1', 'Gene', (162, 167))	('ovarian cancer', 'Disease', 'MESH:D010051', (26, 40))	('MiR-34b', 'Gene', (153, 160))	('MiR-34b', 'Gene', '407041', (153, 160))	('Hoxa10', 'Gene', (145, 151))	('ovarian cancer', 'Disease', (26, 40))	('Hoxa10', 'Gene', '3206', (145, 151))	('Sparc', 'Gene', '6678', (178, 183))	('ovarian cancer', 'Phenotype', 'HP:0100615', (26, 40))	('expression level', 'MPA', (233, 249))	('Prom1', 'Gene', '8842', (162, 167))	('Cables1', 'Gene', (169, 176))	('Hoxa9', 'Gene', (138, 143))
10033	33402862	T3M4, a cellosaurus cell line, is known to have stimulated cell proliferation through the formation of HOXB2-A10-PBX HD heterodimers and associated pancreatic carcinogenesis (Aulisa et al., 2009).	('T3M4', 'Var', (0, 4))	('pancreatic carcinogenesis', 'Disease', (148, 173))	('cell proliferation', 'CPA', (59, 77))	('HOXB2', 'Gene', '3212', (103, 108))	('HOXB2', 'Gene', (103, 108))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (148, 173))	('stimulated', 'PosReg', (48, 58))	('HD', 'Disease', 'MESH:D006816', (117, 119))
10036	33402862	Studies have shown that the expression of mitochondrial genes could be downregulated when Meis1 specific siRNA was transfected into PaC cells (Tomoeda et al., 2011).	('downregulated', 'NegReg', (71, 84))	('PaC', 'Phenotype', 'HP:0006699', (132, 135))	('PaC', 'CellLine', 'CVCL:E280', (132, 135))	('expression', 'MPA', (28, 38))	('PaC', 'Phenotype', 'HP:0002894', (132, 135))	('transfected', 'Var', (115, 126))	('mitochondrial genes', 'Gene', (42, 61))
10037	33402862	In addition, MEIS proteins could contribute to the Warburg effect to facilitate the abnormal growth of cells in the hypoxic tumor microenvironment via transactivation of HIFs and cooperation with HOX proteins.	('men', 'Species', '9606', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('facilitate', 'PosReg', (69, 79))	('transactivation', 'Var', (151, 166))	('hypoxic tumor', 'Disease', (116, 129))	('abnormal growth', 'Phenotype', 'HP:0001507', (84, 99))	('HIFs', 'Disease', (170, 174))	('hypoxic tumor', 'Disease', 'MESH:D009369', (116, 129))	('HIFs', 'Disease', 'None', (170, 174))
10047	33402862	Binding of the HOTTIP to WDR5 induces Hoxa9 expression, which is also a significant factor for PCSCs maintenance (Cheng et al., 2015; Fu et al., 2017).	('PC', 'Phenotype', 'HP:0012125', (95, 97))	('Hoxa9', 'Protein', (38, 43))	('WDR5', 'Gene', '11091', (25, 29))	('HOTTIP', 'Gene', '100316868', (15, 21))	('Binding', 'Var', (0, 7))	('WDR5', 'Gene', (25, 29))	('HOTTIP', 'Gene', (15, 21))	('induces', 'Reg', (30, 37))
10052	33402862	Mutations in Hoxb13 generate a critical risk of developing prostate cancer (PC) (Johng et al., 2019).	('risk', 'Reg', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('Hoxb13', 'Gene', (13, 19))	('Hoxb13', 'Gene', '10481', (13, 19))	('PC', 'Phenotype', 'HP:0012125', (76, 78))	('Mutations', 'Var', (0, 9))	('prostate cancer', 'Disease', (59, 74))
10055	33402862	Depletion of Meis1 and Meis2 in vivo may cause tumor growth and an increase in the expression of protumorigenic genes c-Myc and CD142 (Bhanvadia et al., 2018).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Meis2', 'Gene', (23, 28))	('tumor', 'Disease', (100, 105))	('CD142', 'Gene', '2152', (128, 133))	('c-Myc', 'Gene', '4609', (118, 123))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('increase', 'PosReg', (67, 75))	('cause', 'Reg', (41, 46))	('c-Myc', 'Gene', (118, 123))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CD142', 'Gene', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (47, 52))	('Meis1', 'Gene', (13, 18))
10084	33402862	In addition, the expression of Meis1/2 is associated with antimetastasis in PC (Bhanvadia et al., 2018).	('associated', 'Reg', (42, 52))	('PC', 'Phenotype', 'HP:0012125', (76, 78))	('Meis1/2', 'Gene', (31, 38))	('antimetastasis', 'Disease', (58, 72))	('expression', 'Var', (17, 27))	('Meis1/2', 'Gene', '150365', (31, 38))
10089	33402862	Sarcoma is genetically complicated as well, such that an increase in mutational burden, complex karyotype, translocation, and amplification could be the genetic basis of the disease (Dancsok et al., 2017).	('amplification', 'MPA', (126, 139))	('translocation', 'Var', (107, 120))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('mutational burden', 'MPA', (69, 86))	('increase', 'PosReg', (57, 65))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
10092	33402862	In addition, in vivo silencing of Meis1 remarkably suppresses xenograft tumor growth (Lin et al., 2019).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Meis1', 'Gene', (34, 39))	('tumor', 'Disease', (72, 77))	('suppresses', 'NegReg', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('silencing', 'Var', (21, 30))
10097	33402862	The vascular invasion, cellular necrosis, and perinephric fat invasion seen in both cases indicated that the Meis1-Ncoa2 fusion gene could be malignant (Argani et al., 2018).	('Ncoa2', 'Gene', (115, 120))	('fusion', 'Var', (121, 127))	('necrosis', 'Disease', (32, 40))	('necrosis', 'Disease', 'MESH:D009336', (32, 40))	('vascular invasion', 'CPA', (4, 21))	('Ncoa2', 'Gene', '10499', (115, 120))
10103	33402862	On the other hand, Hoxa9 expression is upregulated in OS tissues, and the silencing of Hoxa9 recovers the miR-873 downregulation effects.	('miR-873', 'Gene', (106, 113))	('Hoxa9', 'Gene', (19, 24))	('expression', 'MPA', (25, 35))	('upregulated', 'PosReg', (39, 50))	('OS', 'Phenotype', 'HP:0002669', (54, 56))	('recovers', 'NegReg', (93, 101))	('silencing', 'Var', (74, 83))	('miR-873', 'Gene', '100126316', (106, 113))	('downregulation', 'NegReg', (114, 128))	('Hoxa9', 'Gene', (87, 92))
10106	33402862	The silencing of Meis1 in the xenograft model was found to suppress tumor size in sarcoma (Lin et al., 2019).	('tumor', 'Disease', (68, 73))	('Meis1', 'Gene', (17, 22))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sarcoma', 'Disease', (82, 89))	('suppress', 'NegReg', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('silencing', 'Var', (4, 13))
10163	33402862	MEIS1 could trigger cell proliferation in colorectal cancer, while MEIS2 determines the relationship between colorectal cancer growth and death (Wan et al., 2019).	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('cell proliferation', 'CPA', (20, 38))	('MEIS1', 'Var', (0, 5))	('colorectal cancer', 'Disease', (42, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('death', 'Disease', 'MESH:D003643', (138, 143))	('death', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('trigger', 'Reg', (12, 19))
10164	33402862	MEIS2 could increase colorectal dependent cell death (Wang et al., 2019b).	('colorectal dependent cell death', 'Disease', (21, 52))	('MEIS2', 'Var', (0, 5))	('colorectal dependent cell death', 'Disease', 'MESH:D015179', (21, 52))	('increase', 'PosReg', (12, 20))
10170	33402862	The expression of noncoding RNAs has often been found to impair cancer (Di Leva et al., 2014; Hayes et al., 2014; Sanchez Calle et al., 2018).	('noncoding RNAs', 'Protein', (18, 32))	('RNAs', 'Protein', (28, 32))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('expression', 'Var', (4, 14))	('impair', 'NegReg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
10185	33402862	lncRNA CASC11, TUG1, PCAT6, LOC730100, and LINK-A have important functions in the proliferation and metastasis of the bladder cancer, laryngocarcinoma, cervical, glioblastoma, and ovarian carcinoma (Li et al., 2019c; Luo et al., 2019; Lv et al., 2019; Zhang et al., 2019; Zhuang et al., 2019).	('laryngocarcinoma', 'Disease', (134, 150))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (180, 197))	('CASC11', 'Gene', (7, 13))	('LOC730100', 'Var', (28, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('metastasis of the bladder cancer', 'Disease', (100, 132))	('TUG1', 'Gene', '55000', (15, 19))	('CASC11', 'Gene', '100270680', (7, 13))	('cervical', 'Disease', (152, 160))	('glioblastoma', 'Disease', (162, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('laryngocarcinoma', 'Disease', 'None', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('proliferation', 'CPA', (82, 95))	('metastasis of the bladder cancer', 'Disease', 'MESH:D001749', (100, 132))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (180, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('PCAT6', 'Gene', (21, 26))	('ovarian carcinoma', 'Disease', (180, 197))	('PC', 'Phenotype', 'HP:0012125', (21, 23))	('PCAT6', 'Gene', '100506696', (21, 26))	('TUG1', 'Gene', (15, 19))
10202	33402862	Two small peptides, HXR9 and CXR9, were shown to induce apoptosis in NSCLC cells, breast, ovarian, prostate, and meningioma cells by disrupting the interaction of HOX and PBX (Plowright et al., 2009; Morgan et al., 2010; Morgan et al., 2012; Ando et al., 2014).	('HXR9', 'Var', (20, 24))	('ovarian', 'Disease', 'MESH:D010049', (90, 97))	('meningioma', 'Disease', (113, 123))	('NSCLC', 'Disease', (69, 74))	('disrupting', 'NegReg', (133, 143))	('HOX', 'Protein', (163, 166))	('ovarian', 'Disease', (90, 97))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('interaction', 'Interaction', (148, 159))	('meningioma', 'Phenotype', 'HP:0002858', (113, 123))	('induce', 'PosReg', (49, 55))	('PBX', 'Gene', (171, 174))	('meningioma', 'Disease', 'MESH:D008577', (113, 123))	('apoptosis', 'CPA', (56, 65))	('CXR9', 'Var', (29, 33))
10204	33402862	PHOX2B expression was reported as reduced in neuroblastoma cells as a result of small molecule combination, which included curcumin, SAHA, and trichostatin (Di Zanni et al., 2015).	('reduced', 'NegReg', (34, 41))	('neuroblastoma', 'Phenotype', 'HP:0003006', (45, 58))	('PHOX2B', 'Gene', (0, 6))	('curcumin', 'Chemical', 'MESH:D003474', (123, 131))	('small', 'Var', (80, 85))	('combination', 'Interaction', (95, 106))	('expression', 'MPA', (7, 17))	('PHOX2B', 'Gene', '8929', (0, 6))	('neuroblastoma', 'Disease', 'MESH:D009447', (45, 58))	('trichostatin', 'Chemical', 'MESH:C012589', (143, 155))	('neuroblastoma', 'Disease', (45, 58))
10209	33402862	CCI-006 also impairs mitochondria in the case of CCI-007 and increases apoptosis.	('apoptosis', 'CPA', (71, 80))	('CCI-007', 'Chemical', '-', (49, 56))	('impairs', 'NegReg', (13, 20))	('mitochondria', 'MPA', (21, 33))	('CCI-006', 'Chemical', '-', (0, 7))	('increases', 'PosReg', (61, 70))	('CCI-006', 'Var', (0, 7))	('CCI-007', 'Var', (49, 56))
10228	33402862	Disruption of the MEIS-PBX interaction could also cause caspase-dependent apoptosis in a cell-dependent manner.	('cause', 'Reg', (50, 55))	('interaction', 'Interaction', (27, 38))	('caspase', 'Gene', '841', (56, 63))	('caspase', 'Gene', (56, 63))	('Disruption', 'Var', (0, 10))
10408	29248197	PIK3CA mutation upregulates NF-kappaB, leading to induction of EMT and IL-6 dependent STAT3 activation, and elevation of IL-6 transcription occurs due to the mutated PIK3CA gene.	('EMT', 'CPA', (63, 66))	('STAT3', 'Gene', (86, 91))	('PIK3CA', 'Gene', (166, 172))	('IL-6', 'Gene', '3569', (121, 125))	('IL-6', 'Gene', (71, 75))	('PIK3CA', 'Gene', '5290', (166, 172))	('upregulates', 'PosReg', (16, 27))	('NF-kappaB', 'Gene', '4790', (28, 37))	('PIK3CA', 'Gene', (0, 6))	('NF-kappaB', 'Gene', (28, 37))	('PIK3CA', 'Gene', '5290', (0, 6))	('IL-6', 'Gene', '3569', (71, 75))	('mutation', 'Var', (7, 15))	('mutated', 'Var', (158, 165))	('induction', 'PosReg', (50, 59))	('IL-6', 'Gene', (121, 125))	('elevation', 'PosReg', (108, 117))	('STAT3', 'Gene', '6774', (86, 91))
10409	29248197	Because increased IL-6 is associated with increased risk of VTE via induction of pro-coagulant factors, it may be speculated that PIK3CA mutation in uterine carcinosarcoma induces the IL-6 elevation that causes thromboembolic events.	('carcinosarcoma', 'Disease', (157, 171))	('thromboembolic', 'Disease', 'MESH:D013923', (211, 225))	('VTE', 'Disease', 'MESH:D054556', (60, 63))	('PIK3CA', 'Gene', (130, 136))	('carcinosarcoma', 'Disease', 'MESH:D002296', (157, 171))	('mutation', 'Var', (137, 145))	('thromboembolic', 'Disease', (211, 225))	('induces', 'Reg', (172, 179))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (149, 171))	('causes', 'Reg', (204, 210))	('VTE', 'Disease', (60, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('IL-6', 'Gene', '3569', (18, 22))	('IL-6', 'Gene', '3569', (184, 188))	('thromboembolic events', 'Phenotype', 'HP:0001907', (211, 232))	('IL-6', 'Gene', (18, 22))	('IL-6', 'Gene', (184, 188))	('PIK3CA', 'Gene', '5290', (130, 136))	('-6 elevation', 'Phenotype', 'HP:0030783', (186, 198))	('elevation', 'PosReg', (189, 198))	('increased', 'PosReg', (8, 17))
10441	32468052	We have expanded on our observations by including data relating to mutations and copy number alterations at pan-cancer level.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('copy number alterations', 'Var', (81, 104))
10443	32468052	Based on increasing data, older age and male sex predispose to severe COVID-19, whilst a number of underlying diseases/conditions are also directly related with significantly higher risk for adverse clinical outcomes from COVID-19.	('severe', 'Var', (63, 69))	('COVID-19', 'Disease', (70, 78))	('COVID-19', 'Disease', 'MESH:C000657245', (222, 230))	('COVID-19', 'Disease', (222, 230))	('COVID-19', 'Disease', 'MESH:C000657245', (70, 78))
10463	32468052	Furthermore, using the cBioportal pan-cancer panel, the region and the types of mutations were identified which these two genes have in all the examined cancer types (Figs.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (153, 159))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (38, 44))
10464	32468052	Most of the CTSL mutations are lying on the peptidase region and are mostly found in CESC, ESCA, Mature B-cell Neoplasms, Melanoma and COAD (Fig.	('ESCA', 'Disease', (91, 95))	('B-cell Neoplasms', 'Disease', 'MESH:D016393', (104, 120))	('Melanoma', 'Disease', 'MESH:D008545', (122, 130))	('Melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('found', 'Reg', (76, 81))	('COAD', 'Disease', 'MESH:D029424', (135, 139))	('CTSL', 'Gene', '1514', (12, 16))	('Melanoma', 'Disease', (122, 130))	('CTSL', 'Gene', (12, 16))	('B-cell Neoplasms', 'Disease', (104, 120))	('Neoplasms', 'Phenotype', 'HP:0002664', (111, 120))	('CESC', 'Disease', (85, 89))	('COAD', 'Disease', (135, 139))	('mutations', 'Var', (17, 26))
10465	32468052	Of note, in most of the cancers the majority of the patients had deletions and partly some gains and amplifications (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gains', 'PosReg', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('deletions', 'Var', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))	('patients', 'Species', '9606', (52, 60))
10466	32468052	TMPRSS2 mutations were lying across the whole gene region and mostly consist of gene fusions (TMPRSS2-ERG) in prostate adenocarcinoma (Fig.	('TMPRSS2', 'Gene', '7113', (94, 101))	('prostate adenocarcinoma', 'Disease', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (110, 133))	('TMPRSS2', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('TMPRSS2', 'Gene', (94, 101))	('consist', 'Reg', (69, 76))	('TMPRSS2', 'Gene', '7113', (0, 7))
10474	32468052	In our analysis we also demonstrate that the pancreas is riddled with deep deletions for TMPRSS2 where ACE-2 is co-expressed.	('ACE-2', 'Gene', '59272', (103, 108))	('deletions', 'Var', (75, 84))	('TMPRSS2', 'Gene', (89, 96))	('TMPRSS2', 'Gene', '7113', (89, 96))	('ACE-2', 'Gene', (103, 108))
10585	31739799	Although UTROSCT demonstrates FOXL2 protein positivity, FOXL2 and DICER1 mutations are not identified in this tumor.	('FOXL2', 'Gene', '668', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('DICER1', 'Gene', (66, 72))	('DICER1', 'Gene', '23405', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('FOXL2', 'Gene', (30, 35))	('FOXL2', 'Gene', '668', (56, 61))	('protein', 'Protein', (36, 43))	('positivity', 'Var', (44, 54))	('FOXL2', 'Gene', (56, 61))
10587	31739799	Meanwhile, UTROSCT is found to contain the t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3) translocations, as well as ESR1-NCOA2/3, GREB1-NCOA1/2 and GREB1-CTNNB1 fusions.	('GREB1', 'Gene', (129, 134))	('GREB1', 'Gene', '9687', (147, 152))	('ESR1', 'Gene', '2099', (115, 119))	('NCOA2/3', 'Gene', (120, 127))	('t(X;6)(p22.3;q23.1)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 62))	('NCOA2/3', 'Gene', '10499;8202', (120, 127))	('NCOA1/2', 'Gene', (135, 142))	('GREB1', 'Gene', '9687', (129, 134))	('CTNNB1', 'Gene', '1499', (153, 159))	('translocations', 'Var', (88, 102))	('GREB1', 'Gene', (147, 152))	('ESR1', 'Gene', (115, 119))	('t(4;18)(q21.1;q21.3)', 'STRUCTURAL_ABNORMALITY', 'None', (67, 87))	('CTNNB1', 'Gene', (153, 159))	('NCOA1/2', 'Gene', '8648;10499', (135, 142))
10589	31739799	The characteristic ESR1 or GREB1 rearrangement in UTROSCT might be more useful for pathological diagnosis.	('ESR1', 'Gene', '2099', (19, 23))	('GREB1', 'Gene', (27, 32))	('UTROSCT', 'Disease', (50, 57))	('ESR1', 'Gene', (19, 23))	('GREB1', 'Gene', '9687', (27, 32))	('rearrangement', 'Var', (33, 46))
10591	31739799	described four uterine sarcomas containing the GREB1 fusion genes.	('GREB1', 'Gene', (47, 52))	('GREB1', 'Gene', '9687', (47, 52))	('sarcomas', 'Disease', 'MESH:D012509', (23, 31))	('fusion genes', 'Var', (53, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcomas', 'Disease', (23, 31))
10599	31739799	Among these genes, PHF1 rearrangement has been found to be predominant in the sex cord variant of LGESS.	('PHF1', 'Gene', '5252', (19, 23))	('predominant', 'Reg', (59, 70))	('sex cord variant', 'Disease', (78, 94))	('rearrangement', 'Var', (24, 37))	('LGESS', 'Disease', (98, 103))	('PHF1', 'Gene', (19, 23))
10621	31739799	Molecularly, sequence analysis showed mutations in the exon 3 of beta-catenin gene in the areas of sex cord-like formations.	('mutations in', 'Var', (38, 50))	('beta-catenin', 'Gene', '1499', (65, 77))	('beta-catenin', 'Gene', (65, 77))
10637	31739799	Molecularly, KRAS, ARID1A, AKT1, CSF1R, GNAQ, NOTCH1, PTCH2, PTEN, ABL1, EPHB4, ATM, RET, CDH1, NF1, MET and ATRX mutations have been found in mesonephric adenocarcinomas.	('EPHB4', 'Gene', (73, 78))	('mesonephric adenocarcinomas', 'Disease', 'MESH:D000230', (143, 170))	('mutations', 'Var', (114, 123))	('ATRX', 'Gene', '546', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('ABL1', 'Gene', '25', (67, 71))	('ATM', 'Gene', '472', (80, 83))	('PTEN', 'Gene', (61, 65))	('ARID1A', 'Gene', (19, 25))	('AKT1', 'Gene', '207', (27, 31))	('NOTCH1', 'Gene', (46, 52))	('PTCH2', 'Gene', '8643', (54, 59))	('PTEN', 'Gene', '5728', (61, 65))	('CSF1R', 'Gene', '1436', (33, 38))	('RET', 'Gene', '5979', (85, 88))	('EPHB4', 'Gene', '2050', (73, 78))	('ARID1A', 'Gene', '8289', (19, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('PTCH2', 'Gene', (54, 59))	('ATM', 'Gene', (80, 83))	('NOTCH1', 'Gene', '4851', (46, 52))	('CSF1R', 'Gene', (33, 38))	('NF1', 'Gene', (96, 99))	('AKT1', 'Gene', (27, 31))	('found', 'Reg', (134, 139))	('CDH1', 'Gene', '999', (90, 94))	('GNAQ', 'Gene', '2776', (40, 44))	('MET', 'Gene', (101, 104))	('KRAS', 'Gene', '3845', (13, 17))	('NF1', 'Gene', '4763', (96, 99))	('GNAQ', 'Gene', (40, 44))	('RET', 'Gene', (85, 88))	('mesonephric adenocarcinomas', 'Disease', (143, 170))	('CDH1', 'Gene', (90, 94))	('KRAS', 'Gene', (13, 17))	('ABL1', 'Gene', (67, 71))	('ATRX', 'Gene', (109, 113))
10642	31739799	Genetically, KRAS and PIK3CA mutations have been detected in uterine mesonephric-like adenocarcinomas, while PTEN, TP53, ARID1A, ARID1B, or SMARCA4 alterations were not detected.	('ARID1B', 'Gene', '57492', (129, 135))	('ARID1A', 'Gene', (121, 127))	('PTEN', 'Gene', '5728', (109, 113))	('SMARCA4', 'Gene', '6597', (140, 147))	('ARID1A', 'Gene', '8289', (121, 127))	('TP53', 'Gene', (115, 119))	('detected', 'Reg', (49, 57))	('PIK3CA', 'Gene', '5290', (22, 28))	('mutations', 'Var', (29, 38))	('KRAS', 'Gene', '3845', (13, 17))	('SMARCA4', 'Gene', (140, 147))	('adenocarcinomas', 'Disease', 'MESH:D000230', (86, 101))	('TP53', 'Gene', '7157', (115, 119))	('PTEN', 'Gene', (109, 113))	('adenocarcinomas', 'Disease', (86, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('KRAS', 'Gene', (13, 17))	('ARID1B', 'Gene', (129, 135))	('PIK3CA', 'Gene', (22, 28))
10659	31739799	This research was funded by Science and Technology Development Project of Jilin Province (3D5177723429), Science and Technology of Jilin Province, Jilin Province Key Laboratory (3D517K363429), and The Role and Molecular Mechanism of EMT in the Resistance of ROS1-positive Lung Cancer (20180101014JC), Changchun, Jilin, China.	('Cancer', 'Disease', (277, 283))	('Cancer', 'Disease', 'MESH:D009369', (277, 283))	('Cancer', 'Phenotype', 'HP:0002664', (277, 283))	('ROS1', 'Gene', (258, 262))	('ROS1', 'Gene', '6098', (258, 262))	('20180101014JC', 'Var', (285, 298))	('Lung Cancer', 'Phenotype', 'HP:0100526', (272, 283))
10661	31142515	The highly recurrent PP2A Aalpha-subunit mutation P179R alters protein structure and impairs PP2A enzyme function to promote endometrial tumorigenesis Somatic mutation of the PP2A Aalpha-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma (EMCA).	('impairs', 'NegReg', (85, 92))	('PP2A Aalpha', 'Gene', '5518', (175, 186))	('PPP2R1A', 'Gene', '5518', (200, 207))	('EMCA', 'Phenotype', 'HP:0012114', (265, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('endometrial tumorigenesis', 'Disease', (125, 150))	('endometrial carcinoma', 'Disease', (242, 263))	('P179R', 'Mutation', 'rs786205228', (50, 55))	('PP2A', 'Gene', '5524', (175, 179))	('PP2A Aalpha', 'Gene', (175, 186))	('PP2A Aalpha', 'Gene', '5518', (21, 32))	('PPP2R1A', 'Gene', (200, 207))	('protein structure', 'MPA', (63, 80))	('PP2A', 'Gene', '5524', (21, 25))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (242, 263))	('PP2A Aalpha', 'Gene', (21, 32))	('PP2A', 'Gene', '5524', (93, 97))	('PP2A', 'Gene', (175, 179))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (242, 263))	('alters', 'Reg', (56, 62))	('promote', 'PosReg', (117, 124))	('P179R', 'Var', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('prevalent', 'Reg', (218, 227))	('PP2A', 'Gene', (21, 25))	('function', 'MPA', (105, 113))	('PP2A', 'Gene', (93, 97))
10662	31142515	The structural, molecular, and biological basis by which the most recurrent EMCA-specific mutation site P179 facilitates features of EMCA malignancy have yet to be fully determined.	('EMCA', 'Phenotype', 'HP:0012114', (133, 137))	('EMCA-specific', 'Gene', (76, 89))	('malignancy', 'Disease', 'MESH:D009369', (138, 148))	('EMCA', 'Disease', (133, 137))	('malignancy', 'Disease', (138, 148))	('EMCA', 'Phenotype', 'HP:0012114', (76, 80))	('mutation', 'Var', (90, 98))	('facilitates', 'PosReg', (109, 120))
10663	31142515	Here we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function.	('P179R', 'Mutation', 'rs786205228', (109, 114))	('P179R missense', 'Var', (109, 123))	('PP2A', 'Gene', (136, 140))	('PP2A', 'Gene', '5524', (136, 140))
10664	31142515	Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile.	('stable conformation profile', 'MPA', (136, 163))	('arginine', 'Chemical', 'MESH:D001120', (61, 69))	('arginine-to-proline substitution', 'Var', (61, 93))	('proline', 'Chemical', 'MESH:D011392', (73, 80))	('changes', 'Reg', (114, 121))
10665	31142515	A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation.	('PP2A', 'Gene', '5524', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('PP2A', 'Gene', (41, 45))	('mutant', 'Var', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('A-subunit conformation', 'MPA', (80, 102))	('changes', 'Reg', (69, 76))
10667	31142515	Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wildtype Aalpha in a patient-derived P179R mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutant', 'Var', (146, 152))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Aalpha', 'Gene', '14960', (112, 118))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('attenuated', 'NegReg', (206, 216))	('PP2A', 'Gene', '5524', (31, 35))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patient', 'Species', '9606', (124, 131))	('P179R', 'Mutation', 'rs786205228', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('Aalpha', 'Gene', (112, 118))	('Cancer', 'Disease', (0, 6))	('restored', 'PosReg', (163, 171))	('enzyme function', 'MPA', (172, 187))	('PP2A', 'Gene', (31, 35))	('tumor', 'Disease', (61, 66))
10668	31142515	Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PP2A', 'Gene', '5524', (65, 69))	('tumor', 'Disease', (94, 99))	('PP2A', 'Gene', (65, 69))	('reactivation', 'Var', (49, 61))	('inhibited', 'NegReg', (84, 93))
10670	31142515	Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations.	('PP2A', 'Gene', '5524', (25, 29))	('P179R', 'Mutation', 'rs786205228', (103, 108))	('PP2A', 'Gene', (25, 29))	('P179R', 'Var', (103, 108))	('PPP2R1A', 'Gene', (109, 116))	('patients', 'Species', '9606', (83, 91))	('PPP2R1A', 'Gene', '5518', (109, 116))
10678	31142515	In addition to TP53, PPP2R1A mutation was also more frequent in high-grade subtypes, occurring in ~30% of USC or UCS patients, versus ~5% in patients with the endometrioid subtype (UEC).	('mutation', 'Var', (29, 37))	('PPP2R1A', 'Gene', '5518', (21, 28))	('UCS', 'Disease', (113, 116))	('USC', 'Disease', (106, 109))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('patients', 'Species', '9606', (117, 125))	('frequent', 'Reg', (52, 60))	('high-grade subtypes', 'Disease', (64, 83))	('patients', 'Species', '9606', (141, 149))	('PPP2R1A', 'Gene', (21, 28))
10682	31142515	While a number of mechanisms can underlie diminished PP2A activity in cancer, notable is the occurrence of 'hotspot' mutations to PPP2R1A, the gene encoding the PP2A Aalpha subunit.	('PP2A', 'Gene', '5524', (161, 165))	('mutations', 'Var', (117, 126))	('activity', 'MPA', (58, 66))	('PP2A Aalpha', 'Gene', (161, 172))	('PP2A', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('PP2A Aalpha', 'Gene', '5518', (161, 172))	('PP2A', 'Gene', (161, 165))	('PPP2R1A', 'Gene', (130, 137))	('PPP2R1A', 'Gene', '5518', (130, 137))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('PP2A', 'Gene', '5524', (53, 57))
10688	31142515	Cancer-derived hotspot mutations of PPP2R1A cluster at the structural interface between A- and B-subunits, and have been shown to disrupt subunit binding to varying degrees.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (23, 32))	('PPP2R1A', 'Gene', (36, 43))	('subunit', 'Protein', (138, 145))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('disrupt', 'NegReg', (130, 137))	('PPP2R1A', 'Gene', '5518', (36, 43))
10689	31142515	A recent report characterizing several hotspot mutations found that these mutant proteins have increased binding to the PP2A inhibitor TIPRL, resulting in a dominant negative phenotype.	('TIPRL', 'Gene', '261726', (135, 140))	('mutations', 'Var', (47, 56))	('PP2A', 'Gene', (120, 124))	('proteins', 'Protein', (81, 89))	('TIPRL', 'Gene', (135, 140))	('mutant', 'Var', (74, 80))	('increased', 'PosReg', (95, 104))	('PP2A', 'Gene', '5524', (120, 124))	('binding', 'Interaction', (105, 112))	('dominant', 'MPA', (157, 165))
10690	31142515	Specifically, while PPP2R1A mutations are found in cancers of multiple origins, they are striking for USC and UCS not only for their high prevalence, but also for the nearly exclusive occurrence of mutation at two hotspot sites: P179 and S256.	('PPP2R1A', 'Gene', (20, 27))	('S256', 'Var', (238, 242))	('PPP2R1A', 'Gene', '5518', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('P179', 'Var', (229, 233))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('mutations', 'Var', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
10691	31142515	Our work focuses on P179R, the most common of these recurrent, EMCA-enriched mutations, for which we have developed crystallography, modeling, and biochemical data to describe its impact on PP2A function.	('PP2A', 'Gene', (190, 194))	('P179R', 'Mutation', 'rs786205228', (20, 25))	('P179R', 'Var', (20, 25))	('EMCA-enriched', 'Gene', (63, 76))	('EMCA', 'Phenotype', 'HP:0012114', (63, 67))	('PP2A', 'Gene', '5524', (190, 194))
10692	31142515	The P179R missense mutation induces global changes in A-subunit protein structure and its preferred conformational dynamics, which results in loss of interaction with the catalytic subunit and diminished holoenzyme stability.	('P179R', 'Mutation', 'rs786205228', (4, 9))	('diminished', 'NegReg', (193, 203))	('loss', 'NegReg', (142, 146))	('P179R missense', 'Var', (4, 18))	('preferred conformational dynamics', 'MPA', (90, 123))	('A-subunit protein structure', 'MPA', (54, 81))	('changes', 'Reg', (43, 50))	('interaction', 'Interaction', (150, 161))	('holoenzyme stability', 'MPA', (204, 224))
10693	31142515	When wildtype protein is restored in the P179R mutant context, tumorigenesis is significantly inhibited.	('tumor', 'Disease', (63, 68))	('P179R', 'Mutation', 'rs786205228', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('P179R mutant', 'Var', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('inhibited', 'NegReg', (94, 103))
10695	31142515	Altogether these works demonstrate that PP2A is a key tumor suppressor in EMCA and is functionally disrupted by recurrent P179R PPP2R1A mutation to drive tumorigenesis.	('EMCA', 'Phenotype', 'HP:0012114', (74, 78))	('PP2A', 'Gene', (40, 44))	('P179R', 'Mutation', 'rs786205228', (122, 127))	('P179R', 'Var', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('drive', 'PosReg', (148, 153))	('PPP2R1A', 'Gene', (128, 135))	('PP2A', 'Gene', '5524', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PPP2R1A', 'Gene', '5518', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (154, 159))
10707	31142515	Phosphatase activity rate was then calculated for V5-WT and V5-P179R as fluorescent units per minute incubation time.	('V5-P179R', 'Var', (60, 68))	('Phosphatase activity', 'MPA', (0, 20))	('P179R', 'Mutation', 'rs786205228', (63, 68))
10708	31142515	Approximately 0.6 muM of purified GST-B56alpha, 6 muM of His8-Calpha, and 6 muM of Aalpha wildtype (WT) or mutant protein were incubated with 50 muL of GSH Sepharose 4B resin (GE Healthcare) for 1 hr at 4 C in binding buffer (20 mM Tris pH8.0, 150 mM NaCl, 5% Glycerol, 0.05% Tween 20, 2mM DTT; total volume of 250 muL).	('B56alpha', 'Gene', '5525', (38, 46))	('mutant', 'Var', (107, 113))	('Aalpha', 'Gene', '14960', (83, 89))	('B56alpha', 'Gene', (38, 46))	('DTT', 'Chemical', 'MESH:D004229', (290, 293))	('NaCl', 'Chemical', 'MESH:D012965', (251, 255))	('Glycerol', 'Chemical', 'MESH:D005990', (260, 268))	('GSH Sepharose 4B', 'Chemical', '-', (152, 168))	('His8', 'Chemical', '-', (57, 61))	('Tween 20', 'Chemical', 'MESH:D011136', (276, 284))	('Aalpha', 'Gene', (83, 89))	('Tris', 'Chemical', '-', (232, 236))
10715	31142515	24 hrs after plating, wells received media containing DMSO or SMAP-061, with triplicate wells per treatment condition.	('DMSO', 'Var', (54, 58))	('SMAP-061', 'Gene', (62, 70))	('DMSO', 'Chemical', 'MESH:D004121', (54, 58))
10751	31142515	Details regarding the application and use of previously published algorithms available upon request While three amino acid residues are notable PPP2R1A hotspot mutation sites in cancer (Figure 1a), two of these residues, P179 and S256, display a striking specificity in occurrence that is in contrast to the third, most frequently mutated site, R183 (Figure 1b).	('PPP2R1A', 'Gene', '5518', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('PPP2R1A', 'Gene', (144, 151))	('S256', 'Var', (230, 234))	('P179', 'Var', (221, 225))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))
10752	31142515	Specifically, P179 and S256 mutations are highly enriched in endometrial carcinoma (EMCA), occurring nearly exclusively in uterine serous carcinoma (USC) and carcinosarcoma (UCS), and also accounting for nearly all PPP2R1A mutations in these EMCA subtypes (Figure 1b-c).	('serous carcinoma', 'Disease', 'MESH:D018297', (131, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('S256 mutations', 'Var', (23, 37))	('serous carcinoma', 'Disease', (131, 147))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (61, 82))	('P179', 'Var', (14, 18))	('carcinosarcoma', 'Disease', (158, 172))	('EMCA', 'Phenotype', 'HP:0012114', (242, 246))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 82))	('PPP2R1A', 'Gene', (215, 222))	('PPP2R1A', 'Gene', '5518', (215, 222))	('carcinosarcoma', 'Disease', 'MESH:D002296', (158, 172))	('endometrial carcinoma', 'Disease', (61, 82))	('EMCA', 'Phenotype', 'HP:0012114', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
10754	31142515	Although R183 mutations do occur in EMCA, they are much more prevalent in the less aggressive endometrioid carcinoma (UEC) subtype.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('EMCA', 'Disease', (36, 40))	('R183 mutations', 'Var', (9, 23))	('aggressive endometrioid carcinoma', 'Disease', (83, 116))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (94, 116))	('prevalent', 'Reg', (61, 70))	('aggressive endometrioid carcinoma', 'Disease', 'MESH:D016889', (83, 116))	('EMCA', 'Phenotype', 'HP:0012114', (36, 40))
10755	31142515	Critically, this differential pattern of occurrence may indicate differing mechanistic roles through which these mutations contribute to cancer.	('Critically', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('contribute', 'Reg', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (137, 143))	('Critically', 'Disease', 'MESH:D016638', (0, 10))
10756	31142515	Across cancer, only one tumor was found to harbor two PPP2R1A hotspot mutations: a mixed ductal and lobular breast carcinoma was identified with both R183W and S256F mutations.	('R183W', 'Mutation', 'rs1057519946', (150, 155))	('breast carcinoma', 'Phenotype', 'HP:0003002', (108, 124))	('S256F', 'Mutation', 'rs759936481', (160, 165))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumor', 'Disease', (24, 29))	('PPP2R1A', 'Gene', (54, 61))	('breast carcinoma', 'Disease', 'MESH:D001943', (108, 124))	('breast carcinoma', 'Disease', (108, 124))	('PPP2R1A', 'Gene', '5518', (54, 61))	('S256F', 'Var', (160, 165))	('cancer', 'Disease', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('R183W', 'Var', (150, 155))
10758	31142515	The P179 and S256 mutation sites reside in HEAT domains 5 and 7, respectively, of the PP2A Aalpha subunit.	('PP2A Aalpha', 'Gene', '5518', (86, 97))	('P179', 'Var', (4, 8))	('PP2A Aalpha', 'Gene', (86, 97))	('S256 mutation', 'Var', (13, 26))
10760	31142515	The S256 is mutated to phenylalanine (S256F, 15 cases) or tyrosine (S256Y, 6 cases).	('S256F', 'Var', (38, 43))	('S256Y', 'Mutation', 'rs759936481', (68, 73))	('tyrosine', 'Chemical', 'MESH:D014443', (58, 66))	('S256Y', 'Var', (68, 73))	('S256F', 'Mutation', 'rs759936481', (38, 43))	('S256', 'Var', (4, 8))	('phenylalanine', 'Chemical', 'MESH:D010649', (23, 36))	('tyrosine', 'MPA', (58, 66))	('phenylalanine', 'MPA', (23, 36))
10763	31142515	First, P179 mutant tumors are frequently high-stage, with greater than 50% of patients diagnosed with stage III or IV disease (Supplementary Figure 1b).	('P179 mutant', 'Var', (7, 18))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('IV disease', 'Disease', (115, 125))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('stage III', 'Disease', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
10767	31142515	At the genome-level, P179 tumors present with other defining features of USC and UCS, such as a low overall mutational burden, high copy number alteration, TP53 mutant, and MYC, CCNE1, or ERBB2 amplification (Supplementary Figure 1d-f).	('mutant', 'Var', (161, 167))	('high copy number alteration', 'Var', (127, 154))	('P179', 'Var', (21, 25))	('amplification', 'Var', (194, 207))	('tumors', 'Disease', (26, 32))	('ERBB2', 'Gene', '2064', (188, 193))	('CCNE1', 'Gene', (178, 183))	('CCNE1', 'Gene', '898', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('MYC', 'Gene', (173, 176))	('ERBB2', 'Gene', (188, 193))	('TP53', 'Gene', (156, 160))	('TP53', 'Gene', '7157', (156, 160))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('MYC', 'Gene', '4609', (173, 176))	('USC', 'Disease', (73, 76))
10768	31142515	Hallmarks that distinguish UEC, including microsatellite instability (MSI) or PTEN, ARID1A, or CTNNB1 mutation, are rare in P179 tumors.	('microsatellite instability', 'MPA', (42, 68))	('CTNNB1', 'Gene', (95, 101))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('UEC', 'Disease', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('mutation', 'Var', (102, 110))	('PTEN', 'Gene', (78, 82))	('PTEN', 'Gene', '5728', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CTNNB1', 'Gene', '1499', (95, 101))	('ARID1A', 'Gene', '8289', (84, 90))	('ARID1A', 'Gene', (84, 90))
10769	31142515	We sought to identify patient tumor specimens harboring recurrent PPP2R1A mutations in the Case Comprehensive Cancer Center (Case CCC) Gynecologic Tumor Biobank.	('PPP2R1A', 'Gene', (66, 73))	('Cancer', 'Disease', 'MESH:D009369', (110, 116))	('PPP2R1A', 'Gene', '5518', (66, 73))	('Tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Disease', (110, 116))	('tumor', 'Disease', (30, 35))	('patient', 'Species', '9606', (22, 29))
10771	31142515	16% (15 tumors) were found to harbor PPP2R1A mutations and all were at residues P179, R183, or S256 (Supplementary Figure 2a-b).	('R183', 'Var', (86, 90))	('mutations', 'Var', (45, 54))	('S256', 'Var', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('PPP2R1A', 'Gene', (37, 44))	('PPP2R1A', 'Gene', '5518', (37, 44))
10772	31142515	In addition to the previously reported P179R and P179L variants, we also identified a new variant, P179H, in a mixed serous-/endometrioid-subtype tumor (Supplementary Figure 2b-c).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('P179L', 'Mutation', 'rs786205228', (49, 54))	('mixed serous-/endometrioid-subtype', 'Disease', (111, 145))	('P179H', 'Mutation', 'rs1057519991', (99, 104))	('tumor', 'Disease', (146, 151))	('P179H', 'Var', (99, 104))	('P179R', 'Mutation', 'rs786205228', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
10773	31142515	In this cohort, 38% of USC tumors were found to harbor P179 / S256 site mutations (Supplementary Figure 2a).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('P179 / S256 site', 'Var', (55, 71))	('USC tumors', 'Disease', (23, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('USC tumors', 'Disease', 'MESH:D009369', (23, 33))
10774	31142515	Consistent with previous studies, our Sanger sequencing results demonstrated that these tumors are frequently heterozygous for mutation, with a wildtype allele remaining (Supplementary Figure 2c).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutation', 'Var', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
10775	31142515	However, for a subset of tumors there was no wildtype allele detected, which suggests that mutations can be either homozygous or co-occur with allelic deletion.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutations', 'Var', (91, 100))	('allelic deletion', 'Var', (143, 159))
10776	31142515	Studies have previously reported altered interactome and holoenzyme complex formation with cancer-associated mutant isoforms of the PP2A Aalpha-subunit.	('PP2A Aalpha', 'Gene', (132, 143))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('holoenzyme complex formation', 'MPA', (57, 85))	('altered', 'Reg', (33, 40))	('PP2A Aalpha', 'Gene', '5518', (132, 143))	('mutant', 'Var', (109, 115))	('interactome', 'MPA', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
10778	31142515	For comparison, we also evaluated S256F and R183W.	('R183W', 'Mutation', 'rs1057519946', (44, 49))	('S256F', 'Var', (34, 39))	('R183W', 'Var', (44, 49))	('S256F', 'Mutation', 'rs759936481', (34, 39))
10779	31142515	Cell lines with stable expression of V5-tagged wildtype (WT) or mutant Aalpha-subunit were generated using a lentivirus approach and tagged Aalpha protein was co-immunoprecipitated with its binding partners from whole cell lysates.	('Aalpha', 'Gene', '14960', (140, 146))	('Aalpha', 'Gene', (71, 77))	('Aalpha', 'Gene', (140, 146))	('Aalpha', 'Gene', '14960', (71, 77))	('expression', 'Species', '29278', (23, 33))	('mutant', 'Var', (64, 70))
10781	31142515	Overall, the P179R mutation induced significant disruption of PP2A holoenzyme formation, presenting with a significant reduction in binding to members of each B-subunit family except the Striatins, for which binding remained intact, as well as a significant loss of catalytic C-subunit binding (Figure 2a-c).	('holoenzyme formation', 'MPA', (67, 87))	('loss', 'NegReg', (258, 262))	('P179R', 'Mutation', 'rs786205228', (13, 18))	('PP2A', 'Gene', '5524', (62, 66))	('P179R', 'Var', (13, 18))	('binding', 'Interaction', (286, 293))	('catalytic', 'MPA', (266, 275))	('binding', 'Interaction', (132, 139))	('reduction', 'NegReg', (119, 128))	('disruption', 'NegReg', (48, 58))	('PP2A', 'Gene', (62, 66))
10782	31142515	By comparison, S256F and R183W mutants also demonstrated losses in B-subunit interactions, but in many cases these losses were less severe.	('interactions', 'Interaction', (77, 89))	('B-subunit', 'Protein', (67, 76))	('R183W', 'Var', (25, 30))	('losses', 'NegReg', (57, 63))	('R183W', 'Mutation', 'rs1057519946', (25, 30))	('S256F', 'Var', (15, 20))	('S256F', 'Mutation', 'rs759936481', (15, 20))
10783	31142515	Interestingly, P179R and S256F shared a near-complete loss of binding to the B55alpha-subunit, whereas R183W retained some binding.	('binding', 'Interaction', (123, 130))	('S256F', 'Var', (25, 30))	('binding', 'Interaction', (62, 69))	('R183W', 'Var', (103, 108))	('loss', 'NegReg', (54, 58))	('R183W', 'Mutation', 'rs1057519946', (103, 108))	('B55alpha', 'Gene', (77, 85))	('S256F', 'Mutation', 'rs759936481', (25, 30))	('P179R', 'Mutation', 'rs786205228', (15, 20))	('B55alpha', 'Gene', '5520', (77, 85))	('P179R', 'Var', (15, 20))
10784	31142515	Importantly, P179R was the most severely impaired in its interaction with the PP2A catalytic C-subunit.	('P179R', 'Mutation', 'rs786205228', (13, 18))	('PP2A', 'Gene', (78, 82))	('P179R', 'Var', (13, 18))	('catalytic', 'Protein', (83, 92))	('PP2A', 'Gene', '5524', (78, 82))	('interaction', 'Interaction', (57, 68))
10785	31142515	Finally, a published report identifies increased TIPRL binding to mutant Aalpha as a dominant-negative mechanism through which PP2A is inactivated in cancer.	('PP2A', 'Gene', '5524', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('TIPRL', 'Gene', '261726', (49, 54))	('mutant', 'Var', (66, 72))	('PP2A', 'Gene', (127, 131))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('binding', 'Interaction', (55, 62))	('TIPRL', 'Gene', (49, 54))	('increased', 'PosReg', (39, 48))	('cancer', 'Disease', (150, 156))	('Aalpha', 'Gene', '14960', (73, 79))	('Aalpha', 'Gene', (73, 79))
10786	31142515	We therefore also assessed mutant protein binding to TIPRL.	('mutant', 'Var', (27, 33))	('protein', 'Protein', (34, 41))	('TIPRL', 'Gene', '261726', (53, 58))	('binding', 'Interaction', (42, 49))	('assessed', 'Reg', (18, 26))	('TIPRL', 'Gene', (53, 58))
10787	31142515	From our results, the P179R and S256F mutants do not display increased TIPRL binding in a serous endometrial carcinoma cell line (Figure 2a).	('P179R', 'Var', (22, 27))	('TIPRL', 'Gene', '261726', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('serous endometrial carcinoma', 'Disease', 'MESH:D016889', (90, 118))	('serous endometrial carcinoma', 'Disease', (90, 118))	('S256F', 'Var', (32, 37))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (97, 118))	('S256F', 'Mutation', 'rs759936481', (32, 37))	('TIPRL', 'Gene', (71, 76))	('P179R', 'Mutation', 'rs786205228', (22, 27))
10788	31142515	Meanwhile, R183W did display this gain of binding.	('R183W', 'Var', (11, 16))	('binding', 'Interaction', (42, 49))	('gain', 'PosReg', (34, 38))	('R183W', 'Mutation', 'rs1057519946', (11, 16))
10789	31142515	GST-tagged B56alpha-subunit was incubated with purified C-subunit and purified wildtype (WT) or mutant Aalpha-subunit proteins, and then isolated and assessed for binding.	('mutant', 'Var', (96, 102))	('Aalpha', 'Gene', '14960', (103, 109))	('B56alpha', 'Gene', (11, 19))	('binding', 'Interaction', (163, 170))	('Aalpha', 'Gene', (103, 109))	('B56alpha', 'Gene', '5525', (11, 19))
10790	31142515	When in the presence of P179 mutant Aalpha isoforms, assembly of the complete Aalpha-B56alpha-C holoenzyme heterotrimer was impaired.	('assembly', 'MPA', (53, 61))	('P179 mutant', 'Var', (24, 35))	('impaired', 'NegReg', (124, 132))	('B56alpha', 'Gene', (85, 93))	('Aalpha', 'Gene', (36, 42))	('Aalpha', 'Gene', (78, 84))	('B56alpha', 'Gene', '5525', (85, 93))	('Aalpha', 'Gene', '14960', (36, 42))	('Aalpha', 'Gene', '14960', (78, 84))
10792	31142515	Altogether, these data support the previous literature describing loss of PP2A subunit interactions upon Aalpha mutation.	('loss', 'NegReg', (66, 70))	('mutation', 'Var', (112, 120))	('Aalpha', 'Gene', (105, 111))	('PP2A', 'Gene', (74, 78))	('interactions', 'Interaction', (87, 99))	('PP2A', 'Gene', '5524', (74, 78))	('Aalpha', 'Gene', '14960', (105, 111))
10794	31142515	To understand how the overall protein structure may be altered by the P179R mutation, we determined the crystal structure of the P179R mutant protein at 3.4A resolution (Figure 2d-e).	('P179R', 'Var', (129, 134))	('altered', 'Reg', (55, 62))	('P179R', 'Mutation', 'rs786205228', (70, 75))	('P179R', 'Var', (70, 75))	('P179R', 'Mutation', 'rs786205228', (129, 134))
10795	31142515	Comparison of this PP2A P179R-Aalpha structure with the WT-Aalpha crystal structure (PDB: 1B3U) revealed an obvious conformational difference between the mutant and wildtype proteins (Figure 2d-e, overlays).	('conformational difference', 'MPA', (116, 141))	('PP2A', 'Gene', (19, 23))	('mutant', 'Var', (154, 160))	('P179R', 'Mutation', 'rs786205228', (24, 29))	('Aalpha', 'Gene', '14960', (59, 65))	('Aalpha', 'Gene', (30, 36))	('WT-Aalpha crystal', 'Disease', 'MESH:D000070657', (56, 73))	('PP2A', 'Gene', '5524', (19, 23))	('Aalpha', 'Gene', (59, 65))	('Aalpha', 'Gene', '14960', (30, 36))	('WT-Aalpha crystal', 'Disease', (56, 73))
10798	31142515	Free energy landscape (FES) plots were generated as a function of phi and psi dihedral angles of the P179 and mutant R179 residues, for both apo Aalpha and Aalpha in complex with the C-subunit (Figure 3a-b, Supplementary Figure 4a-p).	('Aalpha', 'Gene', (156, 162))	('mutant R179', 'Var', (110, 121))	('Aalpha', 'Gene', '14960', (145, 151))	('Aalpha', 'Gene', '14960', (156, 162))	('Aalpha', 'Gene', (145, 151))
10799	31142515	These landscapes provide evidence that the R179 residue of the Aalpha mutant is capable of exploring an altered free energy landscape to adopt multiple metastable conformations of the Aalpha subunit protein, which may alter interactions with other PP2A subunits and proteins.	('alter', 'Reg', (218, 223))	('Aalpha', 'Gene', '14960', (63, 69))	('PP2A', 'Gene', '5524', (248, 252))	('Aalpha', 'Gene', '14960', (184, 190))	('R179', 'Var', (43, 47))	('interactions', 'Interaction', (224, 236))	('adopt', 'Reg', (137, 142))	('Aalpha', 'Gene', (63, 69))	('PP2A', 'Gene', (248, 252))	('Aalpha', 'Gene', (184, 190))
10801	31142515	In the resolved crystal structure, the guanidinium side chain of R179 orients towards the solvent, but still interacts with the side chain of Q217 of the adjacent HEAT repeat (Figure 3c, white structure).	('R179', 'Var', (65, 69))	('interacts', 'Reg', (109, 118))	('orients towards the', 'MPA', (70, 89))	('guanidinium', 'Chemical', 'MESH:D019791', (39, 50))
10802	31142515	In both, the interaction of R179 is facilitated by an additional ion pair interaction between R182 and D215.	('facilitated', 'PosReg', (36, 47))	('ion pair interaction', 'MPA', (65, 85))	('R182', 'Var', (94, 98))	('D215', 'Chemical', '-', (103, 107))	('D215', 'Var', (103, 107))	('R179', 'Var', (28, 32))	('interaction', 'Interaction', (13, 24))
10805	31142515	Therefore, mutation of proline can have an influence not only on the conformation of the protein but also on these biological processes.	('proline', 'Chemical', 'MESH:D011392', (23, 30))	('influence', 'Reg', (43, 52))	('conformation of the', 'MPA', (69, 88))	('mutation', 'Var', (11, 19))	('proline', 'Gene', (23, 30))
10808	31142515	By contrast, in the P179R mutant, the omega dihedral of R179 preferentially adopts a cis configuration in apo and complex states (Supplementary Figure 4s, t).	('R179', 'Var', (56, 60))	('P179R', 'Mutation', 'rs786205228', (20, 25))	('P179R', 'Var', (20, 25))	('preferentially', 'PosReg', (61, 75))	('adopts', 'Reg', (76, 82))
10809	31142515	In this cis conformation, R179 makes a strong ion pair with D215, while R182 interacts with N211 (Figure 3d).	('R179', 'Var', (26, 30))	('R182', 'Var', (72, 76))	('D215', 'Var', (60, 64))	('D215', 'Chemical', '-', (60, 64))
10810	31142515	Next, we analyzed the global conformational changes and the effect of mutation on C-subunit binding to the Aalpha subunit.	('binding', 'Interaction', (92, 99))	('Aalpha', 'Gene', (107, 113))	('mutation', 'Var', (70, 78))	('Aalpha', 'Gene', '14960', (107, 113))
10811	31142515	We extracted the representative conformations from the most populated minimum of the Aalpha/C complex FES (basin A in P179 wildtype and C in R179 mutant).	('Aalpha', 'Gene', '14960', (85, 91))	('Aalpha', 'Gene', (85, 91))	('P179', 'Var', (118, 122))
10814	31142515	In the P179R mutant, the Aalpha subunit prefers to adopt a near closed 'donut-shaped' conformation (Figure 3f).	('P179R', 'Mutation', 'rs786205228', (7, 12))	('P179R', 'Var', (7, 12))	('Aalpha', 'Gene', '14960', (25, 31))	('Aalpha', 'Gene', (25, 31))
10816	31142515	We calculated the binding energy for the C-subunit to either the WT or P179R mutant Aalpha-subunit, and determined them to be 236 kJ/mol and 347 kJ/mol, respectively.	('Aalpha', 'Gene', (84, 90))	('P179R', 'Var', (71, 76))	('binding', 'Interaction', (18, 25))	('Aalpha', 'Gene', '14960', (84, 90))	('P179R', 'Mutation', 'rs786205228', (71, 76))
10818	31142515	Altogether, these data show that a P179R mutation of the Aalpha protein leads to conformational disruption and a destabilized interaction with the C-subunit, which in turn lends context to the altered P179R mutant interactome described previously.	('C-subunit', 'Protein', (147, 156))	('interaction', 'Interaction', (126, 137))	('Aalpha', 'Gene', (57, 63))	('P179R', 'Mutation', 'rs786205228', (35, 40))	('destabilized', 'MPA', (113, 125))	('Aalpha', 'Gene', '14960', (57, 63))	('conformational disruption', 'MPA', (81, 106))	('P179R', 'Var', (35, 40))	('P179R', 'Mutation', 'rs786205228', (201, 206))
10819	31142515	Expression of the P179R mutant isoform in UT89 cells was found to reduce total protein levels of C- and B-subunits to a degree that reflected their respective loss of binding in co-IP experiments (Figure 4a).	('P179R', 'Mutation', 'rs786205228', (18, 23))	('loss', 'NegReg', (159, 163))	('Expression', 'Species', '29278', (0, 10))	('P179R', 'Var', (18, 23))	('reduce', 'NegReg', (66, 72))	('binding', 'Interaction', (167, 174))
10820	31142515	Indeed, the loss of catalytic C-subunit total protein, as well as the regulatory B55alpha- and B56alpha-subunit proteins, was significant for the P179R mutant, which had demonstrated marked impairment of binding and conformation-related destabilization of the Aalpha/C complex (Figure 4b).	('B55alpha', 'Gene', '5520', (81, 89))	('catalytic C-subunit total protein', 'MPA', (20, 53))	('destabilization', 'NegReg', (237, 252))	('impairment', 'NegReg', (190, 200))	('Aalpha', 'Gene', (260, 266))	('loss', 'NegReg', (12, 16))	('B56alpha', 'Gene', '5525', (95, 103))	('P179R', 'Mutation', 'rs786205228', (146, 151))	('B55alpha', 'Gene', (81, 89))	('binding', 'Interaction', (204, 211))	('P179R', 'Var', (146, 151))	('Aalpha', 'Gene', '14960', (260, 266))	('B56alpha', 'Gene', (95, 103))
10823	31142515	After a 24-hour treatment, total C-subunit protein was restored to a level comparable to that of EGFP control lines (Figure 4d-e) implicating proteasome-mediated degradation of C-subunit in P179R-expressing lines.	('C-subunit', 'MPA', (177, 186))	('P179R-expressing', 'Var', (190, 206))	('C-subunit protein', 'MPA', (33, 50))	('proteasome-mediated degradation', 'MPA', (142, 173))	('P179R', 'Mutation', 'rs786205228', (190, 195))
10826	31142515	P179R Aalpha-expressing cells demonstrated an increased rate of C-subunit degradation, represented by the slope of protein reduction over time, which was significantly different from both EGFP and WT-Aalpha transduced cells (Figure 4f-g).	('Aalpha', 'Gene', '14960', (6, 12))	('P179R', 'Mutation', 'rs786205228', (0, 5))	('P179R', 'Var', (0, 5))	('Aalpha', 'Gene', '14960', (200, 206))	('reduction', 'NegReg', (123, 132))	('Aalpha', 'Gene', (6, 12))	('Aalpha', 'Gene', (200, 206))	('C-subunit degradation', 'MPA', (64, 85))
10827	31142515	While EGFP and WT demonstrated modest C-subunit degradation within the experiment timeframe (~20-30% reduced relative to time=0 hrs), the higher rate of reduction in P179R allowed for calculation of a half-life of 36 hrs, at which point C-subunit total protein was 50% reduced.	('reduced', 'NegReg', (269, 276))	('C-subunit', 'MPA', (38, 47))	('P179R', 'Mutation', 'rs786205228', (166, 171))	('reduced', 'NegReg', (101, 108))	('C-subunit total protein', 'MPA', (237, 260))	('P179R', 'Var', (166, 171))
10828	31142515	The protein degradation rate of B55alpha was also significantly increased in P179R mutant cells relative to EGFP or WT cells (Figure 4f-g).	('P179R', 'Var', (77, 82))	('B55alpha', 'Gene', (32, 40))	('B55alpha', 'Gene', '5520', (32, 40))	('increased', 'PosReg', (64, 73))	('protein degradation rate', 'MPA', (4, 28))	('P179R', 'Mutation', 'rs786205228', (77, 82))
10829	31142515	Finally, we evaluated a panel of PPP2R1A wildtype and P179R mutant patient tumor specimens from the Case CCC tumor biobank for C- and B-subunit protein levels; wildtype samples representative of both serous and endometrioid EMCA tumors were included (Supplementary Figure 5a).	('P179R', 'Mutation', 'rs786205228', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('patient', 'Species', '9606', (67, 74))	('P179R mutant', 'Var', (54, 66))	('endometrioid EMCA tumors', 'Disease', (211, 235))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('EMCA', 'Phenotype', 'HP:0012114', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (229, 234))	('PPP2R1A', 'Gene', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('endometrioid EMCA tumors', 'Disease', 'MESH:D016889', (211, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('PPP2R1A', 'Gene', '5518', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', (109, 114))
10831	31142515	Overall, P179R mutant tumors had lower levels of C- and B-subunit protein when compared to wildtype serous or endometrioid tumors (Supplementary Figure 5a-c).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('endometrioid tumors', 'Disease', (110, 129))	('P179R', 'Mutation', 'rs786205228', (9, 14))	('tumors', 'Disease', (22, 28))	('lower', 'NegReg', (33, 38))	('endometrioid tumors', 'Disease', 'MESH:D016889', (110, 129))	('P179R', 'Var', (9, 14))
10833	31142515	Given the PP2A Aalpha mutant-driven disruption of PP2A holoenzyme assembly and reduction of catalytic subunit protein, and that PP2A has prominent tumor suppressive functions, we investigated whether expression of P179R-Aalpha in the PPP2R1A wildtype UT89 cell line led to an alteration of in vitro or in vivo tumor cell growth.	('PPP2R1A', 'Gene', (234, 241))	('PP2A', 'Gene', '5524', (10, 14))	('PP2A', 'Gene', '5524', (128, 132))	('alteration', 'Reg', (276, 286))	('PP2A Aalpha', 'Gene', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('mutant-driven', 'Var', (22, 35))	('PP2A', 'Gene', (50, 54))	('tumor', 'Disease', (147, 152))	('Aalpha', 'Gene', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Aalpha', 'Gene', (220, 226))	('P179R', 'Mutation', 'rs786205228', (214, 219))	('PP2A', 'Gene', (10, 14))	('PP2A', 'Gene', (128, 132))	('expression', 'Species', '29278', (200, 210))	('tumor', 'Disease', (310, 315))	('Aalpha', 'Gene', '14960', (15, 21))	('reduction', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('Aalpha', 'Gene', '14960', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('PPP2R1A', 'Gene', '5518', (234, 241))	('PP2A Aalpha', 'Gene', '5518', (10, 21))	('PP2A', 'Gene', '5524', (50, 54))	('catalytic subunit protein', 'MPA', (92, 117))
10835	31142515	We derived another primary patient cell line, UT42, from a patient tumor that harbors the P179R mutation endogenously, in order to directly characterize mutant biology (Supplementary Figure 2).	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('P179R', 'Var', (90, 95))	('patient', 'Species', '9606', (59, 66))	('patient', 'Species', '9606', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('P179R', 'Mutation', 'rs786205228', (90, 95))	('tumor', 'Disease', (67, 72))
10841	31142515	To assess the catalytic activity of reconstituted WT-Aalpha and compare to that of mutant P179R-Aalpha protein, a phosphatase activity assay was performed on the co-immunoprecipitants of WT- or P179R-Aalpha V5-tagged protein from the UT42 isogenic lines.	('Aalpha', 'Gene', (53, 59))	('mutant', 'Var', (83, 89))	('Aalpha', 'Gene', '14960', (96, 102))	('Aalpha', 'Gene', '14960', (200, 206))	('Aalpha', 'Gene', '14960', (53, 59))	('P179R', 'Mutation', 'rs786205228', (90, 95))	('P179R', 'Mutation', 'rs786205228', (194, 199))	('Aalpha', 'Gene', (96, 102))	('Aalpha', 'Gene', (200, 206))
10855	31142515	We carried out the full experiment under the same experimental conditions, injecting UT42 EGFP or WT-Aalpha cells into the left uterine horn of female NSG mice.	('Aalpha', 'Gene', (101, 107))	('UT42 EGFP', 'Var', (85, 94))	('uterine horn', 'Phenotype', 'HP:0000139', (128, 140))	('Aalpha', 'Gene', '14960', (101, 107))	('mice', 'Species', '10090', (155, 159))
10880	31142515	Overall, the UT42 tumor harboring a P179R mutation was highly responsive to SMAP treatment, which significantly reduced its growth in vivo.	('tumor', 'Disease', (18, 23))	('P179R', 'Var', (36, 41))	('reduced', 'NegReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('growth', 'MPA', (124, 130))	('P179R', 'Mutation', 'rs786205228', (36, 41))
10882	31142515	A recurrent mutation of the PP2A Aalpha scaffolding subunit (PPP2R1A) is present in ~30% of high-grade subtypes of endometrial carcinoma (EMCA), with mutation at the P179 site accounting for ~20-25%.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (115, 136))	('PP2A Aalpha', 'Gene', (28, 39))	('PP2A Aalpha', 'Gene', '5518', (28, 39))	('endometrial carcinoma', 'Disease', (115, 136))	('EMCA', 'Phenotype', 'HP:0012114', (138, 142))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (115, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('mutation', 'Var', (12, 20))	('PPP2R1A', 'Gene', (61, 68))	('PPP2R1A', 'Gene', '5518', (61, 68))
10883	31142515	The UT42 patient-derived cell model harbors an endogenous P179R mutation and thus provides a unique system in which to investigate mutant biology as this tumor developed in the immediate context of somatic PPP2R1A mutation.	('PPP2R1A', 'Gene', (206, 213))	('PPP2R1A', 'Gene', '5518', (206, 213))	('P179R', 'Mutation', 'rs786205228', (58, 63))	('P179R', 'Var', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('patient', 'Species', '9606', (9, 16))	('tumor', 'Disease', (154, 159))
10884	31142515	The striking impairment of tumor formation and metastasis that occurred when wildtype Aalpha protein was restored provides evidence that functional disruption of PP2A is critical to this tumor and its malignant features.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('disruption', 'Var', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (27, 32))	('PP2A', 'Gene', '5524', (162, 166))	('Aalpha', 'Gene', '14960', (86, 92))	('impairment of tumor', 'Disease', 'MESH:D060825', (13, 32))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('metastasis', 'CPA', (47, 57))	('impairment of tumor', 'Disease', (13, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('PP2A', 'Gene', (162, 166))	('Aalpha', 'Gene', (86, 92))
10885	31142515	In a similar manner, tumor growth was significantly reduced when treated with a pharmacologic PP2A activator, again highlighting sensitivity of the P179R mutant UT42 tumor to PP2A activity.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('PP2A', 'Gene', '5524', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (21, 26))	('reduced', 'NegReg', (52, 59))	('P179R', 'Mutation', 'rs786205228', (148, 153))	('tumor', 'Disease', (166, 171))	('PP2A', 'Gene', '5524', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('PP2A', 'Gene', (175, 179))	('P179R', 'Var', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('UT42', 'Gene', (161, 165))	('PP2A', 'Gene', (94, 98))
10887	31142515	P179 site mutations are notable for displaying marked disease specificity, occurring almost exclusively in EMCA and the serous carcinoma and carcinosarcoma subtypes.	('P179 site mutations', 'Var', (0, 19))	('occurring', 'Reg', (75, 84))	('carcinosarcoma', 'Disease', 'MESH:D002296', (141, 155))	('EMCA', 'Phenotype', 'HP:0012114', (107, 111))	('serous carcinoma', 'Disease', 'MESH:D018297', (120, 136))	('serous carcinoma', 'Disease', (120, 136))	('carcinosarcoma', 'Disease', (141, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('EMCA', 'Disease', (107, 111))
10888	31142515	This pattern suggests a role for PP2A as a disease driver, in which the biochemical consequences of mutating this residue is specifically advantageous to endometrial tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('advantageous', 'PosReg', (138, 150))	('PP2A', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('PP2A', 'Gene', '5524', (33, 37))	('mutating', 'Var', (100, 108))
10889	31142515	Consistent with this perspective, a large-scale sequencing study has shown that PPP2R1A mutations are somatic and truncal, and so are presumed to be acquired during the early processes of malignant cell transformation.	('PPP2R1A', 'Gene', '5518', (80, 87))	('PPP2R1A', 'Gene', (80, 87))	('mutations', 'Var', (88, 97))
10891	31142515	Interestingly, a majority of developed models rely on co-inactivation of p53 with PP2A for complete transformation, meanwhile, TP53 and PPP2R1A P179 mutations highly co-occur and are both truncal in these otherwise low mutational burden EMCA tumors.	('co-inactivation', 'Var', (54, 69))	('EMCA tumors', 'Disease', (237, 248))	('p53', 'Gene', (73, 76))	('PP2A', 'Gene', (82, 86))	('EMCA tumors', 'Disease', 'MESH:D009369', (237, 248))	('p53', 'Gene', '7157', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('EMCA', 'Phenotype', 'HP:0012114', (237, 241))	('P179', 'Gene', (144, 148))	('PPP2R1A', 'Gene', (136, 143))	('PPP2R1A', 'Gene', '5518', (136, 143))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('PP2A', 'Gene', '5524', (82, 86))
10892	31142515	P179 mutation may therefore be a mechanism through which models of PP2A in transformation bear out in EMCA.	('PP2A', 'Gene', (67, 71))	('EMCA', 'Phenotype', 'HP:0012114', (102, 106))	('P179 mutation', 'Var', (0, 13))	('bear', 'Reg', (90, 94))	('EMCA', 'Disease', (102, 106))	('PP2A', 'Gene', '5524', (67, 71))
10893	31142515	To understand how the P179R mutant alters PP2A function we began with investigation of PP2A subunit binding.	('P179R', 'Var', (22, 27))	('function', 'MPA', (47, 55))	('PP2A', 'Gene', '5524', (42, 46))	('PP2A', 'Gene', '5524', (87, 91))	('binding', 'Interaction', (100, 107))	('PP2A', 'Gene', (42, 46))	('PP2A', 'Gene', (87, 91))	('P179R', 'Mutation', 'rs786205228', (22, 27))
10894	31142515	Our findings are in agreement with previous literature that identified disrupted PP2A subunit interactions due to P179R PPP2R1A mutation.	('PPP2R1A', 'Gene', '5518', (120, 127))	('PP2A', 'Gene', '5524', (81, 85))	('PP2A', 'Gene', (81, 85))	('P179R', 'Mutation', 'rs786205228', (114, 119))	('P179R', 'Var', (114, 119))	('PPP2R1A', 'Gene', (120, 127))
10895	31142515	The consequence for unbound B- and C-subunits, an increased rate of protein degradation, is a novel finding for this cancer-associated mutation but is in support of a standing view that monomeric PP2A B- and C-subunits are less stable than their trimeric counterparts.	('rate', 'MPA', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('increased', 'PosReg', (50, 59))	('PP2A', 'Gene', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('mutation', 'Var', (135, 143))	('protein degradation', 'MPA', (68, 87))	('PP2A', 'Gene', '5524', (196, 200))
10896	31142515	Together these findings suggest that acquisition of a P179R mutation will impede assembly of holoenzymes containing catalytic and regulatory subunits and thereby induce a corresponding loss of canonical PP2A function within the cell.	('P179R', 'Mutation', 'rs786205228', (54, 59))	('P179R', 'Var', (54, 59))	('PP2A', 'Gene', '5524', (203, 207))	('impede', 'NegReg', (74, 80))	('canonical', 'MPA', (193, 202))	('PP2A', 'Gene', (203, 207))	('loss', 'NegReg', (185, 189))	('function', 'MPA', (208, 216))
10899	31142515	The substituted arginine changed the dominant isomerization state and introduced new inter-residue interactions within the protein tertiary structure.	('arginine', 'Chemical', 'MESH:D001120', (16, 24))	('substituted arginine', 'Var', (4, 24))	('inter-residue interactions', 'MPA', (85, 111))	('dominant isomerization state', 'MPA', (37, 65))	('introduced', 'Reg', (70, 80))	('arginine', 'Var', (16, 24))	('changed', 'Reg', (25, 32))
10900	31142515	The P179R substitution modifies the A-subunit's most stable, and preferentially adapted, conformation in a manner that is unfavorable to C-subunit binding, as evidenced by Aalpha/C complex simulations for the mutant isoform as well as its increased binding energy requirement.	('P179R', 'Mutation', 'rs786205228', (4, 9))	('Aalpha', 'Gene', '14960', (172, 178))	('modifies', 'Reg', (23, 31))	('P179R', 'Var', (4, 9))	('Aalpha', 'Gene', (172, 178))	('most stable', 'MPA', (48, 59))
10902	31142515	P179R-Aalpha is the first resolved crystal structure for a cancer-derived mutant PP2A protein and it underscores that mutation is a pathogenic mechanism through which cancer cells can disrupt the PP2A structure.	('Aalpha', 'Gene', '14960', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('P179R', 'Mutation', 'rs786205228', (0, 5))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PP2A', 'Gene', (81, 85))	('PP2A', 'Gene', (196, 200))	('mutation', 'Var', (118, 126))	('disrupt', 'NegReg', (184, 191))	('Aalpha', 'Gene', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('mutant', 'Var', (74, 80))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('PP2A', 'Gene', '5524', (81, 85))	('PP2A', 'Gene', '5524', (196, 200))
10904	31142515	While some PPP2R1A mutations display increased binding to the PP2A inhibitor TIPRL and may be inactivated through a dominant negative mechanism, P179R did not display an increase in TIPRL binding in our model systems.	('PPP2R1A', 'Gene', (11, 18))	('PPP2R1A', 'Gene', '5518', (11, 18))	('PP2A', 'Gene', '5524', (62, 66))	('TIPRL', 'Gene', '261726', (182, 187))	('mutations', 'Var', (19, 28))	('TIPRL', 'Gene', '261726', (77, 82))	('TIPRL', 'Gene', (182, 187))	('P179R', 'Mutation', 'rs786205228', (145, 150))	('increased', 'PosReg', (37, 46))	('binding', 'Interaction', (47, 54))	('PP2A', 'Gene', (62, 66))	('TIPRL', 'Gene', (77, 82))
10905	31142515	This included protein co-immunoprecipitation in both a wildtype serous EMCA cell line (Figure 2a), as well as within a cell line that itself harbors the P179R mutation endogenously (Figure 5c).	('protein', 'Protein', (14, 21))	('P179R', 'Mutation', 'rs786205228', (153, 158))	('P179R', 'Var', (153, 158))	('EMCA', 'Phenotype', 'HP:0012114', (71, 75))
10909	31142515	However, tumors that harbor P179 mutations are unlikely to be amenable to the immunotherapy approach as we show this mutation occurs exclusively in low mutational burden, MSI-negative tumor types.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', (9, 14))	('P179', 'Gene', (28, 32))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
10911	31142515	Finally, in addition to cancer, instances of germline PPP2R1A mutation have been reported in association with developmental and intellectual disabilities.	('association', 'Reg', (93, 104))	('developmental and intellectual disabilities', 'Phenotype', 'HP:0001263', (110, 153))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('intellectual disabilities', 'Phenotype', 'HP:0001249', (128, 153))	('cancer', 'Disease', (24, 30))	('PPP2R1A', 'Gene', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('mutation', 'Var', (62, 70))	('PPP2R1A', 'Gene', '5518', (54, 61))	('reported', 'Reg', (81, 89))
10914	31142515	From our results, one could reasonably predict these mutations lead to significant disruption of PP2A physiologic activity within neuronal cells.	('PP2A', 'Gene', (97, 101))	('disruption', 'NegReg', (83, 93))	('PP2A', 'Gene', '5524', (97, 101))	('mutations', 'Var', (53, 62))
10915	31142515	Overall, this body of work suggests a loss-of-function of PP2A tumor suppressive activity due to P179R mutation of the Aalpha subunit.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PP2A', 'Gene', '5524', (58, 62))	('loss-of-function', 'NegReg', (38, 54))	('Aalpha', 'Gene', (119, 125))	('P179R', 'Mutation', 'rs786205228', (97, 102))	('P179R mutation', 'Var', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PP2A', 'Gene', (58, 62))	('Aalpha', 'Gene', '14960', (119, 125))
10917	31142515	These findings support PPP2R1A P179R mutation as key driver of disease in the 20-30% of high-grade EMCA tumors that harbor one, and present pharmacologic targeting of PP2A as a potential therapeutic direction for this patient population.	('EMCA tumors', 'Disease', 'MESH:D009369', (99, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('patient', 'Species', '9606', (218, 225))	('EMCA', 'Phenotype', 'HP:0012114', (99, 103))	('P179R mutation', 'Var', (31, 45))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PP2A', 'Gene', (167, 171))	('P179R', 'Mutation', 'rs786205228', (31, 36))	('PPP2R1A', 'Gene', '5518', (23, 30))	('PPP2R1A', 'Gene', (23, 30))	('PP2A', 'Gene', '5524', (167, 171))	('EMCA tumors', 'Disease', (99, 110))
10931	31137471	In addition, approximately 3-5% of all women with uterine cancer have Lynch syndrome, a familial cancer syndrome involving a DNA mismatch repair gene deficiency, which increases the risk of both uterine cancer and colorectal cancer.	('Lynch syndrome', 'Disease', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('deficiency', 'Var', (150, 160))	('uterine cancer', 'Phenotype', 'HP:0010784', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('uterine cancer', 'Disease', (195, 209))	('women', 'Species', '9606', (39, 44))	('Lynch syndrome', 'Disease', 'MESH:D003123', (70, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('uterine cancer', 'Disease', 'MESH:D014594', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('familial cancer syndrome', 'Disease', (88, 112))	('colorectal cancer', 'Disease', (214, 231))	('uterine cancer', 'Phenotype', 'HP:0010784', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('uterine cancer', 'Disease', (50, 64))	('uterine cancer', 'Disease', 'MESH:D014594', (195, 209))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (88, 112))
11004	31137471	Second, increasing utilization of genetic testing for women with both uterine and colorectal cancers may be responsible for decreasing rates of postcedent uterine cancer and colorectal cancer cases.	('uterine cancer', 'Disease', 'MESH:D014594', (155, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (174, 191))	('decreasing', 'NegReg', (124, 134))	('postcedent', 'Disease', (144, 154))	('colorectal cancers', 'Disease', 'MESH:D015179', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('uterine cancer', 'Disease', (155, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (174, 191))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('women', 'Species', '9606', (54, 59))	('colorectal cancer', 'Disease', (174, 191))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('uterine cancer', 'Phenotype', 'HP:0010784', (155, 169))	('colorectal cancers', 'Disease', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('genetic', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('uterine', 'Disease', (70, 77))
11092	31231511	Its molecular profile differs from that of type 1 endometrioid histologies; it has a high rate (90%) of TP53 alterations and about a 30% rate of HER2/neu alterations , .	('HER2/neu', 'Gene', '2064', (145, 153))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('HER2/neu', 'Gene', (145, 153))	('alterations', 'Var', (109, 120))	('alterations', 'Var', (154, 165))
11116	31231511	Metformin use and CTNNB1 mutations were associated with increased response rates, PFS, and OS, although these findings were not statistically significant.	('response', 'Disease', (66, 74))	('mutations', 'Var', (25, 34))	('CTNNB1', 'Gene', '1499', (18, 24))	('increased', 'PosReg', (56, 65))	('PFS', 'Disease', (82, 85))	('OS', 'Chemical', '-', (91, 93))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('CTNNB1', 'Gene', (18, 24))
11128	31231511	The four groups were MMR-deficient (MMR-D), POLE exonuclease domain mutations (POLE EDMs), p53 abnormal, and p53 wild-type.	('EDM', 'Disease', 'None', (84, 87))	('EDM', 'Disease', (84, 87))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('abnormal', 'Var', (95, 103))	('domain mutations', 'Var', (61, 77))
11131	31231511	POLE mutants were classified as POLE EDM, and POLE wild-type tumors were assessed for p53 status.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('EDM', 'Disease', 'None', (37, 40))	('p53', 'Gene', '7157', (86, 89))	('EDM', 'Disease', (37, 40))	('mutants', 'Var', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('p53', 'Gene', (86, 89))
11137	31231511	They assessed tumors for mismatch repair (MMR) defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity.	('MLH1', 'Gene', '4292', (74, 78))	('MLH1', 'Gene', (74, 78))	('MSI', 'Disease', 'None', (56, 59))	('tumors', 'Disease', (14, 20))	('defects', 'NegReg', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('loss', 'Var', (113, 117))	('methylation', 'Var', (79, 90))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('MSI', 'Disease', (56, 59))	('mismatch repair', 'MPA', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
11138	31231511	Using four classifications (MMR deficient, copy number altered (CNA), copy number stable, and POLE mutant), they were able to stratify patients by PFS and OS.	('patients', 'Species', '9606', (135, 143))	('OS', 'Chemical', '-', (155, 157))	('altered', 'Reg', (55, 62))	('copy number', 'Var', (43, 54))	('deficient', 'NegReg', (32, 41))
11154	31231511	In the unselected cohort (85% microsatellite stable and 25% PD-L1-positive), 39.6% of patients responded with durable responses (65% had responses greater than 6 months, and median duration of response was not yet achieved) .	('PD-L1', 'Gene', '29126', (60, 65))	('microsatellite', 'Var', (30, 44))	('PD-L1', 'Gene', (60, 65))	('patients', 'Species', '9606', (86, 94))
11270	28795131	In a meta-analysis of studies comparing endometriotic associated ovarian cancers (EAOC) to non-endometriosis associated ovarian cancers (NEAOC), EAOC was associated with early stage and low grade disease.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))	('endometriosis', 'Phenotype', 'HP:0030127', (95, 108))	('EAOC', 'Var', (145, 149))	('non-endometriosis associated ovarian cancers', 'Disease', (91, 135))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('ovarian cancers', 'Phenotype', 'HP:0100615', (120, 135))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('early', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('low grade disease', 'CPA', (186, 203))	('ovarian cancers', 'Phenotype', 'HP:0100615', (65, 80))	('ovarian cancers', 'Disease', 'MESH:D010051', (120, 135))	('ovarian cancers', 'Disease', (65, 80))	('non-endometriosis associated ovarian cancers', 'Disease', 'MESH:D004715', (91, 135))	('associated', 'Reg', (154, 164))	('ovarian cancers', 'Disease', 'MESH:D010051', (65, 80))
11307	28587364	15d-PGJ2 inhibited cell growth and increased apoptosis.	('inhibited', 'NegReg', (9, 18))	('increased', 'PosReg', (35, 44))	('15d-PGJ2', 'Var', (0, 8))	('cell growth', 'CPA', (19, 30))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (0, 8))	('apoptosis', 'CPA', (45, 54))
11321	28587364	Previous studies have shown that 15d-PGJ2 significantly inhibits cell growth and induces apoptosis in cancer cells, indicating it as a potential cancer treatment.	('cancer', 'Disease', (145, 151))	('cell growth', 'CPA', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('apoptosis', 'CPA', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('inhibits', 'NegReg', (56, 64))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (33, 41))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('15d-PGJ2', 'Var', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('induces', 'Reg', (81, 88))
11322	28587364	15d-PGJ2 induces a variety of cellular responses including activation of mitogen-activated protein kinase (MAPK), modulation of Cox-2, inhibition of vascular smooth muscle cell proliferation and upregulation of antioxidant response genes.	('antioxidant', 'Gene', (211, 222))	('inhibition', 'NegReg', (135, 145))	('15d-PGJ2', 'Var', (0, 8))	('Cox-2', 'Gene', '5743', (128, 133))	('vascular smooth muscle cell proliferation', 'CPA', (149, 190))	('Cox-2', 'Gene', (128, 133))	('modulation', 'MPA', (114, 124))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (0, 8))	('upregulation', 'PosReg', (195, 207))	('activation', 'PosReg', (59, 69))
11325	28587364	Peroxisome proliferator-activated receptors (PPAR) omicron, beta and gamma are nuclear hormone receptors that regulate a multitude of downstream metabolic processes.	('Peroxisome proliferator-activated receptors', 'Gene', (0, 43))	('Peroxisome proliferator-activated receptors', 'Gene', '5465', (0, 43))	('omicron', 'Var', (51, 58))	('PPAR', 'Gene', '5465', (45, 49))	('PPAR', 'Gene', (45, 49))	('regulate', 'Reg', (110, 118))
11340	28587364	MEK and phospho-MEK (ser217/221) antibodies were purchased from Santa Cruz Biotechnology, Inc., and SRC, phospho-SRC (tyr416), ERK, phospho-ERK (tyr204), AKT, phospho-AKT and beta-actin antibodies were purchased from Cell Signaling Technology, Inc. (Beverly, MA, USA).	('AKT', 'Gene', (167, 170))	('MEK', 'Gene', (0, 3))	('SRC', 'Gene', (113, 116))	('beta-actin', 'Gene', '728378', (175, 185))	('tyr204', 'Chemical', '-', (145, 151))	('ERK', 'Gene', (140, 143))	('tyr416', 'Chemical', '-', (118, 124))	('ERK', 'Gene', '5594', (127, 130))	('AKT', 'Gene', '207', (167, 170))	('AKT', 'Gene', (154, 157))	('SRC', 'Gene', '6714', (100, 103))	('beta-actin', 'Gene', (175, 185))	('ser217', 'Chemical', '-', (21, 27))	('SA', 'Chemical', 'MESH:C012546', (264, 266))	('ERK', 'Gene', (127, 130))	('SRC', 'Gene', (100, 103))	('MEK', 'Gene', '5609', (16, 19))	('tyr416', 'Var', (118, 124))	('SRC', 'Gene', '6714', (113, 116))	('AKT', 'Gene', '207', (154, 157))	('MEK', 'Gene', '5609', (0, 3))	('ERK', 'Gene', '5594', (140, 143))	('MEK', 'Gene', (16, 19))
11355	28587364	Together our results showed that 15d-PGJ2 significantly inhibited the growth of all three uterine sarcoma cell lines in a dose- and time-dependent manner.	('growth', 'CPA', (70, 76))	('uterine sarcoma', 'Disease', 'MESH:D012509', (90, 105))	('uterine sarcoma', 'Disease', (90, 105))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (33, 41))	('15d-PGJ2', 'Var', (33, 41))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (90, 105))	('inhibited', 'NegReg', (56, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
11359	28587364	These studies indicated that 15d-PGJ2 exerts a cytotoxic effect, inhibiting uterine sarcoma cell growth.	('15d-PGJ2', 'Chemical', 'MESH:C097240', (29, 37))	('uterine sarcoma', 'Disease', 'MESH:D012509', (76, 91))	('uterine sarcoma', 'Disease', (76, 91))	('inhibiting', 'NegReg', (65, 75))	('15d-PGJ2', 'Var', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (76, 91))
11361	28587364	Other reports demonstrated that 15-d-PGJ2 induced ERK activation.	('ERK', 'Gene', '5594', (50, 53))	('ERK', 'Gene', (50, 53))	('15-d-PGJ2', 'Var', (32, 41))	('activation', 'PosReg', (54, 64))	('15-d-PGJ2', 'Chemical', 'MESH:C477819', (32, 41))
11366	28587364	The western blot results showed that phosphorylation of AKT was decreased by 15d-PGJ2 in uterine sarcoma cells, indicating that 15d-PGJ2 represses the AKT pathway.	('AKT', 'Gene', (151, 154))	('AKT', 'Gene', '207', (56, 59))	('uterine sarcoma', 'Disease', (89, 104))	('phosphorylation', 'MPA', (37, 52))	('uterine sarcoma', 'Disease', 'MESH:D012509', (89, 104))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (89, 104))	('AKT', 'Gene', (56, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (77, 85))	('AKT', 'Gene', '207', (151, 154))	('represses', 'NegReg', (137, 146))	('15d-PGJ2', 'Var', (77, 85))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (128, 136))	('decreased', 'NegReg', (64, 73))
11373	28587364	The CI was 0.489,0.36428 and 0.36301 in the MES-SA cell, MES-SA/DX5 and SKN cell line, indicating that combined PGJ2 and dasatinib generates synergistic effect (Table I).	('synergistic effect', 'MPA', (141, 159))	('0.36301', 'Var', (29, 36))	('MES-SA', 'Chemical', '-', (57, 63))	('PGJ2', 'Chemical', 'MESH:C037112', (112, 116))	('dasatinib', 'Chemical', 'MESH:D000069439', (121, 130))	('MES-SA', 'Chemical', '-', (44, 50))
11376	28587364	PPAR-gamma is targeted by endogenous ligands such as Delta12.15 prostaglandin J2 and functions as a transcriptional factor in vivo.	('PPAR-gamma', 'Gene', '5468', (0, 10))	('prostaglandin J2', 'Chemical', 'MESH:C037112', (64, 80))	('PPAR-gamma', 'Gene', (0, 10))	('Delta12.15', 'Var', (53, 63))
11381	28587364	The present study shows that 15d-PGJ2 induced downregulation of the AKT pathway with subsequent apoptosis.	('downregulation', 'NegReg', (46, 60))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (29, 37))	('AKT', 'Gene', '207', (68, 71))	('15d-PGJ2', 'Var', (29, 37))	('AKT', 'Gene', (68, 71))
11384	28587364	Our results showed that 15d-PGJ2 inhibited phosphorylation of AKT and also promoted phosphorylation of MAPK.	('phosphorylation', 'MPA', (84, 99))	('AKT', 'Gene', (62, 65))	('phosphorylation', 'MPA', (43, 58))	('15d-PGJ2', 'Var', (24, 32))	('promoted', 'PosReg', (75, 83))	('AKT', 'Gene', '207', (62, 65))	('MAPK', 'Protein', (103, 107))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (24, 32))	('inhibited', 'NegReg', (33, 42))
11385	28587364	Because of its activation of MAPK, the anti-tumor effects of 15d-PGJ2 are limited.	('activation', 'PosReg', (15, 25))	('MAPK', 'Pathway', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('15d-PGJ2', 'Var', (61, 69))
11391	28587364	Activation of these pathways may limit the antiproliferative effects of 15d-PGJ2, and thus the addition of molecular-targeted agents with PGJ2 may help to suppress these growth pathways.	('15d-PGJ2', 'Chemical', 'MESH:C097240', (72, 80))	('PGJ2', 'Gene', (138, 142))	('PGJ2', 'Chemical', 'MESH:C037112', (76, 80))	('PGJ2', 'Chemical', 'MESH:C037112', (138, 142))	('growth pathways', 'Pathway', (170, 185))	('15d-PGJ2', 'Var', (72, 80))	('antiproliferative effects', 'CPA', (43, 68))	('limit', 'NegReg', (33, 38))	('suppress', 'NegReg', (155, 163))
11398	28587364	These results showed that inhibition of SRC has sustained effects on the MAPK cascade and AKT in uterine sarcoma.	('effects', 'Reg', (58, 65))	('SRC', 'Gene', '6714', (40, 43))	('AKT', 'Gene', (90, 93))	('inhibition', 'Var', (26, 36))	('SRC', 'Gene', (40, 43))	('uterine sarcoma', 'Disease', 'MESH:D012509', (97, 112))	('uterine sarcoma', 'Disease', (97, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (97, 112))	('AKT', 'Gene', '207', (90, 93))	('MAPK cascade', 'Pathway', (73, 85))
11400	28587364	The MAPK pathway is activated by 15d-PGJ2 treatment, and combined treatment with 15d-PGJ2 and dasatinib suppresses both the AKT and MAPK pathways, leading to synergistic antiproliferative effects.	('suppresses', 'NegReg', (104, 114))	('antiproliferative effects', 'CPA', (170, 195))	('AKT', 'Gene', '207', (124, 127))	('AKT', 'Gene', (124, 127))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (33, 41))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (81, 89))	('MAPK pathways', 'Pathway', (132, 145))	('dasatinib', 'Chemical', 'MESH:D000069439', (94, 103))	('MAPK pathway', 'Pathway', (4, 16))	('15d-PGJ2', 'Var', (81, 89))
11402	28587364	Treatment with 15d-PGJ2 combined with dasatinib produced a synergistic effect by negatively regulating both AKT and MAPK pathways.	('AKT', 'Gene', '207', (108, 111))	('MAPK pathways', 'Pathway', (116, 129))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (15, 23))	('dasatinib', 'Chemical', 'MESH:D000069439', (38, 47))	('AKT', 'Gene', (108, 111))	('15d-PGJ2', 'Var', (15, 23))	('negatively', 'NegReg', (81, 91))
11411	28331002	The identification of mutations that arise during treatment that confers drug sensitivity is paramount for precision cancer care of patients with advanced disease.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (132, 140))	('drug sensitivity', 'Phenotype', 'HP:0020174', (73, 89))
11434	28331002	WES identified alterations involving known cancer genes in 95.8% (737/769) of the analyzed specimens.	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('alterations', 'Var', (15, 26))
11437	28331002	Based on an expanded list of targeted therapies available at My Cancer Genome, 9.6% (71/737) of the analyzed patients had potentially targetable cancer gene alterations (e.g., EGFR p.L858R; BRAF p.V600E; ERBB2 amplification) though without current FDA approved drug indication (Fig.	('cancer', 'Disease', (145, 151))	('ERBB2', 'Gene', (204, 209))	('Cancer', 'Disease', (64, 70))	('BRAF', 'Gene', (190, 194))	('patients', 'Species', '9606', (109, 117))	('p.L858R', 'Mutation', 'rs121434568', (181, 188))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('EGFR', 'Gene', '1956', (176, 180))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('p.L858R', 'Var', (181, 188))	('p.V600E', 'Mutation', 'rs113488022', (195, 202))	('EGFR', 'Gene', (176, 180))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('p.V600E', 'Var', (195, 202))	('ERBB2', 'Gene', '2064', (204, 209))	('BRAF', 'Gene', '673', (190, 194))
11439	28331002	The most frequently mutated cancer genes with single nucleotide variants (SNVs)/Indels in our cohort (>= 5%) were TP53 (37.4%), APC (11.3%), NOTCH1 (8.4%), EGFR (6.7%), KMT2D (6.6%), ARID1A (6.6%), TET2 (6.3%), KRAS (6.2%), CREBBP (5.5%), and PIK3CA (5.0%) (Fig.	('KMT2D', 'Gene', (169, 174))	('KRAS', 'Gene', (211, 215))	('TP53', 'Gene', '7157', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('NOTCH1', 'Gene', (141, 147))	('PIK3CA', 'Gene', (243, 249))	('TET2', 'Gene', '54790', (198, 202))	('EGFR', 'Gene', '1956', (156, 160))	('single nucleotide variants', 'Var', (46, 72))	('NOTCH1', 'Gene', '4851', (141, 147))	('CREBBP', 'Gene', (224, 230))	('ARID1A', 'Gene', (183, 189))	('KMT2D', 'Gene', '8085', (169, 174))	('ARID1A', 'Gene', '8289', (183, 189))	('TP53', 'Gene', (114, 118))	('cancer', 'Disease', (28, 34))	('CREBBP', 'Gene', '1387', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('PIK3CA', 'Gene', '5290', (243, 249))	('APC', 'Disease', 'MESH:D011125', (128, 131))	('KRAS', 'Gene', '3845', (211, 215))	('EGFR', 'Gene', (156, 160))	('TET2', 'Gene', (198, 202))	('APC', 'Disease', (128, 131))
11459	28331002	The four organoid samples were derived from patients with a uterine carcinosarcoma (Patient A, stage IIIB: PIK3CA p.Q546H; PTEN p.K6fs*4), an endometrial adenocarcinoma (Patient B, IIIC2: PIK3CA p.H1047R; PTEN p.K267fs*9; CTNNB1 p.D32G), a stage IV colorectal cancer with a clinically relevant KRAS p.G13D and TP53 p.R282W mutation (Patient C), and a stage IV colorectal cancer with an APC mutation p.G857X and an APC frameshift insertion p.E1536_fs (Patient D).	('colorectal cancer', 'Disease', (249, 266))	('APC', 'Disease', (414, 417))	('PIK3CA', 'Gene', (188, 194))	('PTEN', 'Gene', '5728', (205, 209))	('Patient', 'Species', '9606', (451, 458))	('colorectal cancer', 'Disease', (360, 377))	('PIK3CA', 'Gene', (107, 113))	('PTEN', 'Gene', (123, 127))	('p.D32G', 'Mutation', 'rs121913396', (229, 235))	('patients', 'Species', '9606', (44, 52))	('p.K267fs*9', 'Var', (210, 220))	('TP53', 'Gene', '7157', (310, 314))	('carcinosarcoma', 'Disease', (68, 82))	('Patient', 'Species', '9606', (84, 91))	('CTNNB1', 'Gene', '1499', (222, 228))	('p.K267fs*9', 'FRAMESHIFT', 'None', (210, 220))	('KRAS', 'Gene', '3845', (294, 298))	('PTEN', 'Gene', '5728', (123, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (249, 266))	('APC', 'Disease', 'MESH:D011125', (386, 389))	('APC', 'Disease', (386, 389))	('carcinosarcoma', 'Disease', 'MESH:D002296', (68, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (360, 377))	('p.G857X', 'Var', (399, 406))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (142, 168))	('Patient', 'Species', '9606', (170, 177))	('p.G857X', 'Mutation', 'p.G857X', (399, 406))	('PIK3CA', 'Gene', '5290', (188, 194))	('KRAS', 'Gene', (294, 298))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('PIK3CA', 'Gene', '5290', (107, 113))	('p.E1536_fs', 'Var', (439, 449))	('p.R282W', 'Var', (315, 322))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('endometrial adenocarcinoma', 'Disease', (142, 168))	('CTNNB1', 'Gene', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('p.Q546H', 'Mutation', 'rs1057519940', (114, 121))	('PTEN', 'Gene', (205, 209))	('p.R282W', 'Mutation', 'rs28934574', (315, 322))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (60, 82))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (142, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (249, 266))	('p.E1536_fs', 'Mutation', 'p.E1536_fsX', (439, 449))	('p.K6fs*4', 'Mutation', 'rs121913290', (128, 136))	('p.H1047R', 'Mutation', 'rs121913279', (195, 203))	('TP53', 'Gene', (310, 314))	('Patient', 'Species', '9606', (333, 340))	('p.G13D', 'Mutation', 'rs112445441', (299, 305))	('APC', 'Disease', 'MESH:D011125', (414, 417))	('colorectal cancer', 'Disease', 'MESH:D015179', (360, 377))
11464	28331002	As proof of principle, screening of patient derived examples of ER+ breast cancer and BRAF mutant melanoma with the drug library identified tamoxifen and BRAF- as well as MEK-Inhibitor as top scoring drugs respectively, indicating the high throughput screens can identify targeted agents that are clinically validated (Supplementary Fig.	('MEK', 'Gene', (171, 174))	('patient', 'Species', '9606', (36, 43))	('MEK', 'Gene', '5609', (171, 174))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('BRAF', 'Gene', '673', (154, 158))	('breast cancer', 'Disease', (68, 81))	('tamoxifen', 'Chemical', 'MESH:D013629', (140, 149))	('BRAF', 'Gene', '673', (86, 90))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('BRAF', 'Gene', (154, 158))	('melanoma', 'Disease', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutant', 'Var', (91, 97))	('BRAF', 'Gene', (86, 90))
11467	28331002	Tumor cells from patients A and B with uterine malignancies demonstrated in vitro responses to PI3K-Inhibitors consistent with PIK3CA mutations in both samples, single-agent chemotherapeutics (e.g., purine synthesis inhibitors such as fludarabine), and HDAC inhibitors (Fig.	('malignancies', 'Disease', 'MESH:D009369', (47, 59))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('fludarabine', 'Chemical', 'MESH:C024352', (235, 246))	('malignancies', 'Disease', (47, 59))	('PIK3CA', 'Gene', (127, 133))	('PIK3CA', 'Gene', '5290', (127, 133))	('purine', 'Chemical', 'MESH:C030985', (199, 205))	('patients', 'Species', '9606', (17, 25))	('mutations', 'Var', (134, 143))	('uterine malignancies', 'Phenotype', 'HP:0010784', (39, 59))
11479	28331002	Although buparlisib was not the top scoring single agent for Patient B (Figure 5D and 5E), it was selected as a modifying agent for a subsequent combinatorial screen because of its effect within the range of therapeutic doses and Patient B's PIK3CA mutation.	('mutation', 'Var', (249, 257))	('PIK3CA', 'Gene', '5290', (242, 248))	('buparlisib', 'Chemical', 'MESH:C571178', (9, 19))	('Patient', 'Species', '9606', (61, 68))	('Patient', 'Species', '9606', (230, 237))	('PIK3CA', 'Gene', (242, 248))
11485	28331002	This result is consistent with a colorectal cancer model showing that EGFR inhibitors synergize with HDAC inhibitors.	('inhibitors', 'Var', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('EGFR', 'Gene', '1956', (70, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('EGFR', 'Gene', (70, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('colorectal cancer', 'Disease', (33, 50))
11494	28331002	Greater inhibition of tumor growth was observed in mice treated with buparlisib as a monotherapy and in combination with vorinostat or olaparib as compared to mice treated with carbotaxol, vorinostat, or olaparib administered as monotherapies (Fig.	('inhibition', 'NegReg', (8, 18))	('vorinostat', 'Chemical', 'MESH:D000077337', (121, 131))	('buparlisib', 'Var', (69, 79))	('mice', 'Species', '10090', (51, 55))	('vorinostat', 'Chemical', 'MESH:D000077337', (189, 199))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('buparlisib', 'Chemical', 'MESH:C571178', (69, 79))	('tumor', 'Disease', (22, 27))	('olaparib', 'Chemical', 'MESH:C531550', (135, 143))	('carbotaxol', 'Chemical', '-', (177, 187))	('olaparib', 'Chemical', 'MESH:C531550', (204, 212))
11504	28331002	Cancer is a set of diseases in which genetic alterations in individual cells give rise to malignant growth.	('malignant growth', 'CPA', (90, 106))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('give rise', 'Reg', (77, 86))	('Cancer', 'Disease', (0, 6))	('genetic alterations', 'Var', (37, 56))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
11509	28331002	The uterine carcinosarcoma and endometrial adenocarcinoma from patients A and B had similar driver mutations in PIK3CA and PTEN yet our screen clearly distinguished the two cases based on their drug response profiles (Figure S S4 A-D).	('carcinosarcoma', 'Disease', (12, 26))	('PIK3CA', 'Gene', '5290', (112, 118))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (31, 57))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (31, 57))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (4, 26))	('mutations', 'Var', (99, 108))	('carcinosarcoma', 'Disease', 'MESH:D002296', (12, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('PTEN', 'Gene', (123, 127))	('patients', 'Species', '9606', (63, 71))	('PTEN', 'Gene', '5728', (123, 127))	('PIK3CA', 'Gene', (112, 118))	('endometrial adenocarcinoma', 'Disease', (31, 57))
11513	28331002	We also compared two stage IV colon cancer cases, one with mutations in KRAS and TP53 (patient C) and the other with mutations in APC (patient D).	('patient', 'Species', '9606', (135, 142))	('IV colon cancer', 'Disease', (27, 42))	('KRAS', 'Gene', (72, 76))	('APC', 'Disease', 'MESH:D011125', (130, 133))	('KRAS', 'Gene', '3845', (72, 76))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('APC', 'Disease', (130, 133))	('patient', 'Species', '9606', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (59, 68))	('IV colon cancer', 'Disease', 'MESH:D015179', (27, 42))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
11532	28331002	Despite, the identification of some mutated cancer genes which could nominate an investigational therapeutic intervention, enrolling advanced cancer patients in clinical trials- after failing standard of care and progression under second and third line treatments is challenging- because patients are heavily pre-treated and/or do not fulfill the entry criteria for trials.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (288, 296))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutated', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (142, 148))
11595	27764792	In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('endometrial cancer', 'Disease', (111, 129))	('migration', 'CPA', (45, 54))	('AXL', 'Protein', (31, 34))	('endometrial cancer', 'Phenotype', 'HP:0012114', (111, 129))	('endometrial cancer', 'Disease', 'MESH:D016889', (111, 129))	('inhibited', 'NegReg', (35, 44))	('genetic silencing', 'Var', (10, 27))	('invasion', 'CPA', (59, 67))
11608	27764792	Binding of growth arrest specific gene-6 (GAS-6), the only known ligand for AXL, induces autophosphorylation of tyrosine residues 779, 821, and 866.	('821', 'Var', (135, 138))	('autophosphorylation of tyrosine residues', 'MPA', (89, 129))	('GAS-6', 'Gene', '2621', (42, 47))	('growth arrest', 'Phenotype', 'HP:0001510', (11, 24))	('growth arrest specific gene-6', 'Gene', (11, 40))	('GAS-6', 'Gene', (42, 47))	('tyrosine', 'Chemical', 'MESH:D014443', (112, 120))	('growth arrest specific gene-6', 'Gene', '2621', (11, 40))	('Binding', 'Interaction', (0, 7))	('induces', 'Reg', (81, 88))
11622	27764792	In a subset of 20 patients for whom we had clinico-pathological and survival information, 8 patients with low AXL expression had longer median survival (96 months) than the 12 patients with high AXL expression (96 vs. 56 months, P= 0.0285, Figure 1B).	('patients', 'Species', '9606', (176, 184))	('longer', 'PosReg', (129, 135))	('patients', 'Species', '9606', (92, 100))	('low', 'Var', (106, 109))	('patients', 'Species', '9606', (18, 26))
11628	27764792	To evaluate the contribution of AXL to tumor cell invasion, we performed matrigel invasion assays and found that AXL-deficient ARK 1 and Hec50a cells were significantly less invasive than controls (Figure 3A).	('AXL-deficient', 'Var', (113, 126))	('less', 'NegReg', (169, 173))	('matrigel invasion', 'CPA', (73, 90))	('ARK 1', 'Gene', '6790', (127, 132))	('ARK 1', 'Gene', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('invasive', 'CPA', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
11630	27764792	We first confirmed the effectiveness of R428 in inhibiting p-AXL expression after stimulation with GAS6 (Supplementary Figure S2A).	('p-AXL expression', 'MPA', (59, 75))	('GAS6', 'Gene', (99, 103))	('inhibiting', 'NegReg', (48, 58))	('GAS6', 'Gene', '2621', (99, 103))	('R428', 'Chemical', '-', (40, 44))	('R428', 'Var', (40, 44))
11631	27764792	We then found that pre-treatment of ARK1 with R428 for four hours inhibited invasion (Supplementary Figure S2B).	('R428', 'Chemical', '-', (46, 50))	('inhibited', 'NegReg', (66, 75))	('R428', 'Var', (46, 50))	('ARK1', 'Protein', (36, 40))	('invasion', 'CPA', (76, 84))
11634	27764792	To determine whether PI3K/AKT signaling is affected by loss of AXL in endometrial cancer cells, we performed Western blot analyses evaluating levels of AKT phosphorylated at Ser473 (P-AKT) on shSCRM and shAXL ARK1 and Hec50a cells.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('AKT', 'Gene', '207', (152, 155))	('endometrial cancer', 'Disease', (70, 88))	('loss', 'Var', (55, 59))	('AKT', 'Gene', '207', (184, 187))	('AKT', 'Gene', '207', (26, 29))	('P-AKT', 'Disease', 'MESH:C000656865', (182, 187))	('endometrial cancer', 'Phenotype', 'HP:0012114', (70, 88))	('AKT', 'Gene', (152, 155))	('endometrial cancer', 'Disease', 'MESH:D016889', (70, 88))	('AKT', 'Gene', (184, 187))	('AKT', 'Gene', (26, 29))	('Ser473', 'Chemical', '-', (174, 180))	('P-AKT', 'Disease', (182, 187))
11638	27764792	Western blot analysis showed that exogenous GAS6 induced phosphorylation of AXL in both endometrial cancer cell lines (Figure 4B).	('GAS6', 'Gene', '2621', (44, 48))	('GAS6', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('endometrial cancer', 'Disease', (88, 106))	('AXL', 'Protein', (76, 79))	('phosphorylation', 'MPA', (57, 72))	('endometrial cancer', 'Phenotype', 'HP:0012114', (88, 106))	('exogenous', 'Var', (34, 43))	('endometrial cancer', 'Disease', 'MESH:D016889', (88, 106))
11660	27764792	Overall, these findings demonstrate that knockdown of AXL expression in ARK 1 cells inhibited endometrial cancer metastasis.	('endometrial cancer metastasis', 'Disease', 'MESH:D009362', (94, 123))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('ARK 1', 'Gene', '6790', (72, 77))	('AXL', 'Gene', (54, 57))	('ARK 1', 'Gene', (72, 77))	('endometrial cancer', 'Phenotype', 'HP:0012114', (94, 112))	('endometrial cancer metastasis', 'Disease', (94, 123))	('knockdown', 'Var', (41, 50))	('inhibited', 'NegReg', (84, 93))
11662	27764792	Therefore tumor growth was due to either incomplete knockdown or growth despite knockdown (Supplementary Figure S3A).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('knockdown', 'Var', (80, 89))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('growth', 'MPA', (65, 71))
11663	27764792	At the mRNA level, AXL knockdown tumors were found to have low expression of AXL (Supplementary Figure S3B).	('knockdown', 'Var', (23, 32))	('expression', 'MPA', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('low', 'NegReg', (59, 62))	('AXL', 'Protein', (77, 80))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
11666	27764792	This is consistent with our findings that AXL inhibition decreases tumor growth via inhibition of metastasis rather than by proliferation.	('inhibition', 'Var', (46, 56))	('inhibition', 'NegReg', (84, 94))	('decreases tumor', 'Disease', (57, 72))	('AXL', 'Protein', (42, 45))	('metastasis', 'CPA', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decreases tumor', 'Disease', 'MESH:D009369', (57, 72))
11675	27764792	Immunohistochemical analysis of Ki-67 expression in ARK1 shAXL and shSCRM mouse xenografts confirms that AXL knockdown has no significant effect on Ki-67.	('Ki-67', 'Gene', '17345', (32, 37))	('Ki-67', 'Gene', (148, 153))	('knockdown', 'Var', (109, 118))	('mouse', 'Species', '10090', (74, 79))	('Ki-67', 'Gene', (32, 37))	('Ki-67', 'Gene', '17345', (148, 153))
11682	27764792	Additionally, GAS6 levels correlated with AXL expression in EC cell lines as well as a decreased level in cells with genetic inactivation of AXL.	('AXL expression', 'MPA', (42, 56))	('correlated', 'Reg', (26, 36))	('GAS6', 'Gene', '2621', (14, 18))	('GAS6', 'Gene', (14, 18))	('genetic inactivation', 'Var', (117, 137))	('EC', 'Phenotype', 'HP:0012114', (60, 62))
11686	27764792	Moreover, we demonstrated that silencing AXL significantly inhibited the expression of proteins involved in the regulation of the extracellular matrix such as MMPs and uPA, unveiling the pathway by which AXL mediates tumor metastasis.	('expression of proteins involved', 'MPA', (73, 104))	('AXL', 'Protein', (41, 44))	('silencing', 'Var', (31, 40))	('MMPs', 'Gene', '4312;4313;4314;4318', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('regulation of the extracellular matrix', 'MPA', (112, 150))	('inhibited', 'NegReg', (59, 68))	('tumor metastasis', 'Disease', 'MESH:D009362', (217, 233))	('uPA', 'Gene', '5328', (168, 171))	('uPA', 'Gene', (168, 171))	('tumor metastasis', 'Disease', (217, 233))	('MMPs', 'Gene', (159, 163))
11688	27764792	Furthermore, uPA has been reported to boost EC cell invasion via increased levels of p-AKT, p-ERK1/2 and p-p38.	('EC', 'Phenotype', 'HP:0012114', (44, 46))	('EC cell invasion', 'CPA', (44, 60))	('increased', 'PosReg', (65, 74))	('ERK', 'Gene', (94, 97))	('AKT', 'Gene', (87, 90))	('ERK', 'Gene', '2048', (94, 97))	('uPA', 'Gene', (13, 16))	('levels', 'MPA', (75, 81))	('uPA', 'Gene', '5328', (13, 16))	('p-p38', 'Var', (105, 110))	('AKT', 'Gene', '207', (87, 90))	('boost', 'PosReg', (38, 43))
11693	27764792	For example, SKI606 (Bosutinib), a multi-kinase inhibitor targeting AXL, has been shown to reduce AXL-specific invasiveness in hepatocellular carcinoma cells and is in Phase 1 and 2 clinical trials for metastatic breast cancer.	('AXL-specific invasiveness', 'MPA', (98, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (127, 151))	('reduce', 'NegReg', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('Bosutinib', 'Chemical', 'MESH:C471992', (21, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('breast cancer', 'Disease', (213, 226))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (127, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('SKI606', 'Var', (13, 19))	('hepatocellular carcinoma', 'Disease', (127, 151))
11694	27764792	Additionally, R428 (BGB324), a small molecule inhibitor of AXL, used in our in vitro experiments, is currently in clinical trials in acute myeloid leukemia and in non-small cell lung cancer.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (139, 155))	('non-small cell lung cancer', 'Disease', (163, 189))	('R428', 'Chemical', '-', (14, 18))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (133, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('R428', 'Var', (14, 18))	('acute myeloid leukemia', 'Disease', (133, 155))	('BGB324', 'Chemical', 'MESH:C548378', (20, 26))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (167, 189))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (163, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('BGB324', 'Gene', (20, 26))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (133, 155))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (163, 189))
11791	26596725	After a mean follow-up of 32 months, 8 recurrences were observed (11.8 %): First, a 71-year-old patient had been diagnosed with FIGO stage IIIc:pT1b, G2, pN1 (3/46, two pelvic and one para-aortic node) and had been treated by PMMR/BSO and pelvic and secondary para-aortic lymphadenectomy; she received carboplatin/liposomal doxorubicin adjuvant chemotherapy and no irradiation; she developed an isolated recurrence in the right common iliac region and had been treated by salvage surgery and postoperative external irradiation; she is presently free of recurrence at 47 months.	('PMMR', 'Chemical', '-', (226, 230))	('pN1', 'Gene', '5270', (154, 157))	('pN1', 'Gene', (154, 157))	('patient', 'Species', '9606', (96, 103))	('pT1b', 'Var', (144, 148))	('carboplatin', 'Chemical', 'MESH:D016190', (302, 313))	('iliac region', 'Phenotype', 'HP:0009780', (435, 447))
11826	26596725	In particular:except for one transient mild bladder dysfunction:no relevant difference in morbidity could be found comparing PMMR/BSO with simple hysterectomy/BSO if not combined with lymphadenectomy in this study.	('bladder dysfunction', 'Disease', 'MESH:D001745', (44, 63))	('PMMR/BSO', 'Var', (125, 133))	('bladder dysfunction', 'Disease', (44, 63))	('PMMR', 'Chemical', '-', (125, 129))
11848	25782154	It is noteworthy that elevated estrogen levels associated with obesity and nulliparity represent the most recognized risk factor for stromal sarcoma and mixed mullerian tumors.	('elevated estrogen levels', 'Phenotype', 'HP:0025134', (22, 46))	('stromal sarcoma', 'Disease', 'MESH:D046152', (133, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('stromal sarcoma', 'Disease', (133, 148))	('elevated', 'PosReg', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('obesity', 'Phenotype', 'HP:0001513', (63, 70))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('estrogen levels', 'MPA', (31, 46))	('obesity', 'Disease', 'MESH:D009765', (63, 70))	('tumors', 'Disease', (169, 175))	('obesity', 'Disease', (63, 70))	('nulliparity', 'Var', (75, 86))
11860	25782154	Taken together, these findings suggested that endometrial stromal cells represent an important regulation target of ovarian hormones, and aberrant hormonal regulation may contribute to the development of endometrial malignancies.	('contribute', 'Reg', (171, 181))	('aberrant', 'Var', (138, 146))	('endometrial malignancies', 'Disease', 'MESH:D014591', (204, 228))	('hormonal regulation', 'MPA', (147, 166))	('endometrial malignancies', 'Disease', (204, 228))
11869	25782154	Estrogen-treated cells became more polymorphic than the control and progesterone treated cells (Figure 2).	('progesterone', 'Chemical', 'MESH:D011374', (68, 80))	('polymorphic', 'MPA', (35, 46))	('Estrogen-treated', 'Var', (0, 16))
11905	25782154	reported that a human trophoblast cell line transfected with SV40 T antigen displayed increased proliferation and invasiveness, but was unable to form colonies on soft agar or tumors in nude mice.	('invasiveness', 'CPA', (114, 126))	('nude mice', 'Species', '10090', (186, 195))	('rat', 'Species', '10116', (103, 106))	('SV40 T', 'Var', (61, 67))	('increased', 'PosReg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('proliferation', 'CPA', (96, 109))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('human', 'Species', '9606', (16, 21))
12045	22075385	Positivity for Trop-2 mRNA by RT-PCR and surface expression by flow cytometry were detected in 2 of 4 cell lines, with high positivity noted in OMMT-ARK-2.	('mRNA', 'Var', (22, 26))	('Trop-2', 'Gene', (15, 21))	('ARK-2', 'Gene', (149, 154))	('Positivity', 'Var', (0, 10))	('ARK-2', 'Gene', '9212', (149, 154))	('surface expression', 'MPA', (41, 59))
12046	22075385	OMMT-ARK-2 was highly sensitive to hRS7 ADCC (range: 34.7-41.0%; P < 0.001) with negligible cytotoxicity seen in the absence of hRS7 or in the presence of control antibody (range: 1.1-2.5%).	('cytotoxicity', 'Disease', (92, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))	('hRS7', 'Var', (35, 39))	('ARK-2', 'Gene', (5, 10))	('ARK-2', 'Gene', '9212', (5, 10))
12122	22075385	Significantly, Trop-2 positivity was confined to the epithelial component of the carcinosarcomas, without exception.	('Trop-2', 'Gene', (15, 21))	('carcinosarcomas', 'Disease', (81, 96))	('positivity', 'Var', (22, 32))	('carcinosarcomas', 'Disease', 'MESH:D002296', (81, 96))
12125	22075385	Consistent with this, Trop-2 has been identified as an oncogene, implicated in colon cancer tumor growth, migration, and invasion, which suggests that Trop-2- specific targeting may inhibit tumor cell growth, migration and invasion.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('colon cancer tumor', 'Disease', (79, 97))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('targeting', 'Var', (168, 177))	('inhibit', 'NegReg', (182, 189))	('tumor', 'Disease', (190, 195))	('colon cancer tumor', 'Disease', 'MESH:D015179', (79, 97))	('tumor', 'Disease', (92, 97))	('Trop-2-', 'Gene', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
12126	22075385	Several human cancers have been shown to express a bicistronic CYCLIN D1-TROP2 mRNA chimera that acts as an oncogene and is able to induce aggressive tumor growth.	('cancers', 'Disease', (14, 21))	('aggressive tumor', 'Disease', (139, 155))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('human', 'Species', '9606', (8, 13))	('CYCLIN D1', 'Gene', '595', (63, 72))	('TROP2', 'Gene', (73, 78))	('TROP2', 'Gene', '4070', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('aggressive tumor', 'Disease', 'MESH:D001523', (139, 155))	('induce', 'PosReg', (132, 138))	('bicistronic', 'Var', (51, 62))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('CYCLIN D1', 'Gene', (63, 72))
12127	22075385	These observations support the possibility that aberrant Trop-2 expression contributes to the enhanced biologic aggressiveness of multiple human cancers, including carcinosarcomas.	('aggressiveness of multiple human cancers', 'Disease', (112, 152))	('aggressiveness', 'Phenotype', 'HP:0000718', (112, 126))	('Trop-2', 'Gene', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('aberrant', 'Var', (48, 56))	('carcinosarcomas', 'Disease', 'MESH:D002296', (164, 179))	('aggressiveness of multiple human cancers', 'Disease', 'MESH:D009369', (112, 152))	('enhanced', 'PosReg', (94, 102))	('carcinosarcomas', 'Disease', (164, 179))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
12130	22075385	This highly expressing cell line was found to have corresponding high sensitivity to hRS7-mediated ADCC, while negligible killing was detected in the presence of allogeneic PBL in the absence of hRS7 or in the presence of rituximab, used as a control antibody.	('hRS7-mediated', 'Var', (85, 98))	('rituximab', 'Chemical', 'MESH:D000069283', (222, 231))	('sensitivity', 'MPA', (70, 81))
12140	33923166	KLF5 Is Activated by Gene Amplification in Gastric Cancer and Is Essential for Gastric Cell Proliferation Gastric cancer is the third leading cause of cancer death worldwide.	('Gene Amplification', 'Var', (21, 39))	('KLF5', 'Gene', (0, 4))	('Gastric cancer', 'Disease', (106, 120))	('KLF5', 'Gene', '688', (0, 4))	('Gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('Activated', 'PosReg', (8, 17))	('Gastric Cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (43, 57))	('Gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Gastric Cancer', 'Disease', 'MESH:D013274', (43, 57))	('cancer death', 'Disease', (151, 163))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer death', 'Disease', 'MESH:D009369', (151, 163))
12144	33923166	We found that KLF5 amplification mainly occurred in the chromosome instable tumors (CIN) and was significantly associated with TP53 mutation.	('CIN', 'Disease', 'MESH:D007674', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('associated', 'Reg', (111, 121))	('KLF5', 'MPA', (14, 18))	('occurred', 'Reg', (40, 48))	('tumors', 'Disease', (76, 82))	('TP53', 'Gene', (127, 131))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (127, 131))	('mutation', 'Var', (132, 140))	('CIN', 'Disease', (84, 87))
12155	33923166	Drugs such as trastuzumab that targeting HER2 had been developed and showed good effects in selected gastric cancer patients with HER2 amplification.	('gastric cancer', 'Disease', (101, 115))	('amplification', 'Var', (135, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('patients', 'Species', '9606', (116, 124))	('trastuzumab', 'Chemical', 'MESH:D000068878', (14, 25))	('HER2', 'Gene', (41, 45))	('HER2', 'Gene', (130, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('HER2', 'Gene', '2064', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('HER2', 'Gene', '2064', (41, 45))
12178	33923166	All four datasets are whole transcriptome profiling studies comparing Klf5 knockout versus wild-type mouse tissues.	('Klf5', 'Gene', (70, 74))	('knockout', 'Var', (75, 83))	('mouse', 'Species', '10090', (101, 106))
12185	33923166	Western blot was probed with antibodies against GAPDH (bsm-0978M, Bioss, Beijing, China) or KLF5 (ab24331, Abcam, Cambridge, UK).	('bsm-0978M', 'Var', (55, 64))	('GAPDH', 'Gene', '2597', (48, 53))	('GAPDH', 'Gene', (48, 53))
12189	33923166	Copy number variation (CNV) of KLF5 is prevalent in different tumor types, according to a previous study.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Copy number variation', 'Var', (0, 21))	('KLF5', 'Gene', (31, 35))	('tumor', 'Disease', (62, 67))	('prevalent', 'Reg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
12191	33923166	In pan-cancer of 33 tumor types, the KLF5 gene showed both amplifications and deletions in different tumor types.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('KLF5 gene', 'Gene', (37, 46))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('deletions', 'Var', (78, 87))
12192	33923166	The rates of KLF5 variation ranged from 3.6% (acute myeloid leukemia, LAML) to 76.8% (uterine carcinosarcoma, UCS).	('acute myeloid leukemia', 'Disease', (46, 68))	('carcinosarcoma', 'Disease', 'MESH:D002296', (94, 108))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (46, 68))	('variation', 'Var', (18, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (86, 108))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (52, 68))	('carcinosarcoma', 'Disease', (94, 108))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (46, 68))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))
12194	33923166	Interestingly, both amplification and deletion of KLF5 could be found at a similar rate in some cancer types, such as uterine carcinosarcoma (UCS) and bladder cancer (BLCA).	('cancer', 'Disease', (159, 165))	('bladder cancer', 'Disease', (151, 165))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinosarcoma', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('KLF5', 'Gene', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('found', 'Reg', (64, 69))	('deletion', 'Var', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('amplification', 'Var', (20, 33))	('carcinosarcoma', 'Disease', 'MESH:D002296', (126, 140))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (96, 102))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (118, 140))
12197	33923166	In gastric cancer and a subset of bladder cancer, there were duplications of chromosome 13q as well as regional amplification of a region close to KLF5 (Figure 1B,C).	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('duplications', 'Var', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('gastric cancer', 'Disease', (3, 17))	('bladder cancer', 'Disease', (34, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
12198	33923166	In prostate cancer or another subset of bladder cancer, long segment deletion of chromosome 13q accounted for the loss of KLF5 (Figure 1B).	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('loss', 'NegReg', (114, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('long segment deletion', 'Var', (56, 77))	('KLF5', 'Protein', (122, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
12199	33923166	In gastrointestinal tumors with predominantly KLF5 amplification, including gastric cancer (STAD), colon cancer (COAD), and rectum cancer (READ), an increase in KLF5 transcripts could be observed (Figure 2, top 3).	('READ', 'Disease', (139, 143))	('gastrointestinal tumors', 'Disease', (3, 26))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (3, 26))	('rectum cancer', 'Disease', 'MESH:D012004', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('KLF5 transcripts', 'MPA', (161, 177))	('increase', 'PosReg', (149, 157))	('colon cancer', 'Disease', (99, 111))	('READ', 'Disease', 'None', (139, 143))	('rectum cancer', 'Disease', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('gastric cancer', 'Disease', (76, 90))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (3, 26))	('COAD', 'Disease', 'MESH:D029424', (113, 117))	('KLF5 amplification', 'Var', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rectum cancer', 'Phenotype', 'HP:0100743', (124, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('COAD', 'Disease', (113, 117))
12200	33923166	For prostate cancer (PRAD), kidney chromophobe (KICH), and testicular germ cell tumors (TGCT), KLF5 deletion was predominant, and a decrease in KLF5 transcription could be observed (Figure 2, middle 3).	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('KLF5 transcription', 'MPA', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('kidney chromophobe', 'Disease', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('KICH', 'Disease', (48, 52))	('kidney chromophobe', 'Disease', 'MESH:D000238', (28, 46))	('prostate cancer', 'Disease', (4, 19))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('KICH', 'Disease', 'None', (48, 52))	('deletion', 'Var', (100, 108))	('germ cell tumors', 'Phenotype', 'HP:0100728', (70, 86))	('decrease', 'NegReg', (132, 140))	('KLF5', 'Gene', (95, 99))
12201	33923166	For other tumor types such as esophageal carcinoma (ESCA), bladder urothelial carcinoma (BLCA) and uterine corpus endometrial carcinoma (UCEC), which had comparable rates of KLF5 amplification and deletion, KLF5 expression changed in accordance to its copy number (Figure 2, bottom 3).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (114, 135))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (30, 50))	('bladder urothelial carcinoma', 'Disease', (59, 87))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (30, 50))	('changed', 'Reg', (223, 230))	('deletion', 'Var', (197, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (114, 135))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (59, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('endometrial carcinoma', 'Disease', (114, 135))	('esophageal carcinoma', 'Disease', (30, 50))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
12210	33923166	This result suggested CNV of KLF5 was related to the overall chromosomal instability of gastric cancer.	('CNV', 'Var', (22, 25))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('KLF5', 'Gene', (29, 33))	('related', 'Reg', (38, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('chromosomal instability', 'Phenotype', 'HP:0040012', (61, 84))
12212	33923166	As shown in Figure 4B, KLF5 CNV was significantly associated with TP53 mutation (chi-square test: p = 4.3 x 10-5).	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('KLF5', 'Var', (23, 27))	('associated', 'Reg', (50, 60))
12216	33923166	KLF5 high expression tumors were less represented in the diffused type of gastric cancer (odds ratio = 0.3, p = 4.0 x 10-5) and TP53 mutated samples (odds ratio = 0.56, p = 0.03) (Figure 5).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KLF5', 'Gene', (0, 4))	('less', 'NegReg', (33, 37))	('diffused', 'Disease', (57, 65))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('high expression', 'PosReg', (5, 20))	('tumors', 'Disease', (21, 27))	('gastric cancer', 'Disease', (74, 88))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('mutated', 'Var', (133, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
12217	33923166	In multivariate logistic regression analysis, the diffused type of Lauren classification, TP53 mutation, and the MSI subtype of molecular classification were independent predictors of KLF5 expression (Supplementary Table S3).	('KLF5 expression', 'MPA', (184, 199))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
12228	33923166	All five studies profiled whole transcriptome of Klf5 knockout transgenic mice.	('Klf5', 'Gene', (49, 53))	('transgenic mice', 'Species', '10090', (63, 78))	('knockout', 'Var', (54, 62))
12229	33923166	Of the 84 genes, Cdkn1c (cyclin-dependent kinase inhibitor 1C) was among the few genes that were upregulated after the knockout of Klf5 (Supplementary Table S5).	('Cdkn1c', 'Gene', '1028', (17, 23))	('cyclin-dependent kinase inhibitor 1C', 'Gene', (25, 61))	('cyclin-dependent kinase inhibitor 1C', 'Gene', '1028', (25, 61))	('knockout', 'Var', (119, 127))	('Cdkn1c', 'Gene', (17, 23))	('upregulated', 'PosReg', (97, 108))
12242	33923166	After the silencing of KLF5, GPRC5A expression was significantly downregulated (Figure 7B).	('downregulated', 'NegReg', (65, 78))	('KLF5', 'Gene', (23, 27))	('GPRC5A', 'Gene', (29, 35))	('expression', 'MPA', (36, 46))	('silencing', 'Var', (10, 19))	('GPRC5A', 'Gene', '9052', (29, 35))
12256	33923166	In addition, KLF5 was inactivated by the hemizygous deletion in prostate cancer, and re-expression of KLF5 inhibits cell growth in vitro.	('cell growth in vitro', 'CPA', (116, 136))	('prostate cancer', 'Disease', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('inhibits', 'NegReg', (107, 115))	('re-expression', 'Var', (85, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (64, 79))	('KLF5', 'Gene', (102, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (64, 79))
12262	33923166	In most other tumor types, both KLF5 amplification and deletion were observed.	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('deletion', 'Var', (55, 63))
12266	33923166	More importantly, in ApcMin/KRAS V12 double transgenic mice that had a great tendency to develop small intestine tumors, deleting one allele of Klf5 led to a 92% reduction in tumor burden.	('tumor', 'Disease', (113, 118))	('reduction', 'NegReg', (162, 171))	('KRAS', 'Gene', (28, 32))	('tumor', 'Disease', (175, 180))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('transgenic mice', 'Species', '10090', (44, 59))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('deleting', 'Var', (121, 129))	('Klf5', 'Gene', (144, 148))	('KRAS', 'Gene', '16653', (28, 32))	('small intestine tumors', 'Phenotype', 'HP:0100833', (97, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
12273	33923166	However, a later study revealed that the nuclear staining of KLF5 was associated with more advanced cancer and poorer survival.	('nuclear staining', 'Var', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (70, 80))	('poorer', 'NegReg', (111, 117))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('KLF5', 'Gene', (61, 65))
12284	33923166	In addition, we also observed decreased clone formation ability of gastric cancer cells when KLF5 was silenced.	('gastric cancer', 'Disease', (67, 81))	('KLF5', 'Gene', (93, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('clone formation ability', 'CPA', (40, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('silenced', 'Var', (102, 110))	('decreased', 'NegReg', (30, 39))
12291	33923166	In summary, this study revealed that KLF5 underwent amplification or deletion in different tumor types, which led to up- or downregulation of KLF5 mRNA expression accordingly.	('tumor', 'Disease', (91, 96))	('amplification', 'Var', (52, 65))	('KLF5', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('up-', 'PosReg', (117, 120))	('deletion', 'Var', (69, 77))	('KLF5', 'Gene', (37, 41))	('downregulation', 'NegReg', (124, 138))
12293	33923166	KLF5 amplification was significantly associated with genome-unstable tumors and TP53 mutation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TP53', 'Gene', '7157', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutation', 'Var', (85, 93))	('TP53', 'Gene', (80, 84))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('associated', 'Reg', (37, 47))	('KLF5 amplification', 'Var', (0, 18))
12337	33649798	Furthermore, using the cBioportal pan-cancer panel, the present study identified specific cancer types with a number of TMPRSS4 amplifications in LGG, LUAD, STAD, deep deletions in BRCA, HNSC, and shallow deletions in BLCA, BRCA, CESC, ESCA, LUAD, LUSC, OV and TGCT.	('ESCA', 'Disease', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('deep deletions', 'Var', (163, 177))	('BRCA', 'Gene', (181, 185))	('LGG', 'Gene', (146, 149))	('TMPRSS4', 'Gene', (120, 127))	('BRCA', 'Gene', (224, 228))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BLCA', 'Gene', (218, 222))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('TMPRSS4', 'Gene', '56649', (120, 127))	('cancer', 'Disease', (38, 44))	('CESC', 'Disease', (230, 234))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('shallow deletions', 'Var', (197, 214))
12338	33649798	Furthermore, there were two datasets for thyroid cancers with a number of patients presenting diploid and not mutated versions of the gene, namely for THYM and THCA.	('THCA', 'Disease', (160, 164))	('diploid', 'Var', (94, 101))	('thyroid cancers', 'Disease', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (74, 82))	('thyroid cancers', 'Disease', 'MESH:D013964', (41, 56))	('THYM', 'Disease', (151, 155))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))
12339	33649798	Of note, in the majority of the studied cancers, the majority of the patients had deletions and partly some gains and amplifications (Fig.	('deletions', 'Var', (82, 91))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('gains', 'PosReg', (108, 113))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
12375	33161227	A pan-cancer analysis of HER2 index revealed transcriptional pattern for precise selection of HER2-targeted therapy The prevalence of HER2 alterations in pan-cancer indicates a broader range of application of HER2-targeted therapies; however, biomarkers for such therapies are still insufficient and limited to breast cancer and gastric cancer.	('breast cancer', 'Disease', 'MESH:D001943', (311, 324))	('cancer', 'Disease', (318, 324))	('breast cancer', 'Disease', (311, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('gastric cancer', 'Phenotype', 'HP:0012126', (329, 343))	('alterations', 'Var', (139, 150))	('cancer', 'Disease', (158, 164))	('HER2', 'Gene', (209, 213))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', '2064', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('HER2', 'Gene', '2064', (94, 98))	('gastric cancer', 'Disease', (329, 343))	('cancer', 'Disease', (337, 343))	('cancer', 'Disease', (6, 12))	('HER2', 'Gene', '2064', (209, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (311, 324))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (329, 343))	('HER2', 'Gene', (134, 138))	('HER2', 'Gene', '2064', (25, 29))	('HER2', 'Gene', (94, 98))
12379	33161227	Increased HER2 somatic copy number alterations (SCNAs) could be divided into two patterns, focal- or arm-level.	('HER2', 'Gene', (10, 14))	('somatic', 'Var', (15, 22))	('HER2', 'Gene', '2064', (10, 14))
12385	33161227	Therapies targeting human epidermal growth factor receptor 2 (HER2) have been routinely applied to patients of breast cancer and gastric cancer harboring HER2 alterations; such applications could be broader given the prevalence of aberrant HER2 status in multi-omics level in pan-cancer.	('cancer', 'Disease', (280, 286))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('human epidermal growth factor receptor 2', 'Gene', (20, 60))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('breast cancer', 'Disease', (111, 124))	('aberrant', 'Var', (231, 239))	('HER2', 'Gene', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('HER2', 'Gene', (240, 244))	('HER2', 'Gene', (154, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('HER2', 'Gene', '2064', (62, 66))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('alterations', 'Var', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (99, 107))	('human epidermal growth factor receptor 2', 'Gene', '2064', (20, 60))	('gastric cancer', 'Disease', (129, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('HER2', 'Gene', '2064', (240, 244))	('HER2', 'Gene', '2064', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
12394	33161227	Since aberrant HER2 status of multiple levels have been identified in a wide range of other tumors, including uterine cancer, gastroesophageal junction cancer, biliary tract cancer, colorectal cancer, non-small-cell lung cancer and bladder cancer, its application may be far beyond than the current.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (232, 246))	('cancer', 'Disease', (193, 199))	('bladder cancer', 'Disease', (232, 246))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (160, 180))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('non-small-cell lung cancer', 'Disease', (201, 227))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (201, 227))	('cancer', 'Disease', (240, 246))	('bladder cancer', 'Phenotype', 'HP:0009725', (232, 246))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('biliary tract cancer', 'Disease', 'MESH:D001661', (160, 180))	('cancer', 'Disease', (152, 158))	('identified', 'Reg', (56, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancer', 'Disease', (174, 180))	('HER2', 'Gene', '2064', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gastroesophageal junction cancer', 'Disease', 'MESH:D009369', (126, 158))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (205, 227))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumors', 'Disease', (92, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('uterine cancer', 'Phenotype', 'HP:0010784', (110, 124))	('cancer', 'Disease', (221, 227))	('aberrant', 'Var', (6, 14))	('colorectal cancer', 'Disease', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (201, 227))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('biliary tract cancer', 'Disease', (160, 180))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('HER2', 'Gene', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('gastroesophageal junction cancer', 'Disease', (126, 158))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
12406	33161227	Samples harbored mutations in ERBB2 were labeled as "mutation", while the rest were labeled as "wild".	('ERBB2', 'Gene', (30, 35))	('mutations', 'Var', (17, 26))	('ERBB2', 'Gene', '2064', (30, 35))
12409	33161227	Five cohorts "GSE81002", "GSE22358", "GSE20194", "GSE50948", and "GSE55348" were utilized to validate the performance of HER2 index in separating HER2-enriched subtype from other samples of BRCA.	('HER2', 'Gene', '2064', (121, 125))	('HER2', 'Gene', '2064', (146, 150))	('HER2', 'Gene', (121, 125))	('BRCA', 'Phenotype', 'HP:0003002', (190, 194))	('BRCA', 'Gene', '672', (190, 194))	('BRCA', 'Gene', (190, 194))	('GSE55348', 'Var', (66, 74))	('HER2', 'Gene', (146, 150))
12442	33161227	We investigated HER2 status of 11020 tumor samples from the TCGA database, encompassing 33 cancer types in aspect of copy number variation (CNV), single nucleotide variant (SNV), mRNA, reverse phase protein and phospho-protein array data (RPPA).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('HER2', 'Gene', (16, 20))	('HER2', 'Gene', '2064', (16, 20))	('tumor', 'Disease', (37, 42))	('mRNA', 'MPA', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('single nucleotide variant', 'Var', (146, 171))
12458	33161227	HER2 is an oncogene targeted by somatic copy-number alterations (SCNAs) to drive cancer growth.	('drive', 'PosReg', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('copy-number alterations', 'Var', (40, 63))
12473	33161227	Focal-amplification at the HER2 gene is associated with overexpressed HER2 mRNA, whereas arm-level gain had little influence on HER2 mRNA expression (Figure S5).	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', (70, 74))	('HER2', 'Gene', '2064', (128, 132))	('HER2', 'Gene', '2064', (70, 74))	('overexpressed', 'PosReg', (56, 69))	('Focal-amplification', 'Var', (0, 19))	('HER2', 'Gene', (27, 31))	('HER2', 'Gene', '2064', (27, 31))
12486	33161227	Luminal B was associated with elevated cell proliferation, in which cell cycle mitotic, G2-M transition, P53 pathway etc.	('P53', 'Gene', (105, 108))	('Luminal B', 'Var', (0, 9))	('Luminal', 'Chemical', 'MESH:D010634', (0, 7))	('P53', 'Gene', '7157', (105, 108))	('cell cycle mitotic', 'CPA', (68, 86))	('G2-M transition', 'CPA', (88, 103))	('elevated', 'PosReg', (30, 38))	('cell proliferation', 'CPA', (39, 57))
12517	33161227	Considering that ERBB3 and EGFR are also targeted by these pan-HER inhibitors, we additionally acquired the genome-scale CRISPR knockout results of HER2 gene across pan-cancer cell lines from depmap (Methods) and assessed the association between HER2 index and HER2-dependency score.	('EGFR', 'Gene', '1956', (27, 31))	('HER2', 'Gene', (148, 152))	('EGFR', 'Gene', (27, 31))	('cancer', 'Disease', (169, 175))	('ERBB3', 'Gene', '2065', (17, 22))	('HER2', 'Gene', '2064', (261, 265))	('HER2', 'Gene', '2064', (148, 152))	('ERBB3', 'Gene', (17, 22))	('HER2', 'Gene', (246, 250))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('HER2', 'Gene', '2064', (246, 250))	('knockout', 'Var', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('HER2', 'Gene', (261, 265))
12533	33161227	As for transcription level, the majority of HER2-aberrant tumors with high HER2 index displayed a HER2 transcription level below the cutoff (log10(HER2 mRNA cutoff) = 1.74).	('HER2-aberrant tumors', 'Disease', (44, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('below', 'NegReg', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HER2-aberrant tumors', 'Disease', 'MESH:D002869', (44, 64))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', (44, 48))	('HER2', 'Gene', (98, 102))	('HER2', 'Gene', '2064', (147, 151))	('HER2', 'Gene', '2064', (44, 48))	('HER2', 'Gene', (147, 151))	('HER2', 'Gene', '2064', (75, 79))	('HER2', 'Gene', '2064', (98, 102))	('high', 'Var', (70, 74))
12534	33161227	HNSC with high HER2 index had a significantly elevated HER2 protein and phosphor-protein level despite few HER2 amplifications and mRNA overexpression, coinciding with the landscape of HER2 status displayed in the total of HNSC samples (Fig.	('HER2', 'Gene', '2064', (107, 111))	('elevated', 'PosReg', (46, 54))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (15, 19))	('high', 'Var', (10, 14))	('HER2', 'Gene', (185, 189))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', '2064', (185, 189))	('HER2', 'Gene', (107, 111))	('HER2', 'Gene', '2064', (55, 59))
12557	33161227	HER2 mutation has been suggested as an alternative mechanism for activating HER2 signaling, and functional analysis have revealed several recurrent HER2 mutations that are likely to be driver alterations.	('HER2', 'Gene', (148, 152))	('HER2', 'Gene', (76, 80))	('HER2', 'Gene', '2064', (148, 152))	('mutations', 'Var', (153, 162))	('HER2', 'Gene', '2064', (76, 80))	('activating', 'PosReg', (65, 75))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
12558	33161227	We found that HER2 mutations were also common in pan-cancer, but they are mainly independent from HER2-amplification.	('HER2', 'Gene', '2064', (14, 18))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (19, 28))	('common', 'Reg', (39, 45))	('HER2', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('HER2', 'Gene', '2064', (98, 102))	('HER2', 'Gene', (14, 18))
12560	33161227	There is a small fraction of tumors having both HER2 amplification and mutation, however, whether they are same with purely HER2-amplified tumors remains uncertain.	('HER2', 'Gene', '2064', (48, 52))	('HER2', 'Gene', '2064', (124, 128))	('mutation', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (29, 35))	('HER2', 'Gene', (48, 52))	('HER2', 'Gene', (124, 128))
12561	33161227	Since oncogenic potentials have been identified in HER2 mutations, amplifications and changes in HER2 protein and variations in different cancers, thus identifying the significance of each alteration in the context of each cancer is needed in the future.	('HER2', 'Gene', (97, 101))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (138, 144))	('HER2', 'Gene', '2064', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('HER2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Disease', (223, 229))	('HER2', 'Gene', '2064', (51, 55))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('protein', 'Protein', (102, 109))
12567	33161227	Besides, we found different frequencies of Chr17q22-23 amplification between gynecologic tumors and gastrointestinal tumors.	('amplification', 'Var', (55, 68))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', (117, 123))	('gastrointestinal tumors', 'Disease', (100, 123))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (100, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('Chr17q22-23', 'Gene', (43, 54))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (100, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
12598	33161227	In recent years, emerging trials exploring the potential efficacy of HER2 targeted therapy in colorectal tumors, non-small cell lung cancer and bladder cancer with HER2 alterations (amplification,overexpression and mutations) exhibited variable responses, some of which are impressive.	('colorectal tumors', 'Disease', (94, 111))	('HER2', 'Gene', (164, 168))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('alterations', 'Var', (169, 180))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('mutations', 'Var', (215, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('HER2', 'Gene', '2064', (69, 73))	('colorectal tumors', 'Disease', 'MESH:D015179', (94, 111))	('HER2', 'Gene', '2064', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('lung cancer', 'Disease', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HER2', 'Gene', (69, 73))
12600	33161227	It is still unknown whether and what kind of HER2 alterations are relevant oncogenic drivers in pan-cancer tumor types, such as in NSCLC.	('cancer tumor', 'Disease', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('NSCLC', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (50, 61))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('cancer tumor', 'Disease', 'MESH:D009369', (100, 112))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (45, 49))
12604	33161227	The findings above suggested that therapeutics for HER2 may have potential value in a certain population of gastrointestinal tumors, HNSC, NSCLC, BLCA, CESC and UCEC identified by transcriptional pattern and HER2 alterations.	('HER2', 'Gene', (208, 212))	('CESC', 'Disease', (152, 156))	('HER2', 'Gene', '2064', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('HER2', 'Gene', '2064', (208, 212))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('NSCLC', 'Disease', (139, 144))	('UCEC', 'Disease', (161, 165))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (108, 131))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (108, 131))	('gastrointestinal tumors', 'Disease', (108, 131))	('alterations', 'Var', (213, 224))	('BLCA', 'Disease', (146, 150))	('HER2', 'Gene', (51, 55))	('HNSC', 'Disease', (133, 137))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))
12605	33161227	Additionally, the discordance between high index and absence of HER2 amplifications and overexpression in some samples may be explained by activating HER2 mutations as in NSCLC or alternative pathway activated in HER2-enriched expression pattern, such as KRAS mutation or AR signaling.	('HER2', 'Gene', '2064', (150, 154))	('KRAS', 'Gene', '3845', (255, 259))	('mutations', 'Var', (155, 164))	('activating', 'PosReg', (139, 149))	('HER2', 'Gene', (64, 68))	('KRAS', 'Gene', (255, 259))	('alternative pathway', 'Pathway', (180, 199))	('HER2', 'Gene', (150, 154))	('HER2', 'Gene', '2064', (64, 68))	('HER2', 'Gene', (213, 217))	('NSCLC', 'Disease', (171, 176))	('HER2', 'Gene', '2064', (213, 217))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
12622	31842516	These results emphasize that, in spite of the heterogeneous mutational burden among different cancers and even within the same tumor, some common hubs do exist.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutational', 'Var', (60, 70))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cancers', 'Disease', (94, 101))
12651	31842516	As expected, point mutations in RAS are not common in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (54, 80))	('point mutations', 'Var', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('RAS', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
12652	31842516	Interestingly, genetic alterations in HDAC4 are more frequent in uterine and stomach cancers, with a conspicuous incidence of truncations and point mutations of still unknown impact on the activities of this deacetylase (Figure 1).	('activities', 'MPA', (189, 199))	('frequent', 'Reg', (53, 61))	('stomach cancers', 'Disease', 'MESH:D013274', (77, 92))	('stomach cancers', 'Disease', (77, 92))	('truncations', 'MPA', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic alterations', 'Var', (15, 34))	('point mutations', 'Var', (142, 157))	('HDAC4', 'Gene', '9759', (38, 43))	('uterine', 'Disease', (65, 72))	('HDAC4', 'Gene', (38, 43))	('stomach cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
12656	31842516	To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC, BJ-hTERT/ST/LT/HRASG12V, and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A, relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.	('S246A', 'Mutation', 'p.S246A', (155, 160))	('HDAC4', 'Gene', (149, 154))	('MYC', 'Gene', (100, 103))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (134, 142))	('HDAC4', 'Gene', '9759', (149, 154))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (85, 93))	('S632A', 'SUBSTITUTION', 'None', (169, 174))	('S632A', 'Var', (169, 174))	('MYC', 'Gene', '4609', (100, 103))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (105, 113))	('S467A', 'Var', (162, 167))	('S467A', 'SUBSTITUTION', 'None', (162, 167))
12688	31842516	Finally, SRPX (sushi repeat containing protein X-linked), known also as ETX1 or DRS, was initially isolated as deleted in patients with X-linked retinitis pigmentosa, as well as downregulated by v-src.	('X-linked retinitis pigmentosa', 'Disease', (136, 165))	('retinitis', 'Phenotype', 'HP:0032118', (145, 154))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (145, 165))	('ETX1', 'Gene', '8406', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', '8406', (15, 55))	('downregulated', 'NegReg', (178, 191))	('SRPX', 'Gene', (9, 13))	('DRS', 'Gene', '8406', (80, 83))	('deleted', 'Var', (111, 118))	('patients', 'Species', '9606', (122, 130))	('SRPX', 'Gene', '8406', (9, 13))	('DRS', 'Gene', (80, 83))	('ETX1', 'Gene', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', (15, 55))	('X-linked retinitis pigmentosa', 'Disease', 'MESH:D012174', (136, 165))
12697	31842516	In fact in ACC, which is a rare, aggressive malignancy, G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal disease, amenable to targeted assessment using routine molecular diagnostics.	('aggressive malignancy', 'Disease', 'MESH:D001523', (33, 54))	('ACC', 'Disease', 'MESH:D018268', (11, 14))	('hypermethylation', 'Var', (61, 77))	('G0S2', 'Gene', (56, 60))	('aggressive malignancy', 'Disease', (33, 54))	('ACC', 'Disease', (11, 14))
12698	31842516	Very low levels of G0S2 mRNA expression characterize tumors with G0S2 hypermethylation.	('hypermethylation', 'Var', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('G0S2', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))	('G0S2', 'Protein', (19, 23))
12733	31842516	G0S2 is abundantly expressed in adipose tissue and G0S2 transgenic mice experience difficulties in shifting from carbohydrate to FA oxidation during fasting.	('transgenic mice', 'Species', '10090', (56, 71))	('shifting from carbohydrate to FA oxidation', 'MPA', (99, 141))	('G0S2', 'Gene', (51, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (113, 125))	('transgenic', 'Var', (56, 66))
12741	31842516	The recent discovery that the targeting of MYC through an epigenetic therapy provides an important advantage for an efficient immunotherapy could represent an important clinical perspective of all these studies.	('MYC', 'Gene', (43, 46))	('MYC', 'Gene', '4609', (43, 46))	('epigenetic therapy', 'Var', (58, 76))	('advantage', 'PosReg', (99, 108))
12752	31842516	In each dataset, the transformation model represented by pre-transformed BJ cells expressing RAS G12V (GSE17941) or MYC (GSE72530) or HDAC4 (GSE120040) was compared to the pre-transformation model which is represented by BJ fibroblasts expressing hTERT, LT, and ST SV40 genes.	('G12V', 'Mutation', 'rs104894230', (97, 101))	('BJ', 'CellLine', 'CVCL:6573', (73, 75))	('BJ', 'CellLine', 'CVCL:6573', (221, 223))	('hTERT', 'Gene', (247, 252))	('MYC', 'Gene', '4609', (116, 119))	('HDAC4', 'Gene', '9759', (134, 139))	('GSE120040', 'Var', (141, 150))	('HDAC4', 'Gene', (134, 139))	('hTERT', 'Gene', '7015', (247, 252))	('GSE17941', 'Var', (103, 111))	('GSE72530', 'Var', (121, 129))	('MYC', 'Gene', (116, 119))
12763	31842516	To evaluate the contribution/disturbance of the inflammatory infiltrate to the prediction of survival based on the transformation signatures, patients were divided into four groups accordingly to the expression levels of genes belonging to the MCPcounter signatures and to the transformation signatures: High-high (high levels of both), high-low (high MCP/low transformation), low-low (low levels of both), or low-high (low MCP-high transformation).	('MCP', 'Gene', (352, 355))	('MCP', 'Gene', (424, 427))	('MCP', 'Gene', '822', (244, 247))	('low-high', 'Var', (410, 418))	('MCP', 'Gene', '822', (352, 355))	('MCP', 'Gene', '822', (424, 427))	('patients', 'Species', '9606', (142, 150))	('MCP', 'Gene', (244, 247))	('low MCP', 'Phenotype', 'HP:0025066', (420, 427))
12796	30741844	For example, significant genetic alterations seen in uterine serous carcinoma and endometrioid carcinoma can be helpful to differentiate these similar histologic types of endometrial cancer (Figure 3).	('endometrial cancer', 'Disease', 'MESH:D016889', (171, 189))	('endometrial cancer', 'Phenotype', 'HP:0012114', (171, 189))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (82, 104))	('serous carcinoma', 'Disease', 'MESH:D018297', (61, 77))	('serous carcinoma', 'Disease', (61, 77))	('endometrioid carcinoma', 'Disease', (82, 104))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('endometrial cancer', 'Disease', (171, 189))	('genetic alterations', 'Var', (25, 44))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (82, 104))
12800	30741844	The analyses identified four categories of endometrial carcinomas with distinct clinical, pathologic, and molecular features: POLE (ultra-mutated) (7%), microsatellite instability (MSI)/hypermutated (28%), copy number low/microsatellite stable (39%), and serous-like/copy number high (26%).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (43, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('endometrial carcinomas', 'Disease', (43, 65))	('copy number low/microsatellite stable', 'Var', (206, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('microsatellite instability', 'MPA', (153, 179))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (43, 65))	('POLE', 'Disease', (126, 130))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (43, 65))
12804	30741844	Similarly, a cohort of POLE-mutated endometrial carcinomas showed favorable prognosis despite a significant proportion exhibiting high-grade histology, morphologic heterogeneity, severe nuclear atypia, and TP53 mutations.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (36, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('endometrial carcinomas', 'Disease', (36, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('mutations', 'Var', (211, 220))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (36, 58))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (36, 58))
12807	30741844	Common mutations in the MSI subgroup include ARID5B mutations, PTEN mutations, and mutations in the phosphatidylinositol-3-kinase family genes including PIK3CA and PIK3R1.	('mutations', 'Var', (52, 61))	('mutations', 'Var', (83, 92))	('PIK3CA', 'Gene', '5290', (153, 159))	('PIK3R1', 'Gene', '5295', (164, 170))	('PTEN', 'Gene', '5728', (63, 67))	('PIK3R1', 'Gene', (164, 170))	('ARID5B', 'Gene', '84159', (45, 51))	('ARID5B', 'Gene', (45, 51))	('mutations', 'Var', (68, 77))	('PIK3CA', 'Gene', (153, 159))	('PTEN', 'Gene', (63, 67))
12811	30741844	In general, tumors in the CN high subgroup exhibit the least favorable prognosis among the four molecular subgroups.	('CN high', 'Var', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
12824	30741844	While the Pap test is generally not successful at detecting endometrial and ovarian cancers, the advantage of the PapSEEK test is the use of ultrasensitive next generation sequencing to detect tumor DNA with cancer driving alterations from early ovarian and endometrial cancer lesions even when cells are not available for histologic assessment.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('Pap', 'Gene', (114, 117))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('Pap', 'Gene', (10, 13))	('ovarian and endometrial cancer lesions', 'Disease', 'MESH:D004714', (246, 284))	('endometrial cancer', 'Phenotype', 'HP:0012114', (258, 276))	('cancer', 'Disease', (270, 276))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('endometrial and ovarian cancers', 'Disease', 'MESH:D004714', (60, 91))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('tumor', 'Disease', (193, 198))	('alterations', 'Var', (223, 234))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Disease', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Pap', 'Gene', '10914', (114, 117))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('Pap', 'Gene', '10914', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('ovarian cancers', 'Phenotype', 'HP:0100615', (76, 91))
12829	30741844	Detection of mutations in 18 genes and tests for aneuploidy were performed on DNA samples purified from plasma, Pap brush samples, and Tao brush samples from patients with endometrial cancer.	('aneuploidy', 'Disease', (49, 59))	('Pap', 'Gene', '10914', (112, 115))	('endometrial cancer', 'Disease', 'MESH:D016889', (172, 190))	('endometrial cancer', 'Phenotype', 'HP:0012114', (172, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Pap', 'Gene', (112, 115))	('aneuploidy', 'Disease', 'MESH:D000782', (49, 59))	('patients', 'Species', '9606', (158, 166))	('mutations', 'Var', (13, 22))	('endometrial cancer', 'Disease', (172, 190))
12841	30741844	In addition, mutations in ESR1 (the gene encoding ERalpha)conferring constitutive activity are emerging as resistance mechanisms to endocrine therapy in gynecologic malignancies, similar to the emergence of these mutations in endocrine resistant breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('malignancies', 'Disease', 'MESH:D009369', (165, 177))	('endocrine resistant breast cancer', 'Disease', (226, 259))	('endocrine resistant breast cancer', 'Disease', 'MESH:D001943', (226, 259))	('ESR1', 'Gene', '2099', (26, 30))	('malignancies', 'Disease', (165, 177))	('ERalpha', 'Gene', '2099', (50, 57))	('mutations', 'Var', (13, 22))	('ERalpha', 'Gene', (50, 57))	('resistance mechanisms to endocrine therapy', 'MPA', (107, 149))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('ESR1', 'Gene', (26, 30))
12842	30741844	ERBB2 oncogene amplification and overexpression of its encoded proteins (HER2/Neu) are significantly associated with uterine serous carcinoma, and are considered a negative prognostic indicator.	('overexpression', 'PosReg', (33, 47))	('serous carcinoma', 'Disease', (125, 141))	('HER2', 'Gene', '2064', (73, 77))	('amplification', 'Var', (15, 28))	('ERBB2', 'Gene', '2064', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ERBB2', 'Gene', (0, 5))	('Neu', 'Gene', (78, 81))	('Neu', 'Gene', '2064', (78, 81))	('associated', 'Reg', (101, 111))	('HER2', 'Gene', (73, 77))	('serous carcinoma', 'Disease', 'MESH:D018297', (125, 141))
12849	30741844	Tumors harboring POLE mutations are also expected to have favorable responses due to the ultra-high mutation burden.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (22, 31))
12856	30741844	ARID1A is the most commonly mutated gene among all members of chromatin remodeling genes, and inactivating ARID1A mutations can frequently be detected in a wide spectrum of human malignancies, particularly in endometrium-derived carcinomas.	('detected', 'Reg', (142, 150))	('inactivating', 'Var', (94, 106))	('mutations', 'Var', (114, 123))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', '8289', (107, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('malignancies', 'Disease', (179, 191))	('ARID1A', 'Gene', (107, 113))	('ARID1A', 'Gene', (0, 6))	('carcinomas', 'Disease', 'MESH:D009369', (229, 239))	('human', 'Species', '9606', (173, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (229, 239))	('carcinomas', 'Disease', (229, 239))
12857	30741844	Inactivating ARID1A mutations are commonly detected in endometrioid endometrial carcinomas and are associated with worse prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('ARID1A', 'Gene', '8289', (13, 19))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (55, 90))	('ARID1A', 'Gene', (13, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('Inactivating', 'Var', (0, 12))	('detected', 'Reg', (43, 51))	('endometrioid endometrial carcinomas', 'Disease', (55, 90))	('mutations', 'Var', (20, 29))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (68, 90))
12859	30741844	ARID1A mutation can be used as a biomarker for identifying early stage cancer or for assessing new therapies.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('ARID1A', 'Gene', '8289', (0, 6))	('cancer', 'Disease', (71, 77))	('ARID1A', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
12861	30741844	ARID1A mutation may also sensitize cancer cells to EZH2 inhibitor therapy because of synthetic lethality.	('EZH2', 'Gene', '2146', (51, 55))	('ARID1A', 'Gene', '8289', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('EZH2', 'Gene', (51, 55))	('ARID1A', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('sensitize', 'Reg', (25, 34))	('cancer', 'Disease', (35, 41))
12862	30741844	Similarly, ARID1A mutation can sensitize tumor cells to PARP inhibitor and conventional chemotherapeutic drugs because of its role in DNA damage repair.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('ARID1A', 'Gene', '8289', (11, 17))	('ARID1A', 'Gene', (11, 17))	('PARP', 'Gene', '1302', (56, 60))	('mutation', 'Var', (18, 26))	('PARP', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('sensitize', 'Reg', (31, 40))
12864	30741844	Although there is no current consensus on which tests to perform, it is clear that certain molecular tests, such as the evaluation of mismatch repair, POLE, and HER2, are important because of the potential efficacy of immune checkpoint inhibitors and other targeted therapies.	('HER2', 'Gene', '2064', (161, 165))	('HER2', 'Gene', (161, 165))	('mismatch', 'Var', (134, 142))
12880	30356358	The level of tumor markers was not elevated: CA125, 17 U/ml; CA19-9, 9 U/ml; CA72-4, 2.9 U/ml; CEA, 1.1 ng/ml; and SCC, 0.9 ng/ml.	('CA72-4', 'Var', (77, 83))	('tumor', 'Disease', (13, 18))	('CA19-9', 'Var', (61, 67))	('CA125', 'Gene', '94025', (45, 50))	('CEA', 'Gene', (95, 98))	('SCC', 'Gene', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('CEA', 'Gene', '1084', (95, 98))	('CA72', 'Chemical', '-', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('SCC', 'Gene', '6317', (115, 118))	('CA125', 'Gene', (45, 50))
13193	27743738	Recognizing that women diagnosed with Type II, high-grade uterine cancer are usually older, possess comorbidities and are more likely to require adjuvant therapies than those with Type I malignancies, there is great interest in minimizing surgical morbidity in this population.	('Type I malignancies', 'Disease', 'MESH:D009369', (180, 199))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Type I malignancies', 'Disease', (180, 199))	('high-grade', 'Var', (47, 57))	('uterine cancer', 'Phenotype', 'HP:0010784', (58, 72))
13252	27503773	Recently, other studies also showed that laparoscopic surgery may lead to malignant planting in operating hole, abdominal and pelvic sarcoma.	('laparoscopic', 'Var', (41, 53))	('malignant planting', 'CPA', (74, 92))	('operating hole', 'Disease', (96, 110))	('pelvic sarcoma', 'Disease', (126, 140))	('lead to', 'Reg', (66, 73))	('pelvic sarcoma', 'Disease', 'MESH:D034161', (126, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
13268	27503773	Even by going through the operating holes, sub broken surgery may cause abdominal and pelvic sarcoma metastasis, resulting in a rapid development of this tumor.	('rapid development', 'MPA', (128, 145))	('pelvic sarcoma metastasis', 'Disease', (86, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cause', 'Reg', (66, 71))	('pelvic sarcoma metastasis', 'Disease', 'MESH:D009362', (86, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('sub broken surgery', 'Var', (43, 61))	('tumor', 'Disease', (154, 159))
13298	27503773	Supplemented treatment or even secondary cytoreductive surgery may improve prognosis for patients with tumor recurrence caused by sub-broken surgery.	('prognosis', 'MPA', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('improve', 'PosReg', (67, 74))	('sub-broken surgery', 'Var', (130, 148))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
13360	26161403	To asses MVD in tumors tissues many markers were used, that is, CD34, CD31, CD105, and von Willebrand factor.	('CD31', 'Gene', '5175', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('CD34', 'Gene', (64, 68))	('CD34', 'Gene', '947', (64, 68))	('CD105', 'Var', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('von Willebrand', 'Disease', (87, 101))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('von Willebrand', 'Disease', 'MESH:D014842', (87, 101))	('CD31', 'Gene', (70, 74))
13361	26161403	The undisputed advantage of glycoprotein CD34 is its high sensitivity and specificity, especially in endothelial cells staining.	('glycoprotein', 'Var', (28, 40))	('CD34', 'Gene', '947', (41, 45))	('CD34', 'Gene', (41, 45))
13424	22557781	MMMT of uterus are associated with a less favorable outcome than uterine carcinoma with 5-year survival rates ranging between 33 and 39%.	('carcinoma', 'Disease', (73, 82))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (65, 82))	('MMMT', 'Var', (0, 4))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
13512	33671587	They reported that miR-323-3p inhibited apoptosis through directly targeting programmed cell death protein 4 (PDCD4) in exosome-treated CCs and thus, it alleviated PCOS.	('PCOS', 'Disease', (164, 168))	('targeting', 'Reg', (67, 76))	('programmed cell death protein 4', 'Gene', (77, 108))	('apoptosis', 'CPA', (40, 49))	('alleviated', 'NegReg', (153, 163))	('inhibited', 'NegReg', (30, 39))	('PCOS', 'Disease', 'MESH:D011085', (164, 168))	('programmed cell death protein 4', 'Gene', '27250', (77, 108))	('miR-323-3p', 'Var', (19, 29))	('PDCD4', 'Gene', (110, 115))	('PDCD4', 'Gene', '27250', (110, 115))	('miR-323-3p', 'Chemical', '-', (19, 29))
13519	33671587	The communication between RNAs for controlling each other's expression through competing for shared sequences in miRNAs is recognized as ceRNA hypothesis.	('expression', 'MPA', (60, 70))	('miR', 'Gene', (113, 116))	('miR', 'Gene', '220972', (113, 116))	('communication', 'Var', (4, 17))
13539	33671587	This effect was mediated by miR-664-5p, as the main RNA in these exosomes, through targeting p53.	('miR-664-5p', 'Chemical', '-', (28, 38))	('p53', 'Gene', '7157', (93, 96))	('p53', 'Gene', (93, 96))	('targeting', 'Reg', (83, 92))	('miR-664-5p', 'Var', (28, 38))
13543	33671587	Furthermore, amniotic fluid stem cells (AFSCs)-derived exosomes inhibited ovarian follicular atresia in POF mice by delivering exosomal miR-10a and miR-146a, thereby regulating their target genes, including Bim, Irak1, and Traf6 in the apoptotic pathway.	('ovarian follicular atresia', 'Disease', (74, 100))	('Irak1', 'Gene', '16179', (212, 217))	('POF', 'Gene', (104, 107))	('inhibited', 'NegReg', (64, 73))	('POF', 'Gene', '79983', (104, 107))	('Traf6', 'Gene', '22034', (223, 228))	('mice', 'Species', '10090', (108, 112))	('miR-146a', 'Var', (148, 156))	('Traf6', 'Gene', (223, 228))	('apoptotic pathway', 'Pathway', (236, 253))	('Irak1', 'Gene', (212, 217))	('POF', 'Phenotype', 'HP:0008209', (104, 107))	('Bim', 'Gene', '12125', (207, 210))	('ovarian follicular atresia', 'Disease', 'MESH:D010049', (74, 100))	('Bim', 'Gene', (207, 210))	('regulating', 'Reg', (166, 176))
13578	33671587	In the study, lncRNA-miRNA-seq analysis exhibited a complicated lncRNA-miR375, miR-30d-5p, and miR-27a-3p axis network, which involved a lower level of lncRNAs LINC00293, LINC00929, MEG8, SNHG25, and RP5-898J17.1 and a higher level of lncRNAs LINC00998, NEAT1, PVT1, H19, and RP4-561L24.3 in exosomes derived from ectopic endometriotic lesions.	('LINC00293', 'Gene', '497634', (160, 169))	('LINC00998', 'Gene', '401397', (243, 252))	('miR', 'Gene', (21, 24))	('miR375', 'Gene', '494324', (71, 77))	('LINC00929', 'Gene', '503519', (171, 180))	('RP5-898J17.1', 'Var', (200, 212))	('higher', 'PosReg', (219, 225))	('NEAT1', 'Gene', (254, 259))	('PVT1', 'Gene', (261, 265))	('MEG8', 'Gene', (182, 186))	('RP4', 'Gene', '6010', (276, 279))	('miR-27a', 'Gene', '407018', (95, 102))	('RP4', 'Gene', (276, 279))	('PVT1', 'Gene', '5820', (261, 265))	('miR', 'Gene', '220972', (71, 74))	('miR', 'Gene', '220972', (95, 98))	('miR-30d', 'Gene', (79, 86))	('lower', 'NegReg', (137, 142))	('miR', 'Gene', '220972', (79, 82))	('SNHG25', 'Gene', '105376843', (188, 194))	('ecto', 'Gene', (314, 318))	('miR375', 'Gene', (71, 77))	('SNHG25', 'Gene', (188, 194))	('miR', 'Gene', (71, 74))	('LINC00998', 'Gene', (243, 252))	('miR', 'Gene', (95, 98))	('NEAT1', 'Gene', '283131', (254, 259))	('MEG8', 'Gene', '79104', (182, 186))	('miR', 'Gene', '220972', (21, 24))	('miR-27a', 'Gene', (95, 102))	('LINC00929', 'Gene', (171, 180))	('miR-30d', 'Gene', '407033', (79, 86))	('miR', 'Gene', (79, 82))	('ecto', 'Gene', '51592', (314, 318))	('LINC00293', 'Gene', (160, 169))
13579	33671587	Together, these non-coding RNAs in this axis regulated many signaling pathway target genes associated with endometriosis, as well as angiogenesis and inflammation.	('non-coding RNAs', 'Var', (16, 31))	('signaling pathway', 'Pathway', (60, 77))	('endometriosis', 'Disease', 'MESH:D004715', (107, 120))	('inflammation', 'Disease', 'MESH:D007249', (150, 162))	('endometriosis', 'Disease', (107, 120))	('endometriosis', 'Phenotype', 'HP:0030127', (107, 120))	('inflammation', 'Disease', (150, 162))	('regulated', 'Reg', (45, 54))
13626	33671587	Another study indicated a higher level of total (TF+), endothelial (CD144+), and monocytic (CD14+) microparticles as candidate biomarkers in peripheral and uterine blood samples of endometrial cancer patients.	('patients', 'Species', '9606', (200, 208))	('higher', 'PosReg', (26, 32))	('CD14+', 'Var', (92, 97))	('endometrial cancer', 'Disease', 'MESH:D016889', (181, 199))	('TF', 'Gene', '2152', (49, 51))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('CD144', 'Gene', '1003', (68, 73))	('endometrial cancer', 'Disease', (181, 199))	('CD144', 'Gene', (68, 73))	('endometrial cancer', 'Phenotype', 'HP:0012114', (181, 199))
13634	33671587	The cargo contents of HeLa-derived survivin-positive exosomes were investigated, and a total of 52 differentially expressed miRNAs were reported, among which 23 of them were affected by E6/E7 silencing.	('affected', 'Reg', (174, 182))	('E6/E7 silencing', 'Var', (186, 201))	('HeLa', 'CellLine', 'CVCL:0030', (22, 26))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', (124, 127))
13638	33671587	Importantly, miR-221-3p is capable of regulating EMT in cancer cells.	('miR-221-3p', 'Var', (13, 23))	('miR-221-3p', 'Chemical', '-', (13, 23))	('regulating', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('EMT in', 'CPA', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (56, 62))
13639	33671587	Moreover, bioinformatics analysis predicted that thrombospondin-2 (THBS2) might be a direct target gene of miR-221-3p.	('thrombospondin-2', 'Gene', (49, 65))	('miR-221-3p', 'Var', (107, 117))	('THBS2', 'Gene', '7058', (67, 72))	('miR-221-3p', 'Chemical', '-', (107, 117))	('thrombospondin-2', 'Gene', '7058', (49, 65))	('THBS2', 'Gene', (67, 72))
13662	33671587	For instance, it is indicated that membrane proteins, such as TSG 101 and Alix; as well as tetraspanins; including CD9, CD24, CD44, and CD63, transferred by exosomes contribute to the development of ovarian cancer.	('CD63', 'Var', (136, 140))	('CD9', 'Gene', (115, 118))	('contribute', 'Reg', (166, 176))	('ovarian cancer', 'Phenotype', 'HP:0100615', (199, 213))	('CD24', 'Var', (120, 124))	('CD44', 'Var', (126, 130))	('ovarian cancer', 'Disease', 'MESH:D010051', (199, 213))	('Alix', 'Gene', (74, 78))	('ovarian cancer', 'Disease', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TSG 101', 'Gene', '7251', (62, 69))	('Alix', 'Gene', '10015', (74, 78))	('CD9', 'Gene', '928', (115, 118))	('TSG 101', 'Gene', (62, 69))
13694	33671587	For example, a study showed a lower expression of miR-23a-3p, miR-125b-2-3p, miR-144-3p, miR-192-5p, miR-205-5p, miR-208a-3p, miR-335-5p, miR-451a, miR-518a-3p, and miR-542-3p and a higher expression of let-7a-5p, miR-17-5p, miR-26a-5p, miR-30c-5p, miR-141-3p, miR-199a-3p, miR-221-3p, miR-584-5p, miR-744-5p, and miR-6724-5p in exosomes isolated from patients with preeclampsia compared to normal women.	('lower', 'NegReg', (30, 35))	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (274, 277))	('miR', 'Gene', '220972', (298, 301))	('miR', 'Gene', (214, 217))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (126, 129))	('miR-30c', 'Gene', '407031', (237, 244))	('miR-451a', 'Gene', (138, 146))	('miR', 'Gene', (165, 168))	('higher', 'PosReg', (182, 188))	('miR', 'Gene', '220972', (138, 141))	('women', 'Species', '9606', (398, 403))	('miR', 'Gene', (148, 151))	('miR', 'Gene', (101, 104))	('miR-192', 'Gene', (89, 96))	('miR', 'Gene', '220972', (225, 228))	('miR', 'Gene', '220972', (314, 317))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', '220972', (249, 252))	('miR-205', 'Gene', '406988', (101, 108))	('miR', 'Gene', (274, 277))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (298, 301))	('miR-744', 'Gene', (298, 305))	('let-7a-5p', 'Var', (203, 212))	('miR', 'Gene', (138, 141))	('preeclampsia', 'Phenotype', 'HP:0100602', (366, 378))	('miR-144', 'Gene', (77, 84))	('miR-144', 'Gene', '100314192', (77, 84))	('miR', 'Gene', (314, 317))	('miR', 'Gene', (225, 228))	('miR', 'Gene', (50, 53))	('miR-30c', 'Gene', (237, 244))	('miR-199a-3p', 'Gene', (261, 272))	('miR', 'Gene', (249, 252))	('miR', 'Gene', (113, 116))	('miR-335', 'Gene', '442904', (126, 133))	('miR', 'Gene', (89, 92))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', '220972', (237, 240))	('miR-451a', 'Gene', '574411', (138, 146))	('miR', 'Gene', '220972', (261, 264))	('miR-199a-3p', 'Gene', '406977', (261, 272))	('miR-17-5p', 'Gene', '406952', (214, 223))	('miR', 'Gene', (286, 289))	('miR', 'Gene', '220972', (286, 289))	('miR-17-5p', 'Gene', (214, 223))	('miR-205', 'Gene', (101, 108))	('miR', 'Gene', '220972', (77, 80))	('miR-192', 'Gene', '406967', (89, 96))	('miR-221-3p', 'Chemical', '-', (274, 284))	('miR', 'Gene', '220972', (214, 217))	('patients', 'Species', '9606', (352, 360))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (62, 65))	('miR-744', 'Gene', '100126313', (298, 305))	('expression', 'MPA', (189, 199))	('miR', 'Gene', (237, 240))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', (261, 264))	('miR-335', 'Gene', (126, 133))	('miR', 'Gene', '220972', (148, 151))	('expression', 'MPA', (36, 46))
13697	33671587	First, miR-525e5p is capable of suppressing the vasoactive intestinal peptide (VIP) as a strong anti-inflammatory factor.	('miR-525e5p', 'Var', (7, 17))	('vasoactive intestinal peptide', 'Gene', (48, 77))	('VIP', 'Gene', '7432', (79, 82))	('VIP', 'Gene', (79, 82))	('miR-525e5p', 'Chemical', '-', (7, 17))	('vasoactive intestinal peptide', 'Gene', '7432', (48, 77))	('suppressing', 'NegReg', (32, 43))
13827	32183290	Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations.	('HER2', 'Gene', '2064', (187, 191))	('patient', 'Species', '9606', (220, 227))	('HER2', 'Gene', (187, 191))	('PI3K3CA', 'Var', (196, 203))
13835	32183290	Type II tumors (nonendometrioid carcinomas), such as serous carcinoma, clear cell carcinoma, carcinosarcoma/malignant-mixed Mullerian tumor, and partial grade 3 endometrioid EC (EEC), are characterized by poorly differentiated histology and deep migration/invasion.	('EC', 'Phenotype', 'HP:0012114', (174, 176))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('partial grade 3', 'Var', (145, 160))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('carcinosarcoma', 'Disease', (93, 107))	('carcinosarcoma', 'Disease', 'MESH:D002296', (93, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('carcinomas', 'Disease', 'MESH:D009369', (32, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('Type II tumors', 'Disease', (0, 14))	('clear cell carcinoma', 'Disease', (71, 91))	('EC', 'Phenotype', 'HP:0012114', (179, 181))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', (134, 139))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (71, 91))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('EEC', 'Chemical', '-', (178, 181))	('serous carcinoma', 'Disease', 'MESH:D018297', (53, 69))	('serous carcinoma', 'Disease', (53, 69))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Disease', (32, 42))	('Type II tumors', 'Disease', 'MESH:D009369', (0, 14))
13846	32183290	In light of poor patient survival and high recurrence rates, the development of targeted therapies specific to USC pathway aberrations would aid in its management.	('patient', 'Species', '9606', (17, 24))	('aberrations', 'Var', (123, 134))	('USC', 'Gene', (111, 114))
13849	32183290	The third subgroup consists ECs that are MMR proficient and have mutations in genes associated with the PI3K/Akt and Wnt signaling pathways.	('mutations', 'Var', (65, 74))	('EC', 'Phenotype', 'HP:0012114', (28, 30))	('Akt', 'Gene', '207', (109, 112))	('Akt', 'Gene', (109, 112))
13850	32183290	The fourth subgroup consists of ECs that are similar to high-grade serous ovarian cancer and have high frequencies of somatic copy number alterations and TP53 mutations.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('TP53', 'Gene', (154, 158))	('mutations', 'Var', (159, 168))	('serous ovarian cancer', 'Disease', (67, 88))	('high-grade', 'Disease', (56, 66))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (67, 88))	('TP53', 'Gene', '7157', (154, 158))	('EC', 'Phenotype', 'HP:0012114', (32, 34))
13858	32183290	In type I EC, unopposed estrogen is considered the predominant driver for tumor initiation, and deregulated balance of pro-growth estrogens and anti-growth progestogens is the potent trigger of the disease.	('EC', 'Phenotype', 'HP:0012114', (10, 12))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor initiation', 'Disease', 'MESH:D009369', (74, 90))	('deregulated', 'Var', (96, 107))	('type', 'Disease', (3, 7))	('tumor initiation', 'Disease', (74, 90))
13860	32183290	Alterations of MMR genes MLH1 and MSH6 exist in about 33% of type I EC patients; these alterations drive non-atypical hyperplasia to complex atypical hyperplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (150, 161))	('hyperplasia', 'Disease', (118, 129))	('EC', 'Phenotype', 'HP:0012114', (68, 70))	('drive', 'Reg', (99, 104))	('type I EC', 'Disease', (61, 70))	('MMR', 'Gene', (15, 18))	('alterations', 'Var', (87, 98))	('Alterations', 'Var', (0, 11))	('patients', 'Species', '9606', (71, 79))	('MSH6', 'Gene', '2956', (34, 38))	('MLH1', 'Gene', '4292', (25, 29))	('MLH1', 'Gene', (25, 29))	('hyperplasia', 'Disease', 'MESH:D006965', (118, 129))	('hyperplasia', 'Disease', (150, 161))	('MSH6', 'Gene', (34, 38))
13861	32183290	PTEN mutation occurs in approximately 40% to 60% of type I ECs, and both MLH1 and MSH6 alterations are considered to be almost exclusively restricted to type I EC.	('MSH6', 'Gene', '2956', (82, 86))	('PTEN', 'Gene', '5728', (0, 4))	('EC', 'Phenotype', 'HP:0012114', (59, 61))	('MLH1', 'Gene', '4292', (73, 77))	('MLH1', 'Gene', (73, 77))	('MSH6', 'Gene', (82, 86))	('PTEN', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('EC', 'Phenotype', 'HP:0012114', (160, 162))
13866	32183290	Based on literature, diffuse strong nuclear accumulation involving more than 80% of EC tumor cells is the typical staining pattern for TP53 missense mutations and is more likely to be observed in USC than in low-grade EC subtypes.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('missense mutations', 'Var', (140, 158))	('TP53', 'Gene', '7157', (135, 139))	('EC tumor', 'Disease', 'MESH:D009369', (84, 92))	('USC', 'Disease', (196, 199))	('TP53', 'Gene', (135, 139))	('EC tumor', 'Disease', (84, 92))	('EC', 'Phenotype', 'HP:0012114', (84, 86))	('EC', 'Phenotype', 'HP:0012114', (218, 220))
13867	32183290	However, the presence of p53 nuclear accumulation is not always linked to TP53 gene mutation.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('TP53', 'Gene', '7157', (74, 78))	('linked', 'Reg', (64, 70))	('TP53', 'Gene', (74, 78))	('mutation', 'Var', (84, 92))
13869	32183290	In addition to TP53, mutations in other tumorigenesis-relevant genes, including PPP2R1A, PIK3CA, PIK3R, HER2, FBXW7, CHD4, and others have been identified in USC patients.	('CHD4', 'Gene', (117, 121))	('PIK3CA', 'Gene', '5290', (89, 95))	('CHD4', 'Gene', '1108', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('identified', 'Reg', (144, 154))	('PIK3R', 'Gene', (97, 102))	('USC', 'Disease', (158, 161))	('TP53', 'Gene', '7157', (15, 19))	('PPP2R1A', 'Gene', '5518', (80, 87))	('HER2', 'Gene', (104, 108))	('FBXW7', 'Gene', (110, 115))	('patients', 'Species', '9606', (162, 170))	('PIK3CA', 'Gene', (89, 95))	('PPP2R1A', 'Gene', (80, 87))	('tumor', 'Disease', (40, 45))	('mutations', 'Var', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('FBXW7', 'Gene', '55294', (110, 115))	('TP53', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (104, 108))
13873	32183290	There are two main categories: (1) small molecules against fundamental enzymes in different metabolic pathways, such as glucose transporters (GLUTs) in glucose uptake, hexokinase 2 in glycolysis, and citrate dehydrogenase in the TCA cycle and (2) competitive molecules of essential metabolites such as 2-deoxy-D-glucose.	('TCA', 'Chemical', 'MESH:D014238', (229, 232))	('hexokinase 2', 'Gene', '3099', (168, 180))	('glucose', 'Chemical', 'MESH:D005947', (152, 159))	('small molecules', 'Var', (35, 50))	('glucose transporters', 'MPA', (120, 140))	('hydrogen', 'Chemical', 'MESH:D006859', (210, 218))	('hexokinase 2', 'Gene', (168, 180))	('2-deoxy-D-glucose', 'MPA', (302, 319))	('citrate dehydrogenase', 'Enzyme', (200, 221))	('2-deoxy-D-glucose', 'Chemical', 'MESH:D003847', (302, 319))	('glucose', 'Chemical', 'MESH:D005947', (312, 319))	('glucose', 'Chemical', 'MESH:D005947', (120, 127))
13888	32183290	Multiple in vitro studies with USC cell lines demonstrated that metformin inhibited cell proliferation and metastasis via inhibiting oxidative phosphorylation (OXPHOS) and ATP consumption, further activating AMPK to suppress its downstream targets such as the mTOR and STAT3 pathways.	('inhibited', 'NegReg', (74, 83))	('metformin', 'Var', (64, 73))	('inhibiting', 'NegReg', (122, 132))	('suppress', 'NegReg', (216, 224))	('AMPK', 'Gene', '5562', (208, 212))	('STAT3', 'Gene', '6774', (269, 274))	('AMPK', 'Gene', (208, 212))	('STAT3', 'Gene', (269, 274))	('ATP', 'Chemical', 'MESH:D000255', (172, 175))	('metformin', 'Chemical', 'MESH:D008687', (64, 73))	('oxidative phosphorylation', 'MPA', (133, 158))	('mTOR', 'Gene', (260, 264))	('mTOR', 'Gene', '2475', (260, 264))	('cell proliferation', 'CPA', (84, 102))	('activating', 'PosReg', (197, 207))	('ATP consumption', 'MPA', (172, 187))
13892	32183290	Epigenetic abnormalities of key factors associated with carcinogenesis are also commonly observed in USC.	('Epigenetic abnormalities', 'Var', (0, 24))	('USC', 'Disease', (101, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('observed', 'Reg', (89, 97))	('carcinogenesis', 'Disease', (56, 70))
13894	32183290	Reversal of epigenetic alteration is considered to be a promising strategy for cancer treatment.	('cancer', 'Disease', (79, 85))	('epigenetic alteration', 'Var', (12, 33))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
13902	32183290	The Pap SEEK test can screen for gene mutations and chromosome alterations that frequently occur in USCs, such as TP53, FBXW7, PIK3CA, and PIK3R mutations, by using a trace of DNA from uterine tissue acquired in a Papanicolaou test.	('FBXW7', 'Gene', '55294', (120, 125))	('FBXW7', 'Gene', (120, 125))	('mutations', 'Var', (145, 154))	('PIK3CA', 'Gene', (127, 133))	('TP53', 'Gene', '7157', (114, 118))	('PIK3CA', 'Gene', '5290', (127, 133))	('PIK3R', 'Gene', (139, 144))	('TP53', 'Gene', (114, 118))
13908	32183290	Clinical trials that treated USC with drug combinations such as carboplatin-paclitaxel and doxorubicin-cisplatin-paclitaxel achieved promising results: these combinations significantly extended survival and decreased recurrence rates (NCT00231868, NCT00147680, NCT00052312, and NCT00052312).	('NCT00052312', 'Var', (261, 272))	('survival', 'CPA', (194, 202))	('carboplatin', 'Chemical', 'MESH:D016190', (64, 75))	('paclitaxel', 'Chemical', 'MESH:D017239', (76, 86))	('NCT00052312', 'Var', (278, 289))	('doxorubicin', 'Chemical', 'MESH:D004317', (91, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('paclitaxel', 'Chemical', 'MESH:D017239', (113, 123))	('recurrence rates', 'CPA', (217, 233))	('NCT00231868', 'Var', (235, 246))	('extended', 'PosReg', (185, 193))	('decreased', 'NegReg', (207, 216))	('NCT00147680', 'Var', (248, 259))
13913	32183290	However, due to the rarity of USC, only two trials (NCT01367002 and NCT03285802) were designed specifically for USC patient cohorts.	('patient', 'Species', '9606', (116, 123))	('NCT01367002', 'Var', (52, 63))	('NCT03285802', 'Var', (68, 79))
13917	32183290	Furthermore, p53-mutated USC cells are sensitive to combination treatment with EGFR inhibitors gefitinib and paclitaxel and treatment with polo-like kinase 1 inhibitor BI2536.	('inhibitors', 'Var', (84, 94))	('polo-like kinase 1', 'Gene', '5347', (139, 157))	('polo-like kinase 1', 'Gene', (139, 157))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('BI2536', 'Chemical', 'MESH:C518477', (168, 174))	('p53', 'Gene', (13, 16))	('paclitaxel', 'Chemical', 'MESH:D017239', (109, 119))	('combination', 'Interaction', (52, 63))	('gefitinib', 'Chemical', 'MESH:D000077156', (95, 104))	('p53', 'Gene', '7157', (13, 16))	('sensitive', 'Reg', (39, 48))
13918	32183290	Moreover, the combination of proteasome and histone deacetylase inhibitors can overcome the effect of p53 mutations.	('p53', 'Gene', '7157', (102, 105))	('mutations', 'Var', (106, 115))	('p53', 'Gene', (102, 105))
13923	32183290	T-DM1 demonstrated encouraging antitumor activity in USC cell lines and USC xenografts.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('T-DM1', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))
13929	32183290	Furthermore, lapatinib showed promising results in a cohort of EC patients with E690K mutation in EGFR.	('EGFR', 'Gene', (98, 102))	('lapatinib', 'Chemical', 'MESH:D000077341', (13, 22))	('E690K', 'Mutation', 'rs1057519794', (80, 85))	('E690K', 'Var', (80, 85))	('EC', 'Phenotype', 'HP:0012114', (63, 65))	('EGFR', 'Gene', '1956', (98, 102))	('patients', 'Species', '9606', (66, 74))
13932	32183290	According to the updated literature, there are four categories of inhibitors targeting PI3K/AKT/mTOR signaling pathway: mTOR inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, and AKT inhibitors.	('mTOR', 'Gene', (96, 100))	('AKT', 'Gene', (185, 188))	('mTOR', 'Gene', '2475', (120, 124))	('mTOR', 'Gene', (159, 163))	('mTOR', 'Gene', '2475', (159, 163))	('AKT', 'Gene', '207', (92, 95))	('AKT', 'Gene', '207', (185, 188))	('mTOR', 'Gene', (120, 124))	('AKT', 'Gene', (92, 95))	('mTOR', 'Gene', '2475', (96, 100))	('PI3K', 'Var', (137, 141))
13936	32183290	Currently, several phase II clinical trials of signal-agent rapalog treatment in mixed cohorts of EC patients, including those with EEC, USC, and clear cell endometrial cancer, have been completed (NCT00087685, NCT00072176, and NCT00122343).	('patients', 'Species', '9606', (101, 109))	('NCT00087685', 'Var', (198, 209))	('EC', 'Phenotype', 'HP:0012114', (98, 100))	('EC', 'Phenotype', 'HP:0012114', (133, 135))	('rapalog', 'Chemical', '-', (60, 67))	('endometrial cancer', 'Phenotype', 'HP:0012114', (157, 175))	('EEC', 'Disease', (132, 135))	('clear cell endometrial cancer', 'Disease', (146, 175))	('USC', 'Disease', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('NCT00122343', 'Var', (228, 239))	('clear cell endometrial cancer', 'Disease', 'MESH:D016889', (146, 175))	('EEC', 'Chemical', '-', (132, 135))	('NCT00072176', 'Var', (211, 222))
13938	32183290	For instance, in an ongoing phase I trial, gamma-secretase/Notch signaling pathway inhibitor RO4929097 was tested together with temsirolimus in 18 patients with advanced solid tumors, including USC (NCT01198184).	('RO4929097', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('temsirolimus', 'Chemical', 'MESH:C401859', (128, 140))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('patients', 'Species', '9606', (147, 155))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('RO4929097', 'Chemical', 'MESH:C545185', (93, 102))
13940	32183290	To overcome the limitations of rapalogs, the so-called second generation of mTOR inhibitors that dually inhibit kinase activities of mTORC1 and mTORC2:which include AZD8055, OSI027, and INK128 (MLN0128):have been studied extensively.	('mTORC1', 'Gene', '382056', (133, 139))	('kinase activities', 'MPA', (112, 129))	('MLN0128', 'Chemical', 'MESH:C572449', (194, 201))	('mTOR', 'Gene', (76, 80))	('rapalogs', 'Chemical', '-', (31, 39))	('mTOR', 'Gene', '2475', (76, 80))	('AZD8055', 'Var', (165, 172))	('mTORC2', 'Gene', (144, 150))	('AZD8055', 'Chemical', 'MESH:C546624', (165, 172))	('mTORC1', 'Gene', (133, 139))	('mTORC2', 'Gene', '74343', (144, 150))	('INK128', 'Chemical', 'MESH:C572449', (186, 192))	('mTOR', 'Gene', '2475', (133, 137))	('mTOR', 'Gene', (133, 137))	('inhibit', 'NegReg', (104, 111))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))
13941	32183290	illustrated that AZD8055 strongly suppressed the proliferation of 22 primary USC cancer cell lines by arresting cells in the G0/G1 phase.	('AZD8055', 'Var', (17, 24))	('AZD8055', 'Chemical', 'MESH:C546624', (17, 24))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('suppressed', 'NegReg', (34, 44))	('proliferation', 'CPA', (49, 62))	('cancer', 'Disease', (81, 87))	('arresting', 'NegReg', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
13943	32183290	Another phase I clinical trial led by Dana-Farber Cancer Institute used the combined intervention of MLN0128 and bevacizumab (an anti-angiogenesis drug) to treat patients with solid carcinomas, including endometrial clear cell adenocarcinoma and USC (NCT02142803).	('endometrial clear cell adenocarcinoma', 'Disease', (204, 241))	('patients', 'Species', '9606', (162, 170))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('USC', 'Disease', (246, 249))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('bevacizumab', 'Chemical', 'MESH:D000068258', (113, 124))	('MLN0128', 'Var', (101, 108))	('endometrial clear cell adenocarcinoma', 'Disease', 'MESH:D008649', (204, 241))	('solid carcinomas', 'Disease', (176, 192))	('solid carcinomas', 'Disease', 'MESH:D009369', (176, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('MLN0128', 'Chemical', 'MESH:C572449', (101, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))
13944	32183290	Other combination strategies in EC, such as MLN0128 plus MLN1117 (a PI3K inhibitor) and MLN0128 plus paclitaxel, are under investigation in a phase II trial (NCT02725268).	('MLN0128', 'Chemical', 'MESH:C572449', (88, 95))	('MLN0128', 'Var', (44, 51))	('paclitaxel', 'Chemical', 'MESH:D017239', (101, 111))	('MLN1117', 'Chemical', 'MESH:C000627413', (57, 64))	('MLN0128', 'Var', (88, 95))	('MLN1117', 'Var', (57, 64))	('MLN0128', 'Chemical', 'MESH:C572449', (44, 51))	('EC', 'Phenotype', 'HP:0012114', (32, 34))
13945	32183290	Pan-PI3K inhibitors were the first generation of PI3K inhibitors, comprising GDC-0941, BKM120, PX866, ZSTK474, and BAY80-6946 (copanlisib).	('copanlisib', 'Chemical', 'MESH:C000589253', (127, 137))	('PX866', 'Var', (95, 100))	('BKM120', 'Var', (87, 93))	('ZSTK474', 'Chemical', 'MESH:C510150', (102, 109))	('PX866', 'Chemical', 'MESH:C496788', (95, 100))	('GDC-0941', 'Var', (77, 85))	('BAY80-6946', 'Chemical', 'MESH:C000589253', (115, 125))	('BKM120', 'Chemical', 'MESH:C571178', (87, 93))	('GDC-0941', 'Chemical', 'MESH:C532162', (77, 85))	('BAY80-6946', 'Var', (115, 125))
13949	32183290	After that, phase II trials of copanlisib in patients with EC opened (NCT02728258, NCT03586661).	('NCT02728258', 'Var', (70, 81))	('copanlisib', 'Chemical', 'MESH:C000589253', (31, 41))	('EC opened', 'Disease', (59, 68))	('EC', 'Phenotype', 'HP:0012114', (59, 61))	('patients', 'Species', '9606', (45, 53))	('NCT03586661', 'Var', (83, 94))
13950	32183290	Isoform-specific PI3K inhibitors:especially those that target the PI3Kalpha subunit, which harbors the majority of PI3K mutations in solid tumors:are another promising therapeutic option for USC.	('PI3Kalpha', 'Gene', '5290', (66, 75))	('PI3Kalpha', 'Gene', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('mutations', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('PI3K', 'Gene', (115, 119))
13952	32183290	(3) mTOR and PI3K Dual Inhibitors mTOR and PI3K dual inhibitors are also applied for USC treatment and have the benefit of blocking the whole signaling pathway without inducing complicated feedback loops, which are often observed in certain malignancies treated with a single inhibitor.	('PI3K', 'Var', (43, 47))	('mTOR', 'Gene', '2475', (34, 38))	('signaling pathway', 'Pathway', (142, 159))	('malignancies', 'Disease', 'MESH:D009369', (241, 253))	('blocking', 'NegReg', (123, 131))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('malignancies', 'Disease', (241, 253))	('mTOR', 'Gene', (34, 38))
13954	32183290	The first-in-human phase I clinical trial of the mTOR and PI3K dual inhibitor LY3023414 in patients with advanced solid tumors, including EC (n = 15), was completed by Bendell et al.	('mTOR', 'Gene', (49, 53))	('tumors', 'Disease', (120, 126))	('mTOR', 'Gene', '2475', (49, 53))	('human', 'Species', '9606', (13, 18))	('patients', 'Species', '9606', (91, 99))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('LY3023414', 'Chemical', 'MESH:C000621566', (78, 87))	('EC', 'Phenotype', 'HP:0012114', (138, 140))	('LY3023414', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
13956	32183290	In patients with PI3KR1- and PTEN-mutated EC, a durable response to LY3023414 was observed.	('EC', 'Phenotype', 'HP:0012114', (42, 44))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('PI3KR1-', 'Var', (17, 24))	('patients', 'Species', '9606', (3, 11))	('LY3023414', 'Chemical', 'MESH:C000621566', (68, 77))	('LY3023414', 'Var', (68, 77))
13962	32183290	For instance, preclinical data for MK-2206, an allosteric inhibitor of AKT, demonstrated remarkable suppressive effects in three distinct patient-derived xenografts: USC1 (uterine serous), EEC2 (endometrioid grade 2), and EEC4 (endometrioid grade 3).	('EEC2', 'Gene', (189, 193))	('MK-2206', 'Var', (35, 42))	('AKT', 'Gene', '207', (71, 74))	('EEC', 'Chemical', '-', (222, 225))	('MK-2206', 'Chemical', 'MESH:C548887', (35, 42))	('EC', 'Phenotype', 'HP:0012114', (223, 225))	('EEC2', 'Gene', '1914', (189, 193))	('EEC', 'Chemical', '-', (189, 192))	('patient', 'Species', '9606', (138, 145))	('EC', 'Phenotype', 'HP:0012114', (190, 192))	('AKT', 'Gene', (71, 74))	('suppressive', 'NegReg', (100, 111))
13963	32183290	Clinical trials of MK-2206 in ECs, including USC, provided valuable evidence for future clinical applications (NCT01312753, NCT01307631).	('EC', 'Phenotype', 'HP:0012114', (30, 32))	('MK-2206', 'Chemical', 'MESH:C548887', (19, 26))	('NCT01312753', 'Var', (111, 122))	('MK-2206', 'Gene', (19, 26))
13966	32183290	Dual inhibition exhibited more favorable efficacy compared with single inhibition and may be important for USC patients with mutations in the PI3K signaling pathway and KRAS or BRAF.	('mutations', 'Var', (125, 134))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('PI3K signaling pathway', 'Pathway', (142, 164))	('KRAS', 'Gene', (169, 173))	('KRAS', 'Gene', '3845', (169, 173))	('efficacy', 'MPA', (41, 49))	('patients', 'Species', '9606', (111, 119))
13967	32183290	Dual inhibition of HER2/PIK3CA was also shown to overcome single treatment-related drug resistance significantly in HER2-amplified USC cells and xenografts.	('HER2', 'Gene', (19, 23))	('overcome', 'PosReg', (49, 57))	('PIK3CA', 'Gene', (24, 30))	('Dual', 'Var', (0, 4))	('drug resistance', 'Phenotype', 'HP:0020174', (83, 98))	('HER2', 'Gene', '2064', (19, 23))	('PIK3CA', 'Gene', '5290', (24, 30))	('HER2', 'Gene', (116, 120))	('HER2', 'Gene', '2064', (116, 120))	('single treatment-related drug resistance', 'MPA', (58, 98))
13968	32183290	A high percentage of alterations in cell cycle-related genes has been observed in USC, and mutations affecting the Fbxw7/Cyclin E pathway are the most frequent in USC.	('USC', 'Disease', (163, 166))	('USC', 'Disease', (82, 85))	('cell cycle-related genes', 'Gene', (36, 60))	('Fbxw7', 'Gene', (115, 120))	('frequent', 'Reg', (151, 159))	('mutations', 'Var', (91, 100))	('Fbxw7', 'Gene', '55294', (115, 120))	('alterations', 'Var', (21, 32))
13972	32183290	CYC065, an inhibitor of CDK2/9, alone or together with taselisib, shrank USC xenografts, which were derived from a USC harboring CCNE1 amplification and PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (153, 159))	('CCNE1', 'Gene', '898', (129, 134))	('CCNE1', 'Gene', (129, 134))	('taselisib', 'Chemical', 'MESH:C582924', (55, 64))	('CYC065', 'Var', (0, 6))	('CDK2/9', 'Gene', (24, 30))	('PIK3CA', 'Gene', (153, 159))	('CDK2/9', 'Gene', '1017;1025', (24, 30))
13992	32183290	This work was supported in part by The University of Texas MD Anderson Cancer Center Uterine SPORE grant P50CA098258 and MD Anderson's Cancer Center Support Grant P30CA016672 from the US Department of Health and Human Services, the National Institutes of Health; by W81XWH-17-1-0126 from the Ovarian Cancer Research Program, Department of Defense; and by the Stephanie C. Stelter Professorship.	('Cancer', 'Disease', (71, 77))	('Cancer', 'Disease', 'MESH:D009369', (135, 141))	('Human', 'Species', '9606', (212, 217))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('P30CA016672', 'Var', (163, 174))	('W81XWH-17-1-0126', 'Var', (266, 282))	('Cancer', 'Disease', (300, 306))	('Cancer', 'Phenotype', 'HP:0002664', (300, 306))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (135, 141))	('Cancer', 'Disease', 'MESH:D009369', (300, 306))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (292, 306))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
14010	29671892	We recently identified frequent genomic inactivation of certain core components of switch/sucrose non-fermentable (SWI/SNF) complex proteins that are associated with histologic dedifferentiation.	('associated', 'Reg', (150, 160))	('sucrose', 'Chemical', 'MESH:D013395', (90, 97))	('genomic', 'Var', (32, 39))
14012	29671892	This is analogous to lung carcinoma and sinonasal carcinoma, where SWI/SNF inactivation has been reported and is associated with undifferentiated histology as well as aggressive clinical behavior.	('inactivation', 'Var', (75, 87))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (167, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('sinonasal carcinoma', 'Disease', 'MESH:C537344', (40, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('lung carcinoma', 'Disease', (21, 35))	('SWI/SNF', 'Gene', (67, 74))	('sinonasal carcinoma', 'Disease', (40, 59))	('lung carcinoma', 'Disease', 'MESH:D008175', (21, 35))	('associated', 'Reg', (113, 123))
14017	29671892	Overexpression of claudin-4 in breast cancer and gastric cancer cell lines has been shown to increase cell proliferation and migration in vitro.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('claudin-4', 'Gene', (18, 27))	('increase', 'PosReg', (93, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('claudin-4', 'Gene', '1364', (18, 27))	('breast cancer', 'Disease', (31, 44))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', (49, 63))	('cell proliferation', 'CPA', (102, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))
14055	29671892	This observation is in keeping with our proposed mechanism of dedifferentiation in endometrial cancer where a significant perturbation such as genomic inactivation of core SWI/SNF protein(s) prevents Mullerian epithelial differentiation, hence arresting the tumor cells in a primitive cellular state that is reflected histologically and immunophenotypically as an undifferentiated tumor.	('arresting', 'Reg', (244, 253))	('Mullerian epithelial differentiation', 'CPA', (200, 236))	('prevents', 'NegReg', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('endometrial cancer', 'Phenotype', 'HP:0012114', (83, 101))	('undifferentiated tumor', 'Disease', 'MESH:D002277', (364, 386))	('tumor', 'Disease', (258, 263))	('inactivation', 'Var', (151, 163))	('tumor', 'Disease', (381, 386))	('endometrial cancer', 'Disease', 'MESH:D016889', (83, 101))	('undifferentiated tumor', 'Disease', (364, 386))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (381, 386))	('endometrial cancer', 'Disease', (83, 101))
14080	31348579	The objective response rate was higher in patients with cervical cancer with PD-L1-positive (n = 5/15; 33%) versus PD-L1-negative (n = 0/5; 0%) tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('objective response', 'CPA', (4, 22))	('higher', 'PosReg', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('PD-L1-positive', 'Var', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (42, 50))	('cervical cancer', 'Disease', (56, 71))	('cervical cancer', 'Disease', 'MESH:D002583', (56, 71))
14091	31348579	Main exclusion criteria were previously receiving antibodies against PD-1, PD-L1, PD-L2, CD137, or CTLA-4, or other therapeutic antibodies or pharmacotherapies for regulation of T cells, and receiving systemic corticosteroids or immunosuppressants within 28 days before enrollment.	('antibodies', 'Var', (50, 60))	('PD-L1', 'Gene', (75, 80))	('CTLA-4', 'Gene', '1493', (99, 105))	('PD-1', 'Gene', (69, 73))	('PD-L2', 'Gene', (82, 87))	('PD-1', 'Gene', '5133', (69, 73))	('CTLA-4', 'Gene', (99, 105))	('CD137', 'Gene', (89, 94))	('CD137', 'Gene', '3604', (89, 94))
14134	31348579	MSI status was determined for eight patients with corpus cancer: the ORR was higher in patients classified as MSI-high (2/2 patients, 100%) than in patients classified as MSS (0/6 patients, 0%) (Table 3).	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (36, 44))	('higher', 'PosReg', (77, 83))	('MSI-high', 'Var', (110, 118))	('corpus cancer', 'Disease', (50, 63))	('patients', 'Species', '9606', (180, 188))	('ORR', 'MPA', (69, 72))	('corpus cancer', 'Disease', 'MESH:D009369', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (124, 132))
14231	31236276	This trial shows that pazopanib increased significantly median progression-free survival to 4.6 months compared to 1.6 months for placebo, although OS was not significantly different.	('progression-free', 'MPA', (63, 79))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))	('pazopanib', 'Var', (22, 31))	('increased', 'PosReg', (32, 41))
14245	30072739	Emerging biomarkers for anti-PD-1 response include the expression level of its ligand PD-L1 , mutation burden or mismatch-repair deficiency , and tumor-infiltrating lymphocytes .	('PD-1', 'Gene', '5133', (29, 33))	('deficiency', 'Disease', 'MESH:D007153', (129, 139))	('expression level', 'MPA', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PD-L1', 'Gene', '29126', (86, 91))	('tumor', 'Disease', (146, 151))	('mismatch-repair', 'MPA', (113, 128))	('mutation burden', 'Var', (94, 109))	('deficiency', 'Disease', (129, 139))	('PD-L1', 'Gene', (86, 91))	('PD-1', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
14250	30072739	Several other types of non-coding RNAs, such as long-noncoding RNAs (lncRNAs) , enhancer RNAs  and circular RNAs  have also been implicated in various cancer types .	('circular RNAs', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('enhancer', 'PosReg', (80, 88))	('implicated', 'Reg', (129, 139))	('long-noncoding', 'Var', (48, 62))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
14260	30072739	Here we performed a pan-cancer analysis of ~22 nt size-selected small RNA-seq (smRNA-seq) datasets from TCGA, exploring the expression of small RNAs mapping to annotated human snoRNAs in 10,262 patient samples across 32 cancer types.	('patient', 'Species', '9606', (194, 201))	('small', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('snoRNA', 'Gene', '85390', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', (220, 226))	('snoRNA', 'Gene', (176, 182))
14274	30072739	This pan-cancer sdRNA transcriptome is derived from several subtypes of snoRNAs with distinct structures and motifs, such as canonical C/D box snoRNAs, H/ACA box snoRNAs, C/D box small Cajal body RNAs (scaRNAs), H/ACA box scaRNAs, hybrid snoRNAs, and several other subtypes (Figure 1b, Table S1, Table S2).	('snoRNA', 'Gene', '85390', (143, 149))	('cancer', 'Disease', (9, 15))	('snoRNA', 'Gene', (162, 168))	('snoRNA', 'Gene', '85390', (72, 78))	('snoRNA', 'Gene', '85390', (162, 168))	('snoRNA', 'Gene', '85390', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('snoRNA', 'Gene', (143, 149))	('C/D box', 'Var', (171, 178))	('snoRNA', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('snoRNA', 'Gene', (238, 244))
14279	30072739	In the case of C/D snoRNAs, these analyses revealed three classes of read distributions, corresponding to 5' sdRNAs, 3' sdRNAs, or mixed sdRNAs (Figure 1c).	('D snoRNAs', 'Phenotype', 'HP:0025267', (17, 26))	('C/D', 'Var', (15, 18))	('snoRNA', 'Gene', (19, 25))	('mixed', 'Disease', (131, 136))	('snoRNA', 'Gene', '85390', (19, 25))	('D snoRNA', 'Phenotype', 'HP:0025267', (17, 25))
14289	30072739	The sdRNA transcriptome exhibited a wide dynamic range of expression across all cancers (Figure S5a), such that 300.13 +- 4.21 (mean +- s.e.m.)	('300.13 +- 4.21', 'Var', (112, 126))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('sdRNA', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
14371	30072739	For instance, high expression of sdRNAs derived from SNORA116, an H/ACA snoRNA, was connected to poorer survival in three independent cohorts: lower grade gliomas (LGG), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7b).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (228, 249))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('expression', 'MPA', (19, 29))	('snoRNA', 'Gene', '85390', (72, 78))	('corpus endometrial carcinoma', 'Disease', (221, 249))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (221, 249))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 200))	('liver hepatocellular carcinoma', 'Disease', (170, 200))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('SNORA116', 'Var', (53, 61))	('poorer', 'NegReg', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('snoRNA', 'Gene', (72, 78))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
14372	30072739	As another example, high levels of sdRNAs from SNORD145, a CD snoRNA, were associated with shorter survival times in kidney clear cell carcinoma (KIRC), sarcoma (SARC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7c).	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (181, 209))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (188, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('sarcoma', 'Disease', (153, 160))	('SARC', 'Phenotype', 'HP:0100242', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (117, 144))	('SNORD145', 'Var', (47, 55))	('shorter', 'NegReg', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('D snoRNA', 'Phenotype', 'HP:0025267', (60, 68))	('snoRNA', 'Gene', (62, 68))	('survival times', 'CPA', (99, 113))	('corpus endometrial carcinoma', 'Disease', (181, 209))	('sdRNAs', 'MPA', (35, 41))	('snoRNA', 'Gene', '85390', (62, 68))	('kidney clear cell carcinoma', 'Disease', (117, 144))
14373	30072739	SdRNAs from SNORA116 and SNORD145 thus appear to be indicators of cancers with a more aggressive course.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SNORA116', 'Var', (12, 20))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('SNORD145', 'Var', (25, 33))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
14391	30072739	Because the ImmuneSurv score analyses were conducted in a cancer type-specific manner, we then sought a global assessment of sdRNAs and their relationships to cancer immunity regardless of cancer type (PANCAN32), by compiling all sdRNAs that were found to be significant in any of the 5 categories: PD-L1, CD8+ T cell abundance, GZMA, survival, or copy number variation (supplemental results, Figure S9) in any cancer type.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cancer immunity regardless of cancer', 'Disease', 'MESH:D009369', (159, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CD8', 'Gene', (306, 309))	('GZMA', 'Gene', '3001', (329, 333))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('GZMA', 'Gene', (329, 333))	('PD-L1', 'Gene', (299, 304))	('PD-L1', 'Gene', '29126', (299, 304))	('cancer', 'Disease', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CD8', 'Gene', '925', (306, 309))	('copy number variation', 'Var', (348, 369))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer immunity regardless of cancer', 'Disease', (159, 195))	('cancer', 'Disease', (58, 64))
14402	30072739	Of note, SNORD115 has been demonstrated to act as a regulator of alternative splicing , and its deletion is sufficient to cause Prader-Willi syndrome.	('SNORD115', 'Gene', '692218', (9, 17))	('cause', 'Reg', (122, 127))	('deletion', 'Var', (96, 104))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (128, 149))	('Prader-Willi syndrome', 'Disease', (128, 149))	('alternative splicing', 'MPA', (65, 85))	('SNORD115', 'Gene', (9, 17))
14429	30072739	GISTIC 2.0 copy number variation calls were obtained from the GDAC Firehose (http://gdac.broadinstitute.org/) on September 2017.	('copy number variation', 'Var', (11, 32))	('DAC', 'Gene', (63, 66))	('DAC', 'Gene', '6468', (63, 66))
14431	30072739	Raw fastq files for independent smRNA-seq datasets (GSE33858, GSE46622, E-MTAB-3494) were accessed by NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) or EBI (https://www.ebi.ac.uk/).	('EBI', 'Gene', (150, 153))	('GSE46622', 'Var', (62, 70))	('GSE33858', 'Var', (52, 60))	('EBI', 'Gene', '6907', (150, 153))	('ebi', 'Gene', '6907', (167, 170))	('ebi', 'Gene', (167, 170))
14457	30072739	As these tables report the precise genomic coordinates in which the amplification or deletion was identified, we utilized a q < 0.05 threshold and subsequently intersected the coordinates with the snoRNA annotations .	('snoRNA', 'Gene', (197, 203))	('deletion', 'Var', (85, 93))	('snoRNA', 'Gene', '85390', (197, 203))
14458	30072739	Amplification and deletion calls for individual snoRNAs were then compiled into separate tables.	('deletion', 'Var', (18, 26))	('snoRNA', 'Gene', (48, 54))	('snoRNA', 'Gene', '85390', (48, 54))
14461	30072739	For pan-cancer analysis, we considered all sdRNAs that were found to be significant in at least one cancer type across the following 5 analyses: CD274 correlation, GMZA correlation, CD8+ T cell abundance, copy number variation, and survival.	('cancer', 'Disease', (8, 14))	('CD8', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CD8', 'Gene', '925', (182, 185))	('CD274', 'Gene', '29126', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('copy number variation', 'Var', (205, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CD274', 'Gene', (145, 150))
14467	30072739	Thus, for the example above (NNSNSN), sdRNAs from snoRNA X were found to be significantly associated with survival and significant for CNV in cancer type Y.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('snoRNA', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated with', 'Reg', (90, 105))	('sdRNAs', 'Var', (38, 44))	('snoRNA', 'Gene', '85390', (50, 56))	('cancer', 'Disease', (142, 148))
14586	30464593	By analyzing the data, we found, of the 29 patients who received adjuvant therapy, 25 patients had some high-risk factors of recurrence, which included advanced age (>60 years), positive LVSI, greater tumor diameter (>2 cm), lower uterine segment involvement, or cervical surface gland infiltration.	('positive', 'Var', (178, 186))	('cervical surface gland infiltration', 'CPA', (263, 298))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('LVSI', 'Gene', (187, 191))	('lower uterine segment involvement', 'CPA', (225, 258))	('patients', 'Species', '9606', (86, 94))
14611	29594046	Hypersialylation, the overexpression of sialic acid, is known to promote tumor progression and to dampen antitumor responses by mechanisms that also involve sialic acid binding immunoglobulin-like lectins (Siglecs), inhibitory immune receptors.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('sialic acid', 'Chemical', 'MESH:D019158', (40, 51))	('sialic acid', 'Protein', (157, 168))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Hypersialylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (73, 78))	('promote', 'PosReg', (65, 72))	('sialic acid', 'Chemical', 'MESH:D019158', (157, 168))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('dampen', 'NegReg', (98, 104))	('tumor', 'Disease', (109, 114))
14623	29594046	It has been suggested that sialic acid containing glycans (sialoglycans) may act as "self-associated molecular patterns (SAMPs)" and that hypersialylation of tumors promotes escape from host immune responses by demonstrating "super-self".	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('escape', 'CPA', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('promotes', 'PosReg', (165, 173))	('glycans', 'Chemical', 'MESH:D011134', (50, 57))	('hypersialylation', 'Var', (138, 154))	('sialic acid containing glycans', 'Protein', (27, 57))	('glycans', 'Chemical', 'MESH:D011134', (64, 71))	('sialic acid', 'Chemical', 'MESH:D019158', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
14626	29594046	As a further mechanism, hypersialylation might "mask" glycan ligands of other immunomodulatory receptors, if sialic acids are covalently linked by sialyltransferases (STs) to respective binding sites.	('glycan', 'Chemical', 'MESH:D011134', (54, 60))	('sialic acids', 'Chemical', 'MESH:D012794', (109, 121))	('hypersialylation', 'Var', (24, 40))	('glycan ligands', 'MPA', (54, 68))
14628	29594046	Interestingly, it appears that glycan epitopes with terminal sialic acids are less immunogenic and may escape humoral IgG responses.	('sialic acids', 'Chemical', 'MESH:D012794', (61, 73))	('escape', 'NegReg', (103, 109))	('glycan', 'Chemical', 'MESH:D011134', (31, 37))	('less', 'NegReg', (78, 82))	('terminal sialic acids', 'Var', (52, 73))	('humoral IgG responses', 'CPA', (110, 131))
14629	29594046	Cancer hypersialylation often involves the increased generation of sialoglycan ligands of selectins, such as sialyl-Lewis X and its structural isomer sialyl-Lewis A, which promotes metastatic spread by heterotypic interactions between cancer cells, leukocytes, and endothelial cells.	('cancer', 'Disease', (235, 241))	('sialoglycan', 'Protein', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('glycan', 'Chemical', 'MESH:D011134', (72, 78))	('promotes', 'PosReg', (172, 180))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('sialyl-Lewis', 'Var', (109, 121))	('metastatic spread', 'CPA', (181, 198))	('increased', 'PosReg', (43, 52))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
14630	29594046	In this context, high expression of sialyl-Lewis X in estrogen receptor (ER)-positive breast cancers was reported to correlate with metastasis to the bone, where sialyl-Lewis X receptor E-selectin is constitutively expressed.	('E-selectin', 'Gene', (186, 196))	('metastasis to the bone', 'CPA', (132, 154))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('breast cancers', 'Phenotype', 'HP:0003002', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Disease', 'MESH:D001943', (86, 100))	('breast cancers', 'Disease', (86, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('sialyl-Lewis X', 'Var', (36, 50))	('E-selectin', 'Gene', '20339', (186, 196))	('expression', 'MPA', (22, 32))
14631	29594046	Interestingly, contrarily to this report, sialyl-Lewis X expression was shown to negatively correlate with progression in a breast cancer animal model.	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('sialyl-Lewis X expression', 'Var', (42, 67))	('breast cancer', 'Disease', (124, 137))	('negatively', 'NegReg', (81, 91))
14633	29594046	Hypersialylation in cancer has been linked to the enhanced expression and activity of STs, which catalyze the covalent attachment of sialic acids via different glycosidic linkages (alpha2-3, alpha2-6, or alpha2-8) to subterminal carbohydrate moieties.	('alpha2-8', 'Gene', (204, 212))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('alpha2-6', 'Gene', '3476', (191, 199))	('Hypersialylation', 'Var', (0, 16))	('activity', 'MPA', (74, 82))	('alpha2-8', 'Gene', '3476', (204, 212))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('expression', 'MPA', (59, 69))	('alpha2-6', 'Gene', (191, 199))	('cancer', 'Disease', (20, 26))	('carbohydrate', 'Chemical', 'MESH:D002241', (229, 241))	('enhanced', 'PosReg', (50, 58))	('sialic acids', 'Chemical', 'MESH:D012794', (133, 145))
14634	29594046	Notably, high alpha2,3-sialyltransferase type I (ST3Gal I) expression is associated with advanced stage epithelial ovarian cancer and has been linked to ovarian cancer cell migration and peritoneal dissemination via an epidermal growth factor receptor-dependent mechanism.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('epidermal growth factor receptor', 'Gene', (219, 251))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ovarian cancer', 'Disease', (153, 167))	('stage epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (98, 129))	('ST3Gal I', 'Gene', '6482', (49, 57))	('peritoneal dissemination', 'CPA', (187, 211))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('epidermal growth factor receptor', 'Gene', '1956', (219, 251))	('ovarian cancer', 'Phenotype', 'HP:0100615', (153, 167))	('associated with', 'Reg', (73, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('linked to', 'Reg', (143, 152))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (104, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (153, 167))	('ST3Gal I', 'Gene', (49, 57))	('stage epithelial ovarian cancer', 'Disease', (98, 129))	('high', 'Var', (9, 13))
14642	29594046	On the other hand, ST expression differences may contribute to divergent tumor behavior, including immune escape or dissimilar responses to immunotherapeutic interventions.	('contribute to', 'Reg', (49, 62))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('differences', 'Var', (33, 44))	('ST expression', 'Gene', (19, 32))	('immune escape', 'CPA', (99, 112))
14664	27979878	Telomere shortening and telomerase dysfunction are therefore implicated as universal features of cellular senescence and ageing as well as the age-related decrease in tissue regeneration and lifespan restriction in long lived mammals.	('Telomere shortening', 'Phenotype', 'HP:0031413', (0, 19))	('rat', 'Species', '10116', (180, 183))	('tissue regeneration', 'CPA', (167, 186))	('telomerase', 'Protein', (24, 34))	('dysfunction', 'Var', (35, 46))	('lifespan restriction', 'CPA', (191, 211))	('decrease', 'NegReg', (155, 163))	('cellular senescence', 'CPA', (97, 116))	('Telomere', 'Protein', (0, 8))
14684	27979878	The single-stranded overhang forms a D-loop (displacement) that prevents the access of telomerase outside of late S-phase when the overhang becomes accessible (Fig.	('prevents', 'NegReg', (64, 72))	('single-stranded', 'Var', (4, 19))	('telomerase', 'Protein', (87, 97))	('men', 'Species', '9606', (53, 56))	('access', 'MPA', (77, 83))
14688	27979878	In addition to the end replication, environmental conditions such as oxidative stress are an additional mechanism of telomere shortening.	('telomere', 'Var', (117, 125))	('telomere shortening', 'Phenotype', 'HP:0031413', (117, 136))	('men', 'Species', '9606', (43, 46))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))	('shortening', 'NegReg', (126, 136))
14702	27979878	As the 'first responders' to hazards of genomic instability, the damaged telomeric DNA initiates a sustained DDR, resulting in a cell cycle arrest and inducing senescence or apoptosis, thereby protecting the organism from dangerous genetic aberrations and mutations.	('damaged', 'Var', (65, 72))	('genetic aberrations', 'Disease', (232, 251))	('inducing', 'Reg', (151, 159))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (129, 146))	('apoptosis', 'CPA', (174, 183))	('senescence', 'CPA', (160, 170))	('genetic aberrations', 'Disease', 'MESH:D030342', (232, 251))	('cell cycle arrest', 'CPA', (129, 146))
14704	27979878	POT1 prevents telomerase accessing an intact telomere complex but after hetero-dimerization with TPP1, it allows telomerase to become active at telomeres and to extend the 3' overhang in late S-phase.	('TPP1', 'Gene', (97, 101))	('extend', 'PosReg', (161, 167))	("3' overhang", 'MPA', (172, 183))	('TPP1', 'Gene', '1200', (97, 101))	('telomerase', 'Enzyme', (113, 123))	('hetero-dimerization', 'Var', (72, 91))	('allows', 'Reg', (106, 112))
14736	27979878	Disease-associated hTERC variants with sequence changes outside the H/ACA domain do not affect hTERC RNA processing or stability; they instead impose a catalytic defect.	('impose', 'Reg', (143, 149))	('variants', 'Var', (25, 33))	('stability', 'MPA', (119, 128))	('hTERC', 'Gene', '7012', (19, 24))	('hTERC', 'Gene', (19, 24))	('catalytic defect', 'MPA', (152, 168))	('hTERC', 'Gene', '7012', (95, 100))	('hTERC', 'Gene', (95, 100))
14739	27979878	Dyskerin is an essential protein for cellular survival; thus DKC1 deletion is lethal.	('DKC1', 'Gene', (61, 65))	('DKC1', 'Gene', '1736', (61, 65))	('deletion', 'Var', (66, 74))
14837	27979878	Androgens appear to regulate telomerase expression and activity mainly by aromatization of testosterone to estrogens through ERalpha in normal peripheral blood lymphocytes and human bone marrow-derived CD34(+) cells in vitro.	('expression', 'MPA', (40, 50))	('activity', 'MPA', (55, 63))	('telomerase', 'Enzyme', (29, 39))	('CD34', 'Gene', '947', (202, 206))	('human', 'Species', '9606', (176, 181))	('regulate', 'Reg', (20, 28))	('ERalpha', 'Gene', (125, 132))	('CD34', 'Gene', (202, 206))	('ERalpha', 'Gene', '2099', (125, 132))	('aromatization', 'Var', (74, 87))	('testosterone', 'Chemical', 'MESH:D013739', (91, 103))
14860	27979878	The only characterized human endometrial epithelial cell subpopulation (cells that express surface marker SSEA-1, nuclear SOX9 and nuclear beta-catenin) that exhibits progenitor properties in vitro, also showed high TA and longer TL compared with their more differentiated epithelial cell counterparts.	('SSEA-1', 'Gene', (106, 112))	('TA', 'Chemical', '-', (216, 218))	('high', 'PosReg', (211, 215))	('SOX9', 'Gene', '6662', (122, 126))	('beta-catenin', 'Gene', (139, 151))	('longer', 'PosReg', (223, 229))	('SSEA-1', 'Gene', '2526', (106, 112))	('human', 'Species', '9606', (23, 28))	('beta-catenin', 'Gene', '1499', (139, 151))	('nuclear', 'Var', (114, 121))	('SOX9', 'Gene', (122, 126))
14881	27979878	Interestingly, the initial induction of endometriosis was associated with activation of epidermal growth factor (EGF) signalling in the eutopic endometrium of the baboon model and EGF signalling was associated with up-regulation of TA in normal ovarian surface epithelial cells.	('endometriosis', 'Disease', 'MESH:D004715', (40, 53))	('endometriosis', 'Disease', (40, 53))	('endometriosis', 'Phenotype', 'HP:0030127', (40, 53))	('EGF signalling', 'Var', (180, 194))	('activation', 'PosReg', (74, 84))	('up-regulation', 'PosReg', (215, 228))	('TA', 'Chemical', '-', (232, 234))	('baboon', 'Species', '9555', (163, 169))
14884	27979878	Ovarian endometriotic epithelial cells were successfully immortalized by combinatorial transfection of human cyclin D1, cdk4 and hTERT genes, whereas the introduction of hTERT alone, or together with cdk4, was insufficient for immortalization of these cells.	('human', 'Species', '9606', (103, 108))	('hTERT', 'Gene', '7015', (170, 175))	('hTERT', 'Gene', '7015', (129, 134))	('cdk4', 'Gene', '1019', (200, 204))	('cyclin D1', 'Gene', '595', (109, 118))	('Ovarian', 'Disease', (0, 7))	('cdk4', 'Gene', (200, 204))	('cyclin D1', 'Gene', (109, 118))	('hTERT', 'Gene', (170, 175))	('cdk4', 'Gene', '1019', (120, 124))	('transfection', 'Var', (87, 99))	('hTERT', 'Gene', (129, 134))	('cdk4', 'Gene', (120, 124))
14889	27979878	ARID1A is a member of the SWI/SNF chromatin remodelling complex, and is reported to be frequently mutated in two epithelial ovarian carcinoma subtypes: ovarian clear cell carcinomas and endometrioid ovarian carcinomas.	('epithelial ovarian carcinoma subtypes', 'Disease', (113, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (199, 217))	('ARID1A', 'Gene', '8289', (0, 6))	('epithelial ovarian carcinoma subtypes', 'Disease', 'MESH:D000077216', (113, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('ARID1A', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (199, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('mutated', 'Var', (98, 105))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (124, 141))	('ovarian clear cell carcinomas and endometrioid ovarian carcinomas', 'Disease', 'MESH:D010051', (152, 217))
14891	27979878	Therefore, it is conceivable that hTERT expression may be potentially involved in carcinogenesis associated with the loss of ARID1A.	('hTERT', 'Gene', (34, 39))	('loss', 'Var', (117, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('ARID1A', 'Gene', '8289', (125, 131))	('carcinogenesis', 'Disease', (82, 96))	('ARID1A', 'Gene', (125, 131))	('involved', 'Reg', (70, 78))	('hTERT', 'Gene', '7015', (34, 39))
14935	27979878	Telomere attrition can result in genomic instability which can subsequently initiate carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('genomic instability', 'MPA', (33, 52))	('initiate', 'Reg', (76, 84))	('result in', 'Reg', (23, 32))	('Telomere attrition', 'Var', (0, 18))	('carcinogenesis', 'Disease', (85, 99))
14937	27979878	There are at least four activating mutations reported in TERT, POT1, TPP1 and TERF2IP (RAP1) genes of the telomerase and telomere complexes which can result in longer TLs while several other telomere and telomerase associated gene mutations (including repressor mutations in POT1 and activating mutations of TRF1/2) result in short TL (reviewed in ).	('result', 'Reg', (150, 156))	('TPP1', 'Gene', '1200', (69, 73))	('mutations', 'Var', (231, 240))	('short TL', 'Disease', (326, 334))	('TERF2IP', 'Gene', (78, 85))	('TRF1/2', 'Gene', (308, 314))	('TERF2IP', 'Gene', '54386', (78, 85))	('POT1', 'Gene', (275, 279))	('longer TLs', 'MPA', (160, 170))	('TPP1', 'Gene', (69, 73))	('TRF1/2', 'Gene', '7013;7014', (308, 314))	('mutations', 'Var', (35, 44))
14938	27979878	Since either lengthening or shortening of telomeres can result in abnormal cell proliferation or genomic instability, they can be implicated in carcinogenesis (reviewed in).	('shortening', 'NegReg', (28, 38))	('abnormal cell proliferation', 'CPA', (66, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (144, 158))	('shortening of telomeres', 'Phenotype', 'HP:0031413', (28, 51))	('implicated', 'Reg', (130, 140))	('genomic instability', 'CPA', (97, 116))	('carcinogenesis', 'Disease', (144, 158))	('lengthening', 'Var', (13, 24))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (66, 93))	('result in', 'Reg', (56, 65))	('rat', 'Species', '10116', (87, 90))
14959	27979878	Therefore, the ongoing proliferation in postmenopausal epithelial cells with short TLs may render them vulnerable to subsequent genetic instability and carcinogenic transformation similar to various other cancer types.	('render', 'Reg', (91, 97))	('carcinogenic transformation', 'Disease', 'MESH:D020518', (152, 179))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('genetic instability', 'CPA', (128, 147))	('cancer', 'Disease', (205, 211))	('rat', 'Species', '10116', (30, 33))	('TLs', 'Gene', (83, 86))	('short', 'Var', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('men', 'Species', '9606', (44, 47))	('carcinogenic transformation', 'Disease', (152, 179))
14960	27979878	Lynch syndrome is an autosomal dominant condition characterized by germ line mutation in DNA mismatch repair genes resulting in increased risk of developing a variety of cancers including EC.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('EC', 'Phenotype', 'HP:0012114', (188, 190))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('germ line mutation', 'Var', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Lynch syndrome', 'Disease', (0, 14))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
14961	27979878	Long telomeres are associated with familial cancer syndromes such as familial melanoma.	('associated', 'Reg', (19, 29))	('familial melanoma', 'Disease', 'OMIM:155600', (69, 86))	('Long telomeres', 'Var', (0, 14))	('familial cancer', 'Disease', (35, 50))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('familial cancer', 'Disease', 'MESH:D009369', (35, 50))	('familial melanoma', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
14965	27979878	Frequent PTEN mutations and P53 loss known to occur in ECs could be associated with telomerase up-regulation but the exact mechanism through which these different events interact is not yet clear.	('telomerase', 'Enzyme', (84, 94))	('loss', 'NegReg', (32, 36))	('PTEN', 'Gene', (9, 13))	('PTEN', 'Gene', '5728', (9, 13))	('P53', 'Gene', (28, 31))	('EC', 'Phenotype', 'HP:0012114', (55, 57))	('up-regulation', 'PosReg', (95, 108))	('mutations', 'Var', (14, 23))	('P53', 'Gene', '7157', (28, 31))
14967	27979878	In a mouse model, simultaneous deletion of p53 and POT1 resulted in precursor lesions of endometrial epithelium and induced ECs with non-endometrioid, Type II phenotype, suggesting that telomeric instability has a critical role to play in Type II ECs.	('EC', 'Phenotype', 'HP:0012114', (247, 249))	('Type II EC', 'Disease', (239, 249))	('induced', 'Reg', (116, 123))	('endometrial epithelium', 'Disease', (89, 111))	('EC', 'Phenotype', 'HP:0012114', (124, 126))	('deletion', 'Var', (31, 39))	('p53', 'Gene', (43, 46))	('mouse', 'Species', '10090', (5, 10))	('POT1', 'Gene', (51, 55))	('ECs', 'Disease', (124, 127))	('Type II EC', 'Disease', 'MESH:D005776', (239, 249))
14968	27979878	TERT promoter mutations seem to be rare in ECs, except for the clear cell (Type II EC) subtype.	('Type II EC', 'Disease', (75, 85))	('TERT promoter', 'Gene', (0, 13))	('ECs', 'Disease', (43, 46))	('EC', 'Phenotype', 'HP:0012114', (83, 85))	('clear cell', 'Disease', (63, 73))	('Type II EC', 'Disease', 'MESH:D005776', (75, 85))	('mutations', 'Var', (14, 23))	('EC', 'Phenotype', 'HP:0012114', (43, 45))
14969	27979878	Activating TERT promotor mutations are a feature of cancers derived from tissues with low relative cellular turnover such as the brain, therefore such mutations are not expected in the highly regenerative endometrial epithelium.	('mutations', 'Var', (25, 34))	('Activating', 'PosReg', (0, 10))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TERT promotor', 'Gene', (11, 24))	('rat', 'Species', '10116', (198, 201))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
15001	28296680	Fluorescence in situ hybridization was successful in all cases and confirmed EWSR1 rearrangement in 2 of 4 tumors demonstrating morphologic features of Ewing sarcoma/peripheral PNET and concurrent CD99 and Fli-1 expression.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('CD99', 'Gene', (197, 201))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Fli-1', 'Gene', '2313', (206, 211))	('rearrangement', 'Var', (83, 96))	('tumors', 'Disease', (107, 113))	('Fli-1', 'Gene', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CD99', 'Gene', '4267', (197, 201))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('Ewing sarcoma', 'Disease', (152, 165))	('EWSR1', 'Gene', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('EWSR1', 'Gene', '2130', (77, 82))
15012	28296680	Some gynecologic PNETs harbor EWSR1 rearrangements and thus are considered of the peripheral type or Ewing sarcoma, a neoplasm with a wide morphologic spectrum that is defined by translocations producing fusion of EWSR1 to various members of the ETS family of transcription factors.	('EWSR1', 'Gene', '2130', (30, 35))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('neoplasm', 'Disease', (118, 126))	('neoplasm', 'Disease', 'MESH:D009369', (118, 126))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('EWSR1', 'Gene', (214, 219))	('EWSR1', 'Gene', (30, 35))	('rearrangements', 'Var', (36, 50))	('fusion', 'Var', (204, 210))	('EWSR1', 'Gene', '2130', (214, 219))	('Ewing sarcoma', 'Disease', (101, 114))
15026	28296680	Endogenous peroxidase activity was blocked by H2O2 before antibody incubation.	('activity', 'MPA', (22, 30))	('H2O2', 'Chemical', 'MESH:D006861', (46, 50))	('H2O2', 'Var', (46, 50))
15095	28296680	FISH analysis was successful in all 19 tumors and detected EWSR1 rearrangement in only 2 (11.1%) cases in the vulva and uterus which both showed morphologic features consistent with Ewing sarcoma/peripheral PNET (Figure 3D).	('EWSR1', 'Gene', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('EWSR1', 'Gene', '2130', (59, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('rearrangement', 'Var', (65, 78))	('Ewing sarcoma', 'Disease', (182, 195))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('tumors', 'Disease', (39, 45))
15102	28296680	Tumors that were composed entirely of sheets of primitive small round blue cells and showed both membranous CD99 and nuclear Fli-1 expression, but absence of GFAP staining by immunohistochemistry were more likely to harbor an EWSR1 rearrangement detectable by FISH, consistent with Ewing sarcoma/peripheral PNET.	('rearrangement', 'Var', (232, 245))	('EWSR1', 'Gene', '2130', (226, 231))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (282, 295))	('CD99', 'Gene', '4267', (108, 112))	('absence', 'NegReg', (147, 154))	('Fli-1', 'Gene', (125, 130))	('GFAP', 'Gene', (158, 162))	('Fli-1', 'Gene', '2313', (125, 130))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Ewing sarcoma', 'Disease', (282, 295))	('CD99', 'Gene', (108, 112))	('EWSR1', 'Gene', (226, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('GFAP', 'Gene', '2670', (158, 162))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (282, 295))
15113	28296680	In many studies without molecular genetic analysis, the diagnosis of PNET particularly of the peripheral type was rendered based on the presence of CD99 positivity in the setting of a predominately small round blue cell tumor with or without rosettes.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('rosettes', 'Phenotype', 'HP:0031925', (242, 250))	('CD99', 'Gene', '4267', (148, 152))	('tumor', 'Disease', (220, 225))	('rosette', 'Phenotype', 'HP:0031925', (242, 249))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('positivity', 'Var', (153, 163))	('CD99', 'Gene', (148, 152))	('presence', 'Var', (136, 144))
15116	28296680	Whether some reports lacking confirmation of EWSR1 rearrangement truly represent Ewing sarcoma/peripheral PNET is subject to debate.	('Ewing sarcoma', 'Disease', (81, 94))	('EWSR1', 'Gene', (45, 50))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('EWSR1', 'Gene', '2130', (45, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('rearrangement', 'Var', (51, 64))
15119	28296680	Absence of EWSR1 rearrangement in our 2 tumors initially classified as Ewing sarcoma/peripheral PNET prompted re-review of the morphologic and immunohistochemical findings.	('Ewing sarcoma', 'Disease', (71, 84))	('EWSR1', 'Gene', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('rearrangement', 'Var', (17, 30))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('EWSR1', 'Gene', '2130', (11, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
15121	28296680	It is possible that these 2 tumors harbor genetic abnormalities other than rearrangement of EWSR1.	('tumors harbor genetic abnormalities', 'Disease', (28, 63))	('EWSR1', 'Gene', '2130', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors harbor genetic abnormalities', 'Disease', 'MESH:D030342', (28, 63))	('EWSR1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('rearrangement', 'Var', (75, 88))
15122	28296680	Presence of an EWSR1 rearrangement in gynecologic PNETs may allow patients with Ewing sarcoma/peripheral PNET to be treated with therapeutic regimens used for the Ewing family of tumors in which a combination of surgery and/or radiation and multiagent systemic chemotherapy result in a 70% 5-year survival rate for localized disease.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('localized disease', 'Disease', (315, 332))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('EWSR1', 'Gene', (15, 20))	('rearrangement', 'Var', (21, 34))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('EWSR1', 'Gene', '2130', (15, 20))	('Ewing sarcoma', 'Disease', (80, 93))	('Presence', 'Var', (0, 8))	('patients', 'Species', '9606', (66, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
15126	28296680	Epigenetic profiling of central PNETs arising in the female genital tract, particularly in the ovary and uterus where central PNETs tend to be encountered, is a worthwhile endeavor and may enable more accurate diagnosis and therapeutic strategies for patients affected by this rare tumor type.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('ovary', 'Disease', 'MESH:D010051', (95, 100))	('central PNETs', 'Disease', (24, 37))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('Epigenetic', 'Var', (0, 10))	('patients', 'Species', '9606', (251, 259))	('ovary', 'Disease', (95, 100))
15142	28296680	However, all published gynecologic Ewing sarcoma/peripheral PNETs and our 2 tumors that harbor EWSR1 rearrangement were CD99-positive; thus, absent CD99 staining should prompt reconsideration of the diagnosis of Ewing sarcoma/peripheral PNET in the setting of a small round blue cell tumor.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('CD99', 'Gene', (120, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (212, 225))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (212, 225))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('Ewing sarcoma', 'Disease', (35, 48))	('CD99', 'Gene', '4267', (120, 124))	('EWSR1', 'Gene', '2130', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('CD99', 'Gene', (148, 152))	('Ewing sarcoma', 'Disease', (212, 225))	('CD99', 'Gene', '4267', (148, 152))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('rearrangement', 'Var', (101, 114))	('EWSR1', 'Gene', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('tumor', 'Disease', (284, 289))
15159	28296680	Tumors that consist of small round blue cells with concurrent strong and diffuse membranous CD99 and nuclear Fli-1 staining likely harbor EWSR1 rearrangement.	('EWSR1', 'Gene', (138, 143))	('rearrangement', 'Var', (144, 157))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('EWSR1', 'Gene', '2130', (138, 143))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CD99', 'Gene', '4267', (92, 96))	('harbor', 'Reg', (131, 137))	('Fli-1', 'Gene', '2313', (109, 114))	('CD99', 'Gene', (92, 96))	('Fli-1', 'Gene', (109, 114))
15190	28186981	Using these cutoffs, patients with higher 18F-FDG SUVs had worse OS (p = 0.007) and a trend toward worse PFS (p = 0.11) than patients with a lower 18F-FDG SUVs (Figure 4).	('18F-FDG SUVs', 'Var', (42, 54))	('OS', 'Chemical', '-', (65, 67))	('patients', 'Species', '9606', (21, 29))	('FDG', 'Chemical', 'MESH:D019788', (46, 49))	('worse', 'NegReg', (99, 104))	('PFS', 'MPA', (105, 108))	('FDG', 'Chemical', 'MESH:D019788', (151, 154))	('patients', 'Species', '9606', (125, 133))
15196	28186981	Despite heterogeneity in treatment regimens, disease stages, and histological types in the patients examined in this retrospective study, 18F-FDG/18F-FES SUV ratio was correlated with both PFS (p = 0.007) and OS (p = 0.005).	('18F-FES', 'Chemical', '-', (146, 153))	('PFS', 'Disease', (189, 192))	('patients', 'Species', '9606', (91, 99))	('FDG', 'Chemical', 'MESH:D019788', (142, 145))	('OS', 'Chemical', '-', (209, 211))	('correlated', 'Reg', (168, 178))	('18F-FDG/18F-FES', 'Var', (138, 153))
15347	26082937	Another point of view implies that morcellation of a uterine leiomyoma in a laparoscopic myomectomy may rarely cause dissemination.	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (53, 70))	('morcellation', 'Var', (35, 47))	('leiomyoma', 'Disease', (61, 70))	('leiomyoma', 'Disease', 'MESH:D007889', (61, 70))
15485	22007228	Risk factors for the development of carcinosarcoma are similar to those of endometrial carcinoma and include nulliparity, advanced age, obesity, exposure to exogenous estrogens, and long-term use of tamoxifen.	('obesity', 'Disease', 'MESH:D009765', (136, 143))	('obesity', 'Phenotype', 'HP:0001513', (136, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (75, 96))	('carcinosarcoma', 'Disease', (36, 50))	('obesity', 'Disease', (136, 143))	('tamoxifen', 'Chemical', 'MESH:D013629', (199, 208))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (75, 96))	('carcinosarcoma', 'Disease', 'MESH:D002296', (36, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('endometrial carcinoma', 'Disease', (75, 96))	('nulliparity', 'Var', (109, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
15548	22007228	T2-weighted images found hyperintensity of uterine carcinosarcomas to the myometrium (92%) and hypointensity (55%) or isointensity (41%) to the endometrium, a finding that is highly comparable to endometrial carcinoma (97% hyperintense to myometrium, 23% isointense, and 68% hypointense to endometrium).	('endometrial carcinoma', 'Disease', (196, 217))	('carcinosarcomas', 'Disease', (51, 66))	('carcinosarcomas', 'Disease', 'MESH:D002296', (51, 66))	('abl', 'Gene', (188, 191))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (196, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (43, 65))	('isointensity', 'Var', (118, 130))	('abl', 'Gene', '25', (188, 191))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (196, 217))
15588	22007228	Lymphadenectomy offers a survival advantage only for node-negative patients, as removal of positive nodes upstages the disease and worsens the prognosis.	('prognosis', 'MPA', (143, 152))	('patients', 'Species', '9606', (67, 75))	('nodes upstages the disease', 'Disease', (100, 126))	('nodes upstages the disease', 'Disease', 'MESH:D012804', (100, 126))	('removal', 'Var', (80, 87))	('worsens', 'NegReg', (131, 138))
15620	22007228	Sorafenib acts by inhibiting wild-type Raf-1, mutant B-Raf and several receptor tyrosine kinases such as vascular endothelial growth factor receptors (VEGFR).	('vascular endothelial growth factor receptors', 'Gene', '3791', (105, 149))	('B-Raf', 'Gene', '673', (53, 58))	('Raf-1', 'Gene', (39, 44))	('B-Raf', 'Gene', (53, 58))	('VEGFR', 'Gene', '3791', (151, 156))	('mutant', 'Var', (46, 52))	('inhibiting', 'NegReg', (18, 28))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('Raf-1', 'Gene', '5894', (39, 44))	('VEGFR', 'Gene', (151, 156))	('vascular endothelial growth factor receptors', 'Gene', (105, 149))
15707	22007228	Tumour characteristics of molecular markers such as expression of p53 in older women are associated with a shorter mean survival, while p53 negative tumours occurring in younger women have a longer survival.	('p53', 'Gene', '7157', (66, 69))	('tumours', 'Disease', (149, 156))	('p53', 'Gene', '7157', (136, 139))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('mean survival', 'MPA', (115, 128))	('shorter', 'NegReg', (107, 114))	('women', 'Species', '9606', (178, 183))	('women', 'Species', '9606', (79, 84))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'Var', (52, 62))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumours', 'Disease', 'MESH:D009369', (149, 156))	('p53', 'Gene', (66, 69))	('p53', 'Gene', (136, 139))
15862	20694075	Perhaps the phase III study, which will evaluate the safety and effectiveness of trabectedin versus doxorubicin-based chemotherapy in patients with translocation-related sarcomas, will provide sufficient evidence for the US Food and Drug Administration to approve this drug in soft-tissue sarcoma for those patients who have exhausted other therapeutic options.	('sarcoma', 'Disease', 'MESH:D012509', (170, 177))	('sarcomas', 'Disease', 'MESH:D012509', (170, 178))	('sarcoma', 'Disease', (289, 296))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('patients', 'Species', '9606', (134, 142))	('sarcoma', 'Disease', (170, 177))	('trabectedin', 'Chemical', 'MESH:D000077606', (81, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('doxorubicin', 'Chemical', 'MESH:D004317', (100, 111))	('sarcomas', 'Disease', (170, 178))	('sarcoma', 'Disease', 'MESH:D012509', (289, 296))	('patients', 'Species', '9606', (307, 315))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (277, 296))	('translocation-related', 'Var', (148, 169))
15883	19356236	Factors associated with poor prognosis include stage, high grade of tumour, adnexal spread and lymph node metastasis.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('high grade', 'Var', (54, 64))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('adnexal spread', 'CPA', (76, 90))	('tumour', 'Disease', (68, 74))	('lymph node metastasis', 'CPA', (95, 116))
15892	19356236	In their retrospective analysis, Callister et al found that patients treated with pelvic irradiation had a lower rate of pelvic recurrence than those treated with surgery alone (28% versus 48%, p = 0.0002), but the 5-year overall survival and distant metastasis rates were not significantly different.	('pelvic', 'Var', (82, 88))	('lower', 'NegReg', (107, 112))	('patients', 'Species', '9606', (60, 68))	('pelvic recurrence', 'Disease', (121, 138))
15900	19356236	Adjusting for stage and age, the recurrence rate was 21% lower for CIM patients than for WAI patients (relative hazard = 0.789, p = 0.245).	('patients', 'Species', '9606', (71, 79))	('CIM', 'Var', (67, 70))	('patients', 'Species', '9606', (93, 101))	('lower', 'NegReg', (57, 62))
15934	19356236	However, in a small phase II study, four cycles of adjuvant chemotherapy with gemcitabine and docetaxel in patients with completely resected stage I-IV, high-grade uterine LMSs resulted in 2-year PFS rates that appear superior to historical rates (this issue will be discussed more detailed in the final section of the article).	('patients', 'Species', '9606', (107, 115))	('docetaxel', 'Chemical', 'MESH:D000077143', (94, 103))	('PFS', 'CPA', (196, 199))	('high-grade uterine', 'Var', (153, 171))	('gemcitabine', 'Chemical', 'MESH:C056507', (78, 89))
15948	19356236	Chu et al evaluated the expression of ER-alpha and ER-beta in low grade ESS and they suggested that loss of ERbeta expression may be a marker for malignancy.	('loss', 'Var', (100, 104))	('ER-alpha', 'Gene', '2099', (38, 46))	('ERbeta', 'Gene', (108, 114))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('ER-beta', 'Gene', '2100', (51, 58))	('expression', 'MPA', (115, 125))	('ER-alpha', 'Gene', (38, 46))	('ERbeta', 'Gene', '2100', (108, 114))	('malignancy', 'Disease', (146, 156))	('ER-beta', 'Gene', (51, 58))
15949	19356236	Accordingly, Balleine et al showed that PR isoform expression, similarly to that of a normal endometrial stroma, is consistent with the highly differentiated phenotype of this tumor and that variant differentiation or disease recurrence was accompanied by an altered PR isoform profile that could impact on hormone response.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('impact', 'Reg', (297, 303))	('PR isoform expression', 'MPA', (40, 61))	('variant', 'Var', (191, 198))	('tumor', 'Disease', (176, 181))	('endometrial stroma', 'Disease', 'MESH:D014591', (93, 111))	('altered', 'Reg', (259, 266))	('PR isoform profile', 'MPA', (267, 285))	('hormone response', 'MPA', (307, 323))	('Balleine', 'Chemical', '-', (13, 21))	('endometrial stroma', 'Disease', (93, 111))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
15997	19356236	Of 75 patients receiving doxorubicin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy, but this difference was not statistically significant.	('suffered', 'Reg', (46, 54))	('doxorubicin', 'Var', (25, 36))	('patients', 'Species', '9606', (6, 14))	('doxorubicin', 'Chemical', 'MESH:D004317', (25, 36))
16051	31437624	TARGET datasets include large-scale genomic data including gene-expression, copy number variation, epigenetics, along with annotated clinical information for a selected set of pediatric cancers (https://ocg.cancer.gov/programs/target/data-matrix).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('copy number variation', 'Var', (76, 97))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
16082	31437624	Using 39 pedigrees, researchers were able to determine that the most common cause of LFS is inherited mutations in the tumor suppressor gene TP53.	('tumor', 'Disease', (119, 124))	('TP53', 'Gene', '7157', (141, 145))	('LFS', 'Disease', 'MESH:D016864', (85, 88))	('TP53', 'Gene', (141, 145))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cause', 'Reg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LFS', 'Disease', (85, 88))
16102	31437624	analyzed the mutation landscape of 12 major cancer types and found that TP53 and PIK3CA were the most commonly mutated genes, ARID1A were frequently mutated in bladder urothelial carcinoma (BLCA), uterine corpus endometrial carcinoma (UCEC), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and EGFR were frequently mutated in GBM and LUAD.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (278, 301))	('mutated', 'Var', (149, 156))	('PIK3CA', 'Gene', '5290', (81, 87))	('lung adenocarcinoma', 'Disease', (242, 261))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (212, 233))	('bladder urothelial carcinoma', 'Disease', (160, 188))	('LUAD', 'Phenotype', 'HP:0030078', (263, 267))	('EGFR', 'Gene', (314, 318))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (212, 233))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (273, 301))	('TP53', 'Gene', '7157', (72, 76))	('lung squamous cell carcinoma', 'Disease', (273, 301))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (160, 188))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GBM', 'Phenotype', 'HP:0012174', (346, 349))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (242, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (242, 261))	('PIK3CA', 'Gene', (81, 87))	('LUAD', 'Phenotype', 'HP:0030078', (354, 358))	('ARID1A', 'Gene', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('EGFR', 'Gene', '1956', (314, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('ARID1A', 'Gene', '8289', (126, 132))	('endometrial carcinoma', 'Disease', (212, 233))	('cancer', 'Disease', (44, 50))	('USC', 'Phenotype', 'HP:0002891', (304, 307))	('TP53', 'Gene', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
16103	31437624	In contrast, VHL and PBRM1 mutations were exclusive to kidney renal clear cell carcinoma (KIRC), and NPM1 and FLT3 mutations were exclusive to AML.	('mutations', 'Var', (27, 36))	('FLT3', 'Gene', (110, 114))	('NPM1', 'Gene', '4869', (101, 105))	('kidney renal clear cell carcinoma', 'Disease', (55, 88))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (55, 88))	('FLT3', 'Gene', '2322', (110, 114))	('PBRM1', 'Gene', (21, 26))	('VHL', 'Gene', (13, 16))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('PBRM1', 'Gene', '55193', (21, 26))	('VHL', 'Gene', '7428', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('AML', 'Disease', (143, 146))	('NPM1', 'Gene', (101, 105))	('AML', 'Phenotype', 'HP:0004808', (143, 146))
16104	31437624	Numerous pan-cancer analyses have been performed, including pan-cancer analyses of copy number alteration, enhancer expression, oncogenic signaling pathways, and transcriptional metabolic dysregulation.	('copy number alteration', 'Var', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('enhancer', 'PosReg', (107, 115))	('oncogenic', 'CPA', (128, 137))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
16114	31437624	To illustrate the integrative clustering analysis, we analyzed 241 sarcoma tumor samples from the TCGA SARC study that had somatic mutation, copy number, methylation and mRNA expression data using the recently developed iClusterBayes software.	('sarcoma tumor', 'Disease', 'MESH:D012509', (67, 80))	('sarcoma tumor', 'Disease', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('copy', 'Var', (141, 145))	('SARC', 'Phenotype', 'HP:0100242', (103, 107))	('mRNA expression', 'MPA', (170, 185))
16122	33214570	Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort PARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', (123, 129))	('BRCA', 'Gene', '672', (222, 226))	('BRCA', 'Gene', (222, 226))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
16127	33214570	We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.	('human', 'Species', '9606', (165, 170))	('HR deficiency', 'Disease', 'MESH:D001919', (306, 319))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('mutations', 'Var', (43, 52))	('cancers', 'Disease', (171, 178))	('HR deficiency', 'Disease', (306, 319))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
16129	33214570	For example, Tyrosine kinase inhibitors such as imatinib, bosutinib, and dasatinib targeting the BCR-ABL fusion protein have improved outcomes in Philadelphia chromosome positive leukemia, and similar approaches have made a considerable impact in breast cancer, non-small cell lung cancer (NSCLC), and several other cancer types.	('imatinib', 'Chemical', 'MESH:D000068877', (48, 56))	('BCR-ABL', 'Gene', '25', (97, 104))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('breast cancer', 'Disease', (247, 260))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (266, 288))	('cancer', 'Disease', (254, 260))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (262, 288))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('Philadelphia chromosome positive leukemia', 'Disease', 'MESH:D010677', (146, 187))	('bosutinib', 'Var', (58, 67))	('non-small cell lung cancer', 'Disease', (262, 288))	('cancer', 'Disease', (316, 322))	('Philadelphia chromosome positive leukemia', 'Disease', (146, 187))	('BCR-ABL', 'Gene', (97, 104))	('NSCLC', 'Disease', 'MESH:D002289', (290, 295))	('leukemia', 'Phenotype', 'HP:0001909', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('improved', 'PosReg', (125, 133))	('NSCLC', 'Disease', (290, 295))	('bosutinib', 'Chemical', 'MESH:C471992', (58, 67))	('cancer', 'Disease', (282, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('NSCLC', 'Phenotype', 'HP:0030358', (290, 295))	('Philadelphia chromosome positive leukemia', 'Phenotype', 'HP:0004848', (146, 187))	('dasatinib', 'Chemical', 'MESH:D000069439', (73, 82))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (262, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('Tyrosine', 'Var', (13, 21))
16132	33214570	This approach has strong scientific rationale, as patients with BRCA mutations are thought to have homologous recombination deficiency (HRD), thereby limiting their ability to repair double stranded DNA breaks.	('mutations', 'Var', (69, 78))	('HRD', 'Disease', 'None', (136, 139))	('patients', 'Species', '9606', (50, 58))	('deficiency', 'Disease', (124, 134))	('BRCA', 'Gene', '672', (64, 68))	('deficiency', 'Disease', 'MESH:D007153', (124, 134))	('ability', 'MPA', (165, 172))	('BRCA', 'Gene', (64, 68))	('HRD', 'Disease', (136, 139))	('limiting', 'NegReg', (150, 158))
16136	33214570	For instance, in metastatic prostate cancer, mutations to genes more modestly associated with the pathway such as ATM, CHEK2, and PALB2 are strongly associated with clinical responses to olaparib.	('mutations', 'Var', (45, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('CHEK2', 'Gene', (119, 124))	('PALB2', 'Gene', '79728', (130, 135))	('ATM', 'Gene', '472', (114, 117))	('PALB2', 'Gene', (130, 135))	('associated with', 'Reg', (149, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('CHEK2', 'Gene', '11200', (119, 124))	('clinical responses to olaparib', 'MPA', (165, 195))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('olaparib', 'Chemical', 'MESH:C531550', (187, 195))	('prostate cancer', 'Disease', (28, 43))	('ATM', 'Gene', (114, 117))
16138	33214570	Likewise, 88% of prostate cancer patients with CHECK2 mutations showed clinical responses to PARP inhibition, with similar results observed in other studies, many including additional cancer histologies.	('cancer', 'Disease', (184, 190))	('prostate cancer', 'Phenotype', 'HP:0012125', (17, 32))	('patients', 'Species', '9606', (33, 41))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inhibition', 'NegReg', (98, 108))	('prostate cancer', 'Disease', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('CHECK2', 'Gene', (47, 53))	('PARP', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (17, 32))
16139	33214570	Similarly, PALB2 mutated breast cancer also appears to be highly sensitive to PARP inhibition.	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('PALB2', 'Gene', (11, 16))	('PALB2', 'Gene', '79728', (11, 16))	('mutated', 'Var', (17, 24))
16145	33214570	For instance, though loss of POLQ appears to upregulate HR activity in HR-proficient cells, loss of POLQ is also seemingly central to PARP inhibitor sensitivity in the setting of topoisomerase, ATR, or FANCD2-deficiency.	('loss', 'Var', (21, 25))	('POLQ', 'Gene', (100, 104))	('POLQ', 'Gene', '10721', (100, 104))	('ATR', 'Gene', (194, 197))	('FANCD2-deficiency', 'Disease', 'OMIM:227646', (202, 219))	('POLQ', 'Gene', (29, 33))	('FANCD2-deficiency', 'Disease', (202, 219))	('loss', 'Var', (92, 96))	('POLQ', 'Gene', '10721', (29, 33))	('upregulate', 'PosReg', (45, 55))	('ATR', 'Gene', '545', (194, 197))
16146	33214570	Hence, it is clear that stratifying patients based solely BRCA mutations will likely under predict for those who will derive clinical benefit from PARP inhibition.	('mutations', 'Var', (63, 72))	('BRCA', 'Gene', (58, 62))	('BRCA', 'Gene', '672', (58, 62))	('patients', 'Species', '9606', (36, 44))
16148	33214570	We then identified the individual cancer types in which these alterations are most frequent.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('frequent', 'Reg', (83, 91))	('alterations', 'Var', (62, 73))
16149	33214570	Though many of the observed mutations are currently of unknown significance, these newly identified genomic alterations warrant further investigation, particularly in the setting of homologous recombination deficiency and PARP inhibition.	('deficiency', 'Disease', 'MESH:D007153', (207, 217))	('mutations', 'Var', (28, 37))	('deficiency', 'Disease', (207, 217))
16159	33214570	HR pathway mutations were common in this cohort, affecting 7117 (13.4%) of patients.	('mutations', 'Var', (11, 20))	('patients', 'Species', '9606', (75, 83))	('HR pathway', 'Pathway', (0, 10))
16160	33214570	ATM and BRCA2 mutations were most common, affecting 2160 (4.1%) and 1452 (2.7%) of patients respectively, followed by BRCA1 (822 or 1.5%), CDK12 (805 or 1.5%), and POLQ (634 or 1.19%).	('POLQ', 'Gene', (164, 168))	('POLQ', 'Gene', '10721', (164, 168))	('BRCA2', 'Gene', (8, 13))	('CDK12', 'Gene', (139, 144))	('BRCA1', 'Gene', '672', (118, 123))	('ATM', 'Gene', (0, 3))	('affecting', 'Reg', (42, 51))	('BRCA2', 'Gene', '675', (8, 13))	('CDK12', 'Gene', '51755', (139, 144))	('patients', 'Species', '9606', (83, 91))	('BRCA1', 'Gene', (118, 123))	('mutations', 'Var', (14, 23))	('ATM', 'Gene', '472', (0, 3))
16162	33214570	Of these 33,633 patients, 4472 (13.3%) had an identifiable mutation to the queried HR genes, whereas 29,161 (86.7%) did not.	('mutation', 'Var', (59, 67))	('patients', 'Species', '9606', (16, 24))	('HR genes', 'Gene', (83, 91))
16165	33214570	While these data suggest that as a whole, HR pathway mutations may have prognostic value, these results may be skewed should HR mutations be more frequently observed in more aggressive cancers.	('aggressive cancers', 'Disease', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (53, 62))	('observed', 'Reg', (157, 165))	('HR pathway', 'Pathway', (42, 52))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('aggressive cancers', 'Disease', 'MESH:D009369', (174, 192))
16169	33214570	Using this new sample set, we determined the rate of mutations to the HR pathway both overall and by by cancer type (Fig.	('HR pathway', 'Pathway', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
16170	33214570	HR pathway mutations were particularly common among diffuse large B cell lymphomas and melanoma patients, with combined mutation rates of 37.5 and 37.33%, respectively (Fig.	('melanoma', 'Disease', (87, 95))	('mutations', 'Var', (11, 20))	('lymphomas', 'Disease', 'MESH:D008223', (73, 82))	('HR pathway', 'Pathway', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('large B cell', 'Phenotype', 'HP:0005404', (60, 72))	('lymphomas', 'Phenotype', 'HP:0002665', (73, 82))	('common', 'Reg', (39, 45))	('B cell lymphoma', 'Disease', 'MESH:D016393', (66, 81))	('B cell lymphoma', 'Disease', (66, 81))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (66, 81))	('patients', 'Species', '9606', (96, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (66, 82))	('lymphomas', 'Disease', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
16173	33214570	Once again, mutations affecting the combined gene set were associated with poor outcomes in the combined cancer cohort (Fig.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
16175	33214570	With respect to ATM, we observed a total of 485 mutations, 339 of which were missense, 142 truncating, and 4 in-frame mutations of unknown significance (Fig.	('missense', 'Var', (77, 85))	('ATM', 'Gene', '472', (16, 19))	('ATM', 'Gene', (16, 19))	('mutations', 'Var', (48, 57))
16177	33214570	While mutations to POLQ, FANCM, CHECK2, CDK12, and FANCD2 were among the most heterogeneous, these had a relatively low frequency, most effecting only one patient (Fig.	('CDK12', 'Gene', '51755', (40, 45))	('FANCM', 'Gene', '57697', (25, 30))	('FANCD2', 'Gene', (51, 57))	('FANCM', 'Gene', (25, 30))	('CDK12', 'Gene', (40, 45))	('POLQ', 'Gene', (19, 23))	('patient', 'Species', '9606', (155, 162))	('effecting', 'Reg', (136, 145))	('POLQ', 'Gene', '10721', (19, 23))	('CHECK2', 'Gene', (32, 38))	('mutations', 'Var', (6, 15))	('FANCD2', 'Gene', '2177', (51, 57))
16178	33214570	While the majority of mutations identified in this study have yet to be uncharacterized, a sizeable fraction was analogous to those reported previously to have a role in PARP inhibitor sensitivity and/or HRD and likely to have oncogenic function, though this requires further exploration (Supplementary Table S3).	('role', 'Reg', (162, 166))	('HRD', 'Disease', (204, 207))	('mutations', 'Var', (22, 31))	('HRD', 'Disease', 'None', (204, 207))	('PARP', 'Protein', (170, 174))
16179	33214570	Interestingly, several HR-associated mutations often co-occurred in the same patients, suggesting patients with select HR-associated mutations are likely to incur additional HR-associated mutations (Supplementary Table S4).	('HR-associated', 'Gene', (119, 132))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (77, 85))	('mutations', 'Var', (133, 142))	('HR-associated', 'Disease', (174, 187))	('mutations', 'Var', (188, 197))
16180	33214570	Additionally, patients with HR-associated mutations also harbored mutations to several non-HR genes with higher frequency than those without HR associated mutations (Supplementary Table S5), several of which were also independent predictors of poor clinical outcomes (Supplementary Table S6).	('mutations', 'Var', (66, 75))	('HR-associated', 'Disease', (28, 41))	('harbored', 'Reg', (57, 65))	('non-HR genes', 'Gene', (87, 99))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (42, 51))
16182	33214570	As mentioned previously, HR mutations were observed most frequently in diffuse large B cell lymphoma, affecting roughly 38% of patients, though this may be inflated given the small sample size of the study (N = 47).	('B cell lymphoma', 'Disease', 'MESH:D016393', (85, 100))	('B cell lymphoma', 'Disease', (85, 100))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (85, 100))	('observed', 'Reg', (43, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('patients', 'Species', '9606', (127, 135))	('large B cell', 'Phenotype', 'HP:0005404', (79, 91))	('mutations', 'Var', (28, 37))
16184	33214570	Also as mentioned, HR mutations were also common in cutaneous melanomas (37.5%), though this represented data from 288 patients.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (52, 71))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (52, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('patients', 'Species', '9606', (119, 127))	('cutaneous melanomas', 'Disease', (52, 71))	('mutations', 'Var', (22, 31))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('common', 'Reg', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
16185	33214570	In this group, BRCA mutations were observed in 11.5% of patients, though mutations to ATM, BRIP1, FANCM, and other genes were also common (Table 3).	('patients', 'Species', '9606', (56, 64))	('ATM', 'Gene', '472', (86, 89))	('FANCM', 'Gene', '57697', (98, 103))	('BRIP1', 'Gene', (91, 96))	('BRIP1', 'Gene', '83990', (91, 96))	('BRCA', 'Gene', (15, 19))	('BRCA', 'Gene', '672', (15, 19))	('ATM', 'Gene', (86, 89))	('observed', 'Reg', (35, 43))	('mutations', 'Var', (20, 29))	('mutations', 'Var', (73, 82))	('FANCM', 'Gene', (98, 103))
16188	33214570	ATM, BRCA, CHECK2, and CDK12 mutations were frequent in cholangiocarcinoma (Supplementary Table S8, N = 34) with similar results in uterine carcinoma (Supplementary Table S9, N = 57), though the significance of these results is limited by small sample sizes.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('carcinoma', 'Disease', (65, 74))	('CDK12', 'Gene', (23, 28))	('carcinoma', 'Disease', 'MESH:D009369', (140, 149))	('BRCA', 'Gene', '672', (5, 9))	('ATM', 'Gene', (0, 3))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (132, 149))	('carcinoma', 'Disease', 'MESH:D009369', (65, 74))	('BRCA', 'Gene', (5, 9))	('CDK12', 'Gene', '51755', (23, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('cholangiocarcinoma', 'Disease', (56, 74))	('mutations', 'Var', (29, 38))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinoma', 'Disease', (140, 149))	('CHECK2', 'Gene', (11, 17))	('frequent', 'Reg', (44, 52))	('ATM', 'Gene', '472', (0, 3))
16189	33214570	In esophageal cancers, HR mutations were common to both adenocarcinoma (N = 89) and squamous (N = 96) cancers, though they were more frequent to the former (Table 5).	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('esophageal cancers', 'Disease', (3, 21))	('esophageal cancers', 'Disease', 'MESH:D004938', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('mutations', 'Var', (26, 35))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('adenocarcinoma', 'Disease', (56, 70))	('squamous', 'Disease', (84, 92))	('cancers', 'Disease', (102, 109))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('common', 'Reg', (41, 47))
16190	33214570	While ATM, BRCA, and POLQ mutations were similarly prevalent in both cancer types, adenocarcinoma patients had a high frequency to mutations effecting FANCM (8.9%) and FANCD2 (5.6%), comprising a majority of the difference between the two cancers in overall HR mutation rate (Table 5).	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('ATM', 'Gene', '472', (6, 9))	('FANCM', 'Gene', '57697', (151, 156))	('POLQ', 'Gene', '10721', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('FANCM', 'Gene', (151, 156))	('cancers', 'Disease', (239, 246))	('adenocarcinoma', 'Disease', (83, 97))	('cancer', 'Disease', (239, 245))	('effecting', 'Reg', (141, 150))	('FANCD2', 'Gene', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('BRCA', 'Gene', '672', (11, 15))	('patients', 'Species', '9606', (98, 106))	('ATM', 'Gene', (6, 9))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('FANCD2', 'Gene', '2177', (168, 174))	('cancer', 'Disease', (69, 75))	('POLQ', 'Gene', (21, 25))	('mutations', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA', 'Gene', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancers', 'Disease', 'MESH:D009369', (239, 246))
16192	33214570	For instance, in the four subtypes represented in the TCGA stomach adenocarcinoma cohort, HR mutations were most common in mucinous adenocarcinoma by percent at 41%, though this represents a very small sample size of only 21 patients (Table 6).	('adenocarcinoma', 'Disease', (67, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (132, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (225, 233))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('mucinous adenocarcinoma', 'Disease', (123, 146))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (123, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('common', 'Reg', (113, 119))	('adenocarcinoma', 'Disease', (132, 146))
16194	33214570	However, the relative distribution of HR mutation among subtypes were varied, though all subtypes had relatively high rates of ATM, BRCA, and POLQ mutations, with FANCM mutations common to mucinous and non-specified carcinomas (Table 6).	('ATM', 'Gene', '472', (127, 130))	('mutations', 'Var', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('carcinomas', 'Disease', (216, 226))	('BRCA', 'Gene', '672', (132, 136))	('POLQ', 'Gene', (142, 146))	('FANCM', 'Gene', '57697', (163, 168))	('POLQ', 'Gene', '10721', (142, 146))	('mucinous', 'Disease', (189, 197))	('ATM', 'Gene', (127, 130))	('BRCA', 'Gene', (132, 136))	('FANCM', 'Gene', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('carcinomas', 'Disease', 'MESH:D009369', (216, 226))
16197	33214570	The efficacy of PARP inhibitors in BRCA-mutated tumors stems largely from the known roles for PARP in mediating single stranded break repair.	('PARP', 'Gene', (16, 20))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('BRCA', 'Gene', (35, 39))	('inhibitors', 'Var', (21, 31))	('BRCA', 'Gene', '672', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
16198	33214570	Thus, initial trials were based on the hypothesis that inhibiting the repair of single stranded breaks will cause synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination.	('tumors', 'Disease', (137, 143))	('repair', 'MPA', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('loss', 'NegReg', (149, 153))	('synthetic lethality', 'CPA', (114, 133))	('single stranded breaks', 'Var', (80, 102))	('inhibiting', 'NegReg', (55, 65))	('cause', 'Reg', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
16205	33214570	While mutations of these and other HR genes are certainly less established indicators of HRD, those affecting ATM and PALB2 have already been shown to associate with responsiveness to PARP inhibition.	('HRD', 'Disease', 'None', (89, 92))	('associate', 'Reg', (151, 160))	('PALB2', 'Gene', '79728', (118, 123))	('responsiveness to PARP inhibition', 'MPA', (166, 199))	('PALB2', 'Gene', (118, 123))	('ATM', 'Gene', '472', (110, 113))	('HRD', 'Disease', (89, 92))	('ATM', 'Gene', (110, 113))	('mutations', 'Var', (6, 15))
16207	33214570	This is consistent to results observed in a similar study, which also found that expanding criteria identifies a larger group of patients who potentially harbor defects to the HR pathway.	('patients', 'Species', '9606', (129, 137))	('defects', 'Var', (161, 168))	('HR pathway', 'Pathway', (176, 186))
16211	33214570	While we cannot conclusively state that the entirety of these patients are in fact HR deficient and would derive clinical benefit from PARP inhibition, as mutations to BARD1, CDK12, DMC1, PALB2, and POLQ seem to predict for poor outcomes in this cohort, their predictive value for PARP inhibition is not established and warrants continued exploration.	('DMC1', 'Gene', (182, 186))	('CDK12', 'Gene', '51755', (175, 180))	('POLQ', 'Gene', '10721', (199, 203))	('mutations', 'Var', (155, 164))	('HR deficient', 'Disease', (83, 95))	('PALB2', 'Gene', '79728', (188, 193))	('DMC1', 'Gene', '11144', (182, 186))	('BARD1', 'Gene', '580', (168, 173))	('PALB2', 'Gene', (188, 193))	('CDK12', 'Gene', (175, 180))	('BARD1', 'Gene', (168, 173))	('patients', 'Species', '9606', (62, 70))	('HR deficient', 'Disease', 'MESH:D001919', (83, 95))	('POLQ', 'Gene', (199, 203))
16213	33214570	For instance, though limited by a small sample size, we found that nearly 40% of diffuse large B cell lymphoma patients harbor mutations to genes associated with the HR pathway, though BRCA mutations were only observed in 6.38%.	('B cell lymphoma', 'Disease', 'MESH:D016393', (95, 110))	('B cell lymphoma', 'Disease', (95, 110))	('BRCA', 'Gene', '672', (185, 189))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (95, 110))	('BRCA', 'Gene', (185, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('HR pathway', 'Pathway', (166, 176))	('large B cell', 'Phenotype', 'HP:0005404', (89, 101))	('mutations', 'Var', (127, 136))	('patients', 'Species', '9606', (111, 119))
16215	33214570	Still, recent evidence points to additional predictive criteria expanding beyond BRCA mutations, with less-studied HR-associated genes such as LMO2 appearing to predict for sensitivity to PARP inhibition.	('BRCA', 'Gene', (81, 85))	('mutations', 'Var', (86, 95))	('predict', 'Reg', (161, 168))	('LMO2', 'Gene', '4005', (143, 147))	('LMO2', 'Gene', (143, 147))	('sensitivity', 'MPA', (173, 184))	('BRCA', 'Gene', '672', (81, 85))
16216	33214570	As discussed, we also identified a high frequency in HR mutations in cutaneous melanoma patients.	('mutations', 'Var', (56, 65))	('cutaneous melanoma', 'Disease', (69, 87))	('patients', 'Species', '9606', (88, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))
16219	33214570	A 2013 phase II study suggests that the PARP inhibitor rucaparib cooperates with temozolomide in metastatic melanoma, though there are a relatively small number of subsequent clinical studies, likely as BRCA1/2 mutations are not typically considered a cause of malignant melanoma.	('temozolomide', 'Chemical', 'MESH:D000077204', (81, 93))	('BRCA1/2', 'Gene', (203, 210))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('malignant melanoma', 'Phenotype', 'HP:0002861', (261, 279))	('BRCA1/2', 'Gene', '672;675', (203, 210))	('mutations', 'Var', (211, 220))	('malignant melanoma', 'Disease', 'MESH:D008545', (261, 279))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('malignant melanoma', 'Disease', (261, 279))	('melanoma', 'Disease', (271, 279))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('rucaparib', 'Chemical', 'MESH:C531549', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
16220	33214570	However, in the TCGA cohort examined in our study, we found that BRCA mutations are represented in as many as 11.5% of cutaneous melanoma patients, with many patients also harboring mutations to ATM, BRIP1, CHECK2, DMC1, FANCD2, FANCM, and POLQ.	('FANCM', 'Gene', '57697', (229, 234))	('harboring', 'Reg', (172, 181))	('FANCD2', 'Gene', '2177', (221, 227))	('CHECK2', 'Gene', (207, 213))	('patients', 'Species', '9606', (158, 166))	('FANCM', 'Gene', (229, 234))	('cutaneous melanoma', 'Disease', (119, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('POLQ', 'Gene', (240, 244))	('BRIP1', 'Gene', (200, 205))	('DMC1', 'Gene', '11144', (215, 219))	('patients', 'Species', '9606', (138, 146))	('ATM', 'Gene', '472', (195, 198))	('mutations', 'Var', (182, 191))	('mutations', 'Var', (70, 79))	('BRCA', 'Gene', '672', (65, 69))	('DMC1', 'Gene', (215, 219))	('BRCA', 'Gene', (65, 69))	('POLQ', 'Gene', '10721', (240, 244))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('BRIP1', 'Gene', '83990', (200, 205))	('FANCD2', 'Gene', (221, 227))	('ATM', 'Gene', (195, 198))
16221	33214570	As 37.5% of this patient cohort had at least one mutation affecting the HR pathway, the use of these and other mutations warrant consideration when exploring PARP inhibitors in subsequent clinical trials.	('mutation', 'Var', (49, 57))	('patient', 'Species', '9606', (17, 24))	('HR pathway', 'Pathway', (72, 82))	('affecting', 'Reg', (58, 67))
16224	33214570	However, we must note that an inherent limitation of our study is though we identified several mutations in HR associated genes, relatively few have been characterized, particularly with respect to either HRD or PARP inhibition.	('PARP', 'MPA', (212, 216))	('HRD', 'Disease', (205, 208))	('mutations', 'Var', (95, 104))	('HRD', 'Disease', 'None', (205, 208))	('HR associated genes', 'Gene', (108, 127))
16229	33214570	Further, should PARP inhibitors be combined with other DNA-damaging agents such as chemo or radiotherapy, a patient's HRD status may become less relevant, as early evidence suggests that such approaches may have efficacy in multiple TP53 mutated but HR-intact tumor types.	('tumor', 'Disease', (260, 265))	('HRD', 'Disease', (118, 121))	('TP53', 'Gene', (233, 237))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('mutated', 'Var', (238, 245))	('HRD', 'Disease', 'None', (118, 121))	('patient', 'Species', '9606', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('TP53', 'Gene', '7157', (233, 237))
16287	30217299	Among 526 homologous sarcoma cases, presence of SD was significantly associated with decreased PFS (unadjusted-HR 1.48, 95%CI 1.13-1.93, P = 0.004) and CSS (unadjusted-HR 1.67, 95%CI 1.22-2.28, P = 0.001).	('decreased', 'NegReg', (85, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('presence', 'Var', (36, 44))	('CSS', 'CPA', (152, 155))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('SD', 'Chemical', '-', (48, 50))	('PFS', 'CPA', (95, 98))	('sarcoma', 'Disease', (21, 28))
16291	30217299	When tumors had SD, postoperative radiotherapy was significantly associated with improved PFS (adjusted-HR: 0.49 for homo/dominance, and 0.36 for hetero/dominance) and CSS (adjusted-HR: 0.37 for homo/dominance, and 0.35 for hetero/dominance) regardless of sarcoma types (all, P < 0.05; Table 4).	('improved', 'PosReg', (81, 89))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('SD', 'Chemical', '-', (16, 18))	('sarcoma', 'Disease', 'MESH:D012509', (256, 263))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CSS', 'MPA', (168, 171))	('PFS', 'MPA', (90, 93))	('sarcoma', 'Disease', (256, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('radiotherapy', 'Var', (34, 46))
16309	30217299	This clearly indicates that presence of SD impacts survival more in homologous type than heterologous type.	('survival', 'CPA', (51, 59))	('SD impacts', 'Disease', 'MESH:D029461', (40, 50))	('presence', 'Var', (28, 36))	('SD impacts', 'Disease', (40, 50))
16381	32127901	High TRIM44 expression was associated with poor overall survival (OS) or disease-free survival (DFS) in EC patients.	('High', 'Var', (0, 4))	('overall survival', 'CPA', (48, 64))	('poor', 'NegReg', (43, 47))	('TRIM44', 'Gene', '54765', (5, 11))	('disease-free survival', 'CPA', (73, 94))	('expression', 'MPA', (12, 22))	('TRIM44', 'Gene', (5, 11))	('patients', 'Species', '9606', (107, 115))
16413	31867319	Some of these differential methylation sites were associated with cancer survival.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (27, 38))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('associated', 'Reg', (50, 60))	('cancer', 'Disease', (66, 72))
16420	31867319	DNA methylation could modulate gene expression during development and cancer progression (Wang et al.,; Zhang et al.,).	('development', 'CPA', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('modulate', 'Reg', (22, 30))	('methylation', 'Var', (4, 15))	('gene expression', 'MPA', (31, 46))	('men', 'Species', '9606', (61, 64))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
16429	31867319	Methylation of SLFN11 is a biomarker for poor prognosis in colorectal cancer and methylations of SLIT1, SLIT2, and SLIT3 are abnormal in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SLIT2', 'Gene', (104, 109))	('SLIT3', 'Gene', '6586', (115, 120))	('SLIT3', 'Gene', (115, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('methylations', 'MPA', (81, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('Methylation', 'Var', (0, 11))	('SLIT2', 'Gene', '9353', (104, 109))	('abnormal', 'Reg', (125, 133))	('SLIT1', 'Gene', (97, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SLFN11', 'Gene', (15, 21))	('SLIT1', 'Gene', '6585', (97, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('colorectal cancer', 'Disease', (59, 76))	('gastric cancer', 'Disease', (137, 151))	('SLFN11', 'Gene', '91607', (15, 21))
16430	31867319	F2RL3 methylation is recently identified as a biomarker closely reflecting both current and past smoking exposure, causing lung cancer (Yan et al.,; Kim et al.,; He et al.,).	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('F2RL3', 'Gene', (0, 5))	('causing', 'Reg', (115, 122))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('methylation', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('F2RL3', 'Gene', '9002', (0, 5))
16437	31867319	For each cancer type, we detected a series of methylation sites, which could influence m-age compared to healthy samples.	('cancer', 'Disease', (9, 15))	('influence', 'Reg', (77, 86))	('m-age', 'CPA', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('methylation sites', 'Var', (46, 63))
16466	31867319	According to the least Mean-Squared Error (MSE, reflect the degree of difference between the estimator and true value, the smaller the MSE, the better the model fit) of LASSO linear regression model, we found that the value beta0 of the model was 34.63 when the adjustment parameter was 0.1419941 (Figure 2C).	('MSE', 'Gene', '101180900', (135, 138))	('MSE', 'Gene', (135, 138))	('0.1419941', 'Var', (287, 296))	('men', 'Species', '9606', (268, 271))	('MSE', 'Gene', (43, 46))	('MSE', 'Gene', '101180900', (43, 46))
16467	31867319	Among the 282 methylation characteristics in the construction of model, the levels of cg08461576, cg05923914, cg27641628, cg13221458, cg05632420, and cg07103722 were significantly and negatively correlated with sample age, and the linear model coefficients of the six sites above were negative as well (Figure 2D).	('cg27641628', 'Var', (110, 120))	('cg13221458', 'Var', (122, 132))	('cg08461576', 'Chemical', '-', (86, 96))	('negatively', 'NegReg', (184, 194))	('cg05923914', 'Chemical', '-', (98, 108))	('cg05632420', 'Chemical', '-', (134, 144))	('cg27641628', 'Chemical', '-', (110, 120))	('cg08461576', 'Var', (86, 96))	('cg05923914', 'Var', (98, 108))	('cg07103722', 'Var', (150, 160))	('cg05632420', 'Var', (134, 144))	('cg13221458', 'Chemical', '-', (122, 132))
16468	31867319	Gene Ontology (GO) analysis of the genes for the 282 model characteristics revealed that these genes were associated with some GO terms such as "lysine catabolic process" (GO:0006554) and "lysine metabolic process" (GO:0006553) (Figure 3A).	('GO:0006553', 'Var', (216, 226))	('lysine', 'Chemical', 'MESH:D008239', (189, 195))	('lysine', 'Chemical', 'MESH:D008239', (145, 151))	('associated', 'Reg', (106, 116))	('metabolic process', 'MPA', (196, 213))
16469	31867319	These results indicated that age-related methylation sites could alter many important biology processes (Supplementary Table S5).	('sites', 'Var', (53, 58))	('methylation sites', 'Var', (41, 58))	('alter', 'Reg', (65, 70))	('men', 'Species', '9606', (111, 114))
16471	31867319	In addition, we found that most methylation sites were enriched in human acute leukemia [-log10 (p) > 50] (Figure 3C, Supplementary Table S6).	('men', 'Species', '9606', (124, 127))	('methylation sites', 'Var', (32, 49))	('acute leukemia', 'Disease', (73, 87))	('acute leukemia', 'Phenotype', 'HP:0002488', (73, 87))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('sites', 'Var', (44, 49))	('acute leukemia', 'Disease', 'MESH:D015470', (73, 87))	('human', 'Species', '9606', (67, 72))
16486	31867319	It is suggested that hyper-methylation of these age-related differences may lead to changes in m-age and cancer development.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('lead to changes', 'Reg', (76, 91))	('men', 'Species', '9606', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hyper-methylation', 'Var', (21, 38))	('m-age', 'CPA', (95, 100))
16490	31867319	In most cancer types, these differential methylation sites in age-related samples were associated with survival (Figure 5).	('survival', 'MPA', (103, 111))	('differential methylation', 'Var', (28, 52))	('cancer', 'Disease', (8, 14))	('methylation', 'Var', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('associated with', 'Reg', (87, 102))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
16492	31867319	The results indicated that differential methylation sites of age-related samples maybe could be an effective prognostic biomarker for cancers.	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('differential methylation sites', 'Var', (27, 57))	('cancers', 'Disease', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
16502	31867319	Previous study also showed that epigenetic age acceleration is associated with colorectal cancer molecular characteristics and can be a significant predictor of overall survival, as well as age and tumor stage (Zheng et al.,).	('epigenetic age', 'Var', (32, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('associated', 'Reg', (63, 73))	('colorectal cancer', 'Disease', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('acceleration', 'PosReg', (47, 59))	('tumor', 'Disease', (198, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
16511	31867319	We further discovered the differential methylation sites between age-related cancer samples and normal samples.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('methylation', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
16512	31867319	These differential methylation sites were associated with survival in cancers.	('methylation sites', 'Var', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated with', 'Reg', (42, 57))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
16565	31717878	Reason suggests that uncontrolled proliferation may lead to additional errors in the DNA sequence that may allow low-grade disease to progress to high-risk histologic carcinomas, although this natural progression of the disease is not well studied.	('progress', 'PosReg', (134, 142))	('low-grade disease', 'Disease', (113, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('allow', 'Reg', (107, 112))	('carcinomas', 'Disease', 'MESH:D009369', (167, 177))	('errors', 'Var', (71, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('lead', 'Reg', (52, 56))	('carcinomas', 'Disease', (167, 177))
16569	31717878	These lesions are confined to the surface of the endometrium without invasion and typically have mutations in p53.	('mutations', 'Var', (97, 106))	('p53', 'Gene', '7157', (110, 113))	('p53', 'Gene', (110, 113))
16606	31717878	Studies using the CS99 cell line, which is derived from uterine carcinosarcomas, showed that inhibition of BMI1 (BMI1 proto-oncogene, polycomb ring finger) with the BMI1 inhibitor, PTC-028, led to increased apoptosis and decreased cell viability in vitro and delayed tumor growth in vivo.	('apoptosis', 'CPA', (207, 216))	('carcinosarcomas', 'Disease', 'MESH:D002296', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('BMI1', 'Gene', '648', (107, 111))	('increased', 'PosReg', (197, 206))	('BMI1', 'Gene', '648', (113, 117))	('CS99', 'CellLine', 'CVCL:U142', (18, 22))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (56, 78))	('decreased', 'NegReg', (221, 230))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('BMI1', 'Gene', (165, 169))	('carcinosarcomas', 'Disease', (64, 79))	('PTC-028', 'Chemical', '-', (181, 188))	('cell viability', 'CPA', (231, 245))	('polycomb ring finger', 'Phenotype', 'HP:0009971', (134, 154))	('BMI1', 'Gene', (107, 111))	('BMI1', 'Gene', '648', (165, 169))	('BMI1', 'Gene', (113, 117))	('tumor', 'Disease', (267, 272))	('delayed', 'NegReg', (259, 266))	('inhibition', 'Var', (93, 103))
16613	31717878	This multi-platform analysis classified carcinomas into four categories: (1) polymerase-epsilon (POLE) ultramutated, with mutations in a subunit of DNA polymerase epsilon; (2) microsatellite instability hypermutated (MSI-H); (3) copy-number low, with a lower mutational load; and (4) copy-number high, with low mutation rates and extensive copy number variation.	('copy-number high', 'Var', (284, 300))	('carcinomas', 'Disease', 'MESH:D009369', (40, 50))	('copy-number low', 'Var', (229, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('mutations', 'Var', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('mutation rates', 'MPA', (311, 325))	('carcinomas', 'Disease', (40, 50))
16614	31717878	Both high-grade endometrioid and serous carcinomas had significant downregulation of estrogen and progesterone receptor expression and mutations in TP53.	('serous carcinomas', 'Disease', 'MESH:D018297', (33, 50))	('downregulation', 'NegReg', (67, 81))	('high-grade endometrioid', 'Disease', (5, 28))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('mutations', 'Var', (135, 144))	('progesterone receptor', 'Gene', (98, 119))	('progesterone receptor', 'Gene', '5241', (98, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('estrogen', 'Protein', (85, 93))	('serous carcinomas', 'Disease', (33, 50))
16615	31717878	Many low-grade endometrioid carcinomas contained mutations in PTEN and ARID1A.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('PTEN', 'Gene', (62, 66))	('contained', 'Reg', (39, 48))	('PTEN', 'Gene', '5728', (62, 66))	('mutations', 'Var', (49, 58))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (15, 38))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (15, 37))	('endometrioid carcinomas', 'Disease', (15, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('ARID1A', 'Gene', '8289', (71, 77))	('ARID1A', 'Gene', (71, 77))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (15, 38))
16619	31717878	Whole exome sequencing of uterine carcinosarcomas revealed that mutations in TP53 were common (67%).	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (26, 48))	('carcinosarcomas', 'Disease', 'MESH:D002296', (34, 49))	('carcinosarcomas', 'Disease', (34, 49))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
16621	31717878	Loss of function mutations in chromatin remodeling genes including ARID1A and ARID1B were also common.	('ARID1B', 'Gene', '57492', (78, 84))	('ARID1A', 'Gene', '8289', (67, 73))	('chromatin remodeling genes', 'Gene', (30, 56))	('Loss of function', 'NegReg', (0, 16))	('ARID1B', 'Gene', (78, 84))	('mutations', 'Var', (17, 26))	('ARID1A', 'Gene', (67, 73))
16622	31717878	Whole exome sequencing of clear cell endometrial carcinomas similarly revealed high-frequency TP53 (39.7%), PIK3CA (23.8%), and ARID1A (15.9%) mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('endometrial carcinomas', 'Disease', (37, 59))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (37, 59))	('PIK3CA', 'Gene', (108, 114))	('ARID1A', 'Gene', '8289', (128, 134))	('ARID1A', 'Gene', (128, 134))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (37, 59))	('mutations', 'Var', (143, 152))	('PIK3CA', 'Gene', '5290', (108, 114))
16642	31717878	Unlike with low-risk early-stage endometrial carcinoma, high-risk histology and late-stage disease have a much higher rate of metastasis and recurrence.	('high-risk', 'Var', (56, 65))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (33, 54))	('metastasis', 'CPA', (126, 136))	('endometrial carcinoma', 'Disease', (33, 54))	('recurrence', 'CPA', (141, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (33, 54))
16667	31717878	Decreased hormone efficacy in endometrial cancer has been proposed to be due to reduced PR expression due to selective hypermethylation.	('expression', 'MPA', (91, 101))	('endometrial cancer', 'Disease', 'MESH:D016889', (30, 48))	('reduced PR', 'Phenotype', 'HP:0032198', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Decreased', 'NegReg', (0, 9))	('reduced', 'NegReg', (80, 87))	('endometrial cancer', 'Disease', (30, 48))	('hypermethylation', 'Var', (119, 135))	('endometrial cancer', 'Phenotype', 'HP:0012114', (30, 48))
16675	31717878	ERBB2 is an epidermal growth factor receptor whose phosphorylation leads to the activation of proliferation and migration.	('epidermal growth factor receptor', 'Gene', '1956', (12, 44))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (0, 5))	('proliferation', 'CPA', (94, 107))	('epidermal growth factor receptor', 'Gene', (12, 44))	('phosphorylation', 'Var', (51, 66))	('activation', 'PosReg', (80, 90))
16677	31717878	Overexpression of ERBB2 in early endometrial carcinomas is associated with disease recurrence.	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('endometrial carcinomas', 'Disease', (33, 55))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (33, 55))	('associated', 'Reg', (59, 69))	('disease', 'Disease', (75, 82))	('ERBB2', 'Gene', '2064', (18, 23))	('Overexpression', 'Var', (0, 14))	('ERBB2', 'Gene', (18, 23))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (33, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (33, 54))
16678	31717878	Whole exome sequencing of clear cell endometrial carcinomas showed 11% of tumors harbored amplification in ERBB2.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('endometrial carcinomas', 'Disease', (37, 59))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (37, 59))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('ERBB2', 'Gene', (107, 112))	('ERBB2', 'Gene', '2064', (107, 112))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (37, 59))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('amplification', 'Var', (90, 103))	('tumors', 'Disease', (74, 80))
16683	31717878	A case report of amplification of ERBB2 in uterine carcinosarcoma led to the treatment of a woman with trastuzumab and complete remission of recurrent disease.	('woman', 'Species', '9606', (92, 97))	('carcinosarcoma', 'Disease', 'MESH:D002296', (51, 65))	('ERBB2', 'Gene', (34, 39))	('ERBB2', 'Gene', '2064', (34, 39))	('trastuzumab', 'Chemical', 'MESH:D000068878', (103, 114))	('amplification', 'Var', (17, 30))	('carcinosarcoma', 'Disease', (51, 65))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (43, 65))
16685	31717878	In vitro experiments in cells that overexpress ERBB2 showed that oncogenic mutations in PI3K resulted in resistance to afatinib, a tyrosine kinase inhibitor that inhibits ErbB signaling.	('ERBB2', 'Gene', (47, 52))	('PI3K', 'Gene', (88, 92))	('ERBB2', 'Gene', '2064', (47, 52))	('resistance', 'MPA', (105, 115))	('ErbB', 'Gene', '1956', (171, 175))	('ErbB', 'Gene', (171, 175))	('mutations', 'Var', (75, 84))	('resulted in', 'Reg', (93, 104))	('afatinib', 'Chemical', 'MESH:D000077716', (119, 127))
16690	31717878	Endometrial cancers are the most frequent cancers to have mismatch repair deficiency.	('cancers', 'Disease', (42, 49))	('deficiency', 'Var', (74, 84))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Disease', (12, 19))	('mismatch', 'Var', (58, 66))	('Endometrial cancer', 'Phenotype', 'HP:0012114', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('Endometrial cancers', 'Disease', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Endometrial cancers', 'Disease', 'MESH:D016889', (0, 19))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
16703	31717878	Low-risk tumors had more actionable mutations.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (36, 45))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
16710	31717878	As many endometrial cancers harbor mutations in PTEN, mammalian target of rapamycin (mTOR) inhibitors are a logical treatment option.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PTEN', 'Gene', (48, 52))	('mammalian target of rapamycin', 'Gene', '2475', (54, 83))	('mammalian target of rapamycin', 'Gene', (54, 83))	('PTEN', 'Gene', '5728', (48, 52))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('mTOR', 'Gene', '2475', (85, 89))	('endometrial cancer', 'Phenotype', 'HP:0012114', (8, 26))	('endometrial cancers', 'Disease', 'MESH:D016889', (8, 27))	('mTOR', 'Gene', (85, 89))	('endometrial cancers', 'Disease', (8, 27))	('mutations', 'Var', (35, 44))
16717	31717878	For example, KRAS mutations lead to resistance to everolimus.	('KRAS', 'Gene', '3845', (13, 17))	('everolimus', 'Chemical', 'MESH:D000068338', (50, 60))	('resistance to everolimus', 'MPA', (36, 60))	('KRAS', 'Gene', (13, 17))	('lead to', 'Reg', (28, 35))	('mutations', 'Var', (18, 27))
16718	31717878	Positively, an in vitro study suggests that inhibition of mTOR increases sensitivity to PARP inhibitors (i.e., olaparib, talazoparib, and BKM-120).	('increases', 'PosReg', (63, 72))	('mTOR', 'Gene', (58, 62))	('talazoparib', 'Chemical', 'MESH:C586365', (121, 132))	('inhibition', 'Var', (44, 54))	('PARP', 'Gene', '142', (88, 92))	('sensitivity', 'MPA', (73, 84))	('olaparib', 'Chemical', 'MESH:C531550', (111, 119))	('BKM-120', 'Chemical', 'MESH:C571178', (138, 145))	('mTOR', 'Gene', '2475', (58, 62))	('PARP', 'Gene', (88, 92))
16722	31717878	Inhibition of the IGF1-R pathway has been shown to have anticancer effects.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('IGF1-R', 'Gene', (18, 24))	('cancer', 'Disease', (60, 66))	('Inhibition', 'Var', (0, 10))	('IGF1-R', 'Gene', '3480', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
16732	31717878	A pooled meta-analysis of seven clinical studies showed that metformin reduced the risk of endometrial carcinoma recurrence (odds ratio (OR) = 0.5, 95% confidence interval (CI) 0.28-0.92, p < 0.05) and improved overall survival (hazard ratio (HR) = 0.61, 95% CI 0.48-0.77, p < 0.05).	('improved', 'PosReg', (202, 210))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('metformin', 'Chemical', 'MESH:D008687', (61, 70))	('reduced', 'NegReg', (71, 78))	('overall', 'MPA', (211, 218))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('metformin', 'Var', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
16736	31717878	PARP inhibitors were first designed to act against cells containing BRCA1 or BRCA2 mutations; however, clinical trials have indicated that these agents may be applicable in other cancers as cells that are deficient in PTEN have been shown to display sensitivity to PARP inhibitors.	('mutations', 'Var', (83, 92))	('BRCA1', 'Gene', '672', (68, 73))	('PARP', 'Gene', '142', (265, 269))	('BRCA2', 'Gene', '675', (77, 82))	('BRCA1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PARP', 'Gene', (0, 4))	('BRCA2', 'Gene', (77, 82))	('PTEN', 'Gene', (218, 222))	('PTEN', 'Gene', '5728', (218, 222))	('PARP', 'Gene', (265, 269))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('sensitivity', 'MPA', (250, 261))	('cancers', 'Disease', (179, 186))	('PARP', 'Gene', '142', (0, 4))
16742	31717878	Similarly, studies in ARID1A-mutated ovarian cancer cell lines showed that the pan histone deacetylase inhibitor, suberoylanilide hydroxamine, also leads to decreased in vitro and in vivo tumor size.	('tumor', 'Disease', (188, 193))	('ovarian cancer', 'Disease', 'MESH:D010051', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('ARID1A', 'Gene', '8289', (22, 28))	('suberoylanilide', 'Var', (114, 129))	('ovarian cancer', 'Disease', (37, 51))	('suberoylanilide hydroxamine', 'Chemical', '-', (114, 141))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('ovarian cancer', 'Phenotype', 'HP:0100615', (37, 51))	('decreased', 'NegReg', (157, 166))	('ARID1A', 'Gene', (22, 28))
16747	31717878	Mutations of epidermal growth factor receptor (EGFR) and its family are found in 43%-67% of endometrial carcinomas.	('endometrial carcinomas', 'Disease', 'MESH:D016889', (92, 114))	('found', 'Reg', (72, 77))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (92, 113))	('epidermal growth factor receptor', 'Gene', (13, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('endometrial carcinomas', 'Disease', (92, 114))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (47, 51))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (92, 114))	('EGFR', 'Gene', (47, 51))
16751	31717878	The response did not correlate with EGFR amplification or mutation.	('mutation', 'Var', (58, 66))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (36, 40))
16771	31717878	In serous carcinoma cell lines, CRISPR technology was used to introduce mutations in FBXW7, F-box, and WD repeat domain containing 7.	('mutations', 'Var', (72, 81))	('FBXW7', 'Gene', (85, 90))	('serous carcinoma', 'Disease', 'MESH:D018297', (3, 19))	('serous carcinoma', 'Disease', (3, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('FBXW7', 'Gene', '55294', (85, 90))
16772	31717878	Both the ARK1 and ARK2 cell lines with FBXW7 mutations showed increased sensitivity to SRC inhibitors as well as dinaciclib, a CDK2 inhibitor.	('CDK2', 'Gene', (127, 131))	('increased', 'PosReg', (62, 71))	('FBXW7', 'Gene', (39, 44))	('mutations', 'Var', (45, 54))	('CDK2', 'Gene', '1017', (127, 131))	('sensitivity to SRC inhibitors', 'MPA', (72, 101))	('ARK2', 'Gene', (18, 22))	('ARK1', 'Gene', (9, 13))	('dinaciclib', 'Chemical', 'MESH:C553669', (113, 123))	('FBXW7', 'Gene', '55294', (39, 44))	('ARK2', 'Gene', '9212', (18, 22))	('dinaciclib', 'MPA', (113, 123))	('ARK1', 'Gene', '6790', (9, 13))
16785	31717878	Potential oncogenic mutations found included PIK3CA, KRAS, PIK3R1, and FGFR2 in benign epithelial endometrium from women with uterine fibroids, and ARID1A mutations in endometrial stroma from women with endometriosis.	('PIK3CA', 'Gene', (45, 51))	('KRAS', 'Gene', (53, 57))	('ARID1A', 'Gene', '8289', (148, 154))	('women', 'Species', '9606', (192, 197))	('oncogenic', 'CPA', (10, 19))	('endometriosis', 'Disease', 'MESH:D004715', (203, 216))	('endometriosis', 'Disease', (203, 216))	('PIK3R1', 'Gene', (59, 65))	('ARID1A', 'Gene', (148, 154))	('uterine fibroids', 'Phenotype', 'HP:0000131', (126, 142))	('endometriosis', 'Phenotype', 'HP:0030127', (203, 216))	('PIK3CA', 'Gene', '5290', (45, 51))	('FGFR2', 'Gene', (71, 76))	('mutations', 'Var', (20, 29))	('women', 'Species', '9606', (115, 120))	('mutations', 'Var', (155, 164))	('PIK3R1', 'Gene', '5295', (59, 65))	('FGFR2', 'Gene', '2263', (71, 76))	('KRAS', 'Gene', '3845', (53, 57))
16796	31217897	In uterine carcinosarcomas (UCS), we identified mutations in KRAS, PIK3CA, and TP53 with a frequency of 6%, 31%, and 75%, respectively, whereas in ovarian carcinosarcomas (OCS), TP53 was the only mutated gene found (30%).	('carcinosarcomas', 'Disease', (11, 26))	('TP53', 'Gene', '7157', (178, 182))	('PIK3CA', 'Gene', '5290', (67, 73))	('carcinosarcomas', 'Disease', (155, 170))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('OCS', 'Phenotype', 'HP:0025318', (172, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('TP53', 'Gene', (178, 182))	('ovarian carcinosarcomas', 'Disease', (147, 170))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (147, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('carcinosarcomas', 'Disease', 'MESH:D002296', (11, 26))	('KRAS', 'Gene', (61, 65))	('carcinosarcomas', 'Disease', 'MESH:D002296', (155, 170))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (147, 170))	('PIK3CA', 'Gene', (67, 73))	('mutations', 'Var', (48, 57))
16805	31217897	Mutations of the tumour protein gene (TP53) are assumed to be the most frequent alteration, observed in 50% of analysed tumours.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('TP53', 'Gene', (38, 42))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('rat', 'Species', '10116', (84, 87))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumour', 'Disease', (120, 126))	('Mutations', 'Var', (0, 9))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumour', 'Disease', (17, 23))	('tumours', 'Disease', (120, 127))	('TP53', 'Gene', '7157', (38, 42))
16806	31217897	Other mutations, reported at lower frequencies, affect the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PI3K3CA), the ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS), the catenin beta 1 gene (CTNNB1), and the neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) gene.	('affect', 'Reg', (48, 54))	('phosphatidylinositol-4,5', 'Chemical', '-', (59, 83))	('sarcoma', 'Disease', 'MESH:D012509', (170, 177))	('catenin beta 1', 'Gene', (213, 227))	('rat', 'Species', '10116', (166, 169))	('neuroblastoma', 'Phenotype', 'HP:0003006', (251, 264))	('CTNNB1', 'Gene', (234, 240))	('sarcoma', 'Disease', (170, 177))	('NRAS', 'Gene', (301, 305))	('catenin beta 1', 'Gene', '84353', (213, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('bisphosphate', 'Chemical', '-', (84, 96))	('mutations', 'Var', (6, 15))	('neuroblastoma RAS viral (V-Ras) oncogene homolog', 'Gene', '24605', (251, 299))
16807	31217897	Dysregulation of chromatin remodelling genes has been shown in CS indicating their importance in CS tumourigenesis.	('Dysregulation', 'Var', (0, 13))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('chromatin remodelling genes', 'Gene', (17, 44))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Disease', (100, 106))
16808	31217897	In UCS, the genes involved in chromatin modification include those encoding AT-rich interactive domain-containing proteins (ARID1A and ARID1B), histone methyltransferase mixed-lineage leukaemia protein 3 (MLL3), histone deacetylase modifier speckle-type POZ (SPOP), and chromatin assembly factor bromodomain adjacent to zinc finger domain 1A (BAZ1A), all of which are mutated at frequencies varying from 18% to 36%.	('ARID1B', 'Gene', (135, 141))	('mixed-lineage leukaemia protein 3', 'Gene', (170, 203))	('mutated', 'Var', (368, 375))	('BAZ1A', 'Gene', '11177', (343, 348))	('MLL3', 'Gene', '58508', (205, 209))	('BAZ1A', 'Gene', (343, 348))	('ARID1A', 'Gene', '8289', (124, 130))	('ARID1A', 'Gene', (124, 130))	('MLL3', 'Gene', (205, 209))	('ARID1B', 'Gene', '57492', (135, 141))	('mixed-lineage leukaemia protein 3', 'Gene', '58508', (170, 203))
16810	31217897	Some of these genes, including BCOR and CHD4, have been identified as mutated also in OCS.	('OCS', 'Disease', (86, 89))	('BCOR', 'Gene', (31, 35))	('OCS', 'Phenotype', 'HP:0025318', (86, 89))	('BCOR', 'Gene', '54880', (31, 35))	('CHD4', 'Gene', (40, 44))	('CHD4', 'Gene', '1108', (40, 44))	('mutated', 'Var', (70, 77))
16811	31217897	Because both UCS and OCS may carry mutations in the histone genes H2 and H3, mutations that may facilitate epithelial-mesenchymal transition (EMT), this has been proposed to lie at the heart of their role in sarcomatous transformation.	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('OCS', 'Phenotype', 'HP:0025318', (21, 24))	('facilitate', 'PosReg', (96, 106))	('sarcomatous transformation', 'Disease', (208, 234))	('sarcomatous transformation', 'Disease', 'MESH:D018316', (208, 234))	('mutations', 'Var', (77, 86))	('epithelial-mesenchymal transition', 'CPA', (107, 140))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (208, 234))	('mutations', 'Var', (35, 44))
16817	31217897	Whereas no tumour showed a mutated sequence for IDH1, IDH2, TERT, BRAF, H3F3A, HRAS, NRAS or CTNNB, a few were found to be mutated in KRAS, PIK3CA, and/or TP53.	('IDH2', 'Gene', (54, 58))	('PIK3CA', 'Gene', (140, 146))	('CTNNB', 'Gene', '1499', (93, 98))	('H3F3A', 'Gene', '3020', (72, 77))	('IDH2', 'Gene', '3418', (54, 58))	('IDH1', 'Gene', (48, 52))	('CTNNB', 'Gene', (93, 98))	('TERT', 'Gene', (60, 64))	('TERT', 'Gene', '7015', (60, 64))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('TP53', 'Gene', (155, 159))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('H3F3A', 'Gene', (72, 77))	('mutated', 'Var', (123, 130))	('tumour', 'Disease', (11, 17))	('IDH1', 'Gene', '3417', (48, 52))	('PIK3CA', 'Gene', '5290', (140, 146))	('HRAS', 'Gene', '3265', (79, 83))	('TP53', 'Gene', '7157', (155, 159))	('HRAS', 'Gene', (79, 83))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))
16819	31217897	PIK3CA mutations were found in five of 16 UCS but in none of the OCS.	('OCS', 'Phenotype', 'HP:0025318', (65, 68))	('found', 'Reg', (22, 27))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('UCS', 'Disease', (42, 45))	('mutations', 'Var', (7, 16))
16820	31217897	More specifically, a c.3073A>G mutation was detected in case 8, a c.1637A>G in case 9, a c.3140A>G in cases 11 and 16, and a c.1634A>G in case 12 (Table 1).	('c.1634A>G', 'Var', (125, 134))	('c.3073A>G', 'Mutation', 'rs397517202', (21, 30))	('c.1634A>G', 'Mutation', 'rs121913274', (125, 134))	('c.3073A>G', 'Var', (21, 30))	('c.3140A>G', 'Var', (89, 98))	('c.1637A>G', 'Var', (66, 75))	('c.1637A>G', 'Mutation', 'rs397517201', (66, 75))	('c.3140A>G', 'Mutation', 'rs121913279', (89, 98))
16821	31217897	TP53 was found mutated in 12 of 16 UCS (cases 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 16, and 17; 75% of the uterine CS) and in three of ten OCS (cases 18, 19, and 22; 30%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('UCS', 'Disease', (35, 38))	('mutated', 'Var', (15, 22))	('OCS', 'Phenotype', 'HP:0025318', (133, 136))
16822	31217897	Details about the TP53 mutations are listed in Table 1.	('mutations', 'Var', (23, 32))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))
16823	31217897	The expression of aberrant TP53 was confirmed by immunohistochemistry (Figure 1).	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('aberrant', 'Var', (18, 26))
16839	31217897	In the present study, mutations in KRAS, PIK3CA, and TP53 were found in 6%, 31%, and 75% of UCS, respectively, in line with previous findings; (COSMIC database https://cancer.sanger.ac.uk/cosmic).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('KRAS', 'Gene', (35, 39))	('UCS', 'Disease', (92, 95))	('PIK3CA', 'Gene', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (168, 174))	('TP53', 'Gene', '7157', (53, 57))	('PIK3CA', 'Gene', '5290', (41, 47))	('found', 'Reg', (63, 68))	('TP53', 'Gene', (53, 57))
16840	31217897	In OCS, KRAS and PIK3CA were not mutated, whereas 30% of OCS carried TP53 mutations.	('TP53', 'Gene', '7157', (69, 73))	('PIK3CA', 'Gene', (17, 23))	('TP53', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('PIK3CA', 'Gene', '5290', (17, 23))	('OCS', 'Phenotype', 'HP:0025318', (57, 60))	('OCS', 'Phenotype', 'HP:0025318', (3, 6))
16841	31217897	Genetic alterations of TP53 have been thoroughly investigated in human cancer.	('human', 'Species', '9606', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('rat', 'Species', '10116', (12, 15))	('cancer', 'Disease', (71, 77))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
16842	31217897	It is known that TP53 mutations occur during CS tumourigenesis, causing the gene to lose its tumour suppressive function, indicating its role as an early pathogenetic driver.	('tumour', 'Disease', (93, 99))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('lose', 'NegReg', (84, 88))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (22, 31))	('tumour', 'Disease', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
16843	31217897	The distribution pattern of TP53 mutations found by us was in line with that found in previous studies.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
16844	31217897	Alterations in TP53 were previously observed in most UCS and OCS analysed.	('UCS', 'Disease', (53, 56))	('observed', 'Reg', (36, 44))	('Alterations', 'Var', (0, 11))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('OCS', 'Disease', (61, 64))	('rat', 'Species', '10116', (4, 7))	('OCS', 'Phenotype', 'HP:0025318', (61, 64))
16845	31217897	The TP53 mutations targeted the core of the DNA-binding domain, resulting in loss of its regulatory function on gene expression and accumulation of non-functional p53 protein.	('TP53', 'Gene', (4, 8))	('non-functional', 'MPA', (148, 162))	('mutations', 'Var', (9, 18))	('regulatory function on gene expression', 'MPA', (89, 127))	('p53 protein', 'Protein', (163, 174))	('accumulation', 'PosReg', (132, 144))	('loss', 'NegReg', (77, 81))	('TP53', 'Gene', '7157', (4, 8))
16846	31217897	We validated p53 expression by immunohistochemistry, finding a correlation between TP53 mutational status and p53 expression pattern.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('mutational', 'Var', (88, 98))	('expression', 'MPA', (114, 124))	('correlation', 'Reg', (63, 74))
16858	31217897	The findings suggest that these pseudogenes may contribute to HMGA1 deregulation in gynaecological CS.	('deregulation', 'MPA', (68, 80))	('contribute', 'Reg', (48, 58))	('HMGA1', 'Gene', (62, 67))	('pseudogenes', 'Var', (32, 43))	('HMGA1', 'Gene', '3159', (62, 67))	('gynaecological CS', 'Disease', (84, 101))
16862	31217897	Another indication pointing in the same direction has been the identification of disrupted forms of HMGA2, due to rearrangements of chromosomal band 12q15 (the band where the gene is located), that are consistently seen in different benign mesenchymal tumours but also in some malignant neoplasms such as ovarian carcinomas and leukemia.	('leukemia', 'Disease', 'MESH:D007938', (328, 336))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (305, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('benign mesenchymal tumours', 'Disease', (233, 259))	('leukemia', 'Disease', (328, 336))	('carcinomas', 'Phenotype', 'HP:0030731', (313, 323))	('malignant neoplasms', 'Disease', 'MESH:D009369', (277, 296))	('neoplasms', 'Phenotype', 'HP:0002664', (287, 296))	('tumours', 'Phenotype', 'HP:0002664', (252, 259))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (305, 323))	('malignant neoplasms', 'Disease', (277, 296))	('rearrangements', 'Var', (114, 128))	('HMGA2', 'Gene', '8091', (100, 105))	('leukemia', 'Phenotype', 'HP:0001909', (328, 336))	('ovarian carcinomas', 'Disease', (305, 323))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('HMGA2', 'Gene', (100, 105))	('benign mesenchymal tumours', 'Disease', 'MESH:D008637', (233, 259))
16863	31217897	These alterations involve exon 3 and cause deletion of downstream regions leading to a truncated transcript that can evade miRNA-dependent gene silencing.	('involve', 'Reg', (18, 25))	('alterations', 'Var', (6, 17))	('deletion', 'Var', (43, 51))	('truncated transcript', 'MPA', (87, 107))	('rat', 'Species', '10116', (10, 13))
16901	31217897	Gene expression was assessed with Real-Time PCR using the TaqMan Gene Expression Assays (Applied Biosystems) for the following genes: HMGA1 (Hs_00852949_g1), HMGA2 (Hs_04397751_m1), FHIT (Hs_00179987_m1), LIN28A (Hs_00702808_Gh), HMGA1P6 (ARYMJHZ), and HMGA1P7 (Hs04232395_m1).	('HMGA1P7', 'Gene', '387065', (253, 260))	('HMGA1', 'Gene', '3159', (230, 235))	('LIN28A', 'Gene', '79727', (205, 211))	('FHIT', 'Gene', (182, 186))	('HMGA2', 'Gene', (158, 163))	('HMGA1', 'Gene', '3159', (253, 258))	('Hs04232395_m1', 'Var', (262, 275))	('HMGA1', 'Gene', (230, 235))	('HMGA1', 'Gene', '3159', (134, 139))	('LIN28A', 'Gene', (205, 211))	('FHIT', 'Gene', '2272', (182, 186))	('Hs_04397751_m1', 'Var', (165, 179))	('HMGA1P7', 'Gene', (253, 260))	('HMGA1', 'Gene', (253, 258))	('HMGA1P6', 'Gene', (230, 237))	('HMGA1', 'Gene', (134, 139))	('HMGA2', 'Gene', '8091', (158, 163))	('Hs_00702808_Gh', 'Var', (213, 227))	('Hs_00179987_m1', 'Var', (188, 202))	('Hs_00852949_g1', 'Var', (141, 155))	('HMGA1P6', 'Gene', '100130029', (230, 237))
16902	31217897	The UBC (Hs01871556_m1) and TBP (Hs00427620_m1) genes were used as references.	('TBP', 'Gene', (28, 31))	('Hs01871556_m1', 'Var', (9, 22))	('TBP', 'Gene', '6908', (28, 31))
16903	31217897	miRNA expression was assessed with Real-Time PCR using the TaqMan microRNA assays (Applied Biosystems) for let-7a (RT: 000377), let-7d (RT: 002283), miR-26a (RT: 000405), miR-16 (RT: 000391), miR-214 (TM: 002306), and miR30c (TM:000419).	('let-7d', 'Gene', (128, 134))	('miR-16', 'Gene', '51573', (171, 177))	('miR-214', 'Gene', '406996', (192, 199))	('let-7d', 'Gene', '406886', (128, 134))	('miR30c', 'Gene', (218, 224))	('miR30c', 'Gene', '407031', (218, 224))	('let-7a', 'Gene', (107, 113))	('miR-26a', 'Gene', '407015', (149, 156))	('RT: 002283', 'Var', (136, 146))	('miR-214', 'Gene', (192, 199))	('miR-26a', 'Gene', (149, 156))	('RT: 000391', 'Var', (179, 189))	('RT: 000405', 'Var', (158, 168))	('miR-16', 'Gene', (171, 177))	('RT: 000377', 'Var', (115, 125))
16932	30207096	We therefore defined the CA-125 levels together with the prior study cutoff as follows: normal <30 IU/L, abnormal 30-124 IU/L, and marked high-risk for recurrence >=125 IU/L.	('CA-125', 'Gene', '94025', (25, 31))	('abnormal 30-124 IU/L', 'Var', (105, 125))	('CA-125', 'Gene', (25, 31))
16938	30207096	The majority of the study population had normal CA-125 (n=355, 57.9%) followed by abnormal CA-125 (n=167, 27.2%), and marked high-risk CA-125 (n=91, 14.8%).	('CA-125', 'Gene', (48, 54))	('CA-125', 'Gene', '94025', (48, 54))	('CA-125', 'Gene', (135, 141))	('CA-125', 'Gene', '94025', (135, 141))	('CA-125', 'Gene', (91, 97))	('abnormal', 'Var', (82, 90))	('CA-125', 'Gene', '94025', (91, 97))
16941	30207096	Additionally, among the 268 cases of stage III-IV disease, CA-125 levels were significantly associated with residual disease at surgery: normal 13.5%, abnormal 25.0%, and marked high-risk 44.9% (p<0.001).	('CA-125', 'Gene', (59, 65))	('CA-125', 'Gene', '94025', (59, 65))	('associated', 'Reg', (92, 102))	('abnormal', 'Var', (151, 159))	('residual disease', 'Disease', (108, 124))
16943	30207096	On univariate analysis, CA-125 level (by group) was significantly correlated with 5-year PFS rates: normal 60.2%, abnormal 36.1%, and marked high-risk 23.3% (p<0.001, Fig.	('CA-125', 'Gene', '94025', (24, 30))	('correlated', 'Reg', (66, 76))	('abnormal', 'Var', (114, 122))	('PFS', 'Disease', (89, 92))	('CA-125', 'Gene', (24, 30))
16946	30207096	The abnormal CA-125 level was associated with a 35% increased risk for recurrence or progression compared to the normal CA-125 level (adjusted-HR=1.35; 95% CI=1.01-1.81; p=0.042); and the marked high-risk CA-125 level was associated with 89% increased risk (adjusted-HR=1.89; 95% CI=1.30-2.74; p<0.001).	('CA-125', 'Gene', '94025', (13, 19))	('progression', 'CPA', (85, 96))	('abnormal', 'Var', (4, 12))	('recurrence', 'CPA', (71, 81))	('CA-125', 'Gene', '94025', (205, 211))	('CA-125', 'Gene', (205, 211))	('CA-125', 'Gene', (120, 126))	('CA-125', 'Gene', '94025', (120, 126))	('CA-125', 'Gene', (13, 19))
16967	28258415	PFS in patients with uterine serous carcinoma undergoing SLN mapping, followed by adjuvant therapy, was similar to PFS in patients undergoing standard lymphadenectomy and adjuvant therapy.	('mapping', 'Var', (61, 68))	('serous carcinoma', 'Disease', (29, 45))	('serous carcinoma', 'Disease', 'MESH:D018284', (29, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (7, 15))
16992	28258415	The presence of lymphovascular space invasion (LVSI) was found in 55 patients (35.9%) in the SLN group and 46 patients (48.4%) in the non-SLN group (p = 0.6).	('patients', 'Species', '9606', (69, 77))	('SLN', 'Var', (93, 96))	('patients', 'Species', '9606', (110, 118))	('lymphovascular space invasion', 'Disease', (16, 45))
16998	28258415	Postoperative therapy was used in 134/153 patients (88%) who underwent SLN mapping and 86/95 patients (91%) who did not (Table 2; p = 0.8).	('SLN', 'Gene', (71, 74))	('patients', 'Species', '9606', (42, 50))	('patients', 'Species', '9606', (93, 101))	('mapping', 'Var', (75, 82))
17035	29240775	ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets.	('recurrence', 'CPA', (73, 83))	('endometrial cancer', 'Disease', (93, 111))	('increased', 'PosReg', (63, 72))	('overall', 'MPA', (42, 49))	('expression', 'Var', (5, 15))	('ODC1', 'Gene', (0, 4))	('endometrial cancer', 'Phenotype', 'HP:0012114', (93, 111))	('ODC1', 'Gene', '4953', (0, 4))	('endometrial cancer', 'Disease', 'MESH:D016889', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('worse', 'NegReg', (36, 41))
17038	29240775	DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023).	('endometrial cancer', 'Phenotype', 'HP:0012114', (38, 56))	('tumor', 'Disease', (64, 69))	('reduced', 'NegReg', (24, 31))	('ACI-98', 'Chemical', '-', (57, 63))	('endometrial cancer', 'Disease', 'MESH:D016889', (38, 56))	('human', 'Species', '9606', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('human', 'CPA', (32, 37))	('DFMO', 'Chemical', 'MESH:D000518', (0, 4))	('mice', 'Species', '10090', (80, 84))	('DFMO', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('endometrial cancer', 'Disease', (38, 56))
17039	29240775	ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006), [Spd] (p<0.0001)) and blood plasma ([Put] (p<0.0001), [Spd] (p = 0.0049)) of treated mice.	('DFMO', 'Chemical', 'MESH:D000518', (146, 150))	('putrescine', 'Chemical', 'MESH:D011700', (26, 36))	('DFMO', 'Var', (146, 150))	('Put', 'Chemical', 'MESH:D011700', (231, 234))	('spermidine', 'Chemical', 'MESH:D013095', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('mice', 'Species', '10090', (279, 283))	('decreased', 'NegReg', (121, 130))	('spermidine', 'MPA', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('polyamines', 'Chemical', 'MESH:D011073', (14, 24))	('Put', 'Chemical', 'MESH:D011700', (175, 178))	('tumor', 'Disease', (160, 165))	('Put', 'Chemical', 'MESH:D011700', (38, 41))	('rat', 'Species', '10116', (100, 103))
17059	29240775	Furthermore, DFMO was found to inhibit growth of HEC-50 endometrial cancer cells in vitro a process that could be reversed following addition of putrescine.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('endometrial cancer', 'Disease', (56, 74))	('endometrial cancer', 'Phenotype', 'HP:0012114', (56, 74))	('HEC-50', 'CellLine', 'CVCL:2929', (49, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (56, 74))	('growth', 'CPA', (39, 45))	('inhibit', 'NegReg', (31, 38))	('DFMO', 'Chemical', 'MESH:D000518', (13, 17))	('putrescine', 'Chemical', 'MESH:D011700', (145, 155))	('DFMO', 'Var', (13, 17))
17110	29240775	Affymetrix probesets used for analysis were; ODC1 (200790_at), SAT1 (203455_s_at), SRM (201516_at), SMS (202043_s_at), PAOX (221941_at) and SMOX (210357_s_at).	('SMS', 'Gene', '6611', (100, 103))	('PAOX', 'Gene', '196743', (119, 123))	('ODC1', 'Gene', (45, 49))	('PAOX', 'Gene', (119, 123))	('203455_s_at', 'Var', (69, 80))	('SMS', 'Gene', (100, 103))	('221941_at', 'Var', (125, 134))	('202043_s_at', 'Var', (105, 116))	('210357_s_at', 'Var', (146, 157))	('SMOX', 'Gene', (140, 144))	('ODC1', 'Gene', '4953', (45, 49))	('200790_at', 'Var', (51, 60))	('SMOX', 'Gene', '54498', (140, 144))	('201516_at', 'Var', (88, 97))
17130	29240775	Taken together these three datasets independently indicate that elevated ODC1 is associated with shorter time to recurrence and decreased survival times.	('time to recurrence', 'CPA', (105, 123))	('survival times', 'CPA', (138, 152))	('ODC1', 'Gene', (73, 77))	('elevated', 'Var', (64, 72))	('decreased', 'NegReg', (128, 137))	('shorter', 'NegReg', (97, 104))	('ODC1', 'Gene', '4953', (73, 77))
17132	29240775	We rigorously tested the ability of DFMO to inhibit growth in a panel of uterine cancer cell lines which cover most important histotypes and feature different underlying driver mutation profiles.	('uterine cancer', 'Phenotype', 'HP:0010784', (73, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('inhibit', 'NegReg', (44, 51))	('DFMO', 'Chemical', 'MESH:D000518', (36, 40))	('cancer', 'Disease', (81, 87))	('DFMO', 'Var', (36, 40))	('growth', 'MPA', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tested', 'Reg', (14, 20))
17139	29240775	We were able to document significant levels of putrescine, spermidine, and spermine in both cell models with ACI-98 expressing 3-fold higher levels of spermidine than ACI-45, whereas ACI-45 expressed higher levels of putrescine (Fig 4E and 4F).	('spermidine', 'Chemical', 'MESH:D013095', (59, 69))	('ACI-98', 'Var', (109, 115))	('ACI-45', 'Chemical', '-', (183, 189))	('putrescine', 'MPA', (47, 57))	('spermine', 'MPA', (75, 83))	('higher', 'PosReg', (134, 140))	('putrescine', 'Chemical', 'MESH:D011700', (47, 57))	('putrescine', 'Chemical', 'MESH:D011700', (217, 227))	('ACI-45', 'Chemical', '-', (167, 173))	('ACI-98', 'Chemical', '-', (109, 115))	('putrescine', 'MPA', (217, 227))	('spermidine', 'Chemical', 'MESH:D013095', (151, 161))	('spermine', 'Chemical', 'MESH:D013096', (75, 83))	('spermidine', 'MPA', (59, 69))	('spermidine', 'MPA', (151, 161))
17150	29240775	DFMO treatments were found to significantly reduce the tumor burden in mice compared to controls with tumor volumes and weights both significantly decreased in DFMO treated animals (Fig 5).	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('reduce', 'NegReg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('DFMO', 'Chemical', 'MESH:D000518', (160, 164))	('DFMO', 'Var', (160, 164))	('decreased', 'NegReg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (55, 60))	('DFMO', 'Chemical', 'MESH:D000518', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
17152	29240775	Importantly, we noted that the ODC-regulated polyamines (putrescine, spermidine) known activators of cell proliferation were strongly decreased in mice treated with DFMO, in both tumor tissue (Fig 6A) and blood plasma (Fig 6B).	('decreased', 'NegReg', (134, 143))	('mice', 'Species', '10090', (147, 151))	('putrescine', 'Chemical', 'MESH:D011700', (57, 67))	('polyamines', 'Chemical', 'MESH:D011073', (45, 55))	('rat', 'Species', '10116', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('DFMO', 'Chemical', 'MESH:D000518', (165, 169))	('DFMO', 'Var', (165, 169))	('spermidine', 'Chemical', 'MESH:D013095', (69, 79))	('tumor', 'Disease', (179, 184))
17153	29240775	The reduction of these surrogate markers confirms that the effect of DFMO is specific and targets ODC by blocking the polyamine biosynthetic pathway.	('polyamine', 'Chemical', 'MESH:D011073', (118, 127))	('blocking', 'NegReg', (105, 113))	('polyamine biosynthetic pathway', 'Pathway', (118, 148))	('DFMO', 'Chemical', 'MESH:D000518', (69, 73))	('DFMO', 'Var', (69, 73))
17155	29240775	The effects of DFMO on putrescine (a diamine) and spermidine (a triamine) with varying/minimal effects on the higher-order polyamine spermine (a tetramine) have previously been reported and can be explained by the fact that frequently, cell proliferation is halted before significant depletion of the polyamine spermine can occur.	('putrescine', 'Chemical', 'MESH:D011700', (23, 33))	('polyamine spermine', 'Chemical', '-', (123, 141))	('effects', 'Reg', (4, 11))	('diamine', 'Chemical', 'MESH:D003959', (37, 44))	('spermidine', 'Chemical', 'MESH:D013095', (50, 60))	('DFMO', 'Chemical', 'MESH:D000518', (15, 19))	('DFMO', 'Var', (15, 19))	('triamine', 'Chemical', '-', (64, 72))	('polyamine spermine', 'Chemical', '-', (301, 319))	('tetramine', 'Chemical', 'MESH:C010349', (145, 154))	('rat', 'Species', '10116', (248, 251))
17157	29240775	Thus any abnormalities in the polyamines metabolism might implicate several pathological processes such as cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('polyamines metabolism', 'MPA', (30, 51))	('abnormalities', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('implicate', 'Reg', (58, 67))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('polyamines', 'Chemical', 'MESH:D011073', (30, 40))
17164	29240775	Specifically, highest expression of ODC was seen in late stage, grade 3, serous histotypes and in those copy number high molecular classified cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('serous', 'Disease', (73, 79))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('copy number high molecular classified', 'Var', (104, 141))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('expression', 'MPA', (22, 32))
17166	29240775	MYC gene amplification and high MYC expression are common events in some high-grade endometrial cancers and this is linked to worse survival characteristics.	('MYC', 'Gene', (0, 3))	('endometrial cancers', 'Disease', 'MESH:D016889', (84, 103))	('endometrial cancers', 'Disease', (84, 103))	('amplification', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MYC', 'Gene', (32, 35))	('endometrial cancer', 'Phenotype', 'HP:0012114', (84, 102))	('MYC', 'Gene', '4609', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('expression', 'MPA', (36, 46))	('MYC', 'Gene', '4609', (32, 35))
17167	29240775	We used cBioPortal and queried endometrial cancers present in the published TCGA cohort and found that those with copy number amplification or gain and elevated expression of MYC also had elevated ODC1 (p = 0.02) (data not shown).	('MYC', 'Gene', (175, 178))	('elevated', 'PosReg', (152, 160))	('expression', 'MPA', (161, 171))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('ODC1', 'Gene', '4953', (197, 201))	('endometrial cancer', 'Phenotype', 'HP:0012114', (31, 49))	('endometrial cancers', 'Disease', 'MESH:D016889', (31, 50))	('gain', 'Disease', (143, 147))	('MYC', 'Gene', '4609', (175, 178))	('elevated', 'PosReg', (188, 196))	('endometrial cancers', 'Disease', (31, 50))	('copy number amplification', 'Var', (114, 139))	('gain', 'Disease', 'MESH:D015430', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ODC1', 'Gene', (197, 201))
17170	29240775	Cancers with gain or amplification in one MYC gene were also likely to have gain in more than one MYC gene (p<0.001) and more than 1/3 of cancers had increased DNA copy number change in at least one MYC gene.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gain', 'Disease', (13, 17))	('amplification', 'Var', (21, 34))	('MYC', 'Gene', (98, 101))	('DNA', 'MPA', (160, 163))	('gain', 'Disease', 'MESH:D015430', (76, 80))	('MYC', 'Gene', (42, 45))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('gain', 'Disease', (76, 80))	('MYC', 'Gene', (199, 202))	('MYC', 'Gene', '4609', (98, 101))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('MYC', 'Gene', '4609', (42, 45))	('gain', 'Disease', 'MESH:D015430', (13, 17))	('MYC', 'Gene', '4609', (199, 202))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('increased', 'PosReg', (150, 159))	('cancers', 'Disease', (138, 145))
17194	29240775	Endometrial cancers are characterized by frequent mutations in oncogenes and tumor suppressors and tumors display different mutator phenotypes.	('tumor', 'Disease', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('oncogenes', 'Protein', (63, 72))	('mutations', 'Var', (50, 59))	('Endometrial cancer', 'Phenotype', 'HP:0012114', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Endometrial cancers', 'Disease', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Endometrial cancers', 'Disease', 'MESH:D016889', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (77, 82))	('tumors', 'Disease', (99, 105))
17195	29240775	DNA mutation frequency and copy number changes have been proposed to divide endometrial cancers into 4 main molecular groups.	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('endometrial cancer', 'Phenotype', 'HP:0012114', (76, 94))	('endometrial cancers', 'Disease', 'MESH:D016889', (76, 95))	('copy number changes', 'Var', (27, 46))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('endometrial cancers', 'Disease', (76, 95))	('N', 'Chemical', 'MESH:D009584', (1, 2))
17196	29240775	These groups are copy number low, typically low grade endometrioid histotypes that are microsatellite stable (MSS), with near diploid genomes and frequent PTEN, KRAS, ARID1A, CTNNB1 and AKT pathway mutations, copy number high (CNH) high grade cancers with frequent genomic gain and loss typified by serous histology and TP53 mutation, the hyper-mutated microsatellite instability-high (MSI-H) group of endometrioid type histology with a defect in DNA mismatch repair, and an ultra-mutated group characterized by high grade endometrioid cancers with defects in the polymerase epsilon (POLE) gene exonuclease domain (Ultra-mutant POLE).	('cancers', 'Phenotype', 'HP:0002664', (536, 543))	('N', 'Chemical', 'MESH:D009584', (228, 229))	('TP53', 'Gene', '7157', (320, 324))	('AKT', 'Gene', '207', (186, 189))	('cancers', 'Disease', (536, 543))	('CTNNB1', 'Gene', '1499', (175, 181))	('endometrioid cancers', 'Disease', (523, 543))	('defects', 'Var', (549, 556))	('ARID1A', 'Gene', (167, 173))	('KRAS', 'Gene', '3845', (161, 165))	('PTEN', 'Gene', (155, 159))	('N', 'Chemical', 'MESH:D009584', (448, 449))	('gain', 'Disease', 'MESH:D015430', (273, 277))	('mutations', 'Var', (198, 207))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('KRAS', 'Gene', (161, 165))	('ARID1A', 'Gene', '8289', (167, 173))	('mutation', 'Var', (325, 333))	('N', 'Chemical', 'MESH:D009584', (177, 178))	('MSI-H', 'Disease', (386, 391))	('cancers', 'Disease', 'MESH:D009369', (536, 543))	('CTNNB1', 'Gene', (175, 181))	('PTEN', 'Gene', '5728', (155, 159))	('gain', 'Disease', (273, 277))	('endometrioid cancers', 'Disease', 'MESH:D016889', (523, 543))	('TP53', 'Gene', (320, 324))	('AKT', 'Gene', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (536, 542))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('MSI-H', 'Disease', 'MESH:D000848', (386, 391))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('cancers', 'Disease', (243, 250))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
17198	29240775	In terms of recurrence and survival, copy number high has the highest rates of recurrence and death whereas the POLE ultra-mutated group the most favorable survival.	('death', 'Disease', 'MESH:D003643', (94, 99))	('copy number high', 'Var', (37, 53))	('death', 'Disease', (94, 99))	('rat', 'Species', '10116', (70, 73))
17210	29240775	Additional chemopreventive opportunities in endometrial cancer exist for those Lynch syndrome family members who inherit a defective DNA mismatch repair gene and are at an extremely high risk for developing endometrial cancer in addition to colon cancers and other cancers in this syndrome.	('Lynch syndrome', 'Disease', 'MESH:D003123', (79, 93))	('colon cancers', 'Phenotype', 'HP:0003003', (241, 254))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('endometrial cancer', 'Disease', (207, 225))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('endometrial cancer', 'Disease', 'MESH:D016889', (207, 225))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('colon cancers', 'Disease', 'MESH:D015179', (241, 254))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('endometrial cancer', 'Phenotype', 'HP:0012114', (44, 62))	('colon cancers', 'Disease', (241, 254))	('defective', 'Var', (123, 132))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('endometrial cancer', 'Disease', (44, 62))	('DNA mismatch repair gene', 'Gene', (133, 157))	('Lynch syndrome', 'Disease', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('endometrial cancer', 'Disease', 'MESH:D016889', (44, 62))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('endometrial cancer', 'Phenotype', 'HP:0012114', (207, 225))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancers', 'Disease', (265, 272))
17220	29183400	Using sequenced tumour DNA downloaded via the cBioPortal for Cancer Genomics, we collected the presence or absence of calls for gene alterations for 6640 tumour samples spanning 28 cancer types, as predictive features.	('gene alterations', 'Var', (128, 144))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('Cancer', 'Disease', (61, 67))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumour', 'Disease', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumour', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', (181, 187))
17221	29183400	We employed three machine-learning techniques, namely linear support vector machines with recursive feature selection, L 1-regularised logistic regression and random forest, to select a small subset of gene alterations that are most informative for cancer-type prediction.	('cancer-type', 'Disease', 'MESH:D009369', (249, 260))	('alterations', 'Var', (207, 218))	('L 1', 'Gene', (119, 122))	('cancer-type', 'Disease', (249, 260))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('L 1', 'Gene', '3897', (119, 122))
17223	29183400	A general cancer diagnostic tool that utilises either only somatic point mutations or only copy number alterations is not sufficient for distinguishing a broad range of cancer types.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('copy number alterations', 'Var', (91, 114))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
17234	29183400	identified a tree-like stratification of cancer types and their oncogenic signatures, based on somatic mutation, copy number alterations and methylation in tumour DNA.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('copy number alterations', 'Var', (113, 136))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
17236	29183400	found a relationship between the chromatin organisation of primary cancer cells and the distribution of mutations along their cancer genome.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (104, 113))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
17238	29183400	In this paper, we evaluate the potential and the limitations of determining the cancer type from a small set of genetic alterations in tumour DNA.	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('genetic alterations', 'Var', (112, 131))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))
17242	29183400	Such large volumes of data allow us to explore the feasibility of identifying the cancer types of tumour DNA based on alterations in the genes, which is a classification problem.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('alterations', 'Var', (118, 129))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('genes', 'Gene', (137, 142))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (98, 104))
17245	29183400	This can be cast as a feature selection problem in machine learning: we will identify and select a small subset of the gene alterations that are most informative about cancer type.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('alterations', 'Var', (124, 135))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
17246	29183400	The type of gene alterations we employ to distinguish one cancer type from another are somatic point mutations and copy number alterations.	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('copy number alterations', 'Var', (115, 138))	('cancer', 'Disease', 'MESH:D009369', (58, 64))
17247	29183400	Although studies on cancer types such as colorectal and breast cancer have shown that genetic alterations in tumours are mostly in the form of somatic point mutations and that somatic mutations alone are sufficient for accurately predicting cancer subtypes, there are cancer types where mutations seem to occur predominantly in the form of copy number alterations.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('colorectal and breast cancer', 'Disease', 'MESH:D015179', (41, 69))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Disease', (109, 116))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', (268, 274))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('copy number alterations', 'Var', (340, 363))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
17248	29183400	This interest is also motivated by a reported improvement in the detection of copy number alterations in tumour DNA.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour', 'Disease', (105, 111))	('copy number alterations', 'Var', (78, 101))
17251	29183400	The analysed data, consisting of somatic mutations and copy number alterations in 6640 tumour samples from 28 cancer types (Table 1), were downloaded via the cBioPortal for Cancer Genomics.	('mutations', 'Var', (41, 50))	('tumour', 'Disease', (87, 93))	('cancer', 'Disease', (110, 116))	('Cancer', 'Disease', 'MESH:D009369', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('copy number alterations', 'Var', (55, 78))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('Cancer', 'Disease', (173, 179))
17253	29183400	We first identified 28 cancer types for our study based on the availability of both somatic mutation and copy number alteration information on the cBioPortal website.	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('copy number alteration', 'Var', (105, 127))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
17254	29183400	We then compiled two separate lists of genes for these cancer types from the same website: somatic point-mutated genes and copy number altered genes.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('point-mutated', 'Var', (99, 112))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('copy number altered', 'Var', (123, 142))	('cancer', 'Disease', (55, 61))
17257	29183400	Since amplification and deletion of chromosome regions affect the copy number of many genes, which may not all be causally related to cancer, it is not surprising that the GISTIC algorithm picked up many more pseudogenes and non-coding genes among the copy number altered genes.	('affect', 'Reg', (55, 61))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('copy number', 'MPA', (66, 77))	('deletion', 'Var', (24, 32))	('amplification', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
17289	29183400	These results indicate that the somatic mutation and copy number alteration profiles of the top-ranked genes are characteristic of and can correctly differentiate these nine cancers.	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('copy number alteration', 'Var', (53, 75))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
17307	29183400	Thus, we tried to quantify the performance of using genetic alterations in sequenced tumour samples to identify cancer type.	('genetic alterations', 'Var', (52, 71))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
17309	29183400	Our results show that by testing 50 genes for somatic point mutations and copy number alterations, the cancer type of an unknown tumour DNA can be identified with an accuracy of around 77 %.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('copy number alterations', 'Var', (74, 97))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('testing', 'Reg', (25, 32))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
17314	29183400	More importantly, our results in Table 2 show that the identification of cancer type using only a small number of somatic point mutations or copy number alterations does not yield satisfactory results.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('copy number alterations', 'Var', (141, 164))
17315	29183400	The inclusion of copy number alterations can dramatically improve the results of cancer-type identification.	('copy number alterations', 'Var', (17, 40))	('improve', 'PosReg', (58, 65))	('cancer-type', 'Disease', 'MESH:D009369', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer-type', 'Disease', (81, 92))
17322	29183400	On the one hand, this relatively small drop in accuracy shows that we had not filtered out all the useful predictors of cancer types when we removed the pseudogenes and non-coding genes early in our procedure.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pseudogenes', 'Var', (153, 164))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
17323	29183400	On the other hand, the drop in accuracy also suggests that at least some of the pseudogenes and non-coding genes might be be helpful in classifying tumour samples into different cancer types.	('tumour', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pseudogenes', 'Var', (80, 91))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumour', 'Disease', 'MESH:D009369', (148, 154))
17325	29183400	Since genetic alterations in tumour DNA can be obtained reliably and cost-effectively from circulating tumour DNA (ctDNA), which is released into the bloodstream from viable or ruptured tumour cells, ctDNA is regarded as having potential for cancer-type detection and identification.	('tumour', 'Disease', (186, 192))	('tumour', 'Disease', (29, 35))	('ruptured tumour', 'Disease', (177, 192))	('cancer-type', 'Disease', 'MESH:D009369', (242, 253))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('ruptured tumour', 'Disease', 'MESH:D012421', (177, 192))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('cancer-type', 'Disease', (242, 253))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', (103, 109))	('genetic alterations', 'Var', (6, 25))
17341	29183400	To our knowledge, our work is the first to show systematically that cancer types can also be identified from somatic point mutations and copy number alterations.	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('copy number alterations', 'Var', (137, 160))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
17343	29183400	This indicates that somatic point mutations may have general carcinogenic effects that will be more similar across cancer types.	('cancer', 'Disease', (115, 121))	('carcinogenic effects', 'Disease', (61, 81))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carcinogenic effects', 'Disease', 'MESH:D020018', (61, 81))	('somatic point mutations', 'Var', (20, 43))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
17344	29183400	In contrast, copy number variants are more specific for each cancer type.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('copy number variants', 'Var', (13, 33))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
17345	29183400	CNA Copy number altered ctDNA Circulating tumour DNA SPM Somatic point-mutated SVM Support vector machine SVM-RFE Support vector machine with recursive feature selection TCGA The Cancer Genome Atlas NB, TS and ES conceived and designed the study.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('Cancer Genome Atlas', 'Disease', (179, 198))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (179, 198))	('tumour', 'Disease', (42, 48))	('Copy number', 'Var', (4, 15))
17356	29234680	Preterm birth and preterm premature rupture of membranes, uterine rupture, postpartum hemorrhage due to uterine atony, and ectopic pregnancy have all been reported in association with adenomyosis.	('rupture', 'Disease', (66, 73))	('adenomyosis', 'Disease', (184, 195))	('postpartum hemorrhage', 'Disease', 'MESH:D006473', (75, 96))	('ectopic pregnancy', 'Phenotype', 'HP:0031456', (123, 140))	('uterine rupture', 'Phenotype', 'HP:0100718', (58, 73))	('rupture', 'Disease', 'MESH:D012421', (66, 73))	('preterm premature', 'Phenotype', 'HP:0001622', (18, 35))	('adenomyosis', 'Disease', 'MESH:D062788', (184, 195))	('ectopic', 'Var', (123, 130))	('preterm premature rupture', 'Disease', 'MESH:C563032', (18, 43))	('association', 'Reg', (167, 178))	('postpartum hemorrhage', 'Disease', (75, 96))	('rupture', 'Disease', 'MESH:D012421', (36, 43))	('rupture', 'Disease', (36, 43))	('preterm premature rupture', 'Disease', (18, 43))	('uterine atony', 'Phenotype', 'HP:0000139', (104, 117))	('Preterm birth', 'Phenotype', 'HP:0001622', (0, 13))	('premature rupture of membranes', 'Phenotype', 'HP:0001788', (26, 56))
17365	29234680	Early menarche, nulliparity, caffeine, and alcohol consumption, obesity, and high blood pressure have all been found to increase the risk, whereas smoking, possibly implicated in relative alteration in estrogen metabolism, has been shown to decrease the risk of developing fibroids.	('obesity', 'Disease', 'MESH:D009765', (64, 71))	('smoking', 'Disease', (147, 154))	('alcohol', 'Chemical', 'MESH:D000438', (43, 50))	('obesity', 'Disease', (64, 71))	('caffeine', 'Chemical', 'MESH:D002110', (29, 37))	('nulliparity', 'Var', (16, 27))	('decrease', 'NegReg', (241, 249))	('high blood pressure', 'Phenotype', 'HP:0000822', (77, 96))	('increase', 'PosReg', (120, 128))	('caffeine', 'Var', (29, 37))	('obesity', 'Phenotype', 'HP:0001513', (64, 71))
17385	29234680	Alteration to the endometrial and myometrial blood supply due to underlying myomas may also interfere with both uterine contractility and implantation, whereas retained menstrual efflux due to a deformity of the uterine cavity may interfere with both sperm transport and implantation.	('interfere', 'NegReg', (231, 240))	('implantation', 'CPA', (271, 283))	('implantation', 'CPA', (138, 150))	('deformity of the uterine', 'Phenotype', 'HP:0000130', (195, 219))	('interfere', 'NegReg', (92, 101))	('deformity', 'Disease', (195, 204))	('Alteration', 'Var', (0, 10))	('myomas', 'Disease', (76, 82))	('uterine contractility', 'CPA', (112, 133))	('deformity', 'Disease', 'MESH:D009140', (195, 204))	('retained menstrual efflux', 'MPA', (160, 185))	('myomas', 'Disease', 'MESH:D009214', (76, 82))	('uterine contractility', 'Phenotype', 'HP:0000139', (112, 133))	('sperm transport', 'CPA', (251, 266))
17386	29234680	Deviation or obstruction of the tubal ostia may compromise tubal patency and alteration of the tubo-ovarian anatomic relation may impede ovum collection from the fimbrial end following ovulation.	('obstruction of the tubal ostia', 'Disease', (13, 43))	('alteration', 'Var', (77, 87))	('ovum collection from the', 'CPA', (137, 161))	('tubal patency', 'CPA', (59, 72))	('compromise', 'NegReg', (48, 58))	('impede', 'NegReg', (130, 136))	('obstruction of the tubal ostia', 'Disease', 'MESH:D005184', (13, 43))	('Deviation', 'Var', (0, 9))
17395	29234680	Despite the fact that a recent systematic review and meta-analysis of controlled studies found that the presence of fibroids irrespective of their location significantly lowers implantation, clinical pregnancy, and ongoing pregnancy/live birth rates, when the analysis was restricted to subserosal myomas, no difference was observed for any of these endpoints.	('subserosal myomas', 'Disease', 'MESH:D009214', (287, 304))	('ongoing pregnancy/live birth rates', 'CPA', (215, 249))	('subserosal myomas', 'Disease', (287, 304))	('lowers', 'NegReg', (170, 176))	('implantation', 'CPA', (177, 189))	('ongoing pregnancy', 'Phenotype', 'HP:0001622', (215, 232))	('clinical pregnancy', 'CPA', (191, 209))	('presence', 'Var', (104, 112))
17410	29234680	In a systematic review and meta-analysis conducted by Pritts, in women undergoing IVF, the presence of submucosal fibroids was associated with lower implantation (RR 0.28; CI 0.10-0.72) and pregnancy rates (RR 0.30; 95% CI 0.13-0.70) as compared with infertile controls devoid of fibroids.	('lower', 'NegReg', (143, 148))	('presence', 'Var', (91, 99))	('implantation', 'CPA', (149, 161))	('IVF', 'Disease', 'MESH:C537182', (82, 85))	('IVF', 'Disease', (82, 85))	('women', 'Species', '9606', (65, 70))	('pregnancy rates', 'CPA', (190, 205))
17412	29234680	A year later, Donnez and Jadoul reviewed the literature and ended up with a conclusion that although clear evidence is lacking, it seems reasonable that myomas distorting intrauterine cavity impair implantation and pregnancy rates in ART cycles.	('myomas', 'Disease', 'MESH:D009214', (153, 159))	('implantation', 'CPA', (198, 210))	('distorting', 'Var', (160, 170))	('myomas', 'Disease', (153, 159))	('impair', 'NegReg', (191, 197))	('pregnancy rates', 'CPA', (215, 230))
17483	29234680	Therefore, the hypothesis that nulliparity may have a protective effect for the development of adenomyosis per se or that adenomyosis may not have a negative impact on the course of pregnancy does not seem to be fully justified.	('adenomyosis', 'Disease', (95, 106))	('nulliparity', 'Var', (31, 42))	('adenomyosis', 'Disease', (122, 133))	('adenomyosis', 'Disease', 'MESH:D062788', (95, 106))	('adenomyosis', 'Disease', 'MESH:D062788', (122, 133))
17492	29234680	Thus, aberrant uterine contractility impairing rapid and sustained directed sperm transport has been proposed as a plausible mechanism of infertility attributed to adenomyosis.	('infertility', 'Disease', 'MESH:D007247', (138, 149))	('adenomyosis', 'Disease', (164, 175))	('uterine contractility', 'CPA', (15, 36))	('aberrant', 'Var', (6, 14))	('infertility', 'Phenotype', 'HP:0000789', (138, 149))	('infertility', 'Disease', (138, 149))	('impairing', 'NegReg', (37, 46))	('uterine contractility', 'Phenotype', 'HP:0000139', (15, 36))	('adenomyosis', 'Disease', 'MESH:D062788', (164, 175))
17501	29234680	In fact, local conversion of androgens to estrogens results in a hyperestrogenic endometrial environment, which sustains the increased expression of the estrogen receptor alpha during the secretory phase, which should have normally declined under the effect of progesterone.	('progesterone', 'Chemical', 'MESH:D011374', (261, 273))	('hyperestrogenic', 'MPA', (65, 80))	('estrogen receptor alpha', 'Gene', '2099', (153, 176))	('increased', 'PosReg', (125, 134))	('conversion', 'Var', (15, 25))	('expression', 'MPA', (135, 145))	('estrogen receptor alpha', 'Gene', (153, 176))
17545	22157934	This latter 9-year old had a DICER1 germline mutation.	('germline mutation', 'Var', (36, 53))	('DICER1', 'Gene', (29, 35))	('DICER1', 'Gene', '23405', (29, 35))
17612	22157934	Additional studies were performed in this child and she was found to have a germline DICER1 mutation, c5104CST, which she had inherited from her mother.	('c5104CST', 'Var', (102, 110))	('DICER1', 'Gene', (85, 91))	('DICER1', 'Gene', '23405', (85, 91))	('child', 'Species', '9606', (42, 47))
17618	22157934	The portion of the polyp with embryonal rhabdomyosarcoma revealed desmin and myogenin (nuclear reactivity) positivity in the population of primitive rhabdomyoblasts around the endocervical glands (Figure 12c and d).	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('positivity', 'Var', (107, 117))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (30, 56))	('embryonal rhabdomyosarcoma', 'Disease', (30, 56))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (30, 56))	('myogenin', 'Protein', (77, 85))	('desmin', 'Protein', (66, 72))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (40, 56))
17661	22157934	A germline mutation in DICER1 has recently been identified in a linkage analysis of four families with an inherited predisposition to pleuropulmonary blastoma.	('DICER1', 'Gene', '23405', (23, 29))	('germline mutation', 'Var', (2, 19))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (134, 158))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (134, 158))	('DICER1', 'Gene', (23, 29))	('pleuropulmonary blastoma', 'Disease', (134, 158))
17675	22157934	The cambium layer with its relationship to the overlying epithelium reflects the perturbation or disruption in the normal epithelial-stromal interaction as a consequence of a loss-of-function mutation of DICER1.	('loss-of-function', 'NegReg', (175, 191))	('DICER1', 'Gene', (204, 210))	('mutation', 'Var', (192, 200))	('disruption', 'NegReg', (97, 107))	('DICER1', 'Gene', '23405', (204, 210))
17847	26230631	When stratified by cancer site, there was no impact of insurance type on stage at the time of diagnosis with the exception of uterine cancer, where dual enrollment was associated with an OR of 1.38 (95% CI 1.06 - 1.79) with advanced stage diagnosis (Table 2).	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('dual', 'Var', (148, 152))	('advanced stage', 'Disease', (224, 238))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('uterine cancer', 'Phenotype', 'HP:0010784', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
17876	26230631	In cases of equal access to cancer care, Black race is associated with poorer patient-physician communication , and more provider distrust .	('patient-physician communication', 'CPA', (78, 109))	('Black race', 'Var', (41, 51))	('patient', 'Species', '9606', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('provider distrust', 'CPA', (121, 138))	('poorer', 'NegReg', (71, 77))	('cancer', 'Disease', (28, 34))
17913	25774118	Survival of patients with a LMS is strongly associated with the number of mitoses per 10 high power fields (x100 magnification): 1-4, 98 %; 5-9, 42 %; >=10, 15 %.	('associated', 'Reg', (44, 54))	('patients', 'Species', '9606', (12, 20))	('LMS', 'Disease', (28, 31))	('LMS', 'Phenotype', 'HP:0100243', (28, 31))	('mitoses', 'Var', (74, 81))
17978	25774118	Not only electromechanical power morcellation is associated with the risk of upstaging but also other 'manipulations' of the sarcomatous tumour, such as myomectomy by laparotomy, subtotal hysterectomy and hysteroscopic resection of submucous fibroids, may affect survival suggesting upstaging.	('upstaging', 'CPA', (283, 292))	('sarcomatous tumour', 'Disease', 'MESH:D018316', (125, 143))	('sarcomatous tumour', 'Disease', (125, 143))	('upstaging', 'Disease', (77, 86))	('electromechanical power morcellation', 'Var', (9, 45))	('sarcomatous tumour', 'Phenotype', 'HP:0100242', (125, 143))	('survival', 'MPA', (263, 271))	('affect', 'Reg', (256, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
18122	23101025	As the metastases to lung from MMMT progressed rapidly, her performance status was getting worse.	('metastases', 'Disease', (7, 17))	('MMMT', 'Var', (31, 35))	('metastases', 'Disease', 'MESH:D009362', (7, 17))
18176	12113415	The following steps were performed during the laparoscopic phase: severing of the round ligament, dissection of the upper portion of the broad ligament, severing of the infundibulopelvic ligament, preparation of the bladder flap, and severing of the bladder pillars.	('bladder flap', 'Disease', 'MESH:D000070600', (216, 228))	('bladder flap', 'Disease', (216, 228))	('severing', 'Var', (66, 74))	('bladder pillars', 'Disease', 'MESH:D001745', (250, 265))	('severing', 'Var', (153, 161))	('bladder pillars', 'Disease', (250, 265))
18190	12113415	We found malignant changes in lymph nodes in 11 women (11.9%) in the laparoscopic group versus 3 women (12.5%) in the control group.	('women', 'Species', '9606', (97, 102))	('laparoscopic', 'Var', (69, 81))	('malignant changes', 'Phenotype', 'HP:0002664', (9, 26))	('women', 'Species', '9606', (48, 53))	('malignant changes', 'CPA', (9, 26))
18256	20117828	Sorafenib is an oral agent that inhibits Raf-1 wild-type and mutant B-Raf, and multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors.	('Raf-1', 'Gene', '5894', (41, 46))	('B-Raf', 'Gene', (68, 73))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('mutant', 'Var', (61, 67))	('vascular endothelial growth factor', 'Gene', (125, 159))	('inhibits', 'NegReg', (32, 40))	('vascular endothelial growth factor', 'Gene', '7422', (125, 159))	('B-Raf', 'Gene', '673', (68, 73))	('Raf-1', 'Gene', (41, 46))
18261	20117828	Patients were required to have: measurable disease, ECOG performance status of 0 to 2, absolute neutrophil count >= 1500/microL, platelet count >= 100,000/microL, serum bilirubin less than or equal to the institutional upper limits of normal (ULN), AST/ALT <= 2.5 times ULN, and serum creatinine <= 1.5 mg/dL.	('AST', 'Gene', '26503', (249, 252))	('ALT <= 2', 'Gene', '84706', (253, 261))	('serum bilirubin', 'MPA', (163, 178))	('platelet', 'MPA', (129, 137))	('creatinine', 'Chemical', 'MESH:D003404', (285, 295))	('Patients', 'Species', '9606', (0, 8))	('less', 'NegReg', (179, 183))	('bilirubin', 'Chemical', 'MESH:D001663', (169, 178))	('>= 1500/microL', 'Var', (113, 127))	('AST', 'Gene', (249, 252))	('ALT <= 2', 'Gene', (253, 261))	('serum creatinine', 'MPA', (279, 295))
18320	20117828	However combinations of chemotherapy plus sorafenib are toxic (for example, 45% grade 3 hand-foot skin reactions with the combination of sorafenib plus capecitabine), and randomization between chemotherapy and a combination of chemotherapy plus targeted agent does not address the ability of the single targeted agent to achieve meaningful disease stabilization.	('skin reactions', 'Phenotype', 'HP:0011123', (98, 112))	('sorafenib', 'Chemical', 'MESH:D000077157', (42, 51))	('grade 3 hand-foot skin reactions', 'Disease', (80, 112))	('capecitabine', 'Chemical', 'MESH:D000069287', (152, 164))	('sorafenib', 'Chemical', 'MESH:D000077157', (137, 146))	('combinations', 'Var', (8, 20))
18323	33875650	We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (119, 128))	('phosphosites', 'Chemical', '-', (95, 107))
18324	33875650	HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches.	('p.Y179', 'Var', (166, 172))	('HRAS', 'Gene', '3265', (128, 132))	('ding', 'Gene', '6045', (92, 96))	('p.S904/Y928', 'Var', (101, 112))	('p.Y96', 'Var', (138, 143))	('IDH1', 'Gene', (149, 153))	('ding', 'Gene', (92, 96))	('IDH2', 'Gene', (161, 165))	('RET', 'Gene', '5979', (97, 100))	('phosphosites', 'Chemical', '-', (73, 85))	('p.S904/Y928', 'Mutation', 'p.S904,928/Y', (101, 112))	('HRAS', 'Gene', (128, 132))	('IDH1', 'Gene', '3417', (149, 153))	('KRAS', 'Gene', (133, 137))	('KRAS', 'Gene', '3845', (133, 137))	('RET', 'Gene', (97, 100))	('IDH2', 'Gene', '3418', (161, 165))
18325	33875650	Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ding', 'Gene', '6045', (136, 140))	('EGFR', 'Gene', '1956', (159, 163))	('p.S720', 'Var', (164, 170))	('cancer', 'Disease', (82, 88))	('MAPK1', 'Gene', (172, 177))	('PTPN12', 'Gene', '5782', (190, 196))	('p.S142', 'Var', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('CTNNB1 p', 'Gene', '1499', (141, 149))	('CTNNB1 p', 'Gene', (141, 149))	('S', 'Chemical', 'MESH:D012694', (199, 200))	('S', 'Chemical', 'MESH:D012694', (166, 167))	('PTPN12', 'Gene', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('EGFR', 'Gene', (159, 163))	('S', 'Chemical', 'MESH:D012694', (150, 151))	('MAPK1', 'Gene', '5594', (172, 177))	('patient', 'Species', '9606', (61, 68))	('S', 'Chemical', 'MESH:D012694', (180, 181))	('phosphosites', 'Chemical', '-', (32, 44))	('ding', 'Gene', (136, 140))	('cancer', 'Disease', (123, 129))	('p.S275', 'Var', (197, 203))
18326	33875650	In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (88, 97))	('phosphosites', 'Chemical', '-', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
18329	33875650	Dysregulated phosphorylation of oncogenic proteins alters pathway activity and contributes to tumor phenotypes.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('phosphorylation', 'MPA', (13, 28))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('activity', 'MPA', (66, 74))	('tumor', 'Disease', (94, 99))	('contributes', 'Reg', (79, 90))	('pathway', 'Pathway', (58, 65))	('Dysregulated', 'Var', (0, 12))	('alters', 'Reg', (51, 57))
18331	33875650	Previous works highlighted the potential functionality of mutations that are linearly adjacent to phosphosites in cancer driver genes, yet these studies did not consider the 3-dimensional structures of proteins.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('phosphosites', 'Chemical', '-', (98, 110))	('cancer', 'Disease', (114, 120))
18332	33875650	We and others previously demonstrated that mutations in cancer genes form 3-dimensional (3D) spatial clusters:defined by high local concentrations of mutations on protein structures:enriched for functional missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('missense mutations', 'Var', (206, 224))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
18333	33875650	We hypothesize that co-clustering mutations and phosphosites in spatial hotspots will also enrich for functional events of both categories.	('enrich', 'Reg', (91, 97))	('mutations', 'Var', (34, 43))	('phosphosites', 'Var', (48, 60))	('phosphosites', 'Chemical', '-', (48, 60))
18336	33875650	We find 474 significant hybrid clusters (defined as clusters containing both co-clustering phosphosites and mutations) that prioritize 1255 phosphosites and 2938 mutations on protein structures from large-scale proteomics and genomics data.	('phosphosites', 'Chemical', '-', (140, 152))	('mutations', 'Var', (162, 171))	('phosphosites', 'Chemical', '-', (91, 103))	('mutations', 'Var', (108, 117))
18337	33875650	Many co-clustering mutations are associated with high functional scores, expression changes, and known recurrent/activating events that expose genetic dependency; whereas many co-clustering phosphosites are found in kinase domains and verified in primary tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('mutations', 'Var', (19, 28))	('expression', 'MPA', (73, 83))	('phosphosites', 'Chemical', '-', (190, 202))	('functional scores', 'MPA', (54, 71))	('tumor', 'Disease', 'MESH:D009369', (255, 260))
18338	33875650	We specifically prioritize phosphosites co-clustering with activating mutations of BRAF, EGFR, and PIK3CA.	('mutations', 'Var', (70, 79))	('phosphosites', 'Chemical', '-', (27, 39))	('EGFR', 'Gene', (89, 93))	('PIK3CA', 'Gene', '5290', (99, 105))	('activating', 'PosReg', (59, 69))	('BRAF', 'Gene', '673', (83, 87))	('EGFR', 'Gene', '1956', (89, 93))	('BRAF', 'Gene', (83, 87))	('PIK3CA', 'Gene', (99, 105))
18343	33875650	We also included 791,489 missense mutations from 9062 samples across 33 cancer types from a filtered set of Multi-Center Mutation Calling in Multiple Cancers project (MC3) mutation calls from the TCGA PanCanAtlas, taken in account their recurrence in the MC3 cohort.	('Cancers', 'Phenotype', 'HP:0002664', (150, 157))	('Multiple Cancers', 'Disease', 'MESH:D009369', (141, 157))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('Multiple Cancers', 'Disease', (141, 157))	('MC3', 'Gene', '4159', (255, 258))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutation', 'Var', (172, 180))	('MC3', 'Gene', (167, 170))	('MC3', 'Gene', '4159', (167, 170))	('MC3', 'Gene', (255, 258))	('cancer', 'Disease', (72, 78))
18347	33875650	First, while this threshold (cluster closeness score = 2.56) may permit false-positives if the simulated phosphosites only contain negatives, we observed many of the clusters containing activating or recurrent mutations with cluster closeness scores close to the threshold (Supplementary Data 1).	('phosphosites', 'Chemical', '-', (105, 117))	('S', 'Chemical', 'MESH:D012694', (274, 275))	('mutations', 'Var', (210, 219))	('activating', 'PosReg', (186, 196))
18348	33875650	It is possible that the spatial distribution of cancer mutations and commonly phosphorylated amino acid residues (i.e., serine, threonine, and tyrosine) is not random and thus retaining additional hybrid clusters is needed to minimize false-negatives.	('serine', 'Chemical', 'MESH:D012694', (120, 126))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('threonine', 'Chemical', 'MESH:D013912', (128, 137))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tyrosine', 'Chemical', 'MESH:D014443', (143, 151))
18357	33875650	Notably, the highest counts of hybrid clusters were found for genes known for recurrent mutations, including TP53 (10 hybrid clusters), PIK3CA (8), CTNNB1 (6), EGFR (6), and other genes involved in cancers, such as HIST1H2BC (6) and PLG (5) (Fig.	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', '5290', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('HIST1H2BC', 'Gene', '8347', (215, 224))	('PLG', 'Gene', (233, 236))	('CTNNB1', 'Gene', (148, 154))	('TP53', 'Gene', '7157', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('EGFR', 'Gene', (160, 164))	('PIK3CA', 'Gene', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('HIST1H2BC', 'Gene', (215, 224))	('ding', 'Gene', (104, 108))	('CTNNB1', 'Gene', '1499', (148, 154))	('EGFR', 'Gene', '1956', (160, 164))	('ding', 'Gene', '6045', (104, 108))	('PLG', 'Gene', '5340', (233, 236))	('TP53', 'Gene', (109, 113))
18362	33875650	Phosphosites prioritized in these clusters include CTNNB1 p.T40, EGFR p.T290, ERBB2 p.T733/T759, KIT p.Y578, and TP53 p.T284.	('p.T284', 'Var', (118, 124))	('ERBB2', 'Gene', '2064', (78, 83))	('p.T290', 'Var', (70, 76))	('ERBB2', 'Gene', (78, 83))	('EGFR', 'Gene', (65, 69))	('KIT', 'Gene', (97, 100))	('EGFR', 'Gene', '1956', (65, 69))	('Phosphosite', 'Chemical', '-', (0, 11))	('T284', 'Chemical', '-', (120, 124))	('TP53', 'Gene', '7157', (113, 117))	('p.T733/T759', 'Var', (84, 95))	('p.Y578', 'Var', (101, 107))	('CTNNB1 p', 'Gene', (51, 59))	('Y578', 'Chemical', '-', (103, 107))	('CTNNB1 p', 'Gene', '1499', (51, 59))	('TP53', 'Gene', (113, 117))	('KIT', 'Gene', '3815', (97, 100))
18363	33875650	We also compared the mutations in the hybrid clusters to those found in a clustering analysis using only TCGA MC3 mutations, which contained 9403 clustered mutations.	('mutations', 'Var', (114, 123))	('MC3', 'Gene', (110, 113))	('MC3', 'Gene', '4159', (110, 113))
18364	33875650	The list of 48 mutations contained mutations of interest in PDE1B (5 mutations), SRSF7 (4 mutations), and PTPN12 p.S275F/C that co-localized with p.S275 and co-clustered with p.S39/p.T40 (Supplementary Data 2).	('SRSF7', 'Gene', (81, 86))	('PDE1B', 'Gene', (60, 65))	('S', 'Chemical', 'MESH:D012694', (188, 189))	('SRSF7', 'Gene', '6432', (81, 86))	('S', 'Chemical', 'MESH:D012694', (83, 84))	('p.S39/p.T40', 'Var', (175, 186))	('S', 'Chemical', 'MESH:D012694', (115, 116))	('S', 'Chemical', 'MESH:D012694', (177, 178))	('PTPN12', 'Gene', '5782', (106, 112))	('S', 'Chemical', 'MESH:D012694', (148, 149))	('p.S275', 'Var', (146, 152))	('p.S275F', 'Var', (113, 120))	('S', 'Chemical', 'MESH:D012694', (81, 82))	('p.S275F', 'SUBSTITUTION', 'None', (113, 120))	('PDE1B', 'Gene', '5153', (60, 65))	('PTPN12', 'Gene', (106, 112))
18370	33875650	These findings suggest the possible involvement of hybrid clusters and co-clustering phosphosites in oncogenic signaling pathways.	('co-clustering', 'Var', (71, 84))	('phosphosites', 'Chemical', '-', (85, 97))	('ding', 'Gene', (9, 13))	('oncogenic signaling pathways', 'Pathway', (101, 129))	('involvement', 'Reg', (36, 47))	('ding', 'Gene', '6045', (9, 13))
18380	33875650	PIK3CA and EGFR are each involved in 4 hybrid clusters containing activating mutations and such clusters are also found in CTNNB1 (3), KIT (3), BRAF (2), ERBB2 (2), KRAS (2), MET (2), and NRAS (2).	('involved', 'Reg', (25, 33))	('ERBB2', 'Gene', '2064', (154, 159))	('BRAF', 'Gene', '673', (144, 148))	('BRAF', 'Gene', (144, 148))	('NRAS', 'Gene', '4893', (188, 192))	('KIT', 'Gene', '3815', (135, 138))	('MET', 'Gene', (175, 178))	('CTNNB1', 'Gene', (123, 129))	('EGFR', 'Gene', (11, 15))	('PIK3CA', 'Gene', '5290', (0, 6))	('NRAS', 'Gene', (188, 192))	('mutations', 'Var', (77, 86))	('MET', 'Gene', '79811', (175, 178))	('KRAS', 'Gene', '3845', (165, 169))	('ERBB2', 'Gene', (154, 159))	('EGFR', 'Gene', '1956', (11, 15))	('KIT', 'Gene', (135, 138))	('activating', 'PosReg', (66, 76))	('PIK3CA', 'Gene', (0, 6))	('CTNNB1', 'Gene', '1499', (123, 129))	('KRAS', 'Gene', (165, 169))
18383	33875650	Both ERBB2 p.T733 and p.T759 are located adjacently to the activating mutation p.L755W.	('ERBB2', 'Gene', '2064', (5, 10))	('ERBB2', 'Gene', (5, 10))	('p.L755W', 'Var', (79, 86))	('p.L755W', 'Mutation', 'rs121913470', (79, 86))	('p.T733', 'Var', (11, 17))	('p.T759', 'Var', (22, 28))
18384	33875650	NRAS phosphosite p.Y64 is co-clustered with two of the most recurrently mutated residues p.G12 and p.Q61.	('p.Q61', 'Var', (99, 104))	('p.Y64', 'Var', (17, 22))	('NRAS', 'Gene', (0, 4))	('phosphosite', 'Chemical', '-', (5, 16))	('p.G12', 'Var', (89, 94))	('NRAS', 'Gene', '4893', (0, 4))
18386	33875650	These prioritized phosphosites include KIT p.Y578, MET p.Y1093/Y1159/Y1230, and RET p.Y928.	('RET', 'Gene', (80, 83))	('phosphosites', 'Chemical', '-', (18, 30))	('MET', 'Gene', '79811', (51, 54))	('RET', 'Gene', '5979', (80, 83))	('KIT', 'Gene', '3815', (39, 42))	('MET', 'Gene', (51, 54))	('Y578', 'Chemical', '-', (45, 49))	('p.Y1093/Y1159/Y1230', 'Var', (55, 74))	('KIT', 'Gene', (39, 42))	('p.Y578', 'Var', (43, 49))	('p.Y928', 'Var', (84, 90))
18387	33875650	Two hybrid clusters containing activating mutations were found on a protein complex formed by PIK3CA/PIK3R1: PIK3R1 phospho-tyrosines p.Y470 and p.Y556 clustered with activating mutations PIK3CA p.N344G/M, p.N345K, p.C420R, and PIK3R1 p.N564D.	('PIK3CA', 'Gene', (188, 194))	('phospho-tyrosines', 'Chemical', 'MESH:D019000', (116, 133))	('PIK3R1 p', 'Gene', '5295', (109, 117))	('PIK3R1', 'Gene', (101, 107))	('p.C420R', 'Mutation', 'rs121913272', (215, 222))	('PIK3R1 p', 'Gene', '5295', (228, 236))	('PIK3R1', 'Gene', '5295', (228, 234))	('p.N345K', 'Mutation', 'rs121913284', (206, 213))	('PIK3R1', 'Gene', '5295', (109, 115))	('PIK3CA', 'Gene', '5290', (94, 100))	('p.N564D', 'Mutation', 'rs1057519841', (235, 242))	('PIK3R1 p', 'Gene', (109, 117))	('p.N345K', 'Var', (206, 213))	('PIK3CA', 'Gene', '5290', (188, 194))	('p.C420R', 'Var', (215, 222))	('PIK3R1', 'Gene', '5295', (101, 107))	('p.Y556', 'Var', (145, 151))	('PIK3R1 p', 'Gene', (228, 236))	('p.Y470', 'Var', (134, 140))	('PIK3CA', 'Gene', (94, 100))	('PIK3R1', 'Gene', (228, 234))	('PIK3R1', 'Gene', (109, 115))	('p.N344G', 'Var', (195, 202))	('p.N344G', 'SUBSTITUTION', 'None', (195, 202))
18388	33875650	In the other hybrid cluster, PIK3R1 p.T463 clustered with activating mutations PIK3CA p.E453K/Q.	('p.E453K', 'SUBSTITUTION', 'None', (86, 93))	('PIK3R1 p', 'Gene', (29, 37))	('p.E453K', 'Var', (86, 93))	('PIK3R1 p', 'Gene', '5295', (29, 37))	('PIK3CA', 'Gene', (79, 85))	('PIK3CA', 'Gene', '5290', (79, 85))
18390	33875650	We hypothesized that phosphosites co-clustering with highly-recurrent mutations in a cancer cohort might imply functionality in the specific cancer type.	('phosphosites', 'Var', (21, 33))	('mutations', 'Var', (70, 79))	('phosphosites', 'Chemical', '-', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('imply', 'Reg', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (141, 147))
18391	33875650	We calculated the frequency of each of the co-clustering mutations within each of the TCGA cancer cohorts and identified their spatially adjacent phosphosites (Supplementary Data 6).	('TCGA', 'Gene', (86, 90))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('phosphosites', 'Chemical', '-', (146, 158))	('mutations', 'Var', (57, 66))	('S', 'Chemical', 'MESH:D012694', (160, 161))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
18392	33875650	We found that co-clustering phosphosites of the most recurrent mutations aggregate in proteins, including CTNNB1, HRAS, IDH1, KRAS, NRAS, PIK3CA, and TP53 (Fig.	('aggregate', 'Reg', (73, 82))	('TP53', 'Gene', (150, 154))	('proteins', 'Protein', (86, 94))	('IDH1', 'Gene', (120, 124))	('CTNNB1', 'Gene', '1499', (106, 112))	('ding', 'Gene', (101, 105))	('mutations', 'Var', (63, 72))	('NRAS', 'Gene', '4893', (132, 136))	('PIK3CA', 'Gene', (138, 144))	('ding', 'Gene', '6045', (101, 105))	('IDH1', 'Gene', '3417', (120, 124))	('TP53', 'Gene', '7157', (150, 154))	('phosphosites', 'Chemical', '-', (28, 40))	('CTNNB1', 'Gene', (106, 112))	('HRAS', 'Gene', '3265', (114, 118))	('KRAS', 'Gene', (126, 130))	('HRAS', 'Gene', (114, 118))	('NRAS', 'Gene', (132, 136))	('KRAS', 'Gene', '3845', (126, 130))	('PIK3CA', 'Gene', '5290', (138, 144))
18394	33875650	In PIK3CA, we identified p.T957 co-clustering with the highly recurrent p.H1047R that affects many gynecologic cancer cases, including 13.8% of breast invasive carcinoma (BRCA), 7% of uterine carcinosarcoma (UCS), and 5.8% of uterine corpus endometrial carcinoma (UCEC).	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('breast invasive carcinoma', 'Disease', (144, 169))	('p.H1047R', 'Var', (72, 80))	('cancer', 'Disease', (111, 117))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (144, 169))	('S', 'Chemical', 'MESH:D012694', (210, 211))	('PIK3CA', 'Gene', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('endometrial carcinoma', 'Disease', (241, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('p.T957', 'Var', (25, 31))	('p.H1047R', 'Mutation', 'rs121913279', (72, 80))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (144, 169))	('carcinosarcoma', 'Disease', (192, 206))	('ding', 'Gene', (130, 134))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (241, 262))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('carcinosarcoma', 'Disease', 'MESH:D002296', (192, 206))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (241, 262))	('ding', 'Gene', '6045', (130, 134))	('PIK3CA', 'Gene', '5290', (3, 9))	('UCS', 'Phenotype', 'HP:0002891', (208, 211))	('affects', 'Reg', (86, 93))	('BRCA', 'Phenotype', 'HP:0003002', (171, 175))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (184, 206))
18395	33875650	In TP53, phosphosites p.R249 and p.T284 co-cluster with p.R273C/H that affects 11.4% of brain lower-grade glioma (LGG), 5.3% of UCS, and 3.8% of esophageal carcinoma (ESCA); TP53 p.T155 and P.S183 co-cluster with p.R175H that affects 8.3% of rectum adenocarcinoma (READ), 6.3% of colon adenocarcinoma (COAD), 6% of ESCA, 3.7% of ovarian serous cystadenocarcinoma (OV), and 3.5% of UCS.	('carcinoma', 'Phenotype', 'HP:0030731', (353, 362))	('TP53', 'Gene', '7157', (3, 7))	('COAD', 'Disease', 'MESH:D029424', (302, 306))	('TP53', 'Gene', (174, 178))	('p.R273C', 'SUBSTITUTION', 'None', (56, 63))	('S', 'Chemical', 'MESH:D012694', (130, 131))	('p.R273C', 'Var', (56, 63))	('rectum adenocarcinoma', 'Disease', (242, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (145, 165))	('ESCA', 'Phenotype', 'HP:0011459', (315, 319))	('S', 'Chemical', 'MESH:D012694', (383, 384))	('COAD', 'Disease', (302, 306))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (280, 300))	('glioma', 'Disease', (106, 112))	('OV', 'Phenotype', 'HP:0025318', (364, 366))	('S', 'Chemical', 'MESH:D012694', (192, 193))	('TP53', 'Gene', '7157', (174, 178))	('S', 'Chemical', 'MESH:D012694', (168, 169))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (329, 362))	('TP53', 'Gene', (3, 7))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('OV', 'Phenotype', 'HP:0012887', (364, 366))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (145, 165))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (242, 263))	('p.R175H', 'Mutation', 'rs28934578', (213, 220))	('ESCA', 'Phenotype', 'HP:0011459', (167, 171))	('p.T155', 'Var', (179, 185))	('ovarian serous cystadenocarcinoma', 'Disease', (329, 362))	('ESCA', 'Disease', (315, 319))	('UCS', 'Phenotype', 'HP:0002891', (128, 131))	('S', 'Chemical', 'MESH:D012694', (316, 317))	('T284', 'Chemical', '-', (35, 39))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('colon adenocarcinoma', 'Disease', (280, 300))	('esophageal carcinoma', 'Disease', (145, 165))	('phosphosites', 'Chemical', '-', (9, 21))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (329, 362))	('P.S183', 'Var', (190, 196))	('UCS', 'Phenotype', 'HP:0002891', (381, 384))
18397	33875650	IDH1 phosphosites p.Y135 and p.Y139 co-clustered with p.R132H, which is highly recurrent in brain tumors (73.6% of LGG and 6.1% of glioblastoma multiforme [GBM]), as well as p.R132C implicated in several cancer types (17.1% of cholangiocarcinoma [CHOL], 4.3% of acute myeloid leukemia [LAML], 3.4% of LGG, and 3.2% of skin cutaneous melanoma [SKCM]).	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cholangiocarcinoma', 'Disease', (227, 245))	('p.Y139', 'Var', (29, 35))	('CHOL', 'Disease', (247, 251))	('LAML', 'Chemical', '-', (286, 290))	('p.R132H', 'Mutation', 'rs121913500', (54, 61))	('brain tumors', 'Disease', (92, 104))	('leukemia', 'Phenotype', 'HP:0001909', (276, 284))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (227, 245))	('p.Y135', 'Var', (18, 24))	('IDH1', 'Gene', (0, 4))	('LGG', 'Disease', (301, 304))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (318, 341))	('p.R132H', 'Var', (54, 61))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (262, 284))	('skin cutaneous melanoma', 'Disease', (318, 341))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (323, 341))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (262, 284))	('melanoma', 'Phenotype', 'HP:0002861', (333, 341))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (268, 284))	('S', 'Chemical', 'MESH:D012694', (343, 344))	('phosphosites', 'Chemical', '-', (5, 17))	('glioblastoma multiforme', 'Disease', (131, 154))	('IDH1', 'Gene', '3417', (0, 4))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (131, 154))	('cancer', 'Disease', (204, 210))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CHOL', 'Disease', 'None', (247, 251))	('p.R132C', 'Mutation', 'rs121913499', (174, 181))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('brain tumors', 'Disease', 'MESH:D001932', (92, 104))	('brain tumors', 'Phenotype', 'HP:0030692', (92, 104))	('acute myeloid leukemia', 'Disease', (262, 284))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (227, 245))
18398	33875650	In its homolog protein IDH2, p.Y179 co-clustered with p.R140Q affecting 6.5% of LAML (Fig.	('p.R140Q', 'Var', (54, 61))	('IDH2', 'Gene', (23, 27))	('LAML', 'Chemical', '-', (80, 84))	('p.R140Q', 'Mutation', 'rs121913502', (54, 61))	('affecting', 'Reg', (62, 71))	('IDH2', 'Gene', '3418', (23, 27))	('p.Y179', 'Var', (29, 35))
18399	33875650	For the Ras proteins, KRAS/HRAS/NRAS all harbor highly recurrent mutations for residues p.G12/G13 that affect large fractions of pancreatic adenocarcinoma (PAAD), COAD, READ, lung adenocarcinoma (LUAD), and UCEC.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (175, 194))	('p.G12/G13', 'Var', (88, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (175, 194))	('KRAS', 'Gene', (22, 26))	('HRAS', 'Gene', '3265', (27, 31))	('NRAS', 'Gene', (32, 36))	('HRAS', 'Gene', (27, 31))	('LUAD', 'Phenotype', 'HP:0030078', (196, 200))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (129, 154))	('COAD', 'Disease', 'MESH:D029424', (163, 167))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (129, 154))	('PAAD', 'Phenotype', 'HP:0006725', (156, 160))	('lung adenocarcinoma', 'Disease', (175, 194))	('affect', 'Reg', (103, 109))	('NRAS', 'Gene', '4893', (32, 36))	('COAD', 'Disease', (163, 167))	('KRAS', 'Gene', '3845', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('pancreatic adenocarcinoma', 'Disease', (129, 154))	('mutations', 'Var', (65, 74))
18402	33875650	Using the TCGA Reverse Phase Protein Arrays (RPPA) dataset for each of the 33 cancer types, we conducted a differential expression analysis to search for protein/phosphoprotein markers expressed at different levels in carriers of clustered mutations ("Methods"), identifying 24 significant (FDR < 0.05, linear regression) gene-cancer associations (Fig.	('cancer', 'Disease', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (240, 249))
18404	33875650	TP53 mutations in hybrid clusters are significantly correlated with higher p53 protein expression in 14 cancer types, most strikingly in UCEC, BRCA, COAD, and OV, consistent with the previously reported cis-effect of functional TP53 missense mutations.	('TP53', 'Gene', '7157', (0, 4))	('OV', 'Phenotype', 'HP:0025318', (159, 161))	('TP53', 'Gene', (0, 4))	('COAD', 'Disease', 'MESH:D029424', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('BRCA', 'Disease', (143, 147))	('higher', 'PosReg', (68, 74))	('UCEC', 'Disease', (137, 141))	('mutations', 'Var', (5, 14))	('COAD', 'Disease', (149, 153))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('TP53', 'Gene', (228, 232))	('TP53', 'Gene', '7157', (228, 232))	('OV', 'Phenotype', 'HP:0012887', (159, 161))	('BRCA', 'Phenotype', 'HP:0003002', (143, 147))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
18405	33875650	Clustered EGFR mutations are likewise associated with higher EGFR protein and EGFR p.Y1068 expression in LGG, GBM, and LUAD, cancer types largely affected by activating mutations of EGFR.	('EGFR', 'Gene', '1956', (10, 14))	('expression', 'MPA', (91, 101))	('EGFR', 'Gene', '1956', (182, 186))	('higher', 'PosReg', (54, 60))	('EGFR', 'Gene', (182, 186))	('Y1068', 'Chemical', '-', (85, 90))	('EGFR', 'Gene', (10, 14))	('cancer', 'Disease', (125, 131))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('EGFR', 'Gene', (61, 65))	('EGFR', 'Gene', '1956', (78, 82))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('EGFR', 'Gene', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('EGFR', 'Gene', '1956', (61, 65))	('p.Y1068', 'Var', (83, 90))
18406	33875650	We also found clustered KIT mutations to be associated with higher c-Kit in TGCT and SKCM (Fig.	('c-Kit', 'Gene', (67, 72))	('higher', 'PosReg', (60, 66))	('c-Kit', 'Gene', '3815', (67, 72))	('TGCT', 'Disease', (76, 80))	('SKCM', 'Disease', (85, 89))	('KIT', 'Gene', '3815', (24, 27))	('S', 'Chemical', 'MESH:D012694', (85, 86))	('mutations', 'Var', (28, 37))	('KIT', 'Gene', (24, 27))
18407	33875650	At a single residue level, we noted clustered mutations showing high protein or phosphoprotein expressions above the 95th percentile in the same cancer cohort (Fig.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (46, 55))	('high', 'PosReg', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('phosphoprotein expressions', 'MPA', (80, 106))
18408	33875650	These include recurrent TP53 mutations p.R248Q/W, p.R273H/C/L, p.R175H, p.R282W/G, and p.R337C.	('p.R282W', 'Var', (72, 79))	('p.R337C', 'Mutation', 'rs587782529', (87, 94))	('TP53', 'Gene', (24, 28))	('p.R248Q', 'Var', (39, 46))	('p.R175H', 'Mutation', 'rs28934578', (63, 70))	('p.R248Q', 'SUBSTITUTION', 'None', (39, 46))	('p.R273H', 'SUBSTITUTION', 'None', (50, 57))	('p.R282W', 'SUBSTITUTION', 'None', (72, 79))	('p.R273H', 'Var', (50, 57))	('p.R337C', 'Var', (87, 94))	('p.R175H', 'Var', (63, 70))	('TP53', 'Gene', '7157', (24, 28))
18409	33875650	Top mutations in EGFR differ between brain and lung tumors: in LGG, EGFR p.R108K, p.R252C/P, and p.R263I, which are adjacent to the phospho-threonine p.T290, are associated with high EGFR protein and phosphoproteins.	('p.R108K', 'Mutation', 'rs1057519828', (73, 80))	('phosphoproteins', 'MPA', (200, 215))	('high', 'PosReg', (178, 182))	('EGFR', 'Gene', (17, 21))	('p.R263I', 'Var', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('EGFR', 'Gene', (183, 187))	('p.R263I', 'Mutation', 'p.R263I', (97, 104))	('EGFR', 'Gene', '1956', (68, 72))	('LGG', 'Gene', (63, 66))	('lung tumors', 'Disease', 'MESH:D008175', (47, 58))	('p.R252C', 'Var', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lung tumors', 'Phenotype', 'HP:0100526', (47, 58))	('EGFR', 'Gene', '1956', (17, 21))	('p.R108K', 'Var', (73, 80))	('EGFR', 'Gene', '1956', (183, 187))	('phospho-threonine p', 'Chemical', '-', (132, 151))	('lung tumors', 'Disease', (47, 58))	('p.R252C', 'SUBSTITUTION', 'None', (82, 89))	('EGFR', 'Gene', (68, 72))
18410	33875650	Many samples with top EGFR expression in GBM also carry mutations in the same hybrid cluster, p.A289V/T and p.R252C/P, whereas in LUAD the associated mutation is the recurrent EGFR p.L858R (4.3% of LUAD) co-clustering with phosphosites p.Y869 and p.Y891.	('phosphosites', 'Chemical', '-', (223, 235))	('p.R252C', 'SUBSTITUTION', 'None', (108, 115))	('p.L858R', 'Mutation', 'rs121434568', (181, 188))	('p.A289V', 'Var', (94, 101))	('p.Y869', 'Var', (236, 242))	('EGFR', 'Gene', '1956', (176, 180))	('Y869', 'Chemical', '-', (238, 242))	('p.R252C', 'Var', (108, 115))	('p.L858R', 'Var', (181, 188))	('EGFR', 'Gene', (176, 180))	('p.Y891', 'Var', (247, 253))	('p.A289V', 'SUBSTITUTION', 'None', (94, 101))	('EGFR', 'Gene', '1956', (22, 26))	('LUAD', 'Phenotype', 'HP:0030078', (198, 202))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))	('EGFR', 'Gene', (22, 26))
18411	33875650	KIT mutation p.D816V and p.829P is associated with high c-kit and it clustered with p.Y362 and p.Y823 (Fig.	('p.D816V', 'Var', (13, 20))	('Y362', 'Chemical', '-', (86, 90))	('p.D816V', 'Mutation', 'rs121913507', (13, 20))	('c-kit', 'Gene', (56, 61))	('c-kit', 'Gene', '3815', (56, 61))	('p.829P', 'Var', (25, 31))	('KIT', 'Gene', '3815', (0, 3))	('p.Y823', 'Var', (95, 101))	('KIT', 'Gene', (0, 3))	('p.Y362', 'Var', (84, 90))
18412	33875650	To further validate these findings, we conducted similar analyses of the mutational impact on protein expression using global proteomics datasets from retrospective and prospective CPTAC cohorts of breast, ovarian, and colorectal cancers (2 cohorts/cancer) each comprised of 78-126 samples ("Methods", Supplementary Data 8, Supplementary Fig.	('cancer', 'Disease', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('ovarian', 'Disease', 'MESH:D010049', (206, 213))	('colorectal cancer', 'Phenotype', 'HP:0003003', (219, 236))	('ding', 'Gene', (29, 33))	('colorectal cancers', 'Disease', (219, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancer', 'Disease', (230, 236))	('ding', 'Gene', '6045', (29, 33))	('S', 'Chemical', 'MESH:D012694', (302, 303))	('mutational', 'Var', (73, 83))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ovarian', 'Disease', (206, 213))	('colorectal cancers', 'Disease', 'MESH:D015179', (219, 237))	('S', 'Chemical', 'MESH:D012694', (324, 325))	('breast', 'Disease', (198, 204))	('protein expression', 'MPA', (94, 112))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
18413	33875650	Given the limited sample sizes, no associations passed multiple testing thresholds (FDR < 0.05) and only suggestive associations (Wilcoxon rank-sum test, P < 0.05) are highlighted herein: we validated that TP53 co-clustering mutations associated with higher protein expression in all three cancer types.	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('mutations', 'Var', (225, 234))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('protein expression', 'MPA', (258, 276))	('cancer', 'Disease', (290, 296))	('higher', 'PosReg', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
18414	33875650	In colorectal cancer, KRAS mutations in cluster 9458.0 affecting p.G12, p.G13, p.V14, and p.Q61 are associated with higher KRAS expression, whereas HNF4A mutations in cluster 7977.0 are associated with low HNF4A expression.	('HNF4A', 'Gene', '3172', (148, 153))	('higher', 'PosReg', (116, 122))	('p.V14', 'Var', (79, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('HNF4A', 'Gene', (206, 211))	('HNF4A', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('KRAS', 'Gene', (22, 26))	('p.Q61', 'Var', (90, 95))	('KRAS', 'Gene', (123, 127))	('p.G13', 'Var', (72, 77))	('KRAS', 'Gene', '3845', (22, 26))	('KRAS', 'Gene', '3845', (123, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('p.G12', 'Var', (65, 70))	('HNF4A', 'Gene', '3172', (206, 211))
18415	33875650	Other notable findings include that ESR1 mutations in cluster 1357.1 are associated with high ESR1 in ovarian cancer, whereas AKT1 mutations in cluster 756.0 (Supplementary Fig.	('ESR1', 'Gene', '2099', (94, 98))	('mutations', 'Var', (131, 140))	('S', 'Chemical', 'MESH:D012694', (95, 96))	('AKT1', 'Gene', '207', (126, 130))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('AKT1', 'Gene', (126, 130))	('ESR1', 'Gene', '2099', (36, 40))	('ding', 'Gene', '6045', (17, 21))	('S', 'Chemical', 'MESH:D012694', (159, 160))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ding', 'Gene', (17, 21))	('ovarian cancer', 'Disease', (102, 116))	('S', 'Chemical', 'MESH:D012694', (37, 38))	('ESR1', 'Gene', (94, 98))	('high', 'PosReg', (89, 93))	('ESR1', 'Gene', (36, 40))	('mutations in', 'Var', (41, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))
18416	33875650	6) are associated with high AKT1 proteins.	('AKT1', 'Gene', '207', (28, 32))	('AKT1', 'Gene', (28, 32))	('high', 'Var', (23, 27))
18417	33875650	Finally, given the potential functionality of co-clustering mutations, we characterized the mutational landscape across cancer types in the TCGA MC3 dataset of ~10 thousand tumors.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('MC3', 'Gene', '4159', (145, 148))	('MC3', 'Gene', (145, 148))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (60, 69))
18418	33875650	By considering missense mutations (1) directly overlapping phosphosites, (2) proximal to phosphosites, and (3) co-clustering with phosphosites, we noticed that considering co-clustering mutations contribute significantly to the fraction of potentially functional mutations in many cancer genes including EGFR, KRAS, and PIK3CA (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('phosphosites', 'Chemical', '-', (59, 71))	('KRAS', 'Gene', (310, 314))	('mutations', 'Var', (263, 272))	('cancer', 'Disease', (281, 287))	('phosphosites', 'Chemical', '-', (130, 142))	('PIK3CA', 'Gene', (320, 326))	('KRAS', 'Gene', '3845', (310, 314))	('EGFR', 'Gene', '1956', (304, 308))	('ding', 'Gene', '6045', (299, 303))	('S', 'Chemical', 'MESH:D012694', (328, 329))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('EGFR', 'Gene', (304, 308))	('ding', 'Gene', (299, 303))	('phosphosites', 'Chemical', '-', (89, 101))	('PIK3CA', 'Gene', '5290', (320, 326))	('S', 'Chemical', 'MESH:D012694', (313, 314))
18420	33875650	To test for activating mutations that confer clonal selection advantages, we assessed experimental data from 1054 somatic mutations in the Ba/F3 and MCF10A cells, including 549 found in genes with hybrid clusters.	('ding', 'Gene', (168, 172))	('mutations', 'Var', (122, 131))	('MCF10A', 'CellLine', 'CVCL:0598', (149, 155))	('ding', 'Gene', '6045', (168, 172))
18422	33875650	There was a striking enrichment of activation in hybrid mutations co-clustering with phosphosites.	('phosphosites', 'Chemical', '-', (85, 97))	('hybrid mutations', 'Var', (49, 65))	('activation', 'PosReg', (35, 45))
18423	33875650	For mutations functionally assessed in MCF10A, 67.6% (46/68) of the co-clustering mutations were activating compared to only 35.2% (146/415) of the other mutations being activating (P = 5.03E-7, Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (39, 45))	('mutations', 'Var', (82, 91))	('activating', 'PosReg', (97, 107))	('mutations', 'Var', (4, 13))	('MCF10A', 'Gene', (39, 45))
18426	33875650	Co-clustering mutations of PIK3CA are significantly enriched for activating events in both cell lines (One-tailed Fisher's exact test, P <= 1.22E-3), with 33/35 co-clustering mutations being validated in Ba/F3 and 21/22 in MCF10A; its binding partner PIK3R1 also shows suggestive enrichment in Ba/F3 (P = 0.072, 3/3).	('PIK3R1', 'Gene', '5295', (251, 257))	('MCF10A', 'CellLine', 'CVCL:0598', (223, 229))	('ding', 'Gene', (238, 242))	('PIK3R1', 'Gene', (251, 257))	('activating events', 'MPA', (65, 82))	('PIK3CA', 'Gene', (27, 33))	('Ba/F3', 'Disease', (294, 299))	('PIK3CA', 'Gene', '5290', (27, 33))	('mutations', 'Var', (14, 23))	('ding', 'Gene', '6045', (238, 242))
18427	33875650	Significant enrichment of activating mutations was also observed for EGFR (P = 1.63E-4, 10/11) and BRAF (P = 1.11E-3, 12/18) co-clustering mutations in Ba/F3.	('activating', 'PosReg', (26, 36))	('EGFR', 'Gene', '1956', (69, 73))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('EGFR', 'Gene', (69, 73))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('mutations', 'Var', (37, 46))	('Ba/F3', 'Gene', (152, 157))
18428	33875650	In MCF10A, we also noted suggestive associations for BRAF, where 7/18 co-clustering mutations are activating (P = 0.068), and ESR1, where 7/18 co-clustering mutations are activating (P = 0.068).	('BRAF', 'Gene', '673', (53, 57))	('ESR1', 'Gene', (126, 130))	('MCF10A', 'Gene', (3, 9))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (84, 93))	('ESR1', 'Gene', '2099', (126, 130))	('MCF10A', 'CellLine', 'CVCL:0598', (3, 9))	('activating', 'PosReg', (98, 108))
18429	33875650	The enrichment of activating mutations in hybrid clusters suggests structural adjacency to phosphosites implies functional significance in oncogenes.	('mutations', 'Var', (29, 38))	('activating', 'PosReg', (18, 28))	('phosphosites', 'Chemical', '-', (91, 103))
18432	33875650	Second, using a multivariate logistic regression model corrected for the mutated gene, we found that the recurrence of mutations in the TCGA MC3 cohort was significantly associated with the mutation functionality in both the BAF3 (P = 2.8e-3) or MCF10A (P = 0.023) cell lines.	('mutation', 'Var', (190, 198))	('MC3', 'Gene', (141, 144))	('MC3', 'Gene', '4159', (141, 144))	('MCF10A', 'CellLine', 'CVCL:0598', (246, 252))	('mutations', 'Var', (119, 128))	('associated', 'Reg', (170, 180))	('S', 'Chemical', 'MESH:D012694', (0, 1))
18435	33875650	Altogether, these results suggest that spatial co-clustering with phosphosites may improve the prediction of mutation functionality beyond the commonly used mutation recurrence.	('phosphosites', 'Chemical', '-', (66, 78))	('improve', 'PosReg', (83, 90))	('mutation functionality', 'Var', (109, 131))
18436	33875650	Next, we sought to test whether the co-clustered mutations may confer genetic dependency to the mutated cancer cells.	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
18437	33875650	In this case, cancer cells with co-clustered mutations would show higher vulnerability in a CRISPR-knockout screen targeting the mutated genes than cells with other mutations.	('cancer', 'Disease', (14, 20))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('S', 'Chemical', 'MESH:D012694', (95, 96))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
18439	33875650	Strikingly, cancer cell lines with co-clustered mutations showed significantly higher dependency (or more vulnerability upon genetic knockout) than those with missenses in 14 lineages (Wilcoxon rank-sum test, FDR < 0.05), most notably lung, colorectal, skin, pancreas, and gastric cancer cells (FDR <= 3.3E-7, Fig.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('higher', 'PosReg', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('cancer', 'Disease', (12, 18))	('dependency', 'MPA', (86, 96))	('gastric cancer', 'Disease', (273, 287))	('cancer', 'Disease', (281, 287))	('gastric cancer', 'Disease', 'MESH:D013274', (273, 287))	('skin', 'Disease', (253, 257))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (273, 287))	('lung', 'Disease', (235, 239))	('colorectal', 'Disease', (241, 251))	('mutations', 'Var', (48, 57))	('pancreas', 'Disease', (259, 267))
18441	33875650	Overall, these analyses showed that co-clustered mutations adjacent to phosphosites are enriched for activating events and highlight the genetic vulnerability of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', (162, 168))	('activating events', 'MPA', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('phosphosites', 'Chemical', '-', (71, 83))
18445	33875650	Some phosphosites may be cancer-type specific: we uniquely observed BRAF p.S467/Y472 in BRCA and p.S465 in UCEC.	('BRCA', 'Disease', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('BRAF', 'Gene', '673', (68, 72))	('p.S465', 'Var', (97, 103))	('BRAF', 'Gene', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('S', 'Chemical', 'MESH:D012694', (75, 76))	('observed', 'Reg', (59, 67))	('phosphosites', 'Chemical', '-', (5, 17))	('cancer', 'Disease', (25, 31))	('S', 'Chemical', 'MESH:D012694', (99, 100))	('UCEC', 'Disease', (107, 111))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('p.S467/Y472', 'Var', (73, 84))
18446	33875650	For TP53, we uniquely observed p.S149 in breast cancer versus TP53 p.T150 in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('TP53', 'Gene', '7157', (62, 66))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('ovarian cancer', 'Disease', 'MESH:D010051', (77, 91))	('TP53', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('TP53', 'Gene', (62, 66))	('p.S149', 'Var', (31, 37))	('ovarian cancer', 'Disease', (77, 91))	('observed', 'Reg', (22, 30))	('S', 'Chemical', 'MESH:D012694', (33, 34))	('p.T150', 'Var', (67, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('TP53', 'Gene', '7157', (4, 8))
18448	33875650	6b); for instance, AKT1 p.T308 was seen in both breast and ovarian cancers.	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (48, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('p.T308', 'Var', (24, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (59, 73))	('T308', 'Chemical', '-', (26, 30))	('seen', 'Reg', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('AKT1', 'Gene', '207', (19, 23))	('ovarian cancers', 'Phenotype', 'HP:0100615', (59, 74))	('AKT1', 'Gene', (19, 23))
18449	33875650	Notably, phosphosites (p.S29/Y30/T40/T41/T42) near the section-terminus of the CTNNB1 protein were commonly seen in breast and ovarian cancers (p.T41 was also observed in UCEC), and p.S675 was detected in substantial numbers of samples in all 5 cancers (Fig.	('ovarian cancer', 'Phenotype', 'HP:0100615', (127, 141))	('S', 'Chemical', 'MESH:D012694', (25, 26))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (135, 142))	('S', 'Chemical', 'MESH:D012694', (184, 185))	('seen', 'Reg', (108, 112))	('cancers', 'Disease', (245, 252))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('ovarian cancers', 'Phenotype', 'HP:0100615', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('p.S29/Y30/T40/T41/T42', 'Var', (23, 44))	('CTNNB1 p', 'Gene', '1499', (79, 87))	('phosphosites', 'Chemical', '-', (9, 21))	('CTNNB1 p', 'Gene', (79, 87))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
18454	33875650	These include AKT1 p.T308 and CTNNB1 p.T41 found in CPTAC patient tumors, as well as sites with known kinase regulations, including EGFR p.S768/Y869/Y1016, ESR1 p.Y537, and TP53 p.S376/378.	('AKT1', 'Gene', '207', (14, 18))	('ESR1', 'Gene', '2099', (156, 160))	('ding', 'Gene', '6045', (127, 131))	('S', 'Chemical', 'MESH:D012694', (139, 140))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('ESR1', 'Gene', (156, 160))	('TP53', 'Gene', (173, 177))	('EGFR', 'Gene', '1956', (132, 136))	('p.T308', 'Var', (19, 25))	('AKT1', 'Gene', (14, 18))	('p.S768/Y869/Y1016', 'Var', (137, 154))	('Y869', 'Chemical', '-', (144, 148))	('CTNNB1 p', 'Gene', '1499', (30, 38))	('CPTAC', 'Disease', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CTNNB1 p', 'Gene', (30, 38))	('TP53', 'Gene', '7157', (173, 177))	('S', 'Chemical', 'MESH:D012694', (157, 158))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('p.Y537', 'Var', (161, 167))	('S', 'Chemical', 'MESH:D012694', (180, 181))	('patient', 'Species', '9606', (58, 65))	('p.S376/378', 'Var', (178, 188))	('tumors', 'Disease', (66, 72))	('EGFR', 'Gene', (132, 136))	('ding', 'Gene', (127, 131))	('T308', 'Chemical', '-', (21, 25))
18455	33875650	Other co-clustering phosphosites showing functionality related to cancer include: MAPK1 p.S142 that was previously shown to be critical to the ERK2 docking domain and its mutated form p.S142L confers gain-of-function; CTCF p.T374 that, along with a few nearby residues, were shown to be phosphorylated during mitosis and to decrease its DNA-binding activity; BRAF p.T599 and p.S602 that are conserved from C. elegans to mammals and required for activation of the B-Raf kinase, and RB1 (Rb) p.S567 that is uniquely phosphorylated by MAPK11 (p38), triggering Rb-Hdm2 interaction and apoptosis.	('ding', 'Gene', '6045', (344, 348))	('BRAF', 'Gene', (359, 363))	('S', 'Chemical', 'MESH:D012694', (186, 187))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('T599', 'Chemical', '-', (366, 370))	('triggering', 'Reg', (546, 556))	('B-Raf', 'Gene', (463, 468))	('C. elegans', 'Species', '6239', (406, 416))	('CTCF', 'Gene', (218, 222))	('decrease', 'NegReg', (324, 332))	('MAPK1', 'Gene', (82, 87))	('p38', 'Gene', '5594', (540, 543))	('S', 'Chemical', 'MESH:D012694', (377, 378))	('RB1 (Rb', 'Gene', (481, 488))	('mitosis', 'Disease', 'None', (309, 316))	('S', 'Chemical', 'MESH:D012694', (90, 91))	('p.S602', 'Var', (375, 381))	('ERK2', 'Gene', '5594', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('MAPK1', 'Gene', '5594', (532, 537))	('phosphosites', 'Chemical', '-', (20, 32))	('S', 'Chemical', 'MESH:D012694', (492, 493))	('Hdm2', 'Gene', (560, 564))	('ERK2', 'Gene', (143, 147))	('B-Raf', 'Gene', '673', (463, 468))	('p.T599', 'Var', (364, 370))	('apoptosis', 'CPA', (581, 590))	('CTCF', 'Gene', '10664', (218, 222))	('ding', 'Gene', (344, 348))	('p.S567', 'Var', (490, 496))	('p38', 'Gene', (540, 543))	('MAPK1', 'Gene', (532, 537))	('MAPK1', 'Gene', '5594', (82, 87))	('interaction', 'Interaction', (565, 576))	('p.S142L', 'Mutation', 'p.S142L', (184, 191))	('Hdm2', 'Gene', '4193', (560, 564))	('BRAF', 'Gene', '673', (359, 363))	('cancer', 'Disease', (66, 72))	('mitosis', 'Disease', (309, 316))
18458	33875650	HotPho successfully identifies likely functional mutational clusters and phosphosites in known cancer proteins, including EGFR, KIT, and KRAS/HRAS/NRAS, many of which are in kinase domains (Fig.	('EGFR', 'Gene', '1956', (122, 126))	('HRAS', 'Gene', '3265', (142, 146))	('mutational', 'Var', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('KIT', 'Gene', (128, 131))	('cancer', 'Disease', (95, 101))	('phosphosites', 'Chemical', '-', (73, 85))	('HRAS', 'Gene', (142, 146))	('NRAS', 'Gene', (147, 151))	('KRAS', 'Gene', (137, 141))	('ding', 'Gene', '6045', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('KRAS', 'Gene', '3845', (137, 141))	('NRAS', 'Gene', '4893', (147, 151))	('EGFR', 'Gene', (122, 126))	('ding', 'Gene', (117, 121))	('KIT', 'Gene', '3815', (128, 131))
18460	33875650	Concurrently, co-clustering phosphosites show multiple characteristics supporting their contributions in oncogenesis, including co-clustering with validated activating and recurrent mutations in multiple cancer types (Fig.	('phosphosites', 'Chemical', '-', (28, 40))	('ding', 'Gene', '6045', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('multiple cancer', 'Disease', (195, 210))	('ding', 'Gene', (123, 127))	('mutations', 'Var', (182, 191))	('multiple cancer', 'Disease', 'MESH:D009369', (195, 210))
18466	33875650	For example, we found that these phosphosites and mutations are enriched in functional domains of kinases and histones, that co-clustering mutations tend to be functionally active and confer genetic dependency.	('mutations', 'Var', (139, 148))	('functionally', 'MPA', (160, 172))	('phosphosites', 'Chemical', '-', (33, 45))	('mutations', 'Var', (50, 59))
18469	33875650	More, multiple co-clustering phosphosites were located in activation loops of kinase proteins, including RET p.S904, MET p.Y1248, AKT1 p.T308, EGFR p.Y827/869, as well as the MAPK3-regulated site MAPK8 p.Y185.	('Y1248', 'Chemical', '-', (123, 128))	('p.Y185', 'Var', (202, 208))	('MET', 'Gene', '79811', (117, 120))	('p.Y827/869', 'Var', (148, 158))	('activation', 'PosReg', (58, 68))	('p.S904', 'Var', (109, 115))	('ding', 'Gene', (100, 104))	('RET', 'Gene', (105, 108))	('MAPK8', 'Gene', (196, 201))	('T308', 'Chemical', '-', (137, 141))	('ding', 'Gene', '6045', (100, 104))	('phosphosites', 'Chemical', '-', (29, 41))	('p.T308', 'Var', (135, 141))	('AKT1', 'Gene', '207', (130, 134))	('EGFR', 'Gene', (143, 147))	('S', 'Chemical', 'MESH:D012694', (111, 112))	('MAPK3', 'Gene', (175, 180))	('MET', 'Gene', (117, 120))	('MAPK3', 'Gene', '5595', (175, 180))	('MAPK8', 'Gene', '5599', (196, 201))	('AKT1', 'Gene', (130, 134))	('Y185', 'Chemical', '-', (204, 208))	('RET', 'Gene', '5979', (105, 108))	('EGFR', 'Gene', '1956', (143, 147))
18470	33875650	Crystal structures revealed that PTPN12 p.S275 is found in the Q loop that constitutes the pY+1 pocket demonstrating strong substrate specificity, and the phospho-inhibitory mutant p.S275A significantly decreased the activity of PTPN12 toward all three HER2 phospho-peptides.	('PTPN12', 'Gene', '5782', (33, 39))	('phospho-peptides', 'Chemical', 'MESH:D010748', (258, 274))	('S', 'Chemical', 'MESH:D012694', (42, 43))	('activity', 'MPA', (217, 225))	('decreased', 'NegReg', (203, 212))	('p.S275A', 'Mutation', 'p.S275A', (181, 188))	('p.S275A', 'Var', (181, 188))	('PTPN12', 'Gene', '5782', (229, 235))	('HER2', 'Gene', (253, 257))	('S', 'Chemical', 'MESH:D012694', (183, 184))	('PTPN12', 'Gene', (33, 39))	('HER2', 'Gene', '2064', (253, 257))	('PTPN12', 'Gene', (229, 235))	('p.S275', 'Var', (40, 46))
18471	33875650	Notably, this site also harbored a rare mutation p.S275C in the TCGA MC3 mutation data, which only showed clusters when leveraging the adjacent phosphosite information but was not found in the mutation-only clusters.	('phosphosite', 'Chemical', '-', (144, 155))	('MC3', 'Gene', (69, 72))	('MC3', 'Gene', '4159', (69, 72))	('p.S275C', 'Var', (49, 56))	('p.S275C', 'Mutation', 'p.S275C', (49, 56))
18473	33875650	Currently, we only observed a handful of examples where a single tumor sample carries both of the co-clustering phosphosites and mutations in existing quantitative phosphoproteomics cohorts, precluding systematic investigations of their correlative relationships (Supplementary Fig.	('ding', 'Gene', '6045', (197, 201))	('S', 'Chemical', 'MESH:D012694', (264, 265))	('tumor', 'Disease', (65, 70))	('mutations', 'Var', (129, 138))	('ding', 'Gene', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('phosphosites', 'Chemical', '-', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
18474	33875650	The growing cohort size of CPTAC and other cancer global phosphoproteomic datasets will likely enable us to test the intriguing hypothesis that samples carrying mutations will show disrupted regulation or mutual exclusivity of a co-clustering phosphosite with sufficient statistical power.	('mutual exclusivity', 'MPA', (205, 223))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('regulation', 'MPA', (191, 201))	('disrupted', 'NegReg', (181, 190))	('mutations', 'Var', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('phosphosite', 'Chemical', '-', (243, 254))
18483	33875650	We curated experimentally validated mutations identified as neutral or activating from multiple databases and papers, including the Cancer Biomarkers database within the Cancer Genome Interpreter, OncoKB, KinDriver, and ClinVar.	('Cancer', 'Disease', 'MESH:D009369', (170, 176))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ding', 'Gene', '6045', (123, 127))	('mutations', 'Var', (36, 45))	('ding', 'Gene', (123, 127))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Disease', (132, 138))	('activating', 'PosReg', (71, 81))	('Cancer', 'Disease', (170, 176))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))
18489	33875650	In the resulting pairwise files with phosphosites (.musite and.sites files), we, therefore, filtered out the sites where the mapped residue on the PDB structure differs from those documented in our original input phosphosite file, ultimately retaining 785,867 mutation-mutation pairs, 376,614 mutation-site pairs (78,477 eliminated), and 1,010,011 site-site pairs (267,547 eliminated).	('PDB', 'Gene', (147, 150))	('PDB', 'Gene', '5131', (147, 150))	('phosphosites', 'Chemical', '-', (37, 49))	('phosphosite', 'Chemical', '-', (37, 48))	('phosphosite', 'Chemical', '-', (213, 224))	('mutation-mutation', 'Var', (260, 277))
18491	33875650	Briefly, 3D distances of all missense mutations and phosphosites were calculated using PDB structures, considering the closest atoms on their respective amino acids on PDB structures, to identify proximity pairs.	('PDB', 'Gene', '5131', (168, 171))	('phosphosites', 'Chemical', '-', (52, 64))	('PDB', 'Gene', (87, 90))	('PDB', 'Gene', '5131', (87, 90))	('missense mutations', 'Var', (29, 47))	('PDB', 'Gene', (168, 171))
18497	33875650	The hybrid clusters generated by HotPho was benchmarked by comparison to those obtained through HotPho analyses using a combination of the TCGA MC3 mutation data and permutated phosphosite data.	('MC3', 'Gene', '4159', (144, 147))	('mutation', 'Var', (148, 156))	('phosphosite', 'Chemical', '-', (177, 188))	('MC3', 'Gene', (144, 147))
18501	33875650	HotPho clustering was performed for 100 such simulated phosphosites-datasets and the maintained TCGA MC3 mutation call backbone given the non-random distribution and occurrence count of mutation calls.	('MC3', 'Gene', '4159', (101, 104))	('mutation', 'Var', (105, 113))	('phosphosites', 'Chemical', '-', (55, 67))	('MC3', 'Gene', (101, 104))
18508	33875650	The protein/phosphoprotein expression percentile of individual proteins in each cancer cohort was calculated using the empirical cumulative distribution function (ecdf), as implemented in R. Where there are at least 3 carriers within each cancer type, we then applied the linear model to evaluate the protein/phosphoprotein expression percentile between carriers of co-clustered mutations and all other cancer cases.	('cancer', 'Disease', (403, 409))	('mutations', 'Var', (379, 388))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (403, 409))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (403, 409))	('cancer', 'Disease', (80, 86))
18519	33875650	K.H., D.C.Z., L.W., A.E., R.L., Y.W., J.B., S.S., A.D.S., and A.W.	('J.B.', 'Var', (38, 42))	('A.D.S.', 'Var', (50, 56))	('R.L.', 'Var', (26, 30))	('S.S.', 'Var', (44, 48))	('S', 'Chemical', 'MESH:D012694', (46, 47))	('S', 'Chemical', 'MESH:D012694', (54, 55))	('S', 'Chemical', 'MESH:D012694', (44, 45))
18520	33875650	L.D., K.C., M.C.W., K.R., S.H.P., B.R., D.F., and G.M.	('K.R.', 'Var', (20, 24))	('D.F.', 'Var', (40, 44))	('S', 'Chemical', 'MESH:D012694', (26, 27))	('M.C.W.', 'Var', (12, 18))	('B.R.', 'Var', (34, 38))
18532	33311458	Patterns for TP53 mutations can also be detected, with WSI self- and cross-tissue AUCs ranging from 0.65-0.80.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
18544	33311458	trained ResNet-50 CNNs to predict SPOP mutations using WSIs from 177 prostate cancer patients, achieving AUC = 0.74 in cross-validation and AUC = 0.64 on an independent set.	('SPOP', 'Gene', '8405', (34, 38))	('SPOP', 'Gene', (34, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Disease', (69, 84))
18547	33311458	Further, their models were able to predict mutations in ten genes in LUAD with AUCs 0.64-0.86, and subsequently mutations in BRAF (AUC ~0.75) or NRAS (AUC ~0.77) melanomas.	('NRAS', 'Gene', (145, 149))	('LUAD', 'Phenotype', 'HP:0030078', (69, 73))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('LUAD', 'Disease', (69, 73))	('mutations', 'Var', (112, 121))	('NRAS', 'Gene', '4893', (145, 149))	('mutations', 'Var', (43, 52))	('BRAF', 'Gene', '673', (125, 129))	('melanomas', 'Disease', (162, 171))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('BRAF', 'Gene', (125, 129))	('predict', 'Reg', (35, 42))
18626	33311458	To investigate how images can be used to distinguish cancer drivers, we tested the accuracy of CNNs for classifying TP53 mutation status in five TCGA cancer types, namely BRCA, LUAD, STAD, COAD, and BLCA.	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('COAD', 'Disease', 'MESH:D029424', (189, 193))	('BRCA', 'Gene', '672', (171, 175))	('TP53', 'Gene', (116, 120))	('BLCA', 'Chemical', '-', (199, 203))	('STAD', 'Disease', (183, 187))	('cancer', 'Disease', (150, 156))	('mutation', 'Var', (121, 129))	('LUAD', 'Disease', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('BRCA', 'Gene', (171, 175))	('cancer', 'Disease', (53, 59))	('COAD', 'Disease', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TP53', 'Gene', '7157', (116, 120))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('BLCA', 'Disease', (199, 203))	('tested', 'Reg', (72, 78))
18630	33311458	The CNNs achieved a higher AUC compared with a random forest using tumor purity and stage for TP53 mutation prediction (see Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutation', 'Var', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('AUC', 'MPA', (27, 30))
18631	33311458	We also observed that CNNs were able to more accurately identify tumors with TP53 mutations when the allele frequency of the mutation was higher, suggesting that prediction is easier when the tumor is more homogeneous (Supplementary Fig.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', (65, 71))	('mutations', 'Var', (82, 91))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
18635	33311458	Figure 8 shows TP53 mutational heatmaps of one LUAD slide known to be mutant and one LUAD slide known to be wild type from the sequencing data.	('mutant', 'Var', (70, 76))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('mutational', 'Var', (20, 30))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))
18639	33311458	Analogously, the BRCA-trained TP53 mutation status model predicts patterns similar to the LUAD-trained model.	('BRCA', 'Gene', (17, 21))	('TP53', 'Gene', (30, 34))	('predicts', 'Reg', (57, 65))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('patterns', 'MPA', (66, 74))	('mutation', 'Var', (35, 43))	('BRCA', 'Gene', '672', (17, 21))	('TP53', 'Gene', '7157', (30, 34))
18658	33311458	Using this framework, we were able to train extremely accurate slide-based tumor/normal classifiers in nearly all cancer types, and we also were able to classify subtypes and TP53 mutation status with significant though less extreme accuracy.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('TP53', 'Gene', (175, 179))	('mutation status', 'Var', (180, 195))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('TP53', 'Gene', '7157', (175, 179))	('tumor', 'Disease', (75, 80))	('cancer', 'Disease', (114, 120))
18674	33311458	For example, for the TP53 mutation studies we had enough data to identify significant cross-correlations and spatial structures within images, but such analysis will be more challenging for rarer drivers.	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', '7157', (21, 25))	('mutation', 'Var', (26, 34))
18675	33311458	While we have observed that transfer-learning networks excel at tumor/normal classification, they have lower accuracy for cancer subtype and TP53 mutation status predictions.	('tumor', 'Disease', (64, 69))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutation status', 'Var', (146, 161))	('TP53', 'Gene', (141, 145))	('lower', 'NegReg', (103, 108))	('TP53', 'Gene', '7157', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
18676	33311458	reported that TP53 mutation status is associated with the pixel intensity distribution in the cytoplasm and specific texture features within tumor nuclei, and it is possible that such textures are not in ImageNet while tumor/normal classification may be more related to cell shape and size, which are simpler variables more likely to have analogs within ImageNet.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('associated', 'Reg', (38, 48))	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', (141, 146))	('pixel intensity distribution', 'MPA', (58, 86))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
18709	33311458	Impactful TP53 mutations were determined using masked somatic mutations maf files called by MuTect2.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', '7157', (10, 14))
18711	33311458	Table 1 shows the number of wild-type and mutated slides in each cancer type.	('cancer', 'Disease', (65, 71))	('mutated', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
18712	33311458	We utilized the Inception v3 architecture to predict TP53-associated mutations in BRCA, LUAD, and STAD sets.	('mutations', 'Var', (69, 78))	('BRCA', 'Gene', (82, 86))	('TP53', 'Gene', '7157', (53, 57))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('BRCA', 'Gene', '672', (82, 86))	('TP53', 'Gene', (53, 57))
18716	33311458	To predict mutations in the TP53 gene, we trained two-way classifiers, assigning 70% of the images in each tissue to training and the remaining 30% to the test set.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', (28, 32))	('TP53', 'Gene', '7157', (28, 32))
18773	32977421	A total of 7 preoperative variables were associated with increased odds of LMS, including postmenopausal status (p < 0.001, OR 3.08), symptoms of pressure (p = 0.002, OR 2.7), postmenopausal bleeding (p = 0.001, OR 5.01), neutrophil count >=7.5 x 109/L (p < 0.001, OR 5.72), haemoglobin level <118 g/L (p = 0.037, OR 2.22), endometrial biopsy results of cellular atypia or neoplasia (p = 0.001, OR 9.6), and a mass size of >=10 cm on radiological imaging (p < 0.0001, OR 8.52).	('bleeding', 'Disease', 'MESH:D006470', (191, 199))	('neoplasia', 'Phenotype', 'HP:0002664', (373, 382))	('bleeding', 'Disease', (191, 199))	('postmenopausal status', 'Disease', (90, 111))	('atypia or neoplasia', 'Disease', (363, 382))	('postmenopausal status', 'Phenotype', 'HP:0008209', (90, 111))	('LMS', 'Disease', (75, 78))	('LMS', 'Phenotype', 'HP:0100243', (75, 78))	('atypia or neoplasia', 'Disease', 'MESH:D009369', (363, 382))	('>=7.5', 'Var', (239, 244))	('menopausal status', 'Phenotype', 'HP:0008209', (94, 111))
18817	32977421	Our data demonstrated that low Hb and neutrophilia are significantly associated with LMS.	('neutrophilia', 'Phenotype', 'HP:0011897', (38, 50))	('neutrophilia', 'Disease', (38, 50))	('associated', 'Reg', (69, 79))	('low', 'Var', (27, 30))	('LMS', 'Disease', (85, 88))	('neutrophilia', 'Disease', 'MESH:C563010', (38, 50))	('LMS', 'Phenotype', 'HP:0100243', (85, 88))
18827	32977421	Although there are studies reporting low sensitivity in detecting LMS in endometrial biopsy, our data suggest that our finding of atypical cells or neoplasia (without a known origin) on endometrial biopsy is significantly associated with LMS and likely to have some clinical value in preoperative diagnosis.	('neoplasia', 'Disease', (148, 157))	('LMS', 'Disease', (238, 241))	('associated with', 'Reg', (222, 237))	('LMS', 'Phenotype', 'HP:0100243', (66, 69))	('LMS', 'Phenotype', 'HP:0100243', (238, 241))	('neoplasia', 'Disease', 'MESH:D009369', (148, 157))	('neoplasia', 'Phenotype', 'HP:0002664', (148, 157))	('atypical', 'Var', (130, 138))
18970	32911724	Univariate analysis revealed that DFS was significantly influenced by advanced stage (III/IV) of sarcoma, subtype of leiomyosarcoma, high mitotic index, preoperative high NLR, and preoperative high PLR.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (117, 131))	('sarcoma', 'Disease', (124, 131))	('high PLR', 'Var', (193, 201))	('high', 'Var', (133, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('DFS', 'MPA', (34, 37))	('sarcoma', 'Disease', (97, 104))	('leiomyosarcoma', 'Disease', (117, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (117, 131))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('high', 'Var', (166, 170))	('influenced', 'Reg', (56, 66))
18971	32911724	Univariate analysis revealed that advanced stage (III/IV), subtype of leiomyosarcoma, high mitotic index, nuclear atypia, and preoperative high NLR were significant factors associated with OS.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (70, 84))	('leiomyosarcoma', 'Disease', (70, 84))	('associated', 'Reg', (173, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('nuclear atypia', 'CPA', (106, 120))	('high', 'Var', (86, 90))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (70, 84))
18980	32911724	Patients with old age, advanced stage, high tumor grade, and high mitotic index have been found to have worse prognosis.	('high', 'Var', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
18992	32911724	In the area of gynecological cancer, several studies have reported that high NLR is associated with OS and DFS in patients with ovarian, endometrial, or cervical cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (29, 35))	('NLR', 'Gene', (77, 80))	('cancer', 'Disease', (162, 168))	('ovarian', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('ovarian', 'Disease', 'MESH:D010049', (128, 135))	('endometrial', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('associated', 'Reg', (84, 94))	('DFS', 'Disease', (107, 110))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('high', 'Var', (72, 76))
19006	32911724	Our data also showed that high NLR was significantly associated with worse DFS and worse OS of not only advanced stage patients, but also patients with stage I uterine sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (160, 175))	('high', 'Var', (26, 30))	('patients', 'Species', '9606', (119, 127))	('NLR', 'Gene', (31, 34))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('patients', 'Species', '9606', (138, 146))	('sarcoma', 'Disease', (168, 175))	('DFS', 'MPA', (75, 78))
19011	32911724	Our findings suggested that patients in the early stage with high NLR ratio should be considered as having a high risk of poor prognosis.	('patients', 'Species', '9606', (28, 36))	('high', 'Var', (61, 65))	('NLR', 'MPA', (66, 69))
19043	32258332	The final pathological staging was pT1bN1 (FIGO IIIC1) high grade papillary serous adenocarcinoma.	('papillary serous adenocarcinoma', 'Disease', (66, 97))	('papillary serous adenocarcinoma', 'Disease', 'MESH:D000231', (66, 97))	('pT1bN1', 'Var', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))
19047	32258332	This represents intratumoral heterogeneity and emphasizes that the testing when done on a sample with largest volume of tumor, preferably where invasive tumor, tumor emboli or tumor with diverse morphology are present, may increase the likelihood of identifying the Her2/neu amplified clone.	('increase', 'PosReg', (223, 231))	('tumor', 'Disease', (21, 26))	('amplified clone', 'Var', (275, 290))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (153, 158))	('invasive tumor', 'Disease', (144, 158))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Her2/neu', 'Gene', (266, 274))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (160, 165))	('invasive tumor', 'Disease', 'MESH:D009369', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Her2/neu', 'Gene', '2064', (266, 274))
19075	32258332	The testing for Her2/neu amplification by immunohistochemistry is guided by strict guidelines in breast carcinoma.	('Her2/neu', 'Gene', '2064', (16, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('breast carcinoma', 'Phenotype', 'HP:0003002', (97, 113))	('breast carcinoma', 'Disease', (97, 113))	('Her2/neu', 'Gene', (16, 24))	('breast carcinoma', 'Disease', 'MESH:D001943', (97, 113))	('amplification', 'Var', (25, 38))
19092	32258332	As it is deemed predictable that more and more tumors will be tested for Her2/neu amplification, it becomes necessary to come up with a guideline.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('Her2/neu', 'Gene', (73, 81))	('amplification', 'Var', (82, 95))	('Her2/neu', 'Gene', '2064', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
19118	31055453	A number of factors have been suggested as contributing to poorer outcomes among black women, including reduced access to care, lower clinical trial participation, and higher rates of genetic mutations that promote metastatic phenotypes.	('promote', 'PosReg', (207, 214))	('genetic mutations', 'Var', (184, 201))	('reduced', 'NegReg', (104, 111))	('metastatic', 'CPA', (215, 225))	('higher', 'PosReg', (168, 174))	('lower', 'NegReg', (128, 133))	('women', 'Species', '9606', (87, 92))
19148	31055453	In the multivariable model, radiation (HR 0.51 (95% CI 0.27 to 0.95), P=0.04), advanced stage (HR 3.61 (2.11-6.19), P<0.001), and high grade histology (HR 2.34 (1.17-4.70), P=0.02) all remained independent predictors of better overall survival, while Caribbean nativity trended towards reduced risk of death (HR 0.65 (0.40-1.07)).	('better', 'PosReg', (220, 226))	('death', 'Disease', (302, 307))	('death', 'Disease', 'MESH:D003643', (302, 307))	('high grade', 'Var', (130, 140))
19170	31055453	Recent studies have shown that Caribbean women have high rates of inherited mutations in breast cancer genes, which can reach up to 25% of breast cancer patients in some Caribbean islands.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('inherited mutations', 'Var', (66, 85))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('women', 'Species', '9606', (41, 46))
19171	31055453	Additionally, given the recent association between BRCA1 mutations and an increased observation of uterine serous carcinoma, genetic predisposition, or potentially epigenetic modification, may also be driving pathogenesis.	('serous carcinoma', 'Disease', 'MESH:D018297', (107, 123))	('serous carcinoma', 'Disease', (107, 123))	('BRCA1', 'Gene', '672', (51, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('BRCA1', 'Gene', (51, 56))	('mutations', 'Var', (57, 66))
19184	31055453	Given that patients with low grade endometrial cancer have an overall excellent prognosis, as seen in the current study when median survival was not reached for either nativity group, failing to consider the influence of grade limits the interpretation of the data.	('endometrial cancer', 'Disease', (35, 53))	('low grade', 'Var', (25, 34))	('endometrial cancer', 'Phenotype', 'HP:0012114', (35, 53))	('endometrial cancer', 'Disease', 'MESH:D016889', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (11, 19))
19191	31055453	Finally, black women with endometrial cancer are known to have unique mutations in the TP53 gene, leading to increased somatic copy number variations, as well as chromosomal amplifications, such as chr1q, which are associated with higher rates of recurrence and metastatic phenotypes.	('endometrial cancer', 'Disease', 'MESH:D016889', (26, 44))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (87, 91))	('women', 'Species', '9606', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('TP53', 'Gene', (87, 91))	('endometrial cancer', 'Disease', (26, 44))	('increased', 'PosReg', (109, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (26, 44))
19217	31942159	A 55-year-old female, P3003, presented with postmenopausal spotting on and off for the past 6 months, cough with expectoration, and significant weight loss for past 2 months.	('spotting', 'Disease', (59, 67))	('weight loss', 'Disease', (144, 155))	('weight loss', 'Phenotype', 'HP:0001824', (144, 155))	('cough', 'Phenotype', 'HP:0012735', (102, 107))	('cough', 'Disease', (102, 107))	('weight loss', 'Disease', 'MESH:D015431', (144, 155))	('P3003', 'Var', (22, 27))
19249	31942159	Women with low-grade ESS usually present with leiomyoma-like symptoms such as abnormal uterine bleeding, abdominal or pelvic pain or pressure symptoms due to enlarging abdomen, abnormal or foul-smelling vaginal discharge, or postmenopausal bleeding.	('abnormal uterine bleeding', 'Disease', 'MESH:D014592', (78, 103))	('Women', 'Species', '9606', (0, 5))	('pain', 'Phenotype', 'HP:0012531', (125, 129))	('enlarging', 'PosReg', (158, 167))	('abdomen', 'Disease', (168, 175))	('low-grade', 'Var', (11, 20))	('abnormal uterine bleeding', 'Disease', (78, 103))	('postmenopausal bleeding', 'Disease', (225, 248))	('ESS', 'Disease', 'MESH:D018203', (21, 24))	('abnormal uterine', 'Phenotype', 'HP:0000130', (78, 94))	('leiomyoma', 'Disease', (46, 55))	('leiomyoma', 'Disease', 'MESH:D007889', (46, 55))	('ESS', 'Disease', (21, 24))	('pelvic pain', 'Disease', 'MESH:D017699', (118, 129))	('pressure symptoms', 'Disease', (133, 150))	('abnormal uterine bleeding', 'Phenotype', 'HP:0100608', (78, 103))	('postmenopausal bleeding', 'Disease', 'MESH:D015663', (225, 248))	('pelvic pain', 'Disease', (118, 129))
19381	31511074	They are characterised by germline mutations of genes that lead to the early onset of distinctive tumour subtypes in specific organs.	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (35, 44))
19402	31511074	In the American NLST trial, annual low-dose chest CT in long-term smokers reduced lung cancer mortality by 20% compared to annual chest radiography.	('low-dose', 'Var', (35, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('reduced', 'NegReg', (74, 81))
19588	31511074	These tumours also show amplification of MDM2 and CDK4 positivity on FISH testing, whereas lipomas do not.	('lipomas', 'Disease', (91, 98))	('CDK4', 'Gene', (50, 54))	('lipomas', 'Disease', 'MESH:D008067', (91, 98))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('positivity', 'Var', (55, 65))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('MDM', 'Disease', (41, 44))	('lipomas', 'Phenotype', 'HP:0012032', (91, 98))	('amplification', 'Var', (24, 37))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('lipomas', 'Phenotype', 'HP:0001012', (91, 98))	('MDM', 'Disease', 'MESH:D007645', (41, 44))	('lipoma', 'Phenotype', 'HP:0012032', (91, 97))	('tumours', 'Disease', (6, 13))
19640	31511074	Advance DWI and PWI may further improve accuracy of MRI in discriminating various subtype of kidney cancers and has shown potential in discriminating chromophobe RCC from other subtypes.	('chromophobe RCC', 'Disease', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('kidney cancer', 'Phenotype', 'HP:0009726', (93, 106))	('PWI', 'Var', (16, 19))	('kidney cancers', 'Phenotype', 'HP:0009726', (93, 107))	('kidney cancers', 'Disease', 'MESH:D007680', (93, 107))	('chromophobe RCC', 'Disease', 'MESH:D002292', (150, 165))	('kidney cancers', 'Disease', (93, 107))	('improve', 'PosReg', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))
19706	31511074	More than 66% of the responders indicated that the benefits of AI and machine learning are much bigger or slightly bigger than the risks for cancer imaging.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('machine learning', 'Var', (70, 86))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
19955	31511074	2000;20(6):1585-603 High-quality evidence shows that MRI in biopsy-naive men can reduce the number of men who need prostate biopsy and can reduce the number of diagnoses of clinically insignificant cancers that are unlikely to cause harm.	('men', 'Species', '9606', (73, 76))	('reduce', 'NegReg', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('reduce', 'NegReg', (139, 145))	('men', 'Species', '9606', (102, 105))	('MRI', 'Var', (53, 56))
19979	31511074	The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT.	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))	('MDP', 'Chemical', 'MESH:D000119', (83, 86))	('patients', 'Species', '9606', (36, 44))	('prostate cancer', 'Disease', (60, 75))	('bone metastases', 'Disease', (17, 32))	('18F-fluoride', 'Chemical', '-', (152, 164))	('bone metastases', 'Disease', 'MESH:D009362', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('18F-fluoride PET/CT', 'Var', (174, 193))	('18F-fluoride', 'Chemical', '-', (174, 186))	('Tc', 'Chemical', 'MESH:D013667', (80, 82))
20055	31511074	131I-MIBG--a new agent in diagnosis and treatment of pheochromocytoma.	('men', 'Species', '9606', (45, 48))	('131I-MIBG--', 'Var', (0, 11))	('pheochromocytoma', 'Disease', (53, 69))	('pheochromocytoma', 'Disease', 'MESH:D010673', (53, 69))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('131I-MIBG', 'Chemical', '-', (0, 9))
20083	31511074	For both metastatic and myeloma bone disease, deficiencies in the ability of serum biomarkers to reflect disease status particularly in later stages of the disease strengthens the need for quantitative whole body imaging.	('myeloma bone disease', 'Disease', 'MESH:D009101', (24, 44))	('deficiencies', 'Var', (46, 58))	('myeloma bone disease', 'Disease', (24, 44))	('metastatic', 'Disease', (9, 19))
20192	31511074	Probing molecular changes will aid not only cancer diagnosis, but also provide tumour grading, based on gene-expression analysis and imaging measurements of cell proliferation and changes in metabolism; staging, based on imaging of metastatic spread and elevation of protein biomarkers; and the detection of therapeutic response, using serial molecular imaging measurements or monitoring of serum markers.	('changes', 'Var', (18, 25))	('changes', 'Reg', (180, 187))	('men', 'Species', '9606', (368, 371))	('cell proliferation', 'CPA', (157, 175))	('metastatic spread', 'CPA', (232, 249))	('cancer', 'Disease', (44, 50))	('men', 'Species', '9606', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('metabolism', 'MPA', (191, 201))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('protein biomarkers', 'MPA', (267, 285))	('tumour', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
20345	31511074	Methods: Retrospective analysis of 388 prostate cancer patients enrolled in five prospective studies (NCT02940262, NCT03368547, NCT03042312, UCLA IRB#17-001336, NCT03515577).	('NCT02940262', 'Var', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('prostate cancer', 'Disease', (39, 54))	('NCT03368547', 'Var', (115, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (39, 54))	('patients', 'Species', '9606', (55, 63))	('NCT03042312', 'Var', (128, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))
20412	31511074	In this study, we aim to study the value of b800/b0 in addition to ADC values.	('AD', 'Disease', 'MESH:D000544', (67, 69))	('AD', 'Disease', (67, 69))	('b800/b0', 'Var', (44, 51))
20418	31511074	Conclusion The b800/b0 ratio in diffusion weighted imaging could help to differentiate benign from malignant gallbladder lesions, and it may be more reliable than the ADC values in the quantitative assessment of the DWI.	('AD', 'Disease', 'MESH:D000544', (167, 169))	('benign', 'Disease', (87, 93))	('gallbladder lesions', 'Disease', (109, 128))	('AD', 'Disease', (167, 169))	('b800/b0', 'Var', (15, 22))	('men', 'Species', '9606', (204, 207))	('gallbladder lesions', 'Disease', 'MESH:D005705', (109, 128))
20540	31511074	More recently, F18 FDG-PET/CT, imaging which has various oncological applications, has been recommended as an important complementary tool in the detection of bone metastases and evaluation of therapy response.	('men', 'Species', '9606', (126, 129))	('men', 'Species', '9606', (97, 100))	('bone metastases', 'Disease', 'MESH:D009362', (159, 174))	('bone metastases', 'Disease', (159, 174))	('FDG', 'Chemical', 'MESH:D019788', (19, 22))	('F18', 'Var', (15, 18))
20565	31511074	While diagnostic certainty was comparable, ratings for lesion conspicuity were significantly higher for the combination of CI/IO (4(3-5)) compared to CI only (3(3-4);p<0.05).	('higher', 'PosReg', (93, 99))	('CI/IO', 'Var', (123, 128))	('IO', 'Chemical', '-', (126, 128))
20574	31511074	Iodine entropy only slightly improved sensitivity with comparable diagnostic accuracy.	('Iodine', 'Chemical', 'MESH:D007455', (0, 6))	('sensitivity', 'MPA', (38, 49))	('improved', 'PosReg', (29, 37))	('Iodine', 'Var', (0, 6))
20615	31511074	The study was performed in 404 patients with NPC who had undergone MR imaging with a standard protocol which included T1W, T2W- fat-suppressed (FS), contrast-enhanced-T1W (CE-T1W) and CE-T1W-FS sequences.	('NPC', 'Disease', 'MESH:D052556', (45, 48))	('T2W-', 'Var', (123, 127))	('NPC', 'Disease', (45, 48))	('T1W', 'Var', (118, 121))	('patients', 'Species', '9606', (31, 39))
20667	31511074	Distant metastases free survival was significantly better in patients with ypT0-2 (versus ypT3-4, P=0.0028) and ypN0 (versus ypN1-2, P=0.0040).	('metastases', 'Disease', (8, 18))	('ypT0-2', 'Var', (75, 81))	('patients', 'Species', '9606', (61, 69))	('metastases', 'Disease', 'MESH:D009362', (8, 18))	('ypN0', 'Var', (112, 116))	('better', 'PosReg', (51, 57))
20675	31511074	The values of ADCbm were significantly higher (p<0.01) in women, 477.3+-17.7 mum/s (95% IC), than in men, 426.3+-14.0 mum/s (95% IC).	('higher', 'PosReg', (39, 45))	('men', 'Species', '9606', (101, 104))	('477.3+-17.7', 'Var', (65, 76))	('women', 'Species', '9606', (58, 63))	('men', 'Species', '9606', (60, 63))	('AD', 'Disease', 'MESH:D000544', (14, 16))	('AD', 'Disease', (14, 16))
20691	31511074	Methods: Single-site retrospective analysis of histologically confirmed FH-deficient renal cancer, or patients with renal cancer and Germline FH mutation.	('renal cancer', 'Disease', (116, 128))	('FH-deficient renal cancer', 'Disease', (72, 97))	('renal cancer', 'Phenotype', 'HP:0009726', (85, 97))	('FH', 'Gene', '2271', (72, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (116, 128))	('FH-deficient renal cancer', 'Disease', 'MESH:D007680', (72, 97))	('Germline', 'Var', (133, 141))	('patients', 'Species', '9606', (102, 110))	('renal cancer', 'Disease', 'MESH:D007680', (85, 97))	('renal cancer', 'Disease', 'MESH:D007680', (116, 128))	('FH', 'Gene', '2271', (142, 144))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
20783	25476797	Environmental chemical exposure may contribute to uterine cancer development: studies with tetrabromobisphenol A Tetrabromobisphenol A (TBBPA), a widely used flame retardant, caused uterine tumors in rats.	('uterine tumors', 'Phenotype', 'HP:0010784', (182, 196))	('rats', 'Species', '10116', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tetrabromobisphenol A', 'Chemical', 'MESH:C020806', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('caused', 'Reg', (175, 181))	('uterine cancer', 'Phenotype', 'HP:0010784', (50, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Tetrabromobisphenol A', 'Chemical', 'MESH:C020806', (113, 134))	('Tetrabromobisphenol', 'Var', (113, 132))	('TBBPA', 'Chemical', 'MESH:C020806', (136, 141))	('uterine tumor', 'Phenotype', 'HP:0010784', (182, 195))	('tumors', 'Disease', (190, 196))	('cancer', 'Disease', (58, 64))	('flame retardant', 'Disease', (158, 173))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('flame retardant', 'Disease', 'MESH:D008607', (158, 173))
20785	25476797	TBBPA induced uterine epithelial tumors including adenomas, adenocarcinomas, and malignant mixed Mullerian tumors (MMMTs).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('adenocarcinomas', 'Disease', (60, 75))	('Mullerian tumors', 'Disease', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('adenomas', 'Disease', 'MESH:D000236', (50, 58))	('epithelial tumors', 'Disease', (22, 39))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('adenomas', 'Disease', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('epithelial tumors', 'Disease', 'MESH:D002277', (22, 39))	('Mullerian tumors', 'Disease', 'MESH:D002296', (97, 113))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('TBBPA', 'Var', (0, 5))	('adenocarcinomas', 'Disease', 'MESH:D000230', (60, 75))	('TBBPA', 'Chemical', 'MESH:C020806', (0, 5))
20787	25476797	Also found to be related to TBBPA treatment, but at lower incidence and at a lower statistical significance, were testicular tumors in rats, and hepatic tumors, hemangiosarcomas (all organs) and intestinal tumors in male mice.	('testicular tumors', 'Phenotype', 'HP:0010788', (114, 131))	('testicular tumors', 'Disease', 'MESH:D013736', (114, 131))	('hepatic tumors', 'Disease', 'MESH:D056486', (145, 159))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('TBBPA', 'Var', (28, 33))	('hepatic tumors', 'Disease', (145, 159))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('hemangiosarcomas', 'Disease', (161, 177))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('intestinal tumors', 'Disease', (195, 212))	('hemangiosarcomas', 'Disease', 'MESH:D006394', (161, 177))	('testicular tumors', 'Disease', (114, 131))	('rats', 'Species', '10116', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('TBBPA', 'Chemical', 'MESH:C020806', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mice', 'Species', '10090', (221, 225))	('intestinal tumors', 'Disease', 'MESH:D007414', (195, 212))
20805	25476797	Studies have indicated that TBBPA may perturb thyroid and estrogen homeostasis.	('TBBPA', 'Var', (28, 33))	('TBBPA', 'Chemical', 'MESH:C020806', (28, 33))	('perturb', 'Reg', (38, 45))
20904	25476797	Dysregulation of the cell cycle and apoptotic regulatory proteins have been reported to be involved in MMMT cancer pathways.	('involved', 'Reg', (91, 99))	('Dysregulation', 'Var', (0, 13))	('cell cycle', 'CPA', (21, 31))	('apoptotic regulatory proteins', 'Protein', (36, 65))	('MMMT cancer', 'Disease', 'MESH:D009369', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (0, 31))	('MMMT cancer', 'Disease', (103, 114))
20905	25476797	In humans, MMMTs account for about 5% of all malignant tumors derived in the body of the uterus, and are highly malignant and associated with a poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MMMTs', 'Var', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('humans', 'Species', '9606', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
20922	25476797	However, other studies suggest that exposure to TBBPA could result in decreased estrogen metabolism.	('estrogen metabolism', 'MPA', (80, 99))	('TBBPA', 'Chemical', 'MESH:C020806', (48, 53))	('decreased', 'NegReg', (70, 79))	('TBBPA', 'Var', (48, 53))
20929	25476797	Another way by which TBBPA may enhance estrogen activity in rats is suggested by the finding that TBBPA inhibits hydroxysteroid-dehydrogenase-17beta (HSD17beta) in in vitro assays ( (accessed)).	('TBBPA', 'Chemical', 'MESH:C020806', (21, 26))	('inhibits', 'NegReg', (104, 112))	('TBBPA', 'Var', (98, 103))	('enhance', 'PosReg', (31, 38))	('estrogen activity', 'MPA', (39, 56))	('hydroxysteroid-dehydrogenase-17beta', 'MPA', (113, 148))	('TBBPA', 'Chemical', 'MESH:C020806', (98, 103))	('rats', 'Species', '10116', (60, 64))
20937	25476797	That is, cleavage of a bromine-carbon bond of TBBPA could be speculated to result in formation of DNA-damaging free radicals and adducts.	('result', 'Reg', (75, 81))	('TBBPA', 'Chemical', 'MESH:C020806', (46, 51))	('carbon', 'Chemical', 'MESH:D002244', (31, 37))	('cleavage', 'Var', (9, 17))	('DNA-damaging free radicals', 'MPA', (98, 124))	('bromine-carbon bond', 'MPA', (23, 42))	('adducts', 'MPA', (129, 136))	('bromine', 'Chemical', 'MESH:D001966', (23, 30))	('TBBPA', 'Gene', (46, 51))	('free radicals', 'Chemical', 'MESH:D005609', (111, 124))
20958	31417090	Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis Somatic mutations in the RNase IIIb domain of DICER1 arise in cancer and disrupt the cleavage of 5' pre-miRNA arms.	('DICER1', 'Gene', (31, 37))	('cancer', 'Disease', (170, 176))	('disrupt', 'NegReg', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('DICER1', 'Gene', '23405', (154, 160))	('RNase III', 'Gene', (133, 142))	('arise', 'Reg', (161, 166))	('RNase III', 'Gene', (38, 47))	('DICER1', 'Gene', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	("cleavage of 5' pre-miRNA arms", 'MPA', (193, 222))	('RNase III', 'Gene', '29102', (133, 142))	('RNase III', 'Gene', '29102', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (116, 125))	('DICER1', 'Gene', '23405', (31, 37))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (18, 27))
20959	31417090	Here, we characterize an unstudied, recurrent, mutation (S1344L) in the DICER1 RNase IIIa domain in tumors from The Cancer Genome Atlas (TCGA) project and MSK-IMPACT profiling.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Cancer Genome Atlas', 'Disease', (116, 135))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('DICER1', 'Gene', (72, 78))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (116, 135))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('CG', 'Chemical', 'MESH:C028505', (138, 140))	('RNase III', 'Gene', '29102', (79, 88))	('RNase III', 'Gene', (79, 88))	('S1344L', 'Var', (57, 63))	('S1344L', 'Mutation', 'p.S1344L', (57, 63))
20961	31417090	Systematic analysis of TCGA small RNA datasets show that DICER1 RNase IIIa-S1344L tumors deplete 5p-miRNAs, analogous to RNase IIIb hotspot samples.	('S1344L', 'Mutation', 'p.S1344L', (75, 81))	('tumors', 'Disease', (82, 88))	('DICER1', 'Var', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('RNase III', 'Gene', '29102', (64, 73))	('CG', 'Chemical', 'MESH:C028505', (24, 26))	('RNase III', 'Gene', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('5p-miRNAs', 'MPA', (97, 106))	('deplete', 'NegReg', (89, 96))	('RNase III', 'Gene', (121, 130))	('RNase III', 'Gene', '29102', (121, 130))
20962	31417090	Structural and evolutionary coupling analyses reveal constrained proximity of RNase IIIa-S1344 to the RNase IIIb catalytic site, rationalizing why mutation of this site phenocopies known hotspot alterations.	('RNase III', 'Gene', '29102', (78, 87))	('RNase III', 'Gene', '29102', (102, 111))	('RNase III', 'Gene', (78, 87))	('mutation', 'Var', (147, 155))	('RNase III', 'Gene', (102, 111))
20966	31417090	Here, in endometrial cancer, the authors identify an RNase IIIa mutation, which phenocopies mutations in the RNase IIIb domain.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('RNase III', 'Gene', '29102', (53, 62))	('mutation', 'Var', (64, 72))	('RNase III', 'Gene', (53, 62))	('endometrial cancer', 'Disease', (9, 27))	('RNase III', 'Gene', '29102', (109, 118))	('RNase III', 'Gene', (109, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (9, 27))	('endometrial cancer', 'Disease', 'MESH:D016889', (9, 27))
20972	31417090	Strikingly, recent studies reveal that mutation of human DICER1 is cell lethal in human embryonic stem cells.	('mutation', 'Var', (39, 47))	('human', 'Species', '9606', (51, 56))	('DICER1', 'Gene', (57, 63))	('cell lethal', 'CPA', (67, 78))	('human', 'Species', '9606', (82, 87))
20973	31417090	Surprisingly, then, mutations in human DICER1 are recurrent in diverse cancers.	('recurrent', 'Reg', (50, 59))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('DICER1', 'Gene', (39, 45))	('human', 'Species', '9606', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (20, 29))
20974	31417090	Thus, although miRNAs are required for normal cell fitness, selective inactivation of DICER1 can benefit cancer cells.	('selective inactivation', 'Var', (60, 82))	('DICER1', 'Gene', (86, 92))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('benefit', 'PosReg', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
20975	31417090	DICER1 hotspot mutations occur preferentially within the RNase IIIb domain, and usually affect the metal ion-binding residues.	('metal', 'Chemical', 'MESH:D008670', (99, 104))	('DICER1', 'Gene', (0, 6))	('RNase III', 'Gene', '29102', (57, 66))	('affect', 'Reg', (88, 94))	('RNase III', 'Gene', (57, 66))	('mutations', 'Var', (15, 24))	('metal ion-binding residues', 'MPA', (99, 125))
20978	31417090	Accordingly, cancer hotspot mutant variants of DICER1 exhibit selective defects in processing miRNA-5p strands, leading to overall decreases in 5p:3p strand ratios.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('p ', 'Gene', '677663', (148, 150))	('p ', 'Gene', '677663', (101, 103))	('variants', 'Var', (35, 43))	('mutant variants', 'Var', (28, 43))	('decreases', 'NegReg', (131, 140))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('miRNA-5p', 'Chemical', '-', (94, 102))	('DICER1', 'Gene', (47, 53))	('defects', 'NegReg', (72, 79))
20979	31417090	DICER1 hotspot mutants were mostly characterized using cell models and in vitro assays, but consequences of biased miRNA processing on target regulation have not been studied extensively within human tumors.	('DICER1', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('mutants', 'Var', (15, 22))	('human', 'Species', '9606', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))
20981	31417090	In addition, although large numbers of somatic DICER1 mutations appear in cancer genome sequencing, it is relevant to know if additional driver alleles beyond RNase IIIb hotspots can be distinguished.	('RNase III', 'Gene', (159, 168))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (74, 80))	('DICER1', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RNase III', 'Gene', '29102', (159, 168))
20983	31417090	These analyses yield insights into tumor-specificity of DICER1 mutations and their consequences on miRNA and mRNA profiles.	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('DICER1', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mRNA profiles', 'MPA', (109, 122))	('tumor', 'Disease', (35, 40))	('consequences', 'Reg', (83, 95))
20984	31417090	Surprisingly, we reveal that recurrent DICER1 RNase IIIa-S1344L mutants impede miRNA-5p biogenesis and activity, similar to known RNase IIIb mutants.	('RNase III', 'Gene', '29102', (46, 55))	('impede', 'NegReg', (72, 78))	('activity', 'MPA', (103, 111))	('miRNA-5p', 'Chemical', '-', (79, 87))	('RNase III', 'Gene', '29102', (130, 139))	('RNase III', 'Gene', (130, 139))	('DICER1', 'Gene', (39, 45))	('mutants', 'Var', (64, 71))	('p ', 'Gene', '677663', (86, 88))	('RNase III', 'Gene', (46, 55))	('S1344L', 'Mutation', 'p.S1344L', (57, 63))
20986	31417090	Finally, we exploit prevalent DICER1 RNase III hotspot mutations in endometrial cancer to identify targets of specific miRNAs that are derepressed in this setting.	('endometrial cancer', 'Phenotype', 'HP:0012114', (68, 86))	('RNase III', 'Gene', '29102', (37, 46))	('mutations', 'Var', (55, 64))	('endometrial cancer', 'Disease', 'MESH:D016889', (68, 86))	('RNase III', 'Gene', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DICER1', 'Gene', (30, 36))	('endometrial cancer', 'Disease', (68, 86))
20987	31417090	Ever since the finding that certain tumors accumulate DICER1 lesions, especially point mutations within its RNase IIIb domain, many studies analyzed DICER1 alleles in diverse cancers and pathologies.	('point mutations', 'Var', (81, 96))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('lesions', 'Var', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('RNase III', 'Gene', '29102', (108, 117))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancers', 'Disease', (175, 182))	('DICER1', 'Gene', (54, 60))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('analyzed', 'Reg', (140, 148))	('RNase III', 'Gene', (108, 117))
20988	31417090	Here, we summarize the landscape of somatic DICER1 mutations from 9919 TCGA PanCan datasets, and 31,029 IMPACT datasets acquired from targeted sequencing of MSK patients.	('patients', 'Species', '9606', (161, 169))	('mutations', 'Var', (51, 60))	('DICER1', 'Gene', (44, 50))	('CG', 'Chemical', 'MESH:C028505', (72, 74))
20990	31417090	While overall infrequent, the known RNase IIIb mutations comprise clear hotspots in these cross-cancer profilings (Fig.	('RNase III', 'Gene', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('RNase III', 'Gene', '29102', (36, 45))	('mutations', 'Var', (47, 56))	('cross-cancer', 'Disease', 'MESH:C537866', (90, 102))	('cross-cancer', 'Disease', (90, 102))
20991	31417090	Mutations in the metal ion-binding residues at the catalytic center (E1705, D1709, D1810, and E1813) constitute the most frequent hits in RNase IIIb.	('metal', 'Chemical', 'MESH:D008670', (17, 22))	('D1810', 'Var', (83, 88))	('hits', 'Reg', (130, 134))	('E1705', 'Var', (69, 74))	('RNase III', 'Gene', '29102', (138, 147))	('RNase III', 'Gene', (138, 147))	('E1813', 'Var', (94, 99))	('D1709', 'Var', (76, 81))
20992	31417090	Cancer-associated mutation of G1809 partially impairs RNase IIIb activity; this allele was present only once in the TCGA dataset but was clearly recurrent in the IMPACT data with eight cases.	('activity', 'MPA', (65, 73))	('impairs', 'NegReg', (46, 53))	('G1809', 'Var', (30, 35))	('RNase III', 'Gene', (54, 63))	('CG', 'Chemical', 'MESH:C028505', (117, 119))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutation', 'Var', (18, 26))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('RNase III', 'Gene', '29102', (54, 63))
20993	31417090	More recently, mutation of RNase IIIb-D1713 was reported in anaplastic kidney sarcoma and shown to impair RNase IIIb activity.	('mutation', 'Var', (15, 23))	('impair', 'NegReg', (99, 105))	('activity', 'MPA', (117, 125))	('kidney sarcoma', 'Disease', (71, 85))	('kidney sarcoma', 'Phenotype', 'HP:0008663', (71, 85))	('RNase III', 'Gene', '29102', (106, 115))	('reported', 'Reg', (48, 56))	('RNase III', 'Gene', (106, 115))	('RNase III', 'Gene', '29102', (27, 36))	('RNase III', 'Gene', (27, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('kidney sarcoma', 'Disease', 'MESH:D007674', (71, 85))
20995	31417090	In stark contrast to these RNase IIIb mutations, there is a paucity of RNase IIIa mutations affecting catalysis.	('RNase III', 'Gene', (71, 80))	('RNase III', 'Gene', '29102', (71, 80))	('catalysis', 'MPA', (102, 111))	('mutations', 'Var', (82, 91))	('RNase III', 'Gene', '29102', (27, 36))	('RNase III', 'Gene', (27, 36))	('affecting', 'Reg', (92, 101))
20996	31417090	Despite 845 somatic hits in the aggregate DICER1 data, three of the RNase IIIa metal-binding residues (E1316, D1561, and E1564) were never mutated, and only single instances affected the fourth residue (D1320N) in TCGA and IMPACT data (Supplementary Data 1 and 2).	('D1561', 'Var', (110, 115))	('E1316', 'Var', (103, 108))	('E1564', 'Var', (121, 126))	('affected', 'Reg', (174, 182))	('D1320N', 'Var', (203, 209))	('metal', 'Chemical', 'MESH:D008670', (79, 84))	('RNase III', 'Gene', '29102', (68, 77))	('RNase III', 'Gene', (68, 77))	('D1561', 'CellLine', 'CVCL:9G44', (110, 115))	('D1320N', 'Mutation', 'p.D1320N', (203, 209))	('DICER1', 'Gene', (42, 48))	('CG', 'Chemical', 'MESH:C028505', (215, 217))
20997	31417090	Thus, there does not appear to be any selective advantage to inactivate DICER1 RNase IIIa in cancer.	('cancer', 'Disease', (93, 99))	('inactivate', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('DICER1', 'Gene', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('RNase III', 'Gene', '29102', (79, 88))	('RNase III', 'Gene', (79, 88))
20998	31417090	Nevertheless, we were intrigued by a recurrent mutation in RNase IIIa (S1344L, and one instance of S1344T), represented in both TCGA and IMPACT cohorts (Fig.	('RNase III', 'Gene', (59, 68))	('RNase III', 'Gene', '29102', (59, 68))	('S1344T', 'Mutation', 'p.S1344T', (99, 105))	('S1344L', 'Var', (71, 77))	('CG', 'Chemical', 'MESH:C028505', (129, 131))	('S1344L', 'Mutation', 'p.S1344L', (71, 77))
20999	31417090	Two prior studies each recorded single instances of S1344L in Wilms' tumor, although no specific tests of this allele were reported.	("Wilms' tumor", 'Phenotype', 'HP:0002667', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('S1344L', 'Mutation', 'p.S1344L', (52, 58))	('S1344L', 'Var', (52, 58))	("Wilms' tumor", 'Disease', 'MESH:D009396', (62, 74))	("Wilms' tumor", 'Disease', (62, 74))
21000	31417090	Interestingly, we observed that among TCGA cases, alterations of S1344 were similar in frequency to individual RNase IIIb catalytic site mutants.	('S1344', 'Gene', (65, 70))	('alterations', 'Var', (50, 61))	('TCGA', 'Disease', (38, 42))	('CG', 'Chemical', 'MESH:C028505', (39, 41))	('RNase III', 'Gene', (111, 120))	('RNase III', 'Gene', '29102', (111, 120))
21001	31417090	We also note some other uncharacterized somatic mutations shared by both datasets, including ones affecting the PAZ domain (R944Q) and RNase IIIb domain (D1699N/D/Xsplice).	('RNase III', 'Gene', '29102', (135, 144))	('R944Q', 'Var', (124, 129))	('affecting', 'Reg', (98, 107))	('D1699N/D/Xsplice', 'Var', (154, 170))	('R944Q', 'Mutation', 'p.R944Q', (124, 129))	('RNase III', 'Gene', (135, 144))	('D1699N', 'Mutation', 'p.D1699N', (154, 160))
21003	31417090	The current iteration of Cancer Hotspots analysis places a q-value for S1344L/T (0.0281) on par with RNase IIIb-D1709N (0.0130), although q-values for other RNase IIIb hotspots are lower (e.g., D1810 mutations, 8.22E-5; E1813 mutations, 1.04E-10; Supplementary Fig.	('D1709N', 'Mutation', 'p.D1709N', (112, 118))	('S1344L/T', 'Var', (71, 79))	('RNase III', 'Gene', '29102', (157, 166))	('RNase III', 'Gene', (157, 166))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer', 'Disease', (25, 31))	('D1810 mutations', 'Var', (194, 209))	('Cancer', 'Disease', 'MESH:D009369', (25, 31))	('RNase III', 'Gene', '29102', (101, 110))	('E1813 mutations', 'Var', (220, 235))	('RNase III', 'Gene', (101, 110))	('S1344L', 'Mutation', 'p.S1344L', (71, 77))
21006	31417090	However, other studies indicate that DICER1 hotspot mutations are biallelic in cancer, and act in trans to nonsense or inactivating alleles of DICER1.	('mutations', 'Var', (52, 61))	('nonsense', 'Var', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('DICER1', 'Gene', (37, 43))	('act', 'Reg', (91, 94))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('DICER1', 'Gene', (143, 149))
21008	31417090	This may be the case in human pineoblastoma, for which germline DICER1 mutation combined with loss-of-heterozygosity was detected.	('pineoblastoma', 'Disease', 'MESH:D010871', (30, 43))	('human', 'Species', '9606', (24, 29))	('mutation', 'Var', (71, 79))	('loss-of-heterozygosity', 'NegReg', (94, 116))	('pineoblastoma', 'Disease', (30, 43))	('pineoblastoma', 'Phenotype', 'HP:0030408', (30, 43))	('DICER1', 'Gene', (64, 70))
21011	31417090	Moreover, it is more challenging to call indels and deletions compared to point mutations, and IMPACT data are generally underpowered relative to TCGA data for calling copy number variations (CNVs).	('CG', 'Chemical', 'MESH:C028505', (147, 149))	('deletions', 'Var', (52, 61))	('indels', 'Var', (41, 47))
21012	31417090	Nevertheless, we used the latest TCGA MC3 MAF files using 2+ callers to screen all somatic DICER1 missense mutant tumors for overt secondary disabling events (nonsense mutations, out-of-frame indels, splice-altering alleles or deep deletions).	('missense mutant', 'Var', (98, 113))	('CG', 'Chemical', 'MESH:C028505', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('nonsense mutations', 'Var', (159, 177))	('DICER1', 'Gene', (91, 97))	('out-of-frame indels', 'Var', (179, 198))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('p ', 'Gene', '677663', (230, 232))
21014	31417090	For example, the recurrent allele R944Q (rarely R944*) could be found with heterozygous copy loss, or with other somatic DICER1 variants of unknown significance, but all of these were strictly found in hypermutated tumors.	('R944*', 'Var', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('R944Q', 'Mutation', 'p.R944Q', (34, 39))	('tumors', 'Disease', (215, 221))	('R944*', 'SUBSTITUTION', 'None', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('R944Q', 'Var', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (215, 221))
21016	31417090	While the vast majority of somatic mutations fell away, many RNase IIIb mutant tumors contained biallelic events (Supplementary Data 1 and 2).	('RNase III', 'Gene', (61, 70))	('mutant', 'Var', (72, 78))	('RNase III', 'Gene', '29102', (61, 70))	('biallelic events', 'MPA', (96, 112))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('contained', 'Reg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
21019	31417090	We subsequently recognized additional biallelic cases involving RNase IIIb hotspot mutations in hypermutated samples (Supplementary Data 1 and 2), suggesting that functional alteration of DICER1 is also relevant in these patients.	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (221, 229))	('RNase III', 'Gene', '29102', (64, 73))	('RNase III', 'Gene', (64, 73))	('hotspot', 'PosReg', (75, 82))
21021	31417090	1a), which was picked up once in a HETLOSS tumor and another time as a splice-inactivating event with an RNase IIIb hotspot (E1813G); other instances of this allele occurred in hypermutated tumors.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('RNase III', 'Gene', '29102', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('RNase III', 'Gene', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (190, 195))	('E1813G);', 'Var', (125, 133))	('p ', 'Gene', '677663', (23, 25))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('E1813G', 'Mutation', 'p.E1813G', (125, 131))	('tumors', 'Disease', (190, 196))	('tumor', 'Disease', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
21023	31417090	Figure 1b highlights S1344L events in trans to deletions, nonsense mutations, and an exceptional case bearing a second S1344 allele (S1344T).	('nonsense mutations', 'Var', (58, 76))	('S1344L', 'Mutation', 'p.S1344L', (21, 27))	('deletions', 'Var', (47, 56))	('S1344T', 'Mutation', 'p.S1344T', (133, 139))
21024	31417090	While prior genome sequencing has not implicated RNase IIIa mutations as pathogenic, and RNase IIIa catalytic site mutations are indeed nearly absent in cancer, these observations further suggest S1344L is functionally relevant during tumorigenesis.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('S1344L', 'Var', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('cancer', 'Disease', (153, 159))	('RNase III', 'Gene', '29102', (89, 98))	('S1344L', 'Mutation', 'p.S1344L', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('RNase III', 'Gene', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', (235, 240))	('RNase III', 'Gene', '29102', (49, 58))	('RNase III', 'Gene', (49, 58))
21028	31417090	Interestingly, the distribution of DICER1 hotspot mutations was not even across cancer types.	('DICER1', 'Gene', (35, 41))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
21029	31417090	For example, visual inspection shows that hotspot mutations and biallelic cases were generally restricted to a few related classes of uterine cancers in both TCGA and MSK-IMPACT datasets (Fig.	('uterine cancers', 'Phenotype', 'HP:0010784', (134, 149))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CG', 'Chemical', 'MESH:C028505', (159, 161))	('uterine cancer', 'Phenotype', 'HP:0010784', (134, 148))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
21030	31417090	By contrast, the strong majority of cancer types completely lacked DICER1 hotspot mutations (Fig.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('lacked', 'NegReg', (60, 66))	('cancer', 'Disease', (36, 42))	('DICER1', 'Gene', (67, 73))	('mutations', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
21032	31417090	This analysis finds uterine cancers are genuinely enriched for hotspot mutations in both TCGA and MSK-IMPACT cohorts.	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('uterine cancers', 'Phenotype', 'HP:0010784', (20, 35))	('CG', 'Chemical', 'MESH:C028505', (90, 92))	('mutations', 'Var', (71, 80))	('hotspot', 'PosReg', (63, 70))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('TCGA', 'Gene', (89, 93))	('MSK-IMPACT', 'Gene', (98, 108))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('uterine cancer', 'Phenotype', 'HP:0010784', (20, 34))
21034	31417090	Similarly, endometrial cancer and uterine sarcoma were significantly enriched for hotspots in MSK-IMPACT (Fig.	('endometrial cancer', 'Disease', (11, 29))	('sarcoma', 'Disease', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (34, 49))	('endometrial cancer', 'Phenotype', 'HP:0012114', (11, 29))	('MSK-IMPACT', 'Var', (94, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (11, 29))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
21040	31417090	Reciprocally, 70% (29/40) of TCGA PanCan and 63% (26/41) of MSK-IMPACT cancer types had zero DICER1 RNase III hotspot mutations (considering only cancer types with sample size >50).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('DICER1', 'Protein', (93, 99))	('cancer', 'Disease', (71, 77))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RNase III', 'Gene', (100, 109))	('CG', 'Chemical', 'MESH:C028505', (30, 32))	('RNase III', 'Gene', '29102', (100, 109))
21042	31417090	This indicates a dearth of DICER1 hotspot mutations across the vast majority of cancer types.	('DICER1', 'Gene', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (80, 86))
21043	31417090	As an example, the observed hotspot mutations in breast cancer (0/4355 patients) are well below the 5% confidence interval from bootstrap resampling, indicating significant depletion (Fig.	('patients', 'Species', '9606', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('depletion', 'MPA', (173, 182))	('p ', 'Gene', '677663', (136, 138))	('mutations', 'Var', (36, 45))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
21044	31417090	We return to the apparent tumor bias of DICER1 RNase IIIa/b inactivation in subsequent gene expression analyses.	('RNase III', 'Gene', (47, 56))	('RNase III', 'Gene', '29102', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('inactivation', 'Var', (60, 72))
21046	31417090	Cell culture and in vitro processing assays established that cancer hotspot mutations in DICER1 RNase IIIb selectively impair miRNA-5p processing (Fig.	('impair', 'NegReg', (119, 125))	('mutations', 'Var', (76, 85))	('miRNA-5p', 'Chemical', '-', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('RNase III', 'Gene', '29102', (96, 105))	('p ', 'Gene', '677663', (133, 135))	('RNase III', 'Gene', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('DICER1', 'Gene', (89, 95))
21047	31417090	Accordingly, cancer-associated DICER1 hotspot mutations bias the relative yield of 5p to 3p miRNAs in tumors.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('DICER1', 'Gene', (31, 37))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('p ', 'Gene', '677663', (84, 86))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('p ', 'Gene', '677663', (90, 92))
21049	31417090	We first compared miRNA levels in 15 RNase IIIb hotspot endometrial mutants with 548 other UCEC cases, combining DICER1 mutants outside of RNase III hotspot sites with all wildtype cases as controls.	('RNase III', 'Gene', (139, 148))	('RNase III', 'Gene', '29102', (37, 46))	('RNase III', 'Gene', (37, 46))	('mutants', 'Var', (68, 75))	('DICER1', 'Gene', (113, 119))	('RNase III', 'Gene', '29102', (139, 148))	('mutants', 'Var', (120, 127))
21052	31417090	Note that 5p strand miRNAs were still detected in RNase IIIb hotspot mutants, suggesting impairment but not abrogation of 5' pre-miRNA arm cleavage.	('RNase III', 'Gene', (50, 59))	('p ', 'Gene', '677663', (11, 13))	('RNase III', 'Gene', '29102', (50, 59))	('mutants', 'Var', (69, 76))
21054	31417090	While this might imply that RNase IIIb mutations enhance miRNA-3p biogenesis, as libraries were globally normalized to equalize depth, it is conceivable that lost 5p reads were taken up by 3p reads.	('p ', 'Gene', '677663', (184, 186))	('p ', 'Gene', '677663', (190, 192))	('enhance', 'PosReg', (49, 56))	('mutations', 'Var', (39, 48))	('p ', 'Gene', '677663', (64, 66))	('RNase III', 'Gene', '29102', (28, 37))	('RNase III', 'Gene', (28, 37))	('p ', 'Gene', '677663', (164, 166))
21055	31417090	In any case, the expression of 5p and 3p strands in RNase IIIb hotspot mutants were significantly different from controls (Supplementary Fig.	('p ', 'Gene', '677663', (39, 41))	('expression', 'MPA', (17, 27))	('p ', 'Gene', '677663', (32, 34))	('mutants', 'Var', (71, 78))	('RNase III', 'Gene', '29102', (52, 61))	('RNase III', 'Gene', (52, 61))	('different', 'Reg', (98, 107))
21057	31417090	These data extend previous observations on the asymmetric effects of RNase IIIb hotspot mutants on pre-miRNA hairpin products.	('RNase III', 'Gene', '29102', (69, 78))	('RNase III', 'Gene', (69, 78))	('pre-miRNA hairpin products', 'MPA', (99, 125))	('mutants', 'Var', (88, 95))
21058	31417090	We were curious whether RNase IIIb cases with overt biallelic-inactivating mutations were distinct from hotspot samples associated with other mutations of unknown significance, or lacking other DICER1 alterations.	('RNase III', 'Gene', (24, 33))	('RNase III', 'Gene', '29102', (24, 33))	('biallelic-inactivating mutations', 'Var', (52, 84))
21061	31417090	However, the biallelic-inactivated cases clearly exhibited more severe bias and were disproportionately responsible for signals detected in the aggregate RNase IIIb mutant analysis (Fig.	('RNase III', 'Gene', '29102', (154, 163))	('mutant', 'Var', (165, 171))	('RNase III', 'Gene', (154, 163))
21062	31417090	Thus, there is a range of functional miRNA pathway alteration among tumors collectively annotated with RNase IIIb hotspot mutations.	('tumors', 'Disease', (68, 74))	('miRNA pathway', 'Pathway', (37, 50))	('alteration', 'Reg', (51, 61))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('RNase III', 'Gene', (103, 112))	('mutations', 'Var', (122, 131))	('RNase III', 'Gene', '29102', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
21065	31417090	Since few DICER1 mutants lack multiple cases in individual tumor types, besides endometrial cancer (Fig.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('endometrial cancer', 'Disease', (80, 98))	('DICER1', 'Gene', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('endometrial cancer', 'Phenotype', 'HP:0012114', (80, 98))	('endometrial cancer', 'Disease', 'MESH:D016889', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutants', 'Var', (17, 24))
21067	31417090	5B illustrates how this metric was applied to example DICER1-wt and RNase IIIb hotspot mutant cases, revealing overall shifts in 5p/3p arm distributions across miRNA loci.	('RNase III', 'Gene', '29102', (68, 77))	('RNase III', 'Gene', (68, 77))	('mutant', 'Var', (87, 93))	('p ', 'Gene', '677663', (133, 135))	('shifts', 'Reg', (119, 125))
21078	31417090	These data lack comparable 5p/3p data for the majority of relevant miRNAs, but conducting the analysis with available data revealed a biallelic RNase IIIb hotspot case among the lowest scores in GBM (Supplementary Fig.	('RNase III', 'Gene', (144, 153))	('p ', 'Gene', '677663', (31, 33))	('biallelic', 'Var', (134, 143))	('RNase III', 'Gene', '29102', (144, 153))
21084	31417090	In this manner, several non-biallelic RNase IIIb hotspot cases still exhibited 5p-miRNA depletion that was substantially low among their respective tumor cohorts (Fig.	('exhibited', 'Reg', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('5p-miRNA depletion', 'MPA', (79, 97))	('tumor', 'Disease', (148, 153))	('RNase III', 'Gene', '29102', (38, 47))	('RNase III', 'Gene', (38, 47))	('non-biallelic', 'Var', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
21086	31417090	Nevertheless, some RNase IIIb hotspot cases exhibited mi53 scores that were typical for their tumor type (Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('RNase III', 'Gene', '29102', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('mi53', 'Var', (54, 58))	('RNase III', 'Gene', (19, 28))
21088	31417090	Since the median mi53 metric had demonstrable utility for largescale analysis of TCGA small RNA data, we investigated whether other DICER1 mutants exhibited characteristic shifts in hairpin arm distribution.	('DICER1', 'Gene', (132, 138))	('hairpin', 'MPA', (182, 189))	('mutants', 'Var', (139, 146))	('shifts', 'Reg', (172, 178))	('CG', 'Chemical', 'MESH:C028505', (82, 84))
21089	31417090	Most other DICER1 mutations (i.e., 217 TCGA DICER1 cases bearing only non-hotspot mutations) did not affect miRNA strand asymmetry (Fig.	('miRNA strand asymmetry', 'MPA', (108, 130))	('DICER1', 'Gene', (11, 17))	('DICER1', 'Gene', (44, 50))	('CG', 'Chemical', 'MESH:C028505', (40, 42))	('mutations', 'Var', (18, 27))
21093	31417090	Their collective mi53 score range was higher than DICER1-RNase IIIb hotspot cases with clear biallelic-inactivating mutations, and similar to the remainder of RNase IIIb hotspot cases (Fig.	('RNase III', 'Gene', (159, 168))	('biallelic-inactivating', 'Var', (93, 115))	('RNase III', 'Gene', '29102', (57, 66))	('mi53', 'Gene', (17, 21))	('RNase III', 'Gene', (57, 66))	('higher', 'PosReg', (38, 44))	('RNase III', 'Gene', '29102', (159, 168))
21094	31417090	Of note, the S1344L subclass exhibited a tighter distribution than the RNase IIIb hotspots that lacked overt biallelic-inactivating mutations (Fig.	('RNase III', 'Gene', (71, 80))	('S1344L', 'Mutation', 'p.S1344L', (13, 19))	('S1344L', 'Var', (13, 19))	('RNase III', 'Gene', '29102', (71, 80))
21095	31417090	This is consistent with the fact that TCGA S1344L cases were all associated with secondary loss-of-function hits in DICER1, or a double hit in S1344 (Fig.	('loss-of-function', 'NegReg', (91, 107))	('hits', 'Var', (108, 112))	('DICER1', 'Gene', (116, 122))	('CG', 'Chemical', 'MESH:C028505', (39, 41))	('TCGA S1344L', 'Gene', (38, 49))	('S1344', 'Var', (143, 148))	('S1344L', 'Mutation', 'p.S1344L', (43, 49))
21096	31417090	The functional consequence of S1344L on miRNA arm distribution was even more apparent when separating cases by cancer type.	('S1344L', 'Var', (30, 36))	('S1344L', 'Mutation', 'p.S1344L', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('miRNA arm distribution', 'MPA', (40, 62))
21097	31417090	For example, the S1344L case with the highest mi53 score was actually the lowest scoring case in its tumor cohort (CHOL), emphasizing it is truly an outlier (Fig.	('mi53', 'Gene', (46, 50))	('S1344L', 'Var', (17, 23))	('S1344L', 'Mutation', 'p.S1344L', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('CHOL', 'Chemical', '-', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
21098	31417090	Similarly, other S1344L cases were among the lowest scores in COAD, SKCM, and UCEC cohorts (Fig.	('S1344L', 'Mutation', 'p.S1344L', (17, 23))	('S1344L', 'Var', (17, 23))	('COAD', 'Disease', (62, 66))	('COAD', 'Disease', 'MESH:D029424', (62, 66))
21100	31417090	3a), the similar effects of RNase IIIa and IIIb mutants on tumor small RNA profiles was unanticipated.	('IIIb', 'Gene', (43, 47))	('tumor', 'Disease', (59, 64))	('mutants', 'Var', (48, 55))	('RNase III', 'Gene', '29102', (28, 37))	('RNase III', 'Gene', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
21102	31417090	We selected several DICER1 hotspot mutations for functional assays: PAZ domain-R944Q, RNase IIIa-S1344L and RNase IIIb-E1813G (Fig.	('domain-R944Q', 'Var', (72, 84))	('E1813G', 'Mutation', 'p.E1813G', (119, 125))	('R944Q', 'Mutation', 'p.R944Q', (79, 84))	('RNase III', 'Gene', (86, 95))	('S1344L', 'Mutation', 'p.S1344L', (97, 103))	('RNase III', 'Gene', '29102', (108, 117))	('RNase III', 'Gene', '29102', (86, 95))	('DICER1', 'Gene', (20, 26))	('RNase III', 'Gene', (108, 117))
21103	31417090	We introduced these into a human DICER1 cDNA, and expressed wt and mutant hDICER1 plasmids in Dicer-KO MEFs that we previously used to analyze Dicer-independent miRNA biogenesis.	('Dicer', 'Gene', '23405', (94, 99))	('hDICER1', 'Gene', (74, 81))	('Dicer', 'Gene', (94, 99))	('human', 'Species', '9606', (27, 32))	('MEFs', 'CellLine', 'CVCL:9115', (103, 107))	('hDICER1', 'Gene', '23405', (74, 81))	('mutant', 'Var', (67, 73))	('Dicer', 'Gene', '23405', (143, 148))	('Dicer', 'Gene', (143, 148))
21105	31417090	To evaluate potentially selective effects of mutant DICER1 proteins on miRNA-5p vs. miRNA-3p biogenesis, we sought miRNAs that accumulate both duplex strands of a given pre-miRNA, thereby providing internal controls.	('DICER1', 'Gene', (52, 58))	('accumulate', 'PosReg', (127, 137))	('mutant', 'Var', (45, 51))	('proteins', 'Protein', (59, 67))	('p ', 'Gene', '677663', (91, 93))	('p ', 'Gene', '677663', (78, 80))	('miRNA-5p', 'Chemical', '-', (71, 79))
21107	31417090	In particular, their processing was arrested as pre-miRNA hairpins in Dicer-KO MEFs indicating full dependence on Dicer, and both partner strands could be detected when DICER1 was reintroduced into mutant cells.	('Dicer', 'Gene', '23405', (70, 75))	('Dicer', 'Gene', (70, 75))	('Dicer', 'Gene', '23405', (114, 119))	('Dicer', 'Gene', (114, 119))	('mutant', 'Var', (198, 204))	('MEFs', 'CellLine', 'CVCL:9115', (79, 83))
21109	31417090	However, both RNase III mutants exhibited specific defects in accumulation of miRNA-5p species, while partner miRNA-3p species were produced at normal levels (Fig.	('mutants', 'Var', (24, 31))	('p ', 'Gene', '677663', (85, 87))	('RNase III', 'Gene', '29102', (14, 23))	('accumulation', 'MPA', (62, 74))	('RNase III', 'Gene', (14, 23))	('p ', 'Gene', '677663', (117, 119))	('defects', 'NegReg', (51, 58))	('miRNA-5p', 'Chemical', '-', (78, 86))
21110	31417090	These tests suggested the primary defect in RNase IIIa/b mutants is indeed depletion of miRNA-5p species, not upregulation of miRNA-3p species (Fig.	('miRNA-5p', 'Chemical', '-', (88, 96))	('RNase III', 'Gene', (44, 53))	('RNase III', 'Gene', '29102', (44, 53))	('p ', 'Gene', '677663', (95, 97))	('depletion', 'MPA', (75, 84))	('p ', 'Gene', '677663', (133, 135))	('mutants', 'Var', (57, 64))
21111	31417090	As further controls, miR-144-3p, Dicer-independent miR-451 and U6 snRNA accumulated similarly in the presence of wt and mutant DICER1 proteins.	('DICER1', 'Gene', (127, 133))	('miR-451', 'Gene', (51, 58))	('miR-144', 'Gene', (21, 28))	('miR-144', 'Gene', '406936', (21, 28))	('Dicer', 'Gene', '23405', (33, 38))	('Dicer', 'Gene', (33, 38))	('miR-451', 'Gene', '574411', (51, 58))	('mutant', 'Var', (120, 126))	('proteins', 'Protein', (134, 142))
21116	31417090	By contrast, S1344L and E1813G rescued miRNA-3p activity, but were impaired in conferring miRNA-5p activity for both miRNAs (Fig.	('S1344L', 'Var', (13, 19))	('p ', 'Gene', '677663', (97, 99))	('S1344L', 'Mutation', 'p.S1344L', (13, 19))	('p ', 'Gene', '677663', (46, 48))	('E1813G', 'Mutation', 'p.E1813G', (24, 30))	('rescued', 'PosReg', (31, 38))	('miRNA-5p', 'Chemical', '-', (90, 98))	('E1813G', 'Var', (24, 30))
21117	31417090	Of note, while mir-151 and mir-199a-1 had overall similar behavior across this panel of DICER1 mutants, miR-199a-1-5p was slightly matured by S1344L compared to E1813G (Fig.	('DICER1', 'Gene', (88, 94))	('mir-151 and mir-199a-1', 'Gene', '442893;406976', (15, 37))	('p ', 'Gene', '677663', (116, 118))	('E1813G', 'Mutation', 'p.E1813G', (161, 167))	('S1344L', 'Var', (142, 148))	('E1813G', 'Var', (161, 167))	('S1344L', 'Mutation', 'p.S1344L', (142, 148))
21118	31417090	4d) and correspondingly had measurable activity on its sensor in S1344L but not in E1813G cells (Fig.	('S1344L', 'Var', (65, 71))	('activity', 'MPA', (39, 47))	('E1813G', 'Mutation', 'p.E1813G', (83, 89))	('S1344L', 'Mutation', 'p.S1344L', (65, 71))
21119	31417090	This is consistent with the globally lower miRNA-5p depletion observed in RNase IIIb biallelic cases compared to S1344L biallelic cases (Fig.	('RNase III', 'Gene', '29102', (74, 83))	('RNase III', 'Gene', (74, 83))	('S1344L', 'Mutation', 'p.S1344L', (113, 119))	('p ', 'Gene', '677663', (50, 52))	('biallelic', 'Var', (85, 94))	('lower', 'NegReg', (37, 42))	('miRNA-5p', 'Chemical', '-', (43, 51))
21125	31417090	On the other hand, these experimental assays validate the unexpected finding that cancer-associated hotspot mutations in DICER1 RNase IIIa and RNase IIIb domains actually have similar biochemical and function consequences.	('RNase III', 'Gene', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('DICER1', 'Gene', (121, 127))	('mutations', 'Var', (108, 117))	('cancer', 'Disease', (82, 88))	('RNase III', 'Gene', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('RNase III', 'Gene', '29102', (143, 152))	('RNase III', 'Gene', '29102', (128, 137))
21126	31417090	As S1344 is located in the RNase IIIa domain, we sought mechanistic insight as to why its mutation leads to 5p, rather than 3p, depletion.	('RNase III', 'Gene', (27, 36))	('mutation', 'Var', (90, 98))	('RNase III', 'Gene', '29102', (27, 36))	('leads to', 'Reg', (99, 107))
21129	31417090	Alignment of human DICER1 RNase III domains shows S1344 is homologous to T1733 in RNase IIIb (Supplementary Fig.	('RNase III', 'Gene', (82, 91))	('human', 'Species', '9606', (13, 18))	('RNase III', 'Gene', '29102', (26, 35))	('RNase III', 'Gene', '29102', (82, 91))	('RNase III', 'Gene', (26, 35))	('S1344', 'Var', (50, 55))
21130	31417090	We modeled S1344 into a model of the RNase IIIa-IIIb heterodimer, as inferred from the RNase IIIb homodimer structure.	('S1344', 'Var', (11, 16))	('RNase III', 'Gene', '29102', (37, 46))	('RNase III', 'Gene', (37, 46))	('RNase III', 'Gene', '29102', (87, 96))	('RNase III', 'Gene', (87, 96))
21131	31417090	In the heterodimer model, S1344L (in RNase IIIa) and its homologous residue T1733 (in RNase IIIb) are far from the active site residues (19.60 +- 2.62 A distance) in their respective domains.	('S1344L', 'Mutation', 'p.S1344L', (26, 32))	('RNase III', 'Gene', '29102', (37, 46))	('RNase III', 'Gene', (37, 46))	('RNase III', 'Gene', (86, 95))	('RNase III', 'Gene', '29102', (86, 95))	('S1344L', 'Var', (26, 32))
21132	31417090	Instead, S1344L is closer (11.7 +- 2.0 A distance) to the active site of domain IIIb (residues E1813, D1810, D1709, E1705) and T1733 in is close to the active site residues of RNase IIIa (Supplementary Fig.	('E1705', 'Var', (116, 121))	('D1810', 'Var', (102, 107))	('S1344L', 'Var', (9, 15))	('D1709', 'Var', (109, 114))	('S1344L', 'Mutation', 'p.S1344L', (9, 15))	('RNase III', 'Gene', '29102', (176, 185))	('RNase III', 'Gene', (176, 185))	('T1733 in', 'Var', (127, 135))
21133	31417090	This suggests how S1344L may disrupt RNase IIIb activity.	('RNase III', 'Gene', '29102', (37, 46))	('activity', 'MPA', (48, 56))	('RNase III', 'Gene', (37, 46))	('S1344L', 'Var', (18, 24))	('disrupt', 'NegReg', (29, 36))	('S1344L', 'Mutation', 'p.S1344L', (18, 24))
21136	31417090	Since F1706 neighbors catalytic residue E1705 that binds the active site Mg2+ (which we modeled into the cryo-EM structure based on 2eb1 [https://www.rcsb.org/structure/2eb1] homodimer structure), this brings S1344 in proximity to the RNase IIIb active site (~8-9 A from E1705, Fig.	('RNase III', 'Gene', (235, 244))	('F1706', 'CellLine', 'CVCL:6C53', (6, 11))	('E1705', 'Var', (271, 276))	('Mg2+', 'Chemical', '-', (73, 77))	('S1344', 'Var', (209, 214))	('F1706', 'Var', (6, 11))	('RNase III', 'Gene', '29102', (235, 244))
21137	31417090	While the published DICER1 structures are not in their catalytic state, nor have high enough resolution for Mg2+ ions to be positioned precisely, it is conceivable that the S1344 side chain hydroxyl group is even closer to the active site in an, as yet, unseen active conformation.	('p ', 'Gene', '677663', (203, 205))	('Mg2+', 'Chemical', '-', (108, 112))	('DICER1', 'Gene', (20, 26))	('S1344', 'Var', (173, 178))
21139	31417090	An independent strategy to evaluate the importance of S1344 is to explore its constraint via interactions with active site residues of the sister RNase III domain across the protein's evolutionary history.	('RNase III', 'Gene', '29102', (146, 155))	('RNase III', 'Gene', (146, 155))	('interactions', 'Interaction', (93, 105))	('S1344', 'Var', (54, 59))
21140	31417090	We subjected human DICER1 1271-1829 comprising the two RNase III domains to evolutionary coupling analysis.	('RNase III', 'Gene', '29102', (55, 64))	('1271-1829', 'Var', (26, 35))	('human', 'Species', '9606', (13, 18))	('RNase III', 'Gene', (55, 64))
21143	31417090	In particular, RNase IIIb E1705-D1709 active site residues comprised the 9th highest ranked coupling, and six couplings between RNase IIIb active site residues and four couplings between RNase IIIa active site resides were detected in the top 140 ECs (Supplementary Data 4).	('RNase III', 'Gene', (128, 137))	('RNase III', 'Gene', (187, 196))	('RNase III', 'Gene', (15, 24))	('RNase III', 'Gene', '29102', (187, 196))	('E1705-D1709', 'Var', (26, 37))	('p ', 'Gene', '677663', (241, 243))	('RNase III', 'Gene', '29102', (128, 137))	('RNase III', 'Gene', '29102', (15, 24))
21146	31417090	Notably, we observe coupling of T1733 (the cognate of S1344) to active site residue RNase IIIb-E1705 in the top L hits, as well as direct coupling of RNase IIIa-S1344 in RNase IIIb-F1706 in the top 1.5% of all detected couplings (Supplementary Data 4).	('p ', 'Gene', '677663', (110, 112))	('RNase III', 'Gene', (84, 93))	('RNase III', 'Gene', (170, 179))	('RNase III', 'Gene', '29102', (84, 93))	('coupling', 'Interaction', (20, 28))	('RNase III', 'Gene', '29102', (150, 159))	('RNase III', 'Gene', (150, 159))	('F1706', 'CellLine', 'CVCL:6C53', (181, 186))	('coupling', 'Interaction', (138, 146))	('p ', 'Gene', '677663', (196, 198))	('RNase III', 'Gene', '29102', (170, 179))	('T1733', 'Var', (32, 37))
21147	31417090	Thus, ECs inferred from sequence information alone, reinforce the notion of an evolutionarily constrained, functionally relevant inter-domain interaction between S1344 and the RNase IIIb catalytic center that is required for proper pre-miRNA processing.	('S1344', 'Var', (162, 167))	('RNase III', 'Gene', (176, 185))	('RNase III', 'Gene', '29102', (176, 185))
21148	31417090	Having expanded the set of functional mutations in human DICER1, we investigated whether these lead to interpretable changes in gene expression.	('human', 'Species', '9606', (51, 56))	('DICER1', 'Gene', (57, 63))	('gene expression', 'MPA', (128, 143))	('changes', 'Reg', (117, 124))	('mutations', 'Var', (38, 47))
21149	31417090	Others modeled effects of DICER1 hotspots on gene expression in mouse Dicer-mutant cell lines, but there have been limited attempts to connect differential miRNA expression in DICER1 hotspot mutants with mRNA changes in human tumors.	('Dicer', 'Gene', '23405', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('Dicer', 'Gene', (70, 75))	('DICER1', 'Gene', (176, 182))	('human', 'Species', '9606', (220, 225))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('mutants', 'Var', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('mouse', 'Species', '10090', (64, 69))
21150	31417090	Since DICER1 hotspot mutations are overall rare in cancer, we focused on UCEC, which contained the largest number of DICER1 hotspot mutants (Figs.	('DICER1', 'Gene', (117, 123))	('mutants', 'Var', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('UCEC', 'Disease', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
21154	31417090	6a), suggesting that gene expression signatures in RNase IIIa/b hotspot mutants are dominated by certain depleted miRNA families rather than common biological pathways.	('RNase III', 'Gene', '29102', (51, 60))	('mutants', 'Var', (72, 79))	('RNase III', 'Gene', (51, 60))
21156	31417090	For both families, the 5p-miRNA is the predominant strand and as expected, 5p-strand miRNAs of these families were downregulated relative to 3p-strands in RNase IIIa/b mutants (Fig.	('RNase III', 'Gene', (155, 164))	('downregulated', 'NegReg', (115, 128))	('RNase III', 'Gene', '29102', (155, 164))	('mutants', 'Var', (168, 175))
21159	31417090	6a; FDR = 11%), although their predominant miRNA strands are 3p, both mature and passenger strands of these families were downregulated in DICER1 RNase IIIa/b mutants (Fig.	('downregulated', 'NegReg', (122, 135))	('DICER1', 'Gene', (139, 145))	('mutants', 'Var', (159, 166))	('RNase III', 'Gene', (146, 155))	('RNase III', 'Gene', '29102', (146, 155))
21162	31417090	Overall, these analyses indicate that alterations in pre-miRNA processing in DICER1 biallelic endometrial tumors yield preferential effects on derepression of cognate direct targets of specific miRNAs, and certain likely indirect miRNA target networks and associated gene expression signatures that may be relevant for DICER1 hotspot uterine cancers.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('uterine cancer', 'Phenotype', 'HP:0010784', (334, 348))	('derepression', 'MPA', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('endometrial tumors', 'Disease', (94, 112))	('uterine cancers', 'Phenotype', 'HP:0010784', (334, 349))	('cancers', 'Phenotype', 'HP:0002664', (342, 349))	('cancers', 'Disease', (342, 349))	('cancers', 'Disease', 'MESH:D009369', (342, 349))	('DICER1', 'Gene', (77, 83))	('endometrial tumors', 'Disease', 'MESH:D016889', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('alterations', 'Var', (38, 49))
21163	31417090	We systematically analyzed the landscape of DICER1 hotspot mutations that lead to miRNA strand asymmetries in cancer.	('cancer', 'Disease', (110, 116))	('lead to', 'Reg', (74, 81))	('miRNA strand asymmetries', 'MPA', (82, 106))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('DICER1', 'Gene', (44, 50))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
21164	31417090	This revealed cancer-subtype enrichments of known RNase IIIb hotspot mutations, which impair processing of miRNA-5p strands, and stratify the effects of tumors with biallelic inactivation on miRNA processing.	('cancer', 'Disease', (14, 20))	('RNase III', 'Gene', (50, 59))	('mutations', 'Var', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('p ', 'Gene', '677663', (114, 116))	('miRNA-5p', 'Chemical', '-', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('impair', 'NegReg', (86, 92))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('RNase III', 'Gene', '29102', (50, 59))
21165	31417090	Importantly, we also functionalize a recurrent biallelic DICER1 mutation in RNase IIIa (S1344L) that causes similar 5p depletion.	('mutation', 'Var', (64, 72))	('biallelic', 'Var', (47, 56))	('p ', 'Gene', '677663', (117, 119))	('RNase III', 'Gene', '29102', (76, 85))	('RNase III', 'Gene', (76, 85))	('S1344L', 'Mutation', 'p.S1344L', (88, 94))
21167	31417090	Interestingly, our cross-cancer analyses reveal DICER1 RNase IIIa/b hotspot mutations in restricted tumor types (Fig.	('cross-cancer', 'Disease', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (76, 85))	('DICER1', 'Gene', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', (100, 105))	('RNase III', 'Gene', '29102', (55, 64))	('cross-cancer', 'Disease', 'MESH:C537866', (19, 31))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('RNase III', 'Gene', (55, 64))
21169	31417090	Although DICER1 RNase IIIb mutations were previously studied in endometrial cancer, we broadly extend this phenomenon and show these events are depleted in many individual cancers, and in cancers in aggregate.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('RNase III', 'Gene', (16, 25))	('endometrial cancer', 'Disease', 'MESH:D016889', (64, 82))	('RNase III', 'Gene', '29102', (16, 25))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('DICER1', 'Gene', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('endometrial cancer', 'Disease', (64, 82))	('endometrial cancer', 'Phenotype', 'HP:0012114', (64, 82))
21173	31417090	These few include known tumor suppressors such as the let-7 and miR-15/16 families, both of which comprise 5p mature miRNA species whose defective biogenesis is a direct consequence of biallelic RNase IIIa/b hotspot mutations in DICER1.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('biogenesis', 'MPA', (147, 157))	('p ', 'Gene', '677663', (108, 110))	('tumor', 'Disease', (24, 29))	('RNase III', 'Gene', (195, 204))	('biallelic', 'Var', (185, 194))	('RNase III', 'Gene', '29102', (195, 204))	('DICER1', 'Gene', (229, 235))	('mutations', 'Var', (216, 225))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('miR-15', 'Chemical', '-', (64, 70))
21174	31417090	The let-7 family has previously been suggested as a tumor suppressor miRNA family that could be compromised by DICER1 RNase IIIb cancer hotspot mutations, but clear linkage to endogenous DICER1 tumor signature has not been established.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RNase III', 'Gene', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('let-7', 'Gene', (4, 9))	('tumor', 'Disease', (194, 199))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('RNase III', 'Gene', '29102', (118, 127))
21175	31417090	We observed that derepression of let-7 targets was the strongest GSEA signature obtained in DICER1 endometrial cancer, with known let-7 oncogene targets HMGA2 and IGFBP2 strongly deregulated (Table 1).	('IGFBP2', 'Gene', '3485', (163, 169))	('endometrial cancer', 'Disease', 'MESH:D016889', (99, 117))	('HMGA2', 'Gene', (153, 158))	('IGFBP2', 'Gene', (163, 169))	('derepression', 'Var', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('deregulated', 'PosReg', (179, 190))	('endometrial cancer', 'Disease', (99, 117))	('endometrial cancer', 'Phenotype', 'HP:0012114', (99, 117))	('DICER1', 'Gene', (92, 98))	('HMGA2', 'Gene', '8091', (153, 158))	('GSEA', 'Chemical', '-', (65, 69))
21176	31417090	In addition, while miR-15/16 is also recognized as tumor suppressor family, its impact has mostly been restricted to liquid cancers, in particular chronic lymphocytic leukemia.	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (147, 175))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('particular chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (136, 175))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('miR-15/16', 'Var', (19, 28))	('miR-15', 'Chemical', '-', (19, 25))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))	('cancers', 'Disease', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('particular chronic lymphocytic leukemia', 'Disease', (136, 175))
21178	31417090	We identify a number of miRNA targets derepressed in DICER1 hotspot tumors (Table 1) as candidates for evaluating potential involvement in oncogenesis.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('DICER1', 'Gene', (53, 59))	('derepressed', 'Var', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
21179	31417090	Overall, these integrated analysis of cancer genome, small RNA, and transcriptome profiling reveal tissue-specific accumulation of DICER1 RNase III hotspot mutations, including an allele within the RNase IIIa domain that affects RNase IIIb function.	('RNase III', 'Gene', (198, 207))	('RNase III', 'Gene', (229, 238))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('RNase III', 'Gene', '29102', (198, 207))	('mutations', 'Var', (156, 165))	('RNase III', 'Gene', (138, 147))	('function', 'MPA', (240, 248))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('RNase III', 'Gene', '29102', (138, 147))	('accumulation', 'PosReg', (115, 127))	('cancer', 'Disease', (38, 44))	('RNase III', 'Gene', '29102', (229, 238))	('affects', 'Reg', (221, 228))
21181	31417090	We used OncoKB (oncokb.org) and Cancer Hotspots (cancerhotspots.org) to identify recurrent hotspot mutations in DICER1.	('hotspot', 'PosReg', (91, 98))	('Cancer', 'Disease', (32, 38))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DICER1', 'Gene', (112, 118))	('mutations', 'Var', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
21182	31417090	These included well-characterized alterations of RNase IIIb metal-binding residues E1813, D1810, D1709, E1705, and the newly characterized allele in RNase IIIa S1344L.	('RNase III', 'Gene', '29102', (149, 158))	('E1813', 'Var', (83, 88))	('S1344L', 'Mutation', 'p.S1344L', (160, 166))	('E1705', 'Var', (104, 109))	('D1810', 'Var', (90, 95))	('RNase III', 'Gene', '29102', (49, 58))	('metal', 'Chemical', 'MESH:D008670', (60, 65))	('D1709', 'Var', (97, 102))	('RNase III', 'Gene', (149, 158))	('RNase III', 'Gene', (49, 58))
21183	31417090	We then identified DICER1 mutations using the TCGA MC3 2+ callers mutation data.	('mutations', 'Var', (26, 35))	('CG', 'Chemical', 'MESH:C028505', (47, 49))	('DICER1', 'Gene', (19, 25))
21184	31417090	Of 9919 samples in the TCGA PanCan dataset, 217 bore somatic DICER1 mutations, of which 31 harbored RNase IIIa/b hotspot mutations (one patient with 2).	('patient', 'Species', '9606', (136, 143))	('CG', 'Chemical', 'MESH:C028505', (24, 26))	('DICER1', 'Gene', (61, 67))	('mutations', 'Var', (68, 77))	('RNase III', 'Gene', (100, 109))	('RNase III', 'Gene', '29102', (100, 109))
21185	31417090	Similarly, analysis of 31,029 MSK-IMPACT patients with annotated clinical data and tumor subtypes yielded 597 somatic DICER1 mutant cases, of which 57 cases contained RNase IIIa/b hotspot mutations.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('contained', 'Reg', (157, 166))	('RNase III', 'Gene', (167, 176))	('mutant', 'Var', (125, 131))	('tumor', 'Disease', (83, 88))	('RNase III', 'Gene', '29102', (167, 176))	('DICER1', 'Gene', (118, 124))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
21204	31417090	To identify shifts in the expression of individual miRNA-5p and miRNA-3p species, we utilized the UCEC cohort, which had sufficient numbers of RNase III hotspot mutants for statistical comparisons.	('mutants', 'Var', (161, 168))	('miRNA-5p', 'Chemical', '-', (51, 59))	('p ', 'Gene', '677663', (71, 73))	('RNase III', 'Gene', (143, 152))	('RNase III', 'Gene', '29102', (143, 152))	('p ', 'Gene', '677663', (58, 60))
21205	31417090	We performed miRNA-arm differential expression analysis with these sets: (1) all RNase IIIb hotspot mutations (15 cases), (2) RNase IIIB non-biallelic mutations (11 cases), (3) RNase IIIb biallelic mutations (four cases), versus all other samples as controls (bearing non-hotspot DICER mutations or DICER-wt alleles, 548 cases).	('RNase III', 'Gene', '29102', (177, 186))	('mutations', 'Var', (100, 109))	('RNase III', 'Gene', (177, 186))	('DICER', 'Gene', (299, 304))	('RNase III', 'Gene', '29102', (81, 90))	('RNase III', 'Gene', '29102', (126, 135))	('biallelic mutations', 'Var', (188, 207))	('RNase III', 'Gene', (126, 135))	('RNase III', 'Gene', (81, 90))	('DICER', 'Gene', '23405', (280, 285))	('DICER', 'Gene', (280, 285))	('DICER', 'Gene', '23405', (299, 304))
21211	31417090	A shift in the median 5p/3p ratio between WT and RNase IIIb hotspot mutations in different cancer types is interpreted as a ratio bias, which can be attributed to compromised processing of miRNA-5p and -3p arms.	('p ', 'Gene', '677663', (204, 206))	('miRNA-5p', 'Chemical', '-', (189, 197))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('p ', 'Gene', '677663', (26, 28))	('WT', 'Disease', 'MESH:C536751', (42, 44))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (68, 77))	('p ', 'Gene', '677663', (196, 198))	('RNase III', 'Gene', '29102', (49, 58))	('RNase III', 'Gene', (49, 58))
21212	31417090	To determine whether certain types of tumors are enriched for DICER1 hotspot mutations in TCGA and MSK-IMPACT datasets, we performed a resampling test where we generated a distribution from random sampling for each tumor type, and assessed significance for enrichment via this bootstrap procedure.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumors', 'Disease', (38, 44))	('TCGA', 'Gene', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mutations', 'Var', (77, 86))	('hotspot', 'PosReg', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (215, 220))	('CG', 'Chemical', 'MESH:C028505', (91, 93))	('MSK-IMPACT', 'Gene', (99, 109))	('DICER1', 'Gene', (62, 68))	('p ', 'Gene', '677663', (285, 287))
21215	31417090	DICER1 RNase III hotspot mutations are overall rare in both TCGA and MSK-IMPACT datasets (31/9919 samples for TCGA and 57/31029 samples for MSK-IMPACT.	('TCGA', 'Disease', (60, 64))	('mutations', 'Var', (25, 34))	('RNase III', 'Gene', (7, 16))	('RNase III', 'Gene', '29102', (7, 16))	('CG', 'Chemical', 'MESH:C028505', (111, 113))	('CG', 'Chemical', 'MESH:C028505', (61, 63))
21219	31417090	Using this approach, we were able to reliably estimate statistical significance for depletion of hotspot mutations for two cancer types in the MSK-IMPACT data.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('depletion', 'MPA', (84, 93))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', (123, 129))
21220	31417090	Still, we note >20 individual cancer types with >200 cases that completely lack DICER1 RNase III hotspot mutations (Supplementary Figs.	('DICER1', 'Gene', (80, 86))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('RNase III', 'Gene', '29102', (87, 96))	('mutations', 'Var', (105, 114))	('RNase III', 'Gene', (87, 96))	('lack', 'NegReg', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
21222	31417090	Thus, there appears to be a general depletion of DICER1 RNase III hotspot mutations across many cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('DICER1', 'Gene', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (74, 83))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('RNase III', 'Gene', '29102', (56, 65))	('RNase III', 'Gene', (56, 65))	('cancers', 'Disease', (96, 103))
21223	31417090	Our analyses of small RNA data and DICER mutant constructs revealed that RNase IIIa-S1344L variant unexpectedly compromised the biogenesis of 5p-strand miRNAs, which are cleaved from pre-miRNA by DICER1 RNase IIIb.	('compromised', 'NegReg', (112, 123))	('DICER', 'Gene', (196, 201))	('variant', 'Var', (91, 98))	('biogenesis of 5p-strand miRNAs', 'MPA', (128, 158))	('DICER', 'Gene', (35, 40))	('RNase III', 'Gene', '29102', (203, 212))	('RNase III', 'Gene', (203, 212))	('RNase III', 'Gene', (73, 82))	('RNase III', 'Gene', '29102', (73, 82))	('S1344L', 'Mutation', 'p.S1344L', (84, 90))	('DICER', 'Gene', '23405', (196, 201))	('DICER', 'Gene', '23405', (35, 40))
21224	31417090	Based on the fact that RNase III dimerization is necessary for proper DICER1 functioning, we wanted to see how S1344L could affect 5p miRNA processing.	('RNase III', 'Gene', '29102', (23, 32))	('p ', 'Gene', '677663', (132, 134))	('RNase III', 'Gene', (23, 32))	('affect', 'Reg', (124, 130))	('S1344L', 'Var', (111, 117))	('S1344L', 'Mutation', 'p.S1344L', (111, 117))
21226	31417090	To test whether DICER1 hotspot mutants had distinct gene expression profiles compared to other samples, we obtained processed and normalized RNA-seq datasets (Level 4) from TCGA analysis runs as generated with the Firehose analysis pipeline [https://gdac.broadinstitute.org/].	('CG', 'Chemical', 'MESH:C028505', (174, 176))	('mutants', 'Var', (31, 38))	('DICER1', 'Gene', (16, 22))
21227	31417090	Most TCGA tumor cohorts had <3 RNA-seq datasets for RNase IIIa/b hotspot mutants, hindering a statistically robust comparison.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('mutants', 'Var', (73, 80))	('CG', 'Chemical', 'MESH:C028505', (6, 8))	('RNase III', 'Gene', '29102', (52, 61))	('RNase III', 'Gene', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
21228	31417090	Therefore, we restricted this analysis to the UCEC study, utilizing there were eight DICER1 RNase IIIa/b hotspot mutant and 222 DICER1 wildtype and non-hotspot samples with RNA-seq data.	('mutant', 'Var', (113, 119))	('DICER1', 'Gene', (85, 91))	('RNase III', 'Gene', '29102', (92, 101))	('RNase III', 'Gene', (92, 101))
21233	31417090	Mutant DICER1 constructs (R944Q, S1344L, E1813G) were made through site-directed mutagenesis protocol (Agilent QuikChange) of mammalian expression construct of Flag-HA-tagged human DICER1, Addgene plasmid #19881.	('DICER1', 'Gene', (7, 13))	('S1344L', 'Mutation', 'p.S1344L', (33, 39))	('human', 'Species', '9606', (175, 180))	('mammalian', 'Species', '9606', (126, 135))	('R944Q', 'Var', (26, 31))	('R944Q', 'Mutation', 'p.R944Q', (26, 31))	('E1813G', 'Mutation', 'p.E1813G', (41, 47))	('E1813G', 'Var', (41, 47))	('S1344L', 'Var', (33, 39))
21238	31417090	Dicer-KO MEF cells were transfected with published constructs expressing pri-miRNA constructs (mir-144/451 and either mir-151 or mir-199a-1) and either wild-type or mutant hDICER1 construct (WT or R944Q or S1344L or E1813G), as indicated.	('WT', 'Disease', 'MESH:C536751', (191, 193))	('mir-151', 'Gene', '442893', (118, 125))	('mir-144', 'Gene', '406936', (95, 102))	('mir-144', 'Gene', (95, 102))	('R944Q', 'Var', (197, 202))	('R944Q', 'Mutation', 'p.R944Q', (197, 202))	('S1344L', 'Var', (206, 212))	('hDICER1', 'Gene', (172, 179))	('Dicer', 'Gene', '23405', (0, 5))	('E1813G', 'Mutation', 'p.E1813G', (216, 222))	('Dicer', 'Gene', (0, 5))	('S1344L', 'Mutation', 'p.S1344L', (206, 212))	('MEF', 'CellLine', 'CVCL:9115', (9, 12))	('mir-199a-1', 'Gene', '406976', (129, 139))	('E1813G', 'Var', (216, 222))	('mir-199a-1', 'Gene', (129, 139))	('hDICER1', 'Gene', '23405', (172, 179))	('mir-151', 'Gene', (118, 125))
21364	30873825	Paclitaxel-based chemotherapy, with or without radiotherapy, compared with observation or non-chemotherapy options (observation or only radiotherapy) had both 22% improvement in DFS; these differences trended toward statistical significance (p=0.079 and p=0.070, respectively).	('DFS', 'MPA', (178, 181))	('Paclitaxel-based chemotherapy', 'Var', (0, 29))	('Paclitaxel', 'Chemical', 'MESH:D017239', (0, 10))	('improvement', 'PosReg', (163, 174))
21463	30202756	Endometrial thickness <=4 mm on TVS in postmenopausal women at average risk has been demonstrated to be an effective test to exclude endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (133, 151))	('TVS', 'Chemical', '-', (32, 35))	('endometrial cancer', 'Disease', 'MESH:D016889', (133, 151))	('women', 'Species', '9606', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('endometrial cancer', 'Disease', (133, 151))	('<=4', 'Var', (22, 25))
21478	26855091	Doing so may worsen the prognosis of uterine sarcoma and confer the need for additional treatment.	('Doing', 'Var', (0, 5))	('sarcoma', 'Disease', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (37, 52))	('worsen', 'NegReg', (13, 19))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))
21603	28424084	5a, b) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (7.6 cm, previous 20 cm) and a fistula between her small intestine and vagina.	('Tumors', 'Phenotype', 'HP:0002664', (58, 64))	('fistula', 'Disease', 'MESH:D005402', (114, 121))	('fistula', 'Disease', (114, 121))	('Solid Tumors', 'Disease', 'MESH:D009369', (52, 64))	('7.6', 'Var', (84, 87))	('Solid Tumors', 'Disease', (52, 64))
21635	27504125	Institutional experience using interstitial brachytherapy for the treatment of primary and recurrent pelvic malignancies The study assessed the outcomes of patients at a single institution with locally advanced primary and recurrent pelvic malignancies treated with interstitial high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy (BT), using a modified Syed-Neblett template.	('patients', 'Species', '9606', (156, 164))	('malignancies', 'Disease', 'MESH:D009369', (240, 252))	('pelvic malignancies', 'Disease', 'MESH:D010386', (101, 120))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('low-dose-rate', 'Var', (303, 316))	('pelvic malignancies', 'Disease', (101, 120))	('malignancies', 'Disease', (240, 252))	('malignancies', 'Disease', (108, 120))	('pelvic malignancies', 'Disease', 'MESH:D010386', (233, 252))	('pelvic malignancies', 'Disease', (233, 252))
21652	27504125	Patients with vaginal recurrence of pelvic tumors such as endometrial cancer are infrequently candidates for repeat surgical excision, however combination BT and EBRT provides excellent long-term control and is a potentially curative option in localized disease.	('combination', 'Var', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('endometrial cancer', 'Disease', 'MESH:D016889', (58, 76))	('endometrial cancer', 'Phenotype', 'HP:0012114', (58, 76))	('pelvic tumors', 'Disease', 'MESH:D010386', (36, 49))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('EBRT', 'Chemical', '-', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('pelvic tumors', 'Disease', (36, 49))	('endometrial cancer', 'Disease', (58, 76))
21739	27504125	On multivariate analysis, combination EBRT and BT was associated with improved LC.	('EBRT', 'Chemical', '-', (38, 42))	('EBRT', 'Var', (38, 42))	('improved', 'PosReg', (70, 78))
21760	26327203	Treatment of SNU539 cells with anti-SAS1B polyclonal antibodies caused growth arrest in the presence of active complement.	('growth arrest', 'Disease', 'MESH:D006323', (71, 84))	('anti-SAS1B', 'Var', (31, 41))	('growth arrest', 'Disease', (71, 84))	('growth arrest', 'Phenotype', 'HP:0001510', (71, 84))
21822	26327203	Second, antibodies in the presence of complement arrest the growth of SAS1Bpos uterine cancer cells.	('SAS1Bpos', 'Var', (70, 78))	('complement arrest', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('complement arrest', 'Disease', 'MESH:D006323', (38, 55))	('uterine cancer', 'Disease', (79, 93))	('growth', 'CPA', (60, 66))	('uterine cancer', 'Disease', 'MESH:D014594', (79, 93))	('uterine cancer', 'Phenotype', 'HP:0010784', (79, 93))
21868	26327203	Reactivation of the male gamatogenic expression program is associated with highly malignant phenotypes and, along with a tumor environment characterized by hypoxia and inflammation, is thought to be limiting for conventional therapy.	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('male gamatogenic expression program', 'Gene', (20, 55))	('tumor', 'Disease', (121, 126))	('Reactivation', 'Var', (0, 12))	('inflammation', 'Disease', 'MESH:D007249', (168, 180))	('inflammation', 'Disease', (168, 180))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
21935	26327871	At laparotomy: status post amputation of the uterine corpus; the bowel was adhered to the cervical stump; no abnormalities were detected in both ovaries, omentum, abdominal organs and abdominal and pelvic peritoneum.	('ovaries', 'Disease', 'MESH:D010051', (145, 152))	('bowel', 'Disease', 'MESH:D015212', (65, 70))	('bowel', 'Disease', (65, 70))	('ovaries', 'Disease', (145, 152))	('amputation', 'Var', (27, 37))
21988	26327871	The authors emphasize the value of thorough assessment of the clinical stage of disease and add that inadvertent morcellation of malignancy is associated with a high risk of dissemination of cancer cells.	('inadvertent', 'Var', (101, 112))	('associated', 'Reg', (143, 153))	('malignancy', 'Disease', (129, 139))	('dissemination of cancer', 'Disease', (174, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('dissemination of cancer', 'Disease', 'MESH:D009369', (174, 197))
22008	26327871	According to Helstrom et al., 21% of women who had amputation of the uterine corpus report deterioration in sexual function.	('deterioration', 'NegReg', (91, 104))	('sexual function', 'CPA', (108, 123))	('amputation', 'Var', (51, 61))	('women', 'Species', '9606', (37, 42))
22064	23707671	Microsatellite instability (MSI) and mutations in the tumor suppressor gene PTEN are more common in type I endometrial cancer, which portends more favorable prognosis.	('common', 'Reg', (90, 96))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('type I endometrial cancer', 'Disease', (100, 125))	('PTEN', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('PTEN', 'Gene', '5728', (76, 80))	('endometrial cancer', 'Phenotype', 'HP:0012114', (107, 125))	('mutations', 'Var', (37, 46))	('Microsatellite instability', 'Disease', (0, 26))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('type I endometrial cancer', 'Disease', 'MESH:D016889', (100, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
22065	23707671	In single-institution studies, PTEN mutations are less common in African American compared to Caucasian women; however, the evidence on MSI is conflicting.	('PTEN', 'Gene', (31, 35))	('PTEN', 'Gene', '5728', (31, 35))	('mutations', 'Var', (36, 45))	('women', 'Species', '9606', (104, 109))
22066	23707671	In a study of 140 cases of endometrial adenocarcinoma, PTEN mutations were seen in 17 of 78 (22%) Caucasian patients compared to 3 out of 62 (5%) African American patients.	('PTEN', 'Gene', '5728', (55, 59))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (108, 116))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (27, 53))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (27, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('seen', 'Reg', (75, 79))	('mutations', 'Var', (60, 69))	('endometrial adenocarcinoma', 'Disease', (27, 53))	('PTEN', 'Gene', (55, 59))
22070	23707671	In contrast, mutations in tumor suppressor gene p53 are more common in type II endometrial cancer and are associated with poorer prognosis.	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (48, 51))	('endometrial cancer', 'Phenotype', 'HP:0012114', (79, 97))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('type II endometrial cancer', 'Disease', (71, 97))	('tumor', 'Disease', (26, 31))	('common', 'Reg', (61, 67))	('type II endometrial cancer', 'Disease', 'MESH:D016889', (71, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutations', 'Var', (13, 22))
22076	23707671	When adjusted for race and age, heavy HER2/neu expression was associated with earlier death (adjusted HR 28.00, p-value=0.02) and presumably more aggressive disease.	('aggressive disease', 'Disease', 'MESH:D001523', (146, 164))	('HER2/neu', 'Gene', (38, 46))	('aggressive disease', 'Disease', (146, 164))	('death', 'Disease', 'MESH:D003643', (86, 91))	('death', 'Disease', (86, 91))	('heavy', 'Var', (32, 37))	('HER2/neu', 'Gene', '2064', (38, 46))
22093	23707671	Other studies have demonstrated alterations affecting the ERBB2 oncogene, which have been associated with poor outcomes and are more common in endometrial cancers from African American compared to Caucasian women.	('endometrial cancer', 'Phenotype', 'HP:0012114', (143, 161))	('endometrial cancers', 'Disease', 'MESH:D016889', (143, 162))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('women', 'Species', '9606', (207, 212))	('ERBB2', 'Gene', '2064', (58, 63))	('endometrial cancers', 'Disease', (143, 162))	('associated', 'Reg', (90, 100))	('ERBB2', 'Gene', (58, 63))	('alterations', 'Var', (32, 43))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('common', 'Reg', (133, 139))
22173	24099838	Patients whose tumors had a DMI <50% were more likely to have positive SLNs on routine H&E (p<0.005) or after ultrastaging (p=0.01) compared to those without myoinvasion.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('DMI', 'Chemical', '-', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Patients', 'Species', '9606', (0, 8))	('H&E', 'Chemical', '-', (87, 90))	('SLNs', 'MPA', (71, 75))	('<50%', 'Var', (32, 36))	('tumors', 'Disease', (15, 21))
22213	24099838	Four hundred sixty-six patients with preoperative G1/G2 endometrioid adenocarcinomas who underwent surgical staging with SLN mapping and biopsy were identified.	('patients', 'Species', '9606', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (56, 83))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (56, 84))	('G1/G2', 'Var', (50, 55))	('endometrioid adenocarcinomas', 'Disease', (56, 84))
22361	21663687	The serum concentrations of cancer markers CEA, AFP, CA 19-9, CA 125, HE4, CA 15-3 are within the norm.	('HE4', 'Gene', (70, 73))	('CA 15-3', 'Gene', '4582', (75, 82))	('HE4', 'Gene', '10406', (70, 73))	('CA 125', 'Var', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CA 19-9', 'Var', (53, 60))	('CEA', 'Gene', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('AFP', 'Gene', (48, 51))	('CA 15-3', 'Gene', (75, 82))	('CEA', 'Gene', '5670', (43, 46))	('cancer', 'Disease', (28, 34))	('AFP', 'Gene', '174', (48, 51))
22437	20838549	Immunohistochemistry showed CD117 positivity and CD 10 positivity in the tumor cells [Figure 2].	('CD117', 'Gene', '3815', (28, 33))	('positivity', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('CD117', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CD 10', 'Gene', (49, 54))	('positivity', 'Var', (55, 65))	('tumor', 'Disease', (73, 78))	('CD 10', 'Gene', '4311', (49, 54))
22450	20838549	C-Kit is expressed in most gastrointestinal stromal tumors, and they usually show c-kit aberrations (most frequently deletions or deletions coexisting with a single or multiple point mutations).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('deletions', 'Var', (130, 139))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (27, 58))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (27, 58))	('C-Kit', 'Gene', '3815', (0, 5))	('gastrointestinal stromal tumors', 'Disease', (27, 58))	('C-Kit', 'Gene', (0, 5))	('deletions', 'Var', (117, 126))	('c-kit', 'Gene', '3815', (82, 87))	('c-kit', 'Gene', (82, 87))
22528	33078591	Genomic and molecular studies of UCCC have been smaller, but have identified uterine clear cell histology to be correlated with being HNF1ss-positive, napsin A-positive, ER-negative, and mutations in TP53, PIK3CA, PPP2R1A, FBXW7, and ARID1A, among others.	('napsin A', 'Gene', '9476', (151, 159))	('uterine clear cell histology', 'CPA', (77, 105))	('HNF1', 'Gene', '6927', (134, 138))	('ER', 'Gene', '2069', (170, 172))	('FBXW7', 'Gene', '55294', (223, 228))	('PPP2R1A', 'Gene', '5518', (214, 221))	('HNF1', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (200, 204))	('TP53', 'Gene', (200, 204))	('mutations', 'Var', (187, 196))	('PIK3CA', 'Gene', (206, 212))	('ARID1A', 'Gene', (234, 240))	('ARID1A', 'Gene', '8289', (234, 240))	('UCCC', 'Phenotype', 'HP:0031522', (33, 37))	('FBXW7', 'Gene', (223, 228))	('napsin A', 'Gene', (151, 159))	('PIK3CA', 'Gene', '5290', (206, 212))	('PPP2R1A', 'Gene', (214, 221))
22530	33078591	Mutations distinguishing UCCC from other histologic subtypes may help identify drivers of this cancer to better understand the differences in incidence rates for each race and ethnicity.	('UCCC', 'Phenotype', 'HP:0031522', (25, 29))	('UCCC', 'Disease', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
22536	32612247	Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population.	('fumarase', 'Gene', (94, 102))	('leiomyomas', 'Disease', 'MESH:D007889', (169, 179))	('Uterine leiomyomas', 'Phenotype', 'HP:0000131', (161, 179))	('deficient uterine', 'Phenotype', 'HP:0000013', (26, 43))	('missense variants', 'Var', (143, 160))	('leiomyomas', 'Disease', (169, 179))	('variants', 'Var', (103, 111))	('leiomyomas', 'Disease', 'MESH:D007889', (44, 54))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (36, 54))	('FH-deficient uterine leiomyomas', 'Disease', (23, 54))	('FH-deficient uterine leiomyomas', 'Disease', 'MESH:D007889', (23, 54))	('fumarase', 'Gene', '2271', (94, 102))	('leiomyomas', 'Disease', (44, 54))	('ULs', 'Phenotype', 'HP:0000131', (181, 184))
22538	32612247	We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all.	('variants', 'Var', (127, 135))	('FH deficient ULs', 'Disease', 'MESH:D006938', (16, 32))	('FH', 'Gene', '2271', (124, 126))	('ULs', 'Phenotype', 'HP:0000131', (29, 32))	('FH', 'Gene', '2271', (16, 18))	('FH deficient ULs', 'Disease', (16, 32))
22539	32612247	In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele.	('missense', 'Var', (61, 69))	('FH', 'Gene', '2271', (22, 24))	('truncating', 'MPA', (45, 55))
22540	32612247	Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency.	('missense variants', 'Var', (37, 54))	('FH deficiency', 'Disease', 'MESH:D006938', (178, 191))	('oligomerization', 'MPA', (102, 117))	('degradation', 'MPA', (134, 145))	('altered', 'Reg', (85, 92))	('FH deficiency', 'Disease', (178, 191))	('fumarase', 'Gene', '2271', (93, 101))	('fumarase', 'Gene', (93, 101))
22541	32612247	Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('FH', 'Gene', '2271', (10, 12))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('deletions', 'Var', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
22543	32612247	Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7-13.9% of females with an FH deficient UL to carry a germline FH variant.	('FH', 'Gene', '2271', (164, 166))	('FH deficient UL', 'Disease', 'MESH:D007889', (33, 48))	('FH deficient UL', 'Disease', 'MESH:D007889', (128, 143))	('FH deficient ULs', 'Disease', 'MESH:D006938', (33, 49))	('FH', 'Gene', '2271', (33, 35))	('FH', 'Gene', '2271', (128, 130))	('variant', 'Var', (167, 174))	('ULs', 'Phenotype', 'HP:0000131', (46, 49))	('FH deficient UL', 'Disease', (128, 143))	('FH deficient ULs', 'Disease', (33, 49))
22551	32612247	The authors could associate the combined polygenic risk with the most common UL subtype, positive for somatic MED12 mutations.	('mutations', 'Var', (116, 125))	('MED12', 'Gene', (110, 115))	('MED12', 'Gene', '9968', (110, 115))
22552	32612247	ULs with either MED12 hotspot driver mutations or with genomic rearrangements involving HMGA2 are the most common and represent up to 90%.	('HMGA2', 'Gene', '8091', (88, 93))	('MED12', 'Gene', (16, 21))	('HMGA2', 'Gene', (88, 93))	('MED12', 'Gene', '9968', (16, 21))	('mutations', 'Var', (37, 46))	('ULs', 'Phenotype', 'HP:0000131', (0, 3))
22553	32612247	The two other known subtypes, defined by typical deletions in the COL4A5/COL4A6 genes or FH deficiency, are much rarer.	('FH deficiency', 'Disease', 'MESH:D006938', (89, 102))	('COL4A5', 'Gene', '1287', (66, 72))	('COL4A6', 'Gene', '1288', (73, 79))	('COL4A6', 'Gene', (73, 79))	('deletions', 'Var', (49, 58))	('FH deficiency', 'Disease', (89, 102))	('COL4A5', 'Gene', (66, 72))
22554	32612247	The COL4A5/COL4A6 deletion positive UL subtype constitutes about 2%.	('COL4A5', 'Gene', '1287', (4, 10))	('deletion positive', 'Var', (18, 35))	('COL4A6', 'Gene', '1288', (11, 17))	('COL4A5', 'Gene', (4, 10))	('COL4A6', 'Gene', (11, 17))
22556	32612247	Recurrent deletions at the COL4A5/COL4A6 gene locus lead to the X-linked dominantly inherited diffuse leiomyomatosis with Alport syndrome (DL-ATS; OMIM #308940).	('COL4A5', 'Gene', '1287', (27, 33))	('leiomyomatosis', 'Disease', (102, 116))	('deletions', 'Var', (10, 19))	('COL4A6', 'Gene', '1288', (34, 40))	('diffuse leiomyomatosis', 'Phenotype', 'HP:0006756', (94, 116))	('COL4A6', 'Gene', (34, 40))	('Alport syndrome', 'Disease', (122, 137))	('COL4A5', 'Gene', (27, 33))	('lead to', 'Reg', (52, 59))	('leiomyomatosis', 'Disease', 'MESH:D018231', (102, 116))
22557	32612247	Germline Loss-of-Function variants (both truncating and missense) in the fumarate hydratase (FH) (fumarase) gene FH cause the dominantly inherited hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC; OMIM #150800).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('fumarase', 'Gene', '2271', (98, 106))	('renal cell cancer', 'Phenotype', 'HP:0005584', (177, 194))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('fumarase', 'Gene', (98, 106))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (207, 210))	('missense', 'Var', (56, 64))	('Loss-of-Function', 'NegReg', (9, 25))	('FH', 'Gene', '2271', (93, 95))	('fumarate hydratase', 'Gene', '2271', (73, 91))	('FH', 'Gene', '2271', (113, 115))	('fumarate hydratase', 'Gene', (73, 91))	('inherited hereditary leiomyomatosis and renal cell cancer syndrome', 'Disease', 'MESH:C535516', (137, 203))	('variants', 'Var', (26, 34))
22563	32612247	Loss of staining for the FH gene product FH is an intuitive direct marker, but recent reports of retained staining in tumors with pathogenic missense variants raised concerns about its validity as marker for FH deficiency.	('FH', 'Gene', '2271', (41, 43))	('FH', 'Gene', '2271', (25, 27))	('FH deficiency', 'Disease', (208, 221))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('FH', 'Gene', '2271', (208, 210))	('tumors', 'Disease', (118, 124))	('FH deficiency', 'Disease', 'MESH:D006938', (208, 221))	('missense variants', 'Var', (141, 158))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
22568	32612247	The The Cancer Genome Atlas Program (TCGA) study has identified frequent monoallelic (78%) and often biallelic (14%) deletions of the tumor suppressor gene RB1 as a driver in ULMSs.	('Cancer', 'Disease', 'MESH:D009369', (8, 14))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', (134, 139))	('RB1', 'Gene', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('RB1', 'Gene', '5925', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('deletions', 'Var', (117, 126))	('biallelic', 'Var', (101, 110))	('Cancer', 'Disease', (8, 14))	('ULMSs', 'Disease', (175, 180))	('ULMSs', 'Phenotype', 'HP:0002891', (175, 180))
22570	32612247	Based on our cohort previously screened on morphological features and by FH IHC, we now analyzed 13 FH deficient ULs with available tumor DNA by targeted panel sequencing to investigate their somatic variant spectrum for both small genetic (single nucleotide variants: SNVs, base insertions or deletions: indels) and copy number variants (CNVs) and additionally characterized these ULs by RB1 IHC.	('RB1', 'Gene', (389, 392))	('base insertions', 'Var', (275, 290))	('FH', 'Gene', '2271', (100, 102))	('FH deficient ULs', 'Disease', (100, 116))	('deletions', 'Var', (294, 303))	('FH', 'Gene', '2271', (73, 75))	('RB1', 'Gene', '5925', (389, 392))	('copy number variants', 'Var', (317, 337))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ULs', 'Phenotype', 'HP:0000131', (382, 385))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('ULs', 'Phenotype', 'HP:0000131', (113, 116))	('FH deficient ULs', 'Disease', 'MESH:D006938', (100, 116))
22575	32612247	FH expression was classified into four categories (intact, loss/deficient, aberrant expression, not assessable).	('FH', 'Gene', '2271', (0, 2))	('aberrant', 'Var', (75, 83))	('loss/deficient', 'Disease', (59, 73))	('loss/deficient', 'Disease', 'MESH:D014786', (59, 73))
22590	32612247	We then plotted the theoretical relationship between tumor purity (TP) and expected variant allele fraction (VAF) for germline and somatic variants (formula: "AF = TP + (1-TP) * initial zygosity in the germline") assuming a somatic second-hit deleting the other allele and compared this to the variant allele frequency observed in our samples (see Figure S3 for methodological details).	('deleting', 'Var', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('AF', 'Disease', 'MESH:D001281', (110, 112))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('AF', 'Disease', 'MESH:D001281', (159, 161))	('tumor', 'Disease', (53, 58))
22591	32612247	To analyze enrichment of likely disease associated FH variants in domains, we downloaded all described variants from the ClinVar, LOVD, and COSMIC databases and scored these with InterVar according to the American College of Medical Genetics and Genomics (ACMG) 5-tier classification, which is typically used to assess the pathogenicity of SNVs/indels in a clinical setting.	('variants', 'Var', (103, 111))	('variants', 'Var', (54, 62))	('FH', 'Gene', '2271', (51, 53))
22595	32612247	We visualized the spatial clustering of identified likely somatic FH missense variants in 3D using the publicly available tertiary protein structure data of human fumarase (PDB-ID: 5D6B) with the Pymol molecular visualization software (Version 1.8.6.0; Schrodinger LLC, New York, USA) installed through Conda (Anaconda Inc., Austin, USA).	('FH', 'Gene', '2271', (66, 68))	('missense variants', 'Var', (69, 86))	('fumarase', 'Gene', '2271', (163, 171))	('human', 'Species', '9606', (157, 162))	('fumarase', 'Gene', (163, 171))
22606	32612247	Tumor-only variant calling for small genetic variants using a somatic variant caller identified a single SNV/indel in the FH gene in 8/13 (61.5%) of ULs.	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('ULs', 'Phenotype', 'HP:0000131', (149, 152))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor', 'Disease', (0, 5))	('ULs', 'Disease', (149, 152))	('single SNV/indel', 'Var', (98, 114))	('FH', 'Gene', '2271', (122, 124))
22607	32612247	The variant c.457delG in individual S06 causes a frame-shift that directly introduces a termination codon (p.(Val153*)).	('causes', 'Reg', (40, 46))	('S06', 'Gene', (36, 39))	('p.(Val153*', 'Var', (107, 117))	('c.457delG', 'Var', (12, 21))	('c.457delG', 'Mutation', 'c.457delG', (12, 21))	('frame-shift', 'MPA', (49, 60))	('p.(Val153*)', 'SUBSTITUTION', 'None', (107, 118))
22608	32612247	The variant c.379-2 A > G in S03 disrupts the conserved splice-acceptor of exon 4, is predicted to cause aberrant splicing (denoted as "r.spl?"	('disrupts', 'NegReg', (33, 41))	('c.379-2 A > G', 'Mutation', 'rs1131691240', (12, 25))	('cause', 'Reg', (99, 104))	('S03', 'Gene', (29, 32))	('conserved splice-acceptor of exon 4', 'MPA', (46, 81))	('c.379-2 A > G', 'Var', (12, 25))	('splicing', 'MPA', (114, 122))
22610	32612247	Only the variant c.1236 G > A, p.(Met412Ile) identified in S09 was predicted as benign by five out of eight scores.	('p.(Met412Ile', 'Var', (31, 43))	('c.1236 G > A', 'Var', (17, 29))	('c.1236 G > A', 'Mutation', 'c.1236G>A', (17, 29))	('p.(Met412Ile)', 'SUBSTITUTION', 'None', (31, 44))
22611	32612247	Instead, this variant is predicted to cause aberrant splicing by four of the five splice prediction tools used (Supplementary file 1 sheet "FH_SNVindel_summary").	('cause', 'Reg', (38, 43))	('variant', 'Var', (14, 21))	('FH', 'Gene', '2271', (140, 142))	('splicing', 'MPA', (53, 61))
22614	32612247	Therefore, it seems likely that the c.1236 G > A variant in fact disrupts normal splicing (HGVS nomenclature "r.spl?")	('disrupts', 'NegReg', (65, 73))	('c.1236 G > A', 'Mutation', 'c.1236G>A', (36, 48))	('c.1236 G > A', 'Var', (36, 48))	('normal splicing', 'MPA', (74, 89))
22616	32612247	As missense variants are not expected to cause protein loss, but all 13 ULs were preselected based on complete FH-loss in IHC, the identification of true missense variants in 5/13 (38.5%) of ULs was unanticipated.	('ULs', 'Phenotype', 'HP:0000131', (72, 75))	('missense variants', 'Var', (154, 171))	('ULs', 'Phenotype', 'HP:0000131', (191, 194))	('FH-loss in IHC', 'Disease', (111, 125))	('FH-loss in IHC', 'Disease', 'MESH:D006938', (111, 125))
22617	32612247	When analyzing the proximity of the missense variants in the tertiary fumarase protein structure, we observed that the variants lie very close to each other (Fig.	('missense variants', 'Var', (36, 53))	('fumarase', 'Gene', (70, 78))	('fumarase', 'Gene', '2271', (70, 78))
22618	32612247	We therefore performed 3D clustering analyses using mutation3D, which showed that the three variants identified in samples S01 (c.944 T > C, p.(Leu315Pro)), S07 (c.824 G > C, p.(Gly275Ala)), and S10 (c.817 G > A, p.(Ala273Thr)) form a protein-wide significant cluster (p value: 0.0411, empirical bootstrapping approach) within the fumarase protein (Figure S2).	('c.944 T > C', 'Mutation', 'c.944T>C', (128, 139))	('p.(Leu315Pro', 'Var', (141, 153))	('fumarase', 'Gene', (331, 339))	('c.824 G > C', 'Mutation', 'rs753763148', (162, 173))	('p.(Gly275Ala)', 'SUBSTITUTION', 'None', (175, 188))	('p.(Ala273Thr)', 'Mutation', 'p.A273T', (213, 226))	('S10', 'Gene', (195, 198))	('S10', 'Gene', '6204', (195, 198))	('p.(Leu315Pro)', 'SUBSTITUTION', 'None', (141, 154))	('c.817 G > A', 'Mutation', 'c.817G>A', (200, 211))	('fumarase', 'Gene', '2271', (331, 339))	('p.(Gly275Ala', 'Var', (175, 187))	('c.944 T > C', 'Var', (128, 139))
22619	32612247	While the genomic position of seven SNV/indel variants showed high read coverage allowing reliable estimation of VAF, only the variant c.824 G > C, p.(Gly275Ala) in individual S07 was covered relatively low with 19 reads.	('c.824 G > C', 'Mutation', 'rs753763148', (135, 146))	('p.(Gly275Ala', 'Var', (148, 160))	('c.824 G > C', 'Var', (135, 146))	('p.(Gly275Ala)', 'SUBSTITUTION', 'None', (148, 161))	('AF', 'Disease', 'MESH:D001281', (114, 116))
22624	32612247	In sample S12, the CNVkit algorithm indeed called a small 15.9 kb deletion affecting exons 3 to 10 of the FH gene and a large 1407.7 kb deletion in the chromosomal band 1q43 affecting the whole FH gene (Fig.	('FH', 'Gene', '2271', (106, 108))	('S12', 'Gene', (10, 13))	('affecting', 'Reg', (174, 183))	('S12', 'Gene', '6268', (10, 13))	('deletion', 'Var', (136, 144))	('FH', 'Gene', '2271', (194, 196))	('deletion', 'Var', (66, 74))
22625	32612247	For seven of the eight ULs with a SNV/indel variant identified, the CN-analysis indicated the deletion of a single allele, confirming the suspicion from the observed high VAF.	('ULs', 'Phenotype', 'HP:0000131', (23, 26))	('SNV/indel', 'Var', (34, 43))	('deletion', 'Var', (94, 102))	('AF', 'Disease', 'MESH:D001281', (172, 174))
22626	32612247	In UL sample S05, with the c.587 A > T, p.(His196Leu) variant at a relatively low VAF of 0.443, a 15.9 kb small deletion was called.	('c.587 A > T', 'Mutation', 'c.587A>T', (27, 38))	('AF', 'Disease', 'MESH:D001281', (83, 85))	('c.587 A > T', 'Var', (27, 38))	('p.(His196Leu)', 'SUBSTITUTION', 'None', (40, 53))	('p.(His196Leu', 'Var', (40, 52))
22628	32612247	The analysis of other genes covered by the panel identified the two pathogenic likely gene disrupting variants c.782 + 1 G > T, p.0?	('p.0?', 'Var', (128, 132))	('p.0?', 'SUBSTITUTION', 'None', (128, 132))	('1 G > T', 'SUBSTITUTION', 'None', (119, 126))	('1 G > T', 'Var', (119, 126))
22629	32612247	and c.309 C > A, p.(Tyr103*) in the TP53 gene in UL sample S04 with VAFs (0.408 and 0.370, respectively) pointing to somatic variants.	('p.(Tyr103*', 'Var', (17, 27))	('p.(Tyr103*)', 'SUBSTITUTION', 'None', (17, 28))	('c.309 C > A', 'Var', (4, 15))	('TP53', 'Gene', '7157', (36, 40))	('AF', 'Disease', 'MESH:D001281', (69, 71))	('TP53', 'Gene', (36, 40))	('c.309 C > A', 'Mutation', 'rs767462997', (4, 15))
22631	32612247	The only other pathogenic variant identified was the c.1001 C > A, p.(Pro334His) in the XPC gene in UL sample S07, which is a known pathogenic variant (dbSNP rs74737358) causing the recessively inherited xeroderma pigmentosum (OMIM #278720) when inherited with a second pathogenic variant on the other allele.	('rs74737358', 'Mutation', 'rs74737358', (158, 168))	('XPC', 'Gene', (88, 91))	('xeroderma pigmentosum', 'Disease', (204, 225))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (204, 225))	('p.(Pro334His', 'Var', (67, 79))	('causing', 'Reg', (170, 177))	('XPC', 'Gene', '7508', (88, 91))	('c.1001 C > A', 'Var', (53, 65))	('c.1001 C > A', 'Mutation', 'rs74737358', (53, 65))	('p.(Pro334His)', 'SUBSTITUTION', 'None', (67, 80))
22634	32612247	Interestingly, the RB1 gene locus indicated a deletion >=500 kb in only three FH deficient ULs (two additional when considering CNVs < 500 kb), despite the reduced expression in IHC in all 12 samples analyzed.	('expression', 'MPA', (164, 174))	('FH deficient ULs', 'Disease', 'MESH:D006938', (78, 94))	('reduced', 'NegReg', (156, 163))	('ULs', 'Phenotype', 'HP:0000131', (91, 94))	('RB1', 'Gene', (19, 22))	('deletion >=500 kb', 'Var', (46, 63))	('FH deficient ULs', 'Disease', (78, 94))	('RB1', 'Gene', '5925', (19, 22))
22636	32612247	Assuming the typically relatively high purity of a usually monoclonal and noninvasive tumor like ULs, the VAF observed in eight ULs with an SNV/indel (between 0.443 and 0.793; see Table 1) are best explained by a somatic two hit model with an somatic SNV/indel on one allele and a second somatic CN-loss on the other allele (Figure S4).	('SNV/indel', 'Var', (251, 260))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('ULs', 'Phenotype', 'HP:0000131', (97, 100))	('ULs', 'Phenotype', 'HP:0000131', (128, 131))	('noninvasive tumor', 'Disease', 'MESH:D009369', (74, 91))	('AF', 'Disease', 'MESH:D001281', (107, 109))	('noninvasive tumor', 'Disease', (74, 91))	('SNV/indel', 'Var', (140, 149))
22638	32612247	By collecting described FH variants from the ClinVar and LOVD databases and classifying them according to ACMG criteria, we summarized 280 unique (likely) pathogenic variants.	('variants', 'Var', (27, 35))	('variants', 'Var', (166, 174))	('FH', 'Gene', '2271', (24, 26))
22642	32612247	Identifying individuals who carry a pathogenic variant in the FH gene is considered important as they have an increased lifetime risk of about 15% for the aggressive RCC type associated with HLRCC.	('associated', 'Reg', (175, 185))	('FH', 'Gene', '2271', (62, 64))	('RCC', 'Disease', (193, 196))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('variant', 'Var', (47, 54))
22651	32612247	The observation that no UL had two SNVs/indels, points to an initial FH mutation (SNV/indel or CNV) in a progenitor cell which then increased the probability for a CN-loss in descendent cells.	('FH', 'Gene', '2271', (69, 71))	('CN-loss', 'MPA', (164, 171))	('mutation', 'Var', (72, 80))
22654	32612247	The combination of CN- and VAF-analyses not only allowed us to detect both FH mutations in all 13 tumors, but also raised the suspicion of intratumoral heterogeneity in one case (S05), a mechanism only recently proposed to further complicate detection of the cause of FH-associated ULs.	('tumor', 'Disease', (144, 149))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('detect', 'Reg', (63, 69))	('ULs', 'Phenotype', 'HP:0000131', (282, 285))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('AF', 'Disease', 'MESH:D001281', (28, 30))	('mutations', 'Var', (78, 87))	('FH', 'Gene', '2271', (268, 270))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('FH', 'Gene', '2271', (75, 77))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
22656	32612247	Rabban and colleagues reported normal FH immunoexpression in tumors of two females with pathogenic germline FH missense variants.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('FH', 'Gene', '2271', (108, 110))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('missense variants', 'Var', (111, 128))	('FH', 'Gene', '2271', (38, 40))
22657	32612247	We observed no difference in IHC and morphology for ULs with biallelic deletions, likely gene disrupting, and missense variants in FH.	('missense variants', 'Var', (110, 127))	('FH', 'Gene', '2271', (131, 133))	('ULs', 'Phenotype', 'HP:0000131', (52, 55))	('biallelic deletions', 'Var', (61, 80))
22658	32612247	3 for the missense variant c.587 A > T, p.(His196Leu), affecting the in our cohort recurrently mutated amino acid residue H196, in comparison to both a case with biallelic deletion and the truncating variant c.457delG, p.(Val153*).	('p.(Val153*', 'Var', (219, 229))	('H196', 'Var', (122, 126))	('p.(Val153*)', 'SUBSTITUTION', 'None', (219, 230))	('c.587 A > T', 'Mutation', 'c.587A>T', (27, 38))	('p.(His196Leu)', 'SUBSTITUTION', 'None', (40, 53))	('c.587 A > T', 'Var', (27, 38))	('c.457delG', 'Mutation', 'c.457delG', (208, 217))	('H196', 'Chemical', '-', (122, 126))	('affecting', 'Reg', (55, 64))	('p.(His196Leu', 'Var', (40, 52))
22659	32612247	The predicted missense variant c.1236 G > A, identified in individual S09, affects the last base of exon 8 and can be expected to result in aberrant splicing.	('affects', 'Reg', (75, 82))	('c.1236 G > A', 'Var', (31, 43))	('result in', 'Reg', (130, 139))	('c.1236 G > A', 'Mutation', 'c.1236G>A', (31, 43))	('splicing', 'MPA', (149, 157))
22661	32612247	A literature search showed that other missense variants (c.922 G > A, p.(Ala308Thr) or A308T; c.952 C > T, p.(His318Tyr) or H318Y) affecting the same domain result in defective fumarase oligomerization and we could show that these two variants significantly colocalize with the missense variants identified herein (Figure S2,B).	('fumarase', 'Gene', '2271', (177, 185))	('p.(His318Tyr', 'Var', (107, 119))	('H318Y', 'Var', (124, 129))	('A308T; c.952 C > T', 'Var', (87, 105))	('c.922 G > A', 'Mutation', 'rs121913118', (57, 68))	('fumarase', 'Gene', (177, 185))	('A308T', 'Mutation', 'rs121913118', (87, 92))	('H318Y', 'Mutation', 'rs398123168', (124, 129))	('defective', 'NegReg', (167, 176))	('p.(His318Tyr)', 'SUBSTITUTION', 'None', (107, 120))	('p.(Ala308Thr)', 'Mutation', 'rs121913118', (70, 83))	('c.952 C > T', 'Mutation', 'rs398123168', (94, 105))	('c.922 G > A', 'Var', (57, 68))
22662	32612247	Interestingly, a case report showed loss of FH IHC staining in an individual with another missense variant (c.953 A > T, p.(His318Leu)) affecting the same His318 amino acid residue.	('p.(His318Leu', 'Var', (121, 133))	('p.(His318Leu)', 'SUBSTITUTION', 'None', (121, 134))	('c.953 A > T', 'Var', (108, 119))	('loss of FH IHC', 'Disease', (36, 50))	('loss of FH IHC', 'Disease', 'MESH:D006938', (36, 50))	('His318', 'Chemical', '-', (124, 130))	('His318', 'Chemical', '-', (155, 161))	('c.953 A > T', 'Mutation', 'rs755449276', (108, 119))
22663	32612247	Altered tetramer formation and a "dominant negative" effect has been shown for one of the most frequently described FH "hot spot" mutations (c.698 G > A, p.(Arg233His) or R233H and often referred to as R190H) and cases with this variant have been shown to have FH loss in IHC.	('FH loss', 'Disease', (261, 268))	('c.698 G > A', 'Var', (141, 152))	('FH', 'Gene', '2271', (261, 263))	('p.(Arg233His', 'Var', (154, 166))	('p.(Arg233His)', 'Mutation', 'rs121913123', (154, 167))	('R190H', 'Mutation', 'rs121913123', (202, 207))	('tetramer formation', 'MPA', (8, 26))	('FH', 'Gene', '2271', (116, 118))	('R233H', 'Mutation', 'rs121913123', (171, 176))	('FH loss', 'Disease', 'MESH:D006938', (261, 268))	('R233H', 'Var', (171, 176))	('c.698 G > A', 'Mutation', 'rs121913123', (141, 152))	('IHC', 'Disease', (272, 275))
22664	32612247	Together our results and the literature indicate altered oligomerization of FH through certain missense variants affecting subunit interactions as a mechanism causing loss of FH expression in IHC.	('loss of FH', 'Disease', (167, 177))	('loss of FH', 'Disease', 'MESH:D006938', (167, 177))	('altered', 'Reg', (49, 56))	('oligomerization', 'MPA', (57, 72))	('affecting', 'Reg', (113, 122))	('FH', 'Gene', '2271', (76, 78))	('missense variants', 'Var', (95, 112))	('expression', 'MPA', (178, 188))	('IHC', 'Disease', (192, 195))	('subunit interactions', 'Protein', (123, 143))	('FH', 'Gene', '2271', (175, 177))
22666	32612247	Nevertheless, our finding of a specific missense cluster causing loss of FH expression also indirectly confirms the concerned observation that other missense variants will be missed by screening methods based on FH IHC.	('FH', 'Gene', '2271', (212, 214))	('FH', 'Gene', '2271', (73, 75))	('loss of FH', 'Disease', (65, 75))	('loss of FH', 'Disease', 'MESH:D006938', (65, 75))	('missense', 'Var', (40, 48))
22668	32612247	Despite the successful complete characterization of the dual FH-hits in all 13 ULs, the question remained whether the identified aberrations are somatic, indicating sporadic disease, or in fact are germline and potentially associated with HLRCC.	('ULs', 'Phenotype', 'HP:0000131', (79, 82))	('sporadic disease', 'Disease', 'MESH:D003141', (165, 181))	('associated', 'Reg', (223, 233))	('sporadic disease', 'Disease', (165, 181))	('FH', 'Gene', '2271', (61, 63))	('aberrations', 'Var', (129, 140))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))
22674	32612247	Panel sequencing further allowed us to identify two somatic likely gene disrupting mutations in TP53 in sample S04, which is comparable to a homozygous TP53 deletion described in a UL sample with FH-loss in IHC and a missense mutation with loss-of-heterozygosity.	('mutations', 'Var', (83, 92))	('TP53', 'Gene', (96, 100))	('TP53', 'Gene', '7157', (152, 156))	('FH-loss in IHC', 'Disease', (196, 210))	('TP53', 'Gene', (152, 156))	('disrupting', 'NegReg', (72, 82))	('FH-loss in IHC', 'Disease', 'MESH:D006938', (196, 210))	('TP53', 'Gene', '7157', (96, 100))
22679	32612247	Our CN-analysis identified an enrichment of CN-gains at ALK-gene locus previously not reported in ULs.	('ALK', 'Gene', (56, 59))	('ULs', 'Phenotype', 'HP:0000131', (98, 101))	('CN-gains', 'Var', (44, 52))	('ALK', 'Gene', '238', (56, 59))
22686	32612247	This successful approach allowed us to identify a cluster of missense variants associated with immunohistochemical protein reduction, proving that missense variants contribute to FH deficient ULs.	('FH deficient ULs', 'Disease', (179, 195))	('missense variants', 'Var', (61, 78))	('missense variants', 'Var', (147, 164))	('FH deficient ULs', 'Disease', 'MESH:D006938', (179, 195))	('contribute', 'Reg', (165, 175))	('ULs', 'Phenotype', 'HP:0000131', (192, 195))
22687	32612247	We agree with previous concerns that some pathogenic missense variants in individuals with HLRCC might be missed using only FH IHC as screening method.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('missense variants', 'Var', (53, 70))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('FH', 'Gene', '2271', (124, 126))
22786	31906221	Resistance to gemcitabine was artificially induced by genetic modifications (transfection) in gene coding deoxynucleoside kinase in MES-SA, although such modifications were not performed in the cell line we used.	('modifications', 'Var', (62, 75))	('Resistance', 'MPA', (0, 10))	('deoxynucleoside kinase', 'Gene', (106, 128))	('MES-SA', 'Chemical', '-', (132, 138))	('gemcitabine', 'Chemical', 'MESH:C056507', (14, 25))	('induced', 'Reg', (43, 50))	('deoxynucleoside kinase', 'Gene', '1633', (106, 128))
22870	32082489	Sacituzumab govitecan (SG) is a new class of ADC targeting Trop-2 antigen to deliver SN-38, the active metabolite of irinotecan, which has a 100- to 1,000 fold higher potency than irinotecan.	('SN-38', 'Var', (85, 90))	('higher', 'PosReg', (160, 166))	('potency', 'MPA', (167, 174))	('irinotecan', 'Chemical', 'MESH:D000077146', (180, 190))	('SN-38', 'Chemical', 'MESH:D000077146', (85, 90))	('Sacituzumab', 'Chemical', '-', (0, 11))	('irinotecan', 'Chemical', 'MESH:D000077146', (117, 127))
22871	32082489	In contrast to other ADCs SG has a hydrolysable linker (CL2A) supporting a time released bystander effect in the tumor environment, SN-38 causes single-stranded DNA breaks that progress into double-stranded breaks if unrepaired leading to activation of the intrinsic apoptotic pathway and cell death.	('cell death', 'CPA', (289, 299))	('tumor', 'Disease', (113, 118))	('CL2A', 'Chemical', '-', (56, 60))	('SN-38', 'Chemical', 'MESH:D000077146', (132, 137))	('single-stranded DNA breaks', 'MPA', (145, 171))	('activation', 'PosReg', (239, 249))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('intrinsic apoptotic pathway', 'Pathway', (257, 284))	('double-stranded breaks', 'MPA', (191, 213))	('causes', 'Reg', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SN-38', 'Var', (132, 137))
22932	32082489	The final immunoreactivity score was calculated by multiplying the staining intensity (1+, 2+, 3+) with the percentage of positive tumor cells, and was classified in 4 ordinal categories: 0-9 negative (score 0), 10-99 weak (score 1), 100-199 moderate (score 2), and 200-300 strong (score 3) (Figures 1, 2).	('negative', 'NegReg', (192, 200))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('100-199', 'Var', (234, 241))	('tumor', 'Disease', (131, 136))
23132	29600231	Other factors which have been associated with etiology of these tumors are use of tamoxifen, exogenous estrogen, obesity, and nulliparity.	('tumors', 'Disease', (64, 70))	('tamoxifen', 'Chemical', 'MESH:D013629', (82, 91))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('obesity', 'Disease', 'MESH:D009765', (113, 120))	('nulliparity', 'Var', (126, 137))	('obesity', 'Disease', (113, 120))	('obesity', 'Phenotype', 'HP:0001513', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
23189	24582865	Van de Lande et al published a review of the literature involving more than 800 patients with cervical cancer in which they described detection rates of 84%, 88%, and 97% using blue dye alone, 99mTc alone, or both blue dye and 99mTc, respectively.	('patients', 'Species', '9606', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('99mTc', 'Var', (193, 198))	('cervical cancer', 'Disease', (94, 109))	('cervical cancer', 'Disease', 'MESH:D002583', (94, 109))
23316	28382802	Among BRCA1 and BRCA2 mutation carriers, the average cumulative risk of ovarian cancer by 80 years of age was 45% and 12%, respectively.	('BRCA1', 'Gene', '672', (6, 11))	('is', 'Gene', '57509', (65, 67))	('mutation', 'Var', (22, 30))	('BRCA1', 'Gene', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('BRCA2', 'Gene', (16, 21))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('BRCA2', 'Gene', '675', (16, 21))	('ovarian cancer', 'Disease', (72, 86))
23317	28382802	There are multiple factors that influence on the likelihood of the development of breast or ovarian cancer in BRCA1 or BRCA2 mutation carriers, for example, positive family history and age.	('breast or ovarian cancer', 'Disease', (82, 106))	('BRCA2', 'Gene', '675', (119, 124))	('influence', 'Reg', (32, 41))	('BRCA1', 'Gene', '672', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (82, 106))	('BRCA1', 'Gene', (110, 115))	('BRCA2', 'Gene', (119, 124))	('is', 'Gene', '57509', (174, 176))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('mutation', 'Var', (125, 133))
23321	28382802	There were accumulating evidence showing that RRSO involved a significant ovarian cancer risk reduction by 80%-90% among BRCA1 and BRCA2 carriers, for whom, therefore, between the ages of 35 and 40 years who have completed their childbearing current guidelines recommend RRSO.	('BRCA2', 'Gene', (131, 136))	('is', 'Gene', '57509', (90, 92))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('reduction', 'NegReg', (94, 103))	('BRCA1', 'Gene', '672', (121, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('BRCA2', 'Gene', '675', (131, 136))	('carriers', 'Var', (137, 145))	('ovarian cancer', 'Disease', (74, 88))	('BRCA1', 'Gene', (121, 126))
23322	28382802	A multicenter prospective cohort study of 2,482 BRCA1 and BRCA2 carriers showed that RRSO group, compared with non-RRSO group, had lower all-cause mortality (hazard ratio [HR]=0.40; 95% CI=0.26-0.61) and ovarian cancer-specific mortality (HR=0.21; 95% CI=0.06-0.80).	('BRCA1', 'Gene', '672', (48, 53))	('ovarian cancer', 'Disease', (204, 218))	('BRCA2', 'Gene', '675', (58, 63))	('RRSO', 'Var', (85, 89))	('BRCA1', 'Gene', (48, 53))	('all-cause mortality', 'CPA', (137, 156))	('carriers', 'Var', (64, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('lower', 'NegReg', (131, 136))	('BRCA2', 'Gene', (58, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
23325	28382802	A multicenter prospective cohort study, which was published in JAMA Oncology, demonstrated the risk for uterine cancer and distribution of specific histologic subtypes in BRCA mutation carriers after RRSO without hysterectomy.	('BRCA', 'Gene', (171, 175))	('is', 'Gene', '57509', (149, 151))	('is', 'Gene', '57509', (124, 126))	('uterine cancer', 'Phenotype', 'HP:0010784', (104, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Oncology', 'Phenotype', 'HP:0002664', (68, 76))	('is', 'Gene', '57509', (54, 56))	('mutation', 'Var', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('BRCA', 'Gene', '672', (171, 175))	('is', 'Gene', '57509', (96, 98))
23326	28382802	During a median 5.1 years (interquartile [IQR]=3.0-8.4 years) follow-up of 1,083 women with BRCA1 or BRCA2 mutation who underwent RRSO without a prior or concomitant hysterectomy, 8 incident uterine cancers including 5 serous and/or serous-like endometrial carcinomas were observed 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [observed to expected ratio 22.2; 95% CI=6.1-56.9; p<0.001]).	('carcinomas', 'Phenotype', 'HP:0030731', (257, 267))	('women', 'Species', '9606', (81, 86))	('serous and/or', 'Disease', (219, 232))	('BRCA1', 'Gene', '672', (312, 317))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (245, 267))	('mutation', 'Var', (107, 115))	('BRCA1', 'Gene', (312, 317))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('uterine cancer', 'Phenotype', 'HP:0010784', (191, 205))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (245, 267))	('uterine cancers', 'Phenotype', 'HP:0010784', (191, 206))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', (199, 206))	('BRCA2', 'Gene', (101, 106))	('endometrial carcinomas', 'Disease', (245, 267))	('BRCA2', 'Gene', '675', (101, 106))	('BRCA1', 'Gene', '672', (92, 97))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('BRCA1', 'Gene', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
23327	28382802	This study suggested that the BRCA1 mutation was linked to an increased risk of uterine serous carcinoma.	('is', 'Gene', '57509', (73, 75))	('BRCA1', 'Gene', (30, 35))	('is', 'Gene', '57509', (2, 4))	('serous carcinoma', 'Disease', (88, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('serous carcinoma', 'Disease', 'MESH:D018284', (88, 104))	('BRCA1', 'Gene', '672', (30, 35))	('mutation', 'Var', (36, 44))
23328	28382802	This risk should be considered when discussing hysterectomy at the time of RRSO in BRCA1 mutation carriers although more studies are needed to determine how beneficial it would be for them.	('is', 'Gene', '57509', (6, 8))	('BRCA1', 'Gene', '672', (83, 88))	('mutation', 'Var', (89, 97))	('is', 'Gene', '57509', (2, 4))	('is', 'Gene', '57509', (37, 39))	('BRCA1', 'Gene', (83, 88))
23358	28382802	However, sensitivity analysis of performance status revealed that if 60% of women receiving NAC had a performance status of 1 to 2 compared with 50% in the PCS group, which would negate the significant association of PCS with improved survival.	('performance', 'MPA', (102, 113))	('is', 'Gene', '57509', (27, 29))	('PCS', 'Chemical', '-', (217, 220))	('PCS', 'Chemical', '-', (156, 159))	('NAC', 'Var', (92, 95))	('women', 'Species', '9606', (76, 81))	('NAC', 'Chemical', '-', (92, 95))
23378	28382802	A post-hoc analysis revealed that the significant difference of PFS between the nintedanib and placebo groups was found only in the non-high-risk subgroup, which was defined as the International Federation of Gynecology and Obstetrics (FIGO) stage III and postoperative residual tumor <=1 cm, or FIGO stage II (median PFS 27.1 vs. 20.8 months, 95% CI=0.61-0.91).	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('is', 'Gene', '57509', (142, 144))	('nintedanib', 'Chemical', 'MESH:C530716', (80, 90))	('tumor', 'Disease', (279, 284))	('<=1', 'Var', (285, 288))	('is', 'Gene', '57509', (17, 19))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
23407	28382802	Specifically, the likelihood of receiving no boost radiotherapy (RT) was increased for patients with lower incomes, Medicaid, or treatment at low-volume centers or non-comprehensive community cancer centers.	('Medicaid', 'Var', (116, 124))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
23441	28382802	Those 5 novel regions contained at least one endometrial cancer risk single nucleotide polymorphism (SNP) with Pmeta<10-7 and most strongly associated SNP in each region was genotyped: rs11841589 (OR=1.15; 95% CI=1.11-1.21; p=4.83x10-11), rs13328298 (OR=1.13; 95% CI=1.09-1.18; p=3.73x10-10), rs4733613 (OR=0.84; 95% CI=0.80-0.89; p=3.09x10-9), rs937213 (OR=0.90; 95% CI=0.86-0.93; p=1.77x10-8), and rs2498796 (OR=0.89; 95% CI=0.85-0.93; p=3.55x10-8), respectively.	('endometrial cancer', 'Disease', (45, 63))	('is', 'Gene', '57509', (65, 67))	('rs937213', 'Mutation', 'rs937213', (345, 353))	('rs4733613', 'Var', (293, 302))	('rs2498796', 'Var', (400, 409))	('rs13328298', 'Var', (239, 249))	('endometrial cancer', 'Disease', 'MESH:D016889', (45, 63))	('rs2498796', 'Mutation', 'rs2498796', (400, 409))	('endometrial cancer', 'Phenotype', 'HP:0012114', (45, 63))	('rs11841589', 'Var', (185, 195))	('rs13328298', 'Mutation', 'rs13328298', (239, 249))	('rs11841589', 'Mutation', 'rs11841589', (185, 195))	('rs4733613', 'Mutation', 'rs4733613', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('is', 'Gene', '57509', (96, 98))
23443	28382802	Specifically, functional studies of the 13q22.1 locus showed that rs9600103 is located in a region of active chromatin that interacts with promoter region of the Kruppel-like factor 5 (KLF5) (pairwise r2=0.98 with rs11841589).	('interacts', 'Interaction', (124, 133))	('is', 'Gene', '57509', (76, 78))	('rs11841589', 'Mutation', 'rs11841589', (214, 224))	('KLF5', 'Gene', (185, 189))	('KLF5', 'Gene', '688', (185, 189))	('is', 'Gene', '57509', (197, 199))	('rs9600103', 'Var', (66, 75))	('Kruppel-like factor 5', 'Gene', '688', (162, 183))	('Kruppel-like factor 5', 'Gene', (162, 183))	('rs9600103', 'Mutation', 'rs9600103', (66, 75))
23445	28382802	Given in vitro suppression of gene expression by rs9600103-T endometrial cancer protective allele in allele-specific luciferase reporter assays using Ishikawa cells, regulation of KLF5 expression could be implicated in tumorigenesis of endometrial cancer.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('endometrial cancer', 'Disease', 'MESH:D016889', (61, 79))	('tumor', 'Disease', (219, 224))	('implicated', 'Reg', (205, 215))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('KLF5', 'Gene', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('endometrial cancer', 'Disease', 'MESH:D016889', (236, 254))	('KLF5', 'Gene', '688', (180, 184))	('endometrial cancer', 'Disease', (236, 254))	('endometrial cancer', 'Disease', (61, 79))	('rs9600103', 'Var', (49, 58))	('suppression', 'NegReg', (15, 26))	('rs9600103', 'DBSNP_MENTION', 'None', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('is', 'Gene', '57509', (230, 232))	('endometrial cancer', 'Phenotype', 'HP:0012114', (236, 254))	('endometrial cancer', 'Phenotype', 'HP:0012114', (61, 79))
23452	28382802	However, severe tingling or numbness, the well-known side-effects of carboplatin and paclitaxel, was still more frequently observed in CCRT group than RT alone group (25% vs. 6%, p<0.001) at 24 months.	('CCRT', 'Var', (135, 139))	('numbness', 'Disease', 'MESH:D006987', (28, 36))	('numbness', 'Disease', (28, 36))	('tingling', 'Phenotype', 'HP:0003401', (16, 24))	('carboplatin', 'Chemical', 'MESH:D016190', (69, 80))	('tingling', 'Disease', (16, 24))	('paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))
23511	28382802	This study findings suggested that ADXS11-001 is well tolerable and active in persistent or recurrent metastatic cervical cancer.	('ADXS11-001', 'Var', (35, 45))	('cervical cancer', 'Disease', 'MESH:D002583', (113, 128))	('is', 'Gene', '57509', (2, 4))	('cervical cancer', 'Disease', (113, 128))	('is', 'Gene', '57509', (46, 48))	('is', 'Gene', '57509', (82, 84))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
23523	28382802	They suggested that alteration of 9p24.1 gene copy number results in increased PD-L1 expression in cervical and vulvar SCC.	('expression', 'MPA', (85, 95))	('increased', 'PosReg', (69, 78))	('SCC', 'Gene', '6317', (119, 122))	('alteration', 'Var', (20, 30))	('PD-L1', 'Gene', (79, 84))	('increased PD', 'Phenotype', 'HP:0008151', (69, 81))	('SCC', 'Gene', (119, 122))
23549	28382802	found 21 germline mutations in 11 genes in 7 consecutive patients with uterine serous carcinoma.	('serous carcinoma', 'Disease', 'MESH:D018284', (79, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('patients', 'Species', '9606', (57, 65))	('germline mutations', 'Var', (9, 27))	('serous carcinoma', 'Disease', (79, 95))
23550	28382802	Nine (42.8%) germline mutations were found in hereditary colon cancer genes, most commonly MLH.	('MLH', 'Disease', (91, 94))	('hereditary colon cancer', 'Disease', (46, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('hereditary colon cancer', 'Disease', 'MESH:D015179', (46, 69))	('germline mutations', 'Var', (13, 31))
23561	28382802	They collected data of liquid-based cytology, HPV-related biomarkers (E6&E7 mRNA and p16INK4a) and colposcopic findings from 2,267 women with or without cervical abnormalities.	('women', 'Species', '9606', (131, 136))	('cervical abnormalities', 'Disease', (153, 175))	('HPV', 'Species', '10566', (46, 49))	('and p16INK4a', 'Var', (81, 93))	('E6', 'Var', (70, 72))	('cervical abnormalities', 'Disease', 'MESH:D002575', (153, 175))
23569	28382802	In consequence, the integrative genomic approach detected more cancer-related somatic mutations (mean 17.3 cancer-relevant somatic mutations/patient, 13.3-, 6.9-, and 4.7-fold more than CHPv2, OCP, and FoundationOne, respectively) and actionable alterations (mean 4.9/patient, 7.5-, 2.0-, and 1.9-fold more than CHPv2, OCP, and FoundationOne, respectively) existing cancer panels.	('mutations', 'Var', (86, 95))	('mutations/patient', 'Var', (131, 148))	('OCP', 'Chemical', '-', (319, 322))	('is', 'Gene', '57509', (359, 361))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patient', 'Species', '9606', (141, 148))	('cancer', 'Disease', (366, 372))	('OCP', 'Chemical', '-', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('patient', 'Species', '9606', (268, 275))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (63, 69))
23586	28382802	With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase III trial.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('veliparib-carboplatin', 'Var', (46, 67))	('breast cancer', 'Disease', (31, 44))	('veliparib-carboplatin', 'Chemical', '-', (46, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))
23746	27550404	Sampath and Gaffney analyzed available prospective and retrospective data that addressed the role of adjuvant RT in all histologic types of uterine sarcoma and suggested that adjuvant RT reduced the local failure rate by 50% among cases of UCS, leiomyosarcoma, and endometrial stromal sarcoma.	('sarcoma', 'Disease', (285, 292))	('sarcoma', 'Disease', 'MESH:D012509', (252, 259))	('endometrial stromal sarcoma', 'Disease', (265, 292))	('local failure', 'Disease', (199, 212))	('sarcoma', 'Disease', (252, 259))	('UCS', 'Disease', (240, 243))	('leiomyosarcoma', 'Disease', (245, 259))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('local failure', 'Disease', 'MESH:D012594', (199, 212))	('adjuvant', 'Var', (175, 183))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (245, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (245, 259))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (265, 292))	('UCS', 'Phenotype', 'HP:0002891', (240, 243))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (140, 155))	('reduced', 'NegReg', (187, 194))	('sarcoma', 'Disease', 'MESH:D012509', (285, 292))
23749	27550404	The impact of PLND with or without adjuvant RT has been investigated, and 2 retrospective analyses of patient data from the Surveillance, Epidemiology, and End Results (SEER) database have demonstrated the clinical benefits of adjuvant RT in UCS patients, especially those not subjected to PLND.	('patient', 'Species', '9606', (246, 253))	('benefits', 'PosReg', (215, 223))	('patients', 'Species', '9606', (246, 254))	('patient', 'Species', '9606', (102, 109))	('UCS', 'Phenotype', 'HP:0002891', (242, 245))	('adjuvant', 'Var', (227, 235))	('UCS', 'Disease', (242, 245))
23757	27550404	A phase III randomized trial of adjuvant chemotherapy for patients with uterine sarcoma (SARCGYN study) found that a combination of doxorubicin, ifosfamide, and cisplatin increased DFS; however, this study was discontinued early because of the unavailability of participants.	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('cisplatin', 'Var', (161, 170))	('doxorubicin', 'Var', (132, 143))	('sarcoma', 'Disease', (80, 87))	('ifosfamide', 'Chemical', 'MESH:D007069', (145, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('DFS', 'MPA', (181, 184))	('participants', 'Species', '9606', (262, 274))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (72, 87))	('patients', 'Species', '9606', (58, 66))	('increased', 'PosReg', (171, 180))	('doxorubicin', 'Chemical', 'MESH:D004317', (132, 143))
23816	27721667	Investigators reported a 3-month increase in progression-free survival for patients who received pazopanib.	('increase', 'PosReg', (33, 41))	('pazopanib', 'Chemical', 'MESH:C516667', (97, 106))	('patients', 'Species', '9606', (75, 83))	('pazopanib', 'Var', (97, 106))
23850	27721667	In a number of cancers, promoter hypermethylation has been shown to result in decreased expression of MGMT and gene as well as diminished DNA repair activity, rendering cells more susceptible to alkylating agents.	('MGMT', 'Gene', '4255', (102, 106))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('diminished', 'NegReg', (127, 137))	('cancers', 'Disease', (15, 22))	('MGMT', 'Gene', (102, 106))	('decreased', 'NegReg', (78, 87))	('DNA repair activity', 'MPA', (138, 157))	('expression', 'MPA', (88, 98))	('promoter hypermethylation', 'Var', (24, 49))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
23851	27721667	Hypermethylation of the MGMT gene promoter has also been observed in uterine sarcomas and thus could serve as a potential marker to identify patients who would benefit from temozolomide use.	('MGMT', 'Gene', '4255', (24, 28))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Hypermethylation', 'Var', (0, 16))	('patients', 'Species', '9606', (141, 149))	('observed', 'Reg', (57, 65))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('temozolomide', 'Chemical', 'MESH:D000077204', (173, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('MGMT', 'Gene', (24, 28))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (69, 84))
23860	27721667	In transgenic mice, inactivation or loss of PTEN leads to the development of uLMS.	('uLMS', 'Phenotype', 'HP:0002891', (77, 81))	('inactivation', 'Var', (20, 32))	('leads to', 'Reg', (49, 57))	('loss', 'Var', (36, 40))	('PTEN', 'Gene', (44, 48))	('uLMS', 'Disease', (77, 81))	('transgenic mice', 'Species', '10090', (3, 18))
23868	27721667	Additional therapeutic benefit was observed when MLN82237 was combined with mTOR inhibition, consistent with AurkA's ability to cross-regulate mTOR pathway activity.	('mTOR', 'MPA', (76, 80))	('MLN82237', 'Var', (49, 57))	('AurkA', 'Gene', '6790', (109, 114))	('AurkA', 'Gene', (109, 114))
23874	27721667	Data has also shown that HDAC inhibitors can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models.	('HDAC', 'Gene', '9734', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('chemotherapy-induced apoptosis', 'CPA', (53, 83))	('enhance', 'PosReg', (45, 52))	('inhibitors', 'Var', (30, 40))	('sarcoma tumor', 'Disease', 'MESH:D012509', (95, 108))	('sarcoma tumor', 'Disease', (95, 108))	('HDAC', 'Gene', (25, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('reduce', 'NegReg', (88, 94))
23936	27441069	MVA showed that EBRT>50 Gy was an independent predictive factor for better OS (P=0.03), CSS (P=0.02) and LRC (P=0.01), reducing the relative risks (RR) by a factor of 3.6 for LRC.	('CSS', 'Disease', (88, 91))	('LRC', 'Disease', (105, 108))	('EBRT', 'Chemical', '-', (16, 20))	('LRC', 'Disease', (175, 178))	('OS', 'Chemical', '-', (75, 77))	('better OS', 'Disease', (68, 77))	('EBRT>50 Gy', 'Var', (16, 26))	('CSS', 'Chemical', '-', (88, 91))	('reducing', 'NegReg', (119, 127))
23959	27441069	Importantly, local recurrence at three years was lowest for patients receiving EBRT and BT highlighting the importance of BT as a boost technique to escalate the dose without increasing toxicity rates.	('local recurrence', 'CPA', (13, 29))	('EBRT', 'Var', (79, 83))	('patients', 'Species', '9606', (60, 68))	('EBRT', 'Chemical', '-', (79, 83))	('toxicity', 'Disease', 'MESH:D064420', (186, 194))	('lowest', 'NegReg', (49, 55))	('toxicity', 'Disease', (186, 194))
24103	24379833	Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.	('tumor', 'Disease', (137, 142))	('GPER', 'Protein', (88, 92))	('pharmacological inhibition', 'Var', (58, 84))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('prevents', 'NegReg', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
24107	24379833	Type I tumors consist of well-differentiated tumors preceded by endometrial hyperplasia and are associated with a loss of PTEN expression as well as abnormalities in beta-catenin, Kras, and DNA mismatch repair genes.	('beta-catenin', 'Protein', (166, 178))	('endometrial hyperplasia', 'Disease', (64, 87))	('abnormalities', 'Var', (149, 162))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (64, 87))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (7, 13))	('PTEN', 'Gene', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Kras', 'Gene', '3845', (180, 184))	('expression', 'MPA', (127, 137))	('tumors', 'Disease', (45, 51))	('loss', 'NegReg', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('Type I tumors', 'Disease', (0, 13))	('PTEN', 'Gene', '5728', (122, 126))	('Kras', 'Gene', (180, 184))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (64, 87))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('DNA mismatch repair genes', 'Gene', (190, 215))
24109	24379833	Over 90% of uterine papillary serous carcinomas are associated with p53 mutations, 45-60% have Her-2/neu mutations, and PTEN mutations are rare.	('mutations', 'Var', (72, 81))	('papillary serous carcinomas', 'Disease', (20, 47))	('associated', 'Reg', (52, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('PTEN', 'Gene', '5728', (120, 124))	('Her-2/neu', 'Gene', (95, 104))	('PTEN', 'Gene', (120, 124))	('Her-2/neu', 'Gene', '2064', (95, 104))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('papillary serous carcinomas', 'Disease', 'MESH:D002291', (20, 47))
24111	24379833	Moreover, recent mutational profiling studies indicate that whereas some carcinosarcomas share mutations with type 1 tumors (PTEN and ARID1A), others share mutations with uterine papillary serous carcinomas (notably p53 and PPP2R1A).	('PTEN', 'Gene', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('PPP2R1A', 'Gene', '5518', (224, 231))	('papillary serous carcinomas', 'Disease', (179, 206))	('p53', 'Gene', (216, 219))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PPP2R1A', 'Gene', (224, 231))	('papillary serous carcinomas', 'Disease', 'MESH:D002291', (179, 206))	('carcinosarcomas', 'Disease', (73, 88))	('PTEN', 'Gene', '5728', (125, 129))	('tumors', 'Disease', (117, 123))	('mutations', 'Var', (95, 104))	('ARID1A', 'Gene', (134, 140))	('mutations', 'Var', (156, 165))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('ARID1A', 'Gene', '8289', (134, 140))	('carcinosarcomas', 'Disease', 'MESH:D002296', (73, 88))	('p53', 'Gene', '7157', (216, 219))
24119	24379833	Furthermore, GPER (over)expression has been associated with many cancers and in particular poor prognosis in a number of cancers, including breast, ovarian, lung, pancreatic, and endometrial although observations to the contrary have also been reported.	('associated', 'Reg', (44, 54))	('pancreatic', 'Disease', 'MESH:D010195', (163, 173))	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('pancreatic', 'Disease', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ovarian', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ovarian', 'Disease', 'MESH:D010051', (148, 155))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('expression', 'Var', (24, 34))	('endometrial', 'Disease', (179, 190))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancers', 'Disease', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('GPER (over', 'Protein', (13, 23))	('breast', 'Disease', (140, 146))	('lung', 'Disease', (157, 161))
24126	24379833	17beta-estradiol, 17alpha-estradiol, 4-hydroxytamoxifen, Raloxifene, genistein, LY294002, bovine serum albumin (BSA), normal goat serum, insulin, transferrin, hydrocortisone, fetuin, pancreatin, and trypsin were from Sigma (St. Louis, MO, USA).	('LY294002', 'Chemical', 'MESH:C085911', (80, 88))	('hydrocortisone', 'Chemical', 'MESH:D006854', (159, 173))	('serum albumin', 'Gene', '213', (97, 110))	('serum albumin', 'Gene', (97, 110))	('genistein', 'Chemical', 'MESH:D019833', (69, 78))	('transferrin', 'Gene', '7018', (146, 157))	('insulin', 'Gene', (137, 144))	('transferrin', 'Gene', (146, 157))	('LY294002', 'Var', (80, 88))	('bovine', 'Species', '9913', (90, 96))	('insulin', 'Gene', '3630', (137, 144))	('17alpha-estradiol', 'Chemical', 'MESH:C519808', (18, 35))	('goat', 'Species', '9925', (125, 129))	('4-hydroxytamoxifen', 'Chemical', 'MESH:C475919', (37, 55))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (0, 16))	('Raloxifene', 'Chemical', 'MESH:D020849', (57, 67))
24127	24379833	AG1478 and GM6001 were from Calbiochem (Billerica, MA, USA).	('GM6001', 'Chemical', 'MESH:C078131', (11, 17))	('AG1478', 'Chemical', 'MESH:C101044', (0, 6))	('GM6001', 'Var', (11, 17))	('AG1478', 'Var', (0, 6))
24180	24379833	This indicated not only that the nuclear localization of the PH-RFP reporter required PI3K activity, but that the membrane localization in unstimulated cells was also due to PI3K activity (as LY294002 treatment in the absence of estrogen yielded an identical distribution, data not shown).	('LY294002', 'Chemical', 'MESH:C085911', (192, 200))	('due', 'Reg', (167, 170))	('PH-RFP', 'Gene', (61, 67))	('membrane localization', 'MPA', (114, 135))	('nuclear localization', 'MPA', (33, 53))	('LY294002', 'Var', (192, 200))
24183	24379833	As observed for estrogen-mediated activation of GPER, PI3K activation in response to G-1 also requires both EGFR kinase and metalloproteinase activity, as AG1478 and GM6001 also blocked nuclear translocation of PH-RFP following G-1 stimulation.	('GM6001', 'Var', (166, 172))	('AG1478', 'Var', (155, 161))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('AG1478', 'Chemical', 'MESH:C101044', (155, 161))	('blocked', 'NegReg', (178, 185))	('nuclear translocation', 'MPA', (186, 207))	('GM6001', 'Chemical', 'MESH:C078131', (166, 172))	('PH-RFP', 'Protein', (211, 217))
24186	24379833	Specifically, we have demonstrated tamoxifen-mediated stimulation of PI3K in GPER-transfected COS7 cells and GPER+ SKBr3 breast cancer cells (both of which do not express ERalpha or for that matter ERbeta).	('PI3K', 'Var', (69, 73))	('ERbeta', 'Gene', (198, 204))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('tamoxifen', 'Chemical', 'MESH:D013629', (35, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('ERbeta', 'Gene', '2100', (198, 204))	('SKBr3', 'CellLine', 'CVCL:0033', (115, 120))	('COS7', 'CellLine', 'CVCL:0224', (94, 98))	('stimulation', 'PosReg', (54, 65))
24195	24379833	As for PI3K activation, estrogen, G-1, 4-hydroxytamoxifen, ICI182,780, and Raloxifene stimulated pERK ~5-8-fold.	('Raloxifene', 'Chemical', 'MESH:D020849', (75, 85))	('G-1', 'Var', (34, 37))	('activation', 'PosReg', (12, 22))	('ICI182', 'Chemical', '-', (59, 65))	('pERK', 'Gene', '9451', (97, 101))	('pERK', 'Gene', (97, 101))	('PI3K', 'Pathway', (7, 11))	('stimulated', 'PosReg', (86, 96))	('4-hydroxytamoxifen', 'Chemical', 'MESH:C475919', (39, 57))
24196	24379833	Activation of ERK by each of these ligands was completely inhibited by G15, indicating an essential role for GPER in the response to each ligand.	('ERK', 'Gene', (14, 17))	('G15', 'Var', (71, 74))	('Activation', 'MPA', (0, 10))	('inhibited', 'NegReg', (58, 67))	('ERK', 'Gene', '5594', (14, 17))
24197	24379833	The phytoestrogen genistein also acted as an agonist of GPER-mediated ERK activation in Hec50 cells and as observed with PI3K activation, PPT (100 nM), but not DPN (at concentrations up to 10 muM), was able to induce ERK activation in a GPER-dependent (i.e., G15-sensitive) manner.	('PPT', 'Chemical', 'MESH:C486184', (138, 141))	('PPT (100 nM', 'Var', (138, 149))	('ERK', 'Gene', (70, 73))	('DPN', 'Chemical', 'MESH:C492519', (160, 163))	('genistein', 'Chemical', 'MESH:D019833', (18, 27))	('muM', 'Gene', (192, 195))	('ERK', 'Gene', (217, 220))	('ERK', 'Gene', '5594', (217, 220))	('ERK', 'Gene', '5594', (70, 73))	('muM', 'Gene', '56925', (192, 195))
24224	24379833	However, type II endometrial cancers are believed to develop through molecular pathways involving p53 mutations, which more closely resemble high-grade serous ovarian tumors in molecular alterations and morphology and commonly do not express either ER or PR, suggesting that estrogen (or its inhibition) should have no effect on the growth of such tumors.	('ovarian tumors', 'Phenotype', 'HP:0100615', (159, 173))	('p53', 'Gene', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('mutations', 'Var', (102, 111))	('tumors', 'Disease', (348, 354))	('tumors', 'Disease', (167, 173))	('type II endometrial cancers', 'Disease', 'MESH:D016889', (9, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (348, 354))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('serous ovarian tumors', 'Disease', (152, 173))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('endometrial cancer', 'Phenotype', 'HP:0012114', (17, 35))	('type II endometrial cancers', 'Disease', (9, 36))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ER', 'Gene', '2099', (249, 251))	('p53', 'Gene', '7157', (98, 101))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (152, 173))	('PR', 'Gene', '5241', (255, 257))
24228	24379833	However, upon supplementation with estrogen, tumor growth was increased about 10-fold (compared to ovariectomized/sham-treated mice).	('increased', 'PosReg', (62, 71))	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('supplementation', 'Var', (14, 29))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
24232	24379833	Estrogen-stimulated tumor growth was reduced by G36 to that of the sham treatment (i.e., estrogen deprived state), demonstrating a critical role for GPER in the estrogen-mediated response of ER- type II endometrial cancer growth.	('ER', 'Gene', '2099', (151, 153))	('G36', 'Var', (48, 51))	('endometrial cancer', 'Phenotype', 'HP:0012114', (203, 221))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('type II endometrial cancer', 'Disease', (195, 221))	('ER', 'Gene', '2099', (191, 193))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('type II endometrial cancer', 'Disease', 'MESH:D016889', (195, 221))	('tumor', 'Disease', (20, 25))
24256	24379833	It is important to note that the effect of estrogen and G-1 might not be easily detectable by measuring total cellular pAkt levels, for example, by Western blot, due to the constitutive activation of PI3K.	('Akt', 'Gene', '207', (120, 123))	('Akt', 'Gene', (120, 123))	('PI3K', 'Var', (200, 204))	('activation', 'PosReg', (186, 196))
24267	24379833	In our current study, we found that PPT (at 100 nM, with a weak response at 10 nM, unpublished observation) also acts as an agonist for GPER.	('agonist', 'MPA', (124, 131))	('PPT', 'Chemical', 'MESH:C486184', (36, 39))	('PPT', 'Var', (36, 39))
24273	24379833	In fact, in a very recent study, knocking down GPER expression in Hec1A endometrial cancer cells (as well as Ishikawa H cells) resulted in a reduction of tumor growth in athymic mice.	('endometrial cancer', 'Disease', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mice', 'Species', '10090', (178, 182))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('GPER', 'Protein', (47, 51))	('Hec1', 'Gene', (66, 70))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('knocking down', 'Var', (33, 46))	('Hec1', 'Gene', '10403', (66, 70))	('reduction', 'NegReg', (141, 150))	('tumor', 'Disease', (154, 159))
24285	24379833	Tumors remained small in untreated mice but were about 10-fold larger in mice treated with slow release estrogen pellets, indicating that the lack of ERalpha did not prevent responsiveness to estrogen.	('ERalpha', 'Gene', (150, 157))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (73, 77))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (35, 39))	('lack', 'Var', (142, 146))
24292	24379833	These results indicate not only that the observed estrogen dependence of Hec50 cell tumors is due to GPER but also that pharmacological inhibition of GPER could represent an important new therapy for women, particularly those with aggressive type II endometrial cancer.	('women', 'Species', '9606', (200, 205))	('endometrial cancer', 'Phenotype', 'HP:0012114', (250, 268))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('pharmacological', 'Var', (120, 135))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('aggressive type II endometrial cancer', 'Disease', (231, 268))	('due', 'Reg', (94, 97))	('aggressive type II endometrial cancer', 'Disease', 'MESH:D016889', (231, 268))
24364	22911740	In in vivo studies in athymic nude mice bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects.	('activities', 'MPA', (275, 285))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (68, 83))	('levels', 'MPA', (239, 245))	('suppression', 'NegReg', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('caspase-3/7', 'Enzyme', (263, 274))	('K252a', 'Var', (158, 163))	('tumor', 'Disease', (89, 94))	('cell proliferation', 'CPA', (206, 224))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('sarcoma cell tumors', 'Disease', (76, 95))	('nude mice', 'Species', '10090', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('sarcoma cell tumors', 'Disease', 'MESH:D012509', (76, 95))	('decreased', 'NegReg', (196, 205))	('tumor', 'Disease', (127, 132))	('increased', 'PosReg', (229, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
24365	22911740	Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (84, 99))	('patients', 'Species', '9606', (204, 212))	('contributed', 'Reg', (69, 80))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (218, 233))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('sarcoma', 'Disease', (92, 99))	('sarcomas', 'Disease', 'MESH:D012509', (226, 234))	('sarcoma', 'Disease', (226, 233))	('sarcomas', 'Phenotype', 'HP:0100242', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcomas', 'Disease', (226, 234))	('endogenous signaling', 'MPA', (28, 48))	('tumors', 'Disease', (155, 161))	('inhibition', 'Var', (117, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('tumors', 'Disease', 'MESH:D009369', (155, 161))
24426	22911740	To determine the roles of endogenous TrkB ligands in cell proliferation and apoptosis of sarcoma cells, MES-SA and MES-SA/Dx5 cells, were incubated with K252a or the TrkB ectodomain.	('MES-SA', 'Chemical', '-', (104, 110))	('K252a', 'Var', (153, 158))	('MES-SA', 'Chemical', '-', (115, 121))	('Dx5', 'Gene', (122, 125))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('Dx5', 'Gene', '16398', (122, 125))
24429	22911740	To determine whether the observed in vitro inhibition of sarcoma cell growth by Trk receptor inhibitors could be translated into in vivo antitumor activity, K252a was administered to athymic nude mice bearing tumor xenografts of MES-SA/Dx5 cells, which were chosen for these studies due to their high BDNF and TrkB expression levels and multidrug-resistant character that could be more severe model of uterine sarcoma for in vivo analyses.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Dx5', 'Gene', (236, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('tumor', 'Disease', (209, 214))	('sarcoma', 'Disease', 'MESH:D012509', (410, 417))	('nude mice', 'Species', '10090', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('K252a', 'Var', (157, 162))	('Dx5', 'Gene', '16398', (236, 239))	('TrkB', 'Protein', (310, 314))	('sarcoma', 'Disease', (410, 417))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('expression levels', 'MPA', (315, 332))	('BDNF', 'MPA', (301, 305))	('MES-SA', 'Chemical', '-', (229, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (410, 417))	('inhibitors', 'Var', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('tumor', 'Disease', (141, 146))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (402, 417))	('sarcoma', 'Disease', (57, 64))
24430	22911740	When the tumor volume reached >80 mm3, animals were given vehicle alone, K252a, or K252b at 1 mg/kg every 3 days for 15 days.	('K252b', 'Var', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('K252a', 'Var', (73, 78))
24431	22911740	Tumors in animals treated with K252a were significantly smaller than those that received vehicle or K252b (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('smaller', 'NegReg', (56, 63))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('K252a', 'Var', (31, 36))
24433	22911740	Excised tumors were further examined to determine the in vivo effects of K252a.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('K252a', 'Var', (73, 78))
24435	22911740	Ki-67 staining confirmed the effects of K252a treatment on the suppression of cell proliferation (Fig.	('Ki-67', 'Chemical', '-', (0, 5))	('K252a', 'Var', (40, 45))	('suppression', 'NegReg', (63, 74))	('cell proliferation', 'CPA', (78, 96))
24436	22911740	Moreover, we characterized K252a-induced apoptosis in tumors by quantifying caspase activities and observed a 2.2-fold increase in the activation of caspase-3/7 within tumors of K252a-treated mice (Fig.	('K252a-induced', 'Var', (27, 40))	('activation', 'PosReg', (135, 145))	('mice', 'Species', '10090', (192, 196))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('K252a-treated', 'Var', (178, 191))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('increase', 'PosReg', (119, 127))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('caspase-3/7', 'Enzyme', (149, 160))	('tumors', 'Disease', (54, 60))
24448	22911740	Overexpression of BDNF and TrkB is also associated with poor outcomes for neuroblastoma patients.	('TrkB', 'Protein', (27, 31))	('BDNF', 'Protein', (18, 22))	('neuroblastoma', 'Disease', 'MESH:D009447', (74, 87))	('patients', 'Species', '9606', (88, 96))	('neuroblastoma', 'Disease', (74, 87))	('Overexpression', 'Var', (0, 14))	('neuroblastoma', 'Phenotype', 'HP:0003006', (74, 87))
24453	22911740	Interestingly, the leiomyosarcoma patients with high BDNF expression also showed significantly high levels of TrkB, but not NT4/5.	('NT4/5', 'Gene', (124, 129))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (19, 33))	('TrkB', 'Protein', (110, 114))	('BDNF', 'Gene', (53, 57))	('high', 'PosReg', (95, 99))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (19, 33))	('expression', 'Var', (58, 68))	('patients', 'Species', '9606', (34, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('high', 'Var', (48, 52))	('NT4/5', 'Gene', '4909', (124, 129))	('leiomyosarcoma', 'Disease', (19, 33))
24455	22911740	In our leiomyosarcoma cases, clinical stage of the group with high-BDNF/TrkB was stage I (n = 1) and stage IV (n = 2), whereas low-BDNF/TrkB group was stage I (n = 2) and stage IV (n = 2).	('leiomyosarcoma', 'Disease', 'MESH:D007890', (7, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('high-BDNF/TrkB', 'Var', (62, 76))	('leiomyosarcoma', 'Disease', (7, 21))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (7, 21))
24465	22911740	In our study, stimulation of cell proliferation by exogenous BDNF was observed in MES-SA/Dx5, but not MES-SA, cells.	('exogenous', 'Var', (51, 60))	('Dx5', 'Gene', (89, 92))	('stimulation', 'PosReg', (14, 25))	('BDNF', 'Gene', (61, 65))	('cell proliferation', 'CPA', (29, 47))	('MES-SA', 'Chemical', '-', (82, 88))	('Dx5', 'Gene', '16398', (89, 92))	('MES-SA', 'Chemical', '-', (102, 108))
24469	22911740	Because the inhibitory effect of K252a on cell proliferation was similar to that of the TrkB ectodomain in vitro, K252a is likely to be specific for TrkB, although other members of the Trk family, including TrkA and TrkC, were expressed in these sarcoma cells (Fig.	('TrkC', 'Gene', '4916', (216, 220))	('K252a', 'Var', (114, 119))	('TrkA', 'Gene', '4914', (207, 211))	('TrkC', 'Gene', (216, 220))	('sarcoma', 'Disease', 'MESH:D012509', (246, 253))	('sarcoma', 'Disease', (246, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('TrkA', 'Gene', (207, 211))
24472	22911740	The suppressive effect of K252a on MES-SA/Dx5 tumor growth in athymic nude mice indicated that BDNF/TrkB signaling also played a significant role in uterine sarcoma growth and protection against apoptosis in vivo.	('Dx5', 'Gene', '16398', (42, 45))	('MES-SA', 'Chemical', '-', (35, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcoma growth', 'Disease', 'MESH:D006130', (157, 171))	('K252a', 'Var', (26, 31))	('tumor', 'Disease', (46, 51))	('Dx5', 'Gene', (42, 45))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (149, 164))	('sarcoma growth', 'Disease', (157, 171))	('suppressive', 'NegReg', (4, 15))	('nude mice', 'Species', '10090', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
24473	22911740	K252a is a small molecule (MW = 467 Da), easily delivered to tumor xenografts via i.p.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (61, 66))	('K252a', 'Var', (0, 5))
24510	22498937	As a key gene for cell survival, HER2/neu gene amplification and protein overexpression lead to malignant transformation.	('gene amplification', 'Var', (42, 60))	('malignant transformation', 'CPA', (96, 120))	('lead to', 'Reg', (88, 95))	('HER2/neu', 'Gene', '2064', (33, 41))	('protein', 'Protein', (65, 72))	('amplification', 'Var', (47, 60))	('HER2/neu', 'Gene', (33, 41))	('overexpression', 'PosReg', (73, 87))
24537	22498937	The clinically marketed anti-HER2/neu trastuzumab (Herceptin, Genentech, San Francisco, CA), a humanized monoclonal antibody (mAb) of the G1 type that binds with high affinity to the extracellular domain of the HER2/neu receptor and commercially available antibodies against membrane-bound complement regulatory protein CD46 (cat#555948), CD55 (cat#555691) and CD59 (cat#555761) (BD Pharmingen, San Diego, CA), were used for our study.	('cat#555691', 'Var', (345, 355))	('human', 'Species', '9606', (95, 100))	('trastuzumab', 'Chemical', 'MESH:D000068878', (38, 49))	('HER2/neu', 'Gene', '2064', (29, 37))	('CD59', 'Gene', (361, 365))	('CD55', 'Gene', '1604', (339, 343))	('CD55', 'Gene', (339, 343))	('HER2/neu', 'Gene', '2064', (211, 219))	('CD59', 'Gene', '966', (361, 365))	('CD46', 'Gene', '4179', (320, 324))	('Herceptin', 'Chemical', 'MESH:D000068878', (51, 60))	('CD46', 'Gene', (320, 324))	('HER2/neu', 'Gene', (29, 37))	('HER2/neu', 'Gene', (211, 219))	('cat#555761', 'Var', (367, 377))	('cat#555948', 'Var', (326, 336))
24583	22498937	As a key gene for cell survival, growth and differentiation, HER2/neu gene amplification and protein overexpression lead to malignant transformation.	('overexpression', 'PosReg', (101, 115))	('malignant transformation', 'CPA', (124, 148))	('protein', 'Protein', (93, 100))	('lead to', 'Reg', (116, 123))	('HER2/neu', 'Gene', '2064', (61, 69))	('amplification', 'Var', (75, 88))	('HER2/neu', 'Gene', (61, 69))
24585	22498937	The reported rate of overexpression and amplification in uterine carcinosarcoma ranged from 17 to 43%.	('amplification', 'Var', (40, 53))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (57, 79))	('carcinosarcoma', 'Disease', 'MESH:D002296', (65, 79))	('carcinosarcoma', 'Disease', (65, 79))
24595	22498937	This percentage of HER2/neu positivity in primary MMT cell lines is in agreement with the reported rate of overexpression and amplification in gynecologic carcinosarcomas.	('MMT', 'Chemical', 'MESH:C009907', (50, 53))	('carcinosarcomas', 'Disease', (155, 170))	('HER2/neu', 'Gene', '2064', (19, 27))	('positivity', 'Var', (28, 38))	('HER2/neu', 'Gene', (19, 27))	('carcinosarcomas', 'Disease', 'MESH:D002296', (155, 170))
24608	22498937	Nevertheless, these data suggest, as previously postulated for ovarian cancer gene therapy, that silencing of mCRPs may potentially synergize with trastuzumab-ADCC in vitro as well as in vivo against chemotherapy resistant carcinosarcomas.	('silencing', 'Var', (97, 106))	('trastuzumab', 'Chemical', 'MESH:D000068878', (147, 158))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('mCRPs', 'Gene', (110, 115))	('carcinosarcomas', 'Disease', 'MESH:D002296', (223, 238))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('carcinosarcomas', 'Disease', (223, 238))	('ovarian cancer', 'Disease', (63, 77))
24627	33804979	Lack of ER was found to be associated with epithelial-mesenchymal transition (EMT), a crucial step during tumor progression and malignant transformation, and reduced survival (p < 0.001).	('ER', 'Gene', '2069', (8, 10))	('epithelial-mesenchymal transition', 'CPA', (43, 76))	('Lack', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('survival', 'CPA', (166, 174))	('reduced', 'NegReg', (158, 165))	('tumor', 'Disease', (106, 111))
24655	33804979	From a molecular point of view, the serous type seems to be correlated with the mutation of p53, which intervenes in the early stages of carcinogenesis.	('serous type', 'Disease', (36, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))	('p53', 'Gene', (92, 95))	('correlated', 'Reg', (60, 70))	('carcinogenesis', 'Disease', (137, 151))	('p53', 'Gene', '7157', (92, 95))	('mutation', 'Var', (80, 88))
24666	33804979	Ultra Mutated POLE: These tumors are characterized by a high percentage of mutations and hot spots mutations in esonucleasic POLE domain (DNA subunit polymerase that has role in DNA replication).	('esonucleasic', 'Gene', (112, 124))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (99, 108))	('mutations', 'Var', (75, 84))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
24668	33804979	Microsatellite instability (MSI): This group is characterized by MSI caused by MLH1 promoter methylation.	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('MLH1', 'Gene', '4292', (79, 83))	('Microsatellite instability', 'Disease', (0, 26))	('MLH1', 'Gene', (79, 83))	('methylation', 'Var', (93, 104))	('caused by', 'Reg', (69, 78))
24670	33804979	Endometrioid Tumors with Low Copy Number: In this class, there are endometrioid tumors of grade 1 and 2 with microsatellite stability.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Tumors', 'Disease', (13, 19))	('Tumors', 'Disease', 'MESH:D009369', (13, 19))	('Tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('microsatellite', 'Var', (109, 123))	('Tumor', 'Phenotype', 'HP:0002664', (13, 18))
24671	33804979	In particular, alteration of beta catenin gene (CTNNB1) is characteristic in this class.	('beta catenin', 'Gene', (29, 41))	('CTNNB1', 'Gene', (48, 54))	('CTNNB1', 'Gene', '1499', (48, 54))	('alteration', 'Var', (15, 25))	('beta catenin', 'Gene', '1499', (29, 41))
24672	33804979	Tumors "Serous Like" with High Number of Copies: These neoplasms are characterized by a high number of aberrations in copy numbers and a low frequency of mutations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('aberrations', 'Var', (103, 114))	('neoplasm', 'Phenotype', 'HP:0002664', (55, 63))	('Tumors', 'Disease', (0, 6))	('neoplasms', 'Disease', 'MESH:D009369', (55, 64))	('neoplasms', 'Disease', (55, 64))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('copy', 'MPA', (118, 122))	('neoplasms', 'Phenotype', 'HP:0002664', (55, 64))
24674	33804979	PTEN and KRAS mutations, instead, are rare.	('KRAS', 'Gene', (9, 13))	('KRAS', 'Gene', '3845', (9, 13))	('PTEN', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('PTEN', 'Gene', '5728', (0, 4))
24678	33804979	For example, DNA mismatch repair deficiency (MMRd), the presence of CTNNB1 exon-3 mutation or TP53 mutation, and p53 overexpression and null expression patterns on IHC analysis are each associated with poor survival in cases of endometrioid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('presence', 'Var', (56, 64))	('mutation', 'Var', (82, 90))	('CTNNB1', 'Gene', (68, 74))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('poor', 'NegReg', (202, 206))	('mutation', 'Var', (99, 107))	('p53', 'Gene', '7157', (113, 116))	('overexpression', 'PosReg', (117, 131))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (228, 250))	('CTNNB1', 'Gene', '1499', (68, 74))	('p53', 'Gene', (113, 116))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (228, 250))	('endometrioid carcinoma', 'Disease', (228, 250))
24685	33804979	Lymphocytes invasion was described to be influenced by genetic factors, such as MUC16 mutations, which increased T cells but not Natural Killer (NK) cells invasion of the tumour.	('mutations', 'Var', (86, 95))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('increased', 'PosReg', (103, 112))	('MUC16', 'Gene', (80, 85))	('tumour', 'Disease', (171, 177))	('T cells', 'CPA', (113, 120))	('Lymphocytes invasion', 'CPA', (0, 20))	('MUC16', 'Gene', '94025', (80, 85))	('increased T cells', 'Phenotype', 'HP:0100828', (103, 120))	('influenced', 'Reg', (41, 51))
24709	33804979	This phase II study (NCT02912572) evaluated the PD-L1 inhibitor Avelumab in two cohorts of EC patients: (1) MMRD/POLE cohort, as defined by IHC loss of expression of >=1 MMR proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMR proficient (MMRP) cohort with normal IHC expression of all MMR proteins.	('loss of', 'NegReg', (144, 151))	('PD-L1', 'Gene', '29126', (48, 53))	('patients', 'Species', '9606', (94, 102))	('MMRD', 'Disease', (108, 112))	('Avelumab', 'Chemical', 'MESH:C000609138', (64, 72))	('PD-L1', 'Gene', (48, 53))	('mutation', 'Var', (201, 209))	('expression', 'MPA', (152, 162))	('MMRD', 'Disease', 'None', (108, 112))
24712	33804979	Hyper-mutation and/or high immune infiltration may be linked to response to PD-L1 blockade (NCT01375842).	('immune infiltration', 'CPA', (27, 46))	('PD-L1', 'Gene', '29126', (76, 81))	('Hyper-mutation', 'Var', (0, 14))	('PD-L1', 'Gene', (76, 81))
24717	33804979	In this context, several phase III trials are ongoing among patients with primary advanced or recurrent EC: The RUBY trial of first-line Dostarlimab (PD-1 inhibitor) plus carboplatin and paclitaxel chemotherapy (NCT03981796); the AtTEndtrial with Atezolizumab (NCT03603184); and the GY018 trail with Pembrolizumab (NCT02549209) in combination with carboplatin and paclitaxel, with the expectation to improve on the previous results observed with monotherapy alone.	('AtTEndtrial with Atezolizumab', 'Disease', (230, 259))	('carboplatin', 'Chemical', 'MESH:D016190', (171, 182))	('paclitaxel', 'Chemical', 'MESH:D017239', (187, 197))	('NCT02549209', 'Var', (315, 326))	('NCT03981796', 'Var', (212, 223))	('AtTEndtrial with Atezolizumab', 'Disease', 'None', (230, 259))	('Dostarlimab', 'Chemical', '-', (137, 148))	('patients', 'Species', '9606', (60, 68))	('carboplatin', 'Chemical', 'MESH:D016190', (348, 359))	('NCT03603184', 'Var', (261, 272))	('paclitaxel', 'Chemical', 'MESH:D017239', (364, 374))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (300, 313))
24718	33804979	Another effort to get better results, consists of combining the oral multikinase inhibitor Lenvatinib with Pembrolizumab for the treatment of advanced EC for patients that are not reflecting dMMR or MSI-H and have progressed following prior therapy (NCT03517449, NCT03884101, NCT03006887).	('Lenvatinib', 'Gene', (91, 101))	('NCT03884101', 'Var', (263, 274))	('Lenvatinib', 'Chemical', 'MESH:C531958', (91, 101))	('NCT03517449', 'Var', (250, 261))	('patients', 'Species', '9606', (158, 166))	('dMMR', 'Chemical', '-', (191, 195))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (107, 120))
24719	33804979	In addition, Pembrolizumab has been also combined with Ataluren, a drug that allows the translation of new target peptides useful for the immune-system to recognize cancer cells (NCT04014530).	('NCT04014530', 'Var', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (13, 26))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
24736	32843721	Conditional uterine deletion of Dicer1 and Pten in mice resulted in poorly-differentiated endometrial adenocarcinomas, which expressed Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B), markers of clear-cell adenocarcinoma.	('resulted in', 'Reg', (56, 67))	('hepatocyte nuclear factor 1 homeobox B', 'Gene', (155, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('mice', 'Species', '10090', (51, 55))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (90, 117))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (90, 116))	('Pten', 'Gene', (43, 47))	('Dicer1', 'Gene', (32, 38))	('clear-cell adenocarcinoma', 'Disease', 'MESH:D008649', (207, 232))	('HNF1B', 'Gene', (148, 153))	('hepatocyte nuclear factor 1 homeobox B', 'Gene', '21410', (155, 193))	('expressed', 'Reg', (125, 134))	('Napsin A', 'Gene', '16541', (135, 143))	('deletion', 'Var', (20, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Napsin A', 'Gene', (135, 143))	('endometrial adenocarcinomas', 'Disease', (90, 117))	('HNF1B', 'Gene', '21410', (148, 153))	('clear-cell adenocarcinoma', 'Disease', (207, 232))
24739	32843721	Computational integration of miRNA with mRNA targets revealed deregulated let-7 and miR-16 target genes, similar to published human DICER1-mutant endometrial cancers from TCGA (The Cancer Genome Atlas).	('human', 'Species', '9606', (126, 131))	('let-7', 'Gene', (74, 79))	('DICER1-mutant', 'Var', (132, 145))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Cancer', 'Disease', (181, 187))	('deregulated', 'PosReg', (62, 73))	('endometrial cancer', 'Phenotype', 'HP:0012114', (146, 164))	('endometrial cancers', 'Disease', 'MESH:D016889', (146, 165))	('miR-16 target genes', 'Gene', (84, 103))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))	('endometrial cancers', 'Disease', (146, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
24748	32843721	Hotspot biallelic mutations in DICER1, the endoribonuclease responsible for miRNA genesis, are enriched in endometrial adenocarcinomas over other cancers profiled in both TCGA (The Cancer Genome Atlas) PanCancer and MSK-IMPACT (Memorial Sloan-Kettering Integrated Mutation Profiling and Actionable Cancer Targets) studies.	('Cancer', 'Disease', (205, 211))	('cancers', 'Disease', (146, 153))	('DICER1', 'Gene', (31, 37))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (107, 133))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (107, 134))	('Cancer', 'Phenotype', 'HP:0002664', (298, 304))	('Cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Cancer', 'Disease', 'MESH:D009369', (205, 211))	('Cancer', 'Disease', (298, 304))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('endometrial adenocarcinomas', 'Disease', (107, 134))	('Cancer', 'Disease', 'MESH:D009369', (298, 304))	('biallelic mutations', 'Var', (8, 27))	('Cancer', 'Phenotype', 'HP:0002664', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
24749	32843721	Studies have shown that recurrent DICER1 hotspot mutations from ovarian and endometrial cancers resulted in altered miRNA processing.	('altered', 'Reg', (108, 115))	('mutations', 'Var', (49, 58))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('endometrial cancer', 'Phenotype', 'HP:0012114', (76, 94))	('ovarian and endometrial cancers', 'Disease', 'MESH:D004714', (64, 95))	('miRNA processing', 'MPA', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('DICER1', 'Gene', (34, 40))
24751	32843721	Uterine-specific deletion of Dicer1 using PgrCre/+; Dicer1flox/flox mice resulted in a uterine phenotype containing a single layer of luminal epithelium, lack of glandular epithelium, and thin to zero endometrial stroma, consistent with atrophic endometrium from postmenopausal women.	('mice', 'Species', '10090', (68, 72))	('Pgr', 'Gene', '18667', (42, 45))	('endometrial stroma', 'Disease', 'MESH:D014591', (201, 219))	('endometrial stroma', 'Disease', (201, 219))	('Dicer1', 'Gene', (29, 35))	('deletion', 'Var', (17, 25))	('luminal', 'Chemical', 'MESH:D010634', (134, 141))	('atrophic', 'Disease', 'MESH:D020966', (237, 245))	('Pgr', 'Gene', (42, 45))	('atrophic', 'Disease', (237, 245))	('women', 'Species', '9606', (278, 283))	('uterine', 'Disease', (87, 94))
24752	32843721	Loss or mutation of the tumor suppressor, phosphatase and tensin homolog (PTEN), occurs in more than 80% of endometrial adenocarcinomas.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('phosphatase and tensin homolog', 'Gene', '19211', (42, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (108, 134))	('tumor', 'Disease', (24, 29))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (108, 135))	('endometrial adenocarcinomas', 'Disease', (108, 135))	('Loss', 'NegReg', (0, 4))	('PTEN', 'Gene', (74, 78))	('mutation', 'Var', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
24754	32843721	To study the role of Dicer1 in endometrial cancer, Dicer1 was conditionally deleted in PgrCre/+; Ptenflox/flox mice.	('endometrial cancer', 'Disease', (31, 49))	('Pgr', 'Gene', '18667', (87, 90))	('Dicer1', 'Gene', (51, 57))	('endometrial cancer', 'Phenotype', 'HP:0012114', (31, 49))	('mice', 'Species', '10090', (111, 115))	('deleted', 'Var', (76, 83))	('endometrial cancer', 'Disease', 'MESH:D016889', (31, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Pgr', 'Gene', (87, 90))
24755	32843721	Because downregulation of DICER1 expression was clinically associated with high FIGO grade endometrial cancer in women, we hypothesized that deletion of Dicer1 with deletion of Pten in the mouse uterus would result in high FIGO grade endometrial adenocarcinomas.	('deletion', 'Var', (141, 149))	('endometrial cancer', 'Disease', 'MESH:D016889', (91, 109))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (234, 261))	('Pten', 'Gene', (177, 181))	('result in', 'Reg', (208, 217))	('endometrial adenocarcinomas', 'Disease', (234, 261))	('mouse', 'Species', '10090', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('endometrial cancer', 'Disease', (91, 109))	('women', 'Species', '9606', (113, 118))	('deletion', 'Var', (165, 173))	('Dicer1', 'Gene', (153, 159))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (234, 260))	('downregulation', 'NegReg', (8, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
24756	32843721	In this study, we present data that underscores the impact of appropriate Dicer1 function in endometrial adenocarcinoma.	('Dicer1', 'Gene', (74, 80))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (93, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (93, 119))	('endometrial adenocarcinoma', 'Disease', (93, 119))	('function', 'Var', (81, 89))
24778	32843721	Based on criteria for humane endpoints, Pten cKO and dcKO mice showed decreased survival compared to Pgr+/+ (Figure 1B and Supplementary Figure S7).	('Pgr', 'Gene', (101, 104))	('Pgr', 'Gene', '18667', (101, 104))	('dcKO', 'Chemical', '-', (53, 57))	('decreased', 'NegReg', (70, 79))	('mice', 'Species', '10090', (58, 62))	('human', 'Species', '9606', (22, 27))	('survival', 'CPA', (80, 88))	('Pten cKO', 'Var', (40, 48))
24785	32843721	With deletion of Dicer1, the frequency of poorly-differentiated adenocarcinoma increased significantly (chi2 = 12.8; P = 0.00035).	('increased', 'PosReg', (79, 88))	('Dicer1', 'Gene', (17, 23))	('deletion', 'Var', (5, 13))	('adenocarcinoma', 'Disease', (64, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
24808	32843721	Gross uterine weight was lower in ovariectomized (ovex) mice compared to intact mice (Supplementary Figure S11A).	('Gross uterine weight', 'CPA', (0, 20))	('lower', 'NegReg', (25, 30))	('S11A', 'Var', (107, 111))	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (80, 84))	('S11A', 'SUBSTITUTION', 'None', (107, 111))
24815	32843721	Treatment of intact mice with long-term progesterone decreased the rate of metastatic adenocarcinoma to the adnexa, but it was only statistically significantly decreased for Pten cKO mice (Supplementary Figure S11B and Table S3).	('S11B', 'Var', (210, 214))	('mice', 'Species', '10090', (20, 24))	('progesterone decreased', 'Phenotype', 'HP:0008233', (40, 62))	('S11B', 'SUBSTITUTION', 'None', (210, 214))	('mice', 'Species', '10090', (183, 187))	('adenocarcinoma', 'Disease', (86, 100))	('progesterone', 'Chemical', 'MESH:D011374', (40, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('decreased', 'NegReg', (160, 169))	('decreased', 'NegReg', (53, 62))	('cKO', 'Var', (179, 182))	('adenocarcinoma', 'Disease', 'MESH:D000230', (86, 100))
24816	32843721	To create an in vitro human model, CRISPR-Cas9 was used to delete DICER1.	('DICER1', 'Gene', (66, 72))	('human', 'Species', '9606', (22, 27))	('delete', 'Var', (59, 65))
24818	32843721	DICER1 deletion in Ishikawa cells led to decreased cellular proliferation and reduced colony formation in soft agar (Figure 4B-C), consistent with the smaller-sized uterine tumors in dcKO mice (Figure 1C).	('mice', 'Species', '10090', (188, 192))	('uterine tumors', 'Phenotype', 'HP:0010784', (165, 179))	('DICER1', 'Gene', (0, 6))	('colony formation in soft agar', 'CPA', (86, 115))	('smaller-sized uterine', 'Phenotype', 'HP:0000013', (151, 172))	('dcKO', 'Chemical', '-', (183, 187))	('decreased', 'NegReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('agar', 'Chemical', 'MESH:D000362', (111, 115))	('tumors', 'Disease', (173, 179))	('reduced', 'NegReg', (78, 85))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('deletion', 'Var', (7, 15))	('cellular proliferation', 'CPA', (51, 73))
24820	32843721	DICER1-/- Ishikawa cells exhibited a 4-fold decrease in CDH1 RNA expression (Figure 4D) and a significant decline in CDH1 expression by immunocytochemistry (Figure 4E and Supplementary Figure S12), consistent with a more poorly-differentiated phenotype.	('expression', 'MPA', (122, 132))	('DICER1-/-', 'Var', (0, 9))	('decrease', 'NegReg', (44, 52))	('CDH1', 'Gene', (117, 121))	('CDH1', 'Gene', (56, 60))	('CDH1', 'Gene', '999', (117, 121))	('CDH1', 'Gene', '999', (56, 60))	('expression', 'MPA', (65, 75))	('decline', 'NegReg', (106, 113))
24821	32843721	DICER1-/- cells exhibited increased expression of the clear cell markers, Napsin A and HNF1B, by immunocytochemistry (Supplementary Figure S12).	('HNF1B', 'Gene', (87, 92))	('DICER1-/-', 'Var', (0, 9))	('Napsin A', 'Gene', (74, 82))	('HNF1B', 'Gene', '21410', (87, 92))	('increased', 'PosReg', (26, 35))	('Napsin A', 'Gene', '16541', (74, 82))	('expression', 'MPA', (36, 46))
24822	32843721	DICER1+/+, DICER1+/-, and DICER1-/- differed significantly in PC2, while DICER1+/+ and DICER1+/- were most similar in PC1 (Figure 4F).	('PC1', 'Gene', '17653', (118, 121))	('DICER1-/-', 'Var', (26, 35))	('PC1', 'Gene', (118, 121))	('DICER1+/-', 'Var', (11, 20))	('PC2', 'Gene', '111469', (62, 65))	('PC2', 'Gene', (62, 65))	('DICER1+/+', 'Var', (0, 9))
24823	32843721	Determination of differentially expressed genes between DICER1+/+ and DICER1-/- revealed 2444 unique protein-coding genes with log2fold change > 1  significantly dysregulated [false discovery rate (FDR)<0.05, Supplementary Table S4], 1154 genes upregulated, and 1290 genes downregulated (Supplementary Figure S13A).	('upregulated', 'PosReg', (245, 256))	('S13A', 'SUBSTITUTION', 'None', (309, 313))	('dysregulated', 'Reg', (162, 174))	('DICER1+/+', 'Var', (56, 65))	('protein-coding genes', 'Gene', (101, 121))	('S13A', 'Var', (309, 313))	('DICER1-/-', 'Var', (70, 79))	('downregulated', 'NegReg', (273, 286))
24825	32843721	Three-week uteri were selected because: 1) PgrCre/+-mediated deletion occurs primarily in the luminal and glandular epithelium; 2) the limited molecular contributions of steroid hormones in pre-adolescent female mice; 3) the ability to explore early molecular contributions; and 4) the similar ratio of cell populations (i.e., epithelium, stroma, and myometrium) across genotypes.	('mice', 'Species', '10090', (212, 216))	('luminal', 'Chemical', 'MESH:D010634', (94, 101))	('deletion', 'Var', (61, 69))	('Pgr', 'Gene', (43, 46))	('Pgr', 'Gene', '18667', (43, 46))	('steroid', 'Chemical', 'MESH:D013256', (170, 177))
24829	32843721	Because all experimental mice have a deletion of Pten, transcriptomic profiles were compared to Pten cKO.	('Pten', 'Gene', (49, 53))	('mice', 'Species', '10090', (25, 29))	('deletion', 'Var', (37, 45))
24830	32843721	Determination of differentially expressed genes between dcKO and Pten cKO showed 1635 unique protein-coding genes with log2fold change > 1  significantly dysregulated (FDR<0.01, Supplementary Figure S14B), 1059 genes upregulated, and 576 genes downregulated (Supplementary Table S4).	('dcKO', 'Chemical', '-', (56, 60))	('upregulated', 'PosReg', (217, 228))	('S14B', 'SUBSTITUTION', 'None', (199, 203))	('S14B', 'Var', (199, 203))	('downregulated', 'NegReg', (244, 257))	('protein-coding genes', 'Gene', (93, 113))	('dysregulated', 'Reg', (154, 166))
24844	32843721	Both high CFL2 and EPHA2 have been associated with increased proliferation in cancers.	('CFL2', 'Gene', (10, 14))	('high', 'Var', (5, 9))	('CFL2', 'Gene', '12632', (10, 14))	('increased', 'PosReg', (51, 60))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('EPHA2', 'Gene', '13836', (19, 24))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('proliferation', 'CPA', (61, 74))	('EPHA2', 'Gene', (19, 24))
24846	32843721	To examine the effects of DICER1 deletion on miRNA expression in endometrial cancer, small RNA sequencing was performed on the same samples as poly-A RNA sequencing.	('endometrial cancer', 'Disease', (65, 83))	('deletion', 'Var', (33, 41))	('endometrial cancer', 'Phenotype', 'HP:0012114', (65, 83))	('DICER1', 'Gene', (26, 32))	('endometrial cancer', 'Disease', 'MESH:D016889', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miRNA expression', 'MPA', (45, 61))
24849	32843721	The genes targeted by miRNAs were involved in the following pathways: microRNAs in cancer, glycosaminoglycan biosynthesis, ephrin-receptor signaling, and transforming growth factor-beta (TGFbeta) signaling (Supplementary Table S6).	('glycosaminoglycan', 'MPA', (91, 108))	('involved', 'Reg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('miRNAs', 'Var', (22, 28))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (91, 108))	('ephrin-receptor signaling', 'MPA', (123, 148))	('transforming', 'MPA', (154, 166))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
24851	32843721	Human DICER1-mutant TCGA endometrial cancers were enriched in miRNA-target genes from five miRNA families: let-7-5p, miR-17-5p, miR-16-5p, miR-29-3p, and miR-101-3p.	('Human', 'Species', '9606', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('miR-16-5p', 'Var', (128, 137))	('miR-29-3p', 'Gene', (139, 148))	('endometrial cancers', 'Disease', 'MESH:D016889', (25, 44))	('endometrial cancer', 'Phenotype', 'HP:0012114', (25, 43))	('miR-29-3p', 'Gene', '100049714', (139, 148))	('miR-17-5p', 'Var', (117, 126))	('endometrial cancers', 'Disease', (25, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('DICER1-mutant', 'Gene', (6, 19))	('miR-101-3p', 'Var', (154, 164))	('miR-16-5p', 'Chemical', '-', (128, 137))	('let-7-5p', 'Var', (107, 115))
24853	32843721	Recent work has shown that dysregulation of TGFbeta signaling in the mouse uterus results in endometrial hyperproliferation and cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('endometrial hyperproliferation', 'Disease', 'MESH:D014591', (93, 123))	('endometrial hyperproliferation', 'Disease', (93, 123))	('mouse', 'Species', '10090', (69, 74))	('endometrial hyperproliferation', 'Phenotype', 'HP:0040298', (93, 123))	('results in', 'Reg', (82, 92))	('dysregulation', 'Var', (27, 40))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TGFbeta signaling', 'Gene', (44, 61))	('cancer', 'Disease', (128, 134))
24854	32843721	Let-7b-5p, miR-16-5p, and miR-26b-5p were mature miRNAs downregulated in both DICER1-/- cells and dcKO uteri and predicted to target TGFbeta signaling genes.	('Let-7b', 'Gene', (0, 6))	('miR-26b', 'Gene', (26, 33))	('dcKO', 'Chemical', '-', (98, 102))	('miR-26b', 'Gene', '387219', (26, 33))	('downregulated', 'NegReg', (56, 69))	('Let-7b', 'Gene', '387245', (0, 6))	('miR-16-5p', 'Chemical', '-', (11, 20))	('miR-16-5p', 'Var', (11, 20))
24855	32843721	By QPCR, DICER1-/- cells had significant downregulation of let-7b-5p, and let-7b-5p was also 2-fold down-regulated in dcKO uteri.	('let-7b', 'Gene', '387245', (74, 80))	('let-7b', 'Gene', (74, 80))	('dcKO', 'Chemical', '-', (118, 122))	('DICER1-/- cells', 'Var', (9, 24))	('down-regulated', 'NegReg', (100, 114))	('let-7b', 'Gene', '387245', (59, 65))	('downregulation', 'NegReg', (41, 55))	('let-7b', 'Gene', (59, 65))
24861	32843721	BMPR1B showed a greater than 14-fold upregulation in DICER1-/- cells.	('BMPR1B', 'Gene', (0, 6))	('BMPR1B', 'Gene', '12167', (0, 6))	('upregulation', 'PosReg', (37, 49))	('DICER1-/-', 'Var', (53, 62))
24866	32843721	Four publicly available datasets of human endometrial cancer were used to determine the frequency of concurrent mutations in PTEN and DICER1 (Table 1).	('endometrial cancer', 'Disease', (42, 60))	('PTEN', 'Gene', (125, 129))	('endometrial cancer', 'Phenotype', 'HP:0012114', (42, 60))	('endometrial cancer', 'Disease', 'MESH:D016889', (42, 60))	('mutations', 'Var', (112, 121))	('DICER1', 'Gene', (134, 140))	('human', 'Species', '9606', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
24871	32843721	These databases showed that mutations in PTEN and DICER1 occur concurrently in up to 11.2% of endometrial cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('endometrial cancer', 'Disease', (94, 112))	('endometrial cancer', 'Phenotype', 'HP:0012114', (94, 112))	('DICER1', 'Gene', (50, 56))	('endometrial cancer', 'Disease', 'MESH:D016889', (94, 112))	('PTEN', 'Gene', (41, 45))	('mutations', 'Var', (28, 37))	('occur', 'Reg', (57, 62))
24872	32843721	Concurrent mutations in PTEN and DICER1 in endometrioid endometrial cancers were frequently grade 3 and disease progression was frequent.	('mutations', 'Var', (11, 20))	('endometrioid endometrial cancers', 'Disease', 'MESH:D016889', (43, 75))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('endometrioid endometrial cancers', 'Disease', (43, 75))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('endometrial cancer', 'Phenotype', 'HP:0012114', (56, 74))	('DICER1', 'Gene', (33, 39))	('PTEN', 'Gene', (24, 28))
24873	32843721	Up to 10% of clear cell tumors contained concurrent mutations in PTEN and DICER1.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('PTEN', 'Gene', (65, 69))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('contained', 'Reg', (31, 40))	('DICER1', 'Gene', (74, 80))
24881	32843721	Because DICER1 mutations are frequently found in ultra-mutated tumors, DICER1 mutations in endometrial adenocarcinoma were thought to be passenger mutations.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mutations', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('DICER1', 'Gene', (8, 14))	('mutations', 'Var', (78, 87))	('endometrial adenocarcinoma', 'Disease', (91, 117))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (91, 117))	('tumors', 'Disease', (63, 69))	('DICER1', 'Gene', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (91, 117))
24882	32843721	However, recent genomic profiling of tumors through TCGA PanCancer and MSK-IMPACT showed enrichment of biallelic DICER1 hotspot mutations in endometrial but not other cancers.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('endometrial', 'Disease', (141, 152))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('mutations', 'Var', (128, 137))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('tumors', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DICER1', 'Gene', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
24883	32843721	DICER1 mutants play a functional role in endometrial cancers, by affecting miRNA processing, miRNA expression, and miRNA-target gene expression.	('mutants', 'Var', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('expression', 'MPA', (133, 143))	('DICER1', 'Gene', (0, 6))	('endometrial cancer', 'Phenotype', 'HP:0012114', (41, 59))	('endometrial cancers', 'Disease', 'MESH:D016889', (41, 60))	('affecting', 'Reg', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('endometrial cancers', 'Disease', (41, 60))	('miRNA processing', 'MPA', (75, 91))	('miRNA expression', 'MPA', (93, 109))
24884	32843721	These studies showed that DICER1 mutations are not passenger mutations in endometrial cancer and suggest that DICER1 may play a unique yet significant role in endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (74, 92))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DICER1', 'Gene', (110, 116))	('mutations', 'Var', (33, 42))	('DICER1', 'Gene', (26, 32))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('endometrial cancer', 'Disease', (74, 92))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (74, 92))
24885	32843721	The frequency of concurrent mutations in PTEN and DICER1 is 2-11% (Table 1), but the number of DICER1 loss-of-function and recurrent hotspot mutations comprise nearly 50% of those concurrent mutations, advocating that our mouse model with deletion of Dicer1, has relevance to human disease.	('loss-of-function', 'NegReg', (102, 118))	('mutations', 'Var', (141, 150))	('mutations', 'Var', (191, 200))	('human', 'Species', '9606', (276, 281))	('mouse', 'Species', '10090', (222, 227))	('DICER1', 'Gene', (95, 101))
24886	32843721	Furthermore, on the molecular level, deregulated miRNA-target genes for let-7-5p and miR-16-5p family members were significantly enriched in published DICER1-mutant TCGA datasets and the present study (both dcKO mouse and DICER1-/- cells; Figure 6).	('DICER1-mutant', 'Var', (151, 164))	('dcKO', 'Chemical', '-', (207, 211))	('miR-16-5p', 'Chemical', '-', (85, 94))	('let-7-5p', 'Gene', (72, 80))	('mouse', 'Species', '10090', (212, 217))
24890	32843721	However, somatic loss-of-function mutations in DICER1 have been discovered in uterine adenosarcomas and rhabdomyosarcomas, suggesting that both the mesenchymal and the epithelial component plays a role in development of cancers.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('loss-of-function', 'NegReg', (17, 33))	('adenosarcomas', 'Disease', 'MESH:D018195', (86, 99))	('adenosarcomas', 'Disease', (86, 99))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (104, 121))	('rhabdomyosarcomas', 'Disease', (104, 121))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('DICER1', 'Gene', (47, 53))	('cancers', 'Disease', (220, 227))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (104, 121))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('mutations', 'Var', (34, 43))
24891	32843721	Women with Cowden Syndrome are at increased risk of endometrial cancer due to germline PTEN mutations, but the role of DICER1 mutations have not been published in women with Cowden Syndrome.	('PTEN', 'Gene', (87, 91))	('Women', 'Species', '9606', (0, 5))	('Cowden Syndrome', 'Disease', (174, 189))	('germline', 'Var', (78, 86))	('Cowden Syndrome', 'Disease', (11, 26))	('women', 'Species', '9606', (163, 168))	('endometrial cancer', 'Phenotype', 'HP:0012114', (52, 70))	('mutations', 'Var', (92, 101))	('endometrial cancer', 'Disease', 'MESH:D016889', (52, 70))	('Cowden Syndrome', 'Disease', 'MESH:D006223', (174, 189))	('Cowden Syndrome', 'Disease', 'MESH:D006223', (11, 26))	('endometrial cancer', 'Disease', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
24892	32843721	Other mouse models suggest that deletion of Pten and Dicer1 is not sufficient for malignant transformation of all epithelial lineages.	('Pten', 'Gene', (44, 48))	('deletion', 'Var', (32, 40))	('Dicer1', 'Gene', (53, 59))	('mouse', 'Species', '10090', (6, 11))
24894	32843721	Similarly, loss of two alleles of Dicer1 in an oncogenic Kras mouse model of lung cancer was protective against aggressive lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Dicer1', 'Gene', (34, 40))	('mouse', 'Species', '10090', (62, 67))	('aggressive lung cancer', 'Disease', 'MESH:D008175', (112, 134))	('Kras', 'Gene', (57, 61))	('loss', 'Var', (11, 15))	('Kras', 'Gene', '16653', (57, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('aggressive lung cancer', 'Disease', (112, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('lung cancer', 'Disease', (77, 88))
24896	32843721	Thus, loss of Pten and Dicer1 leading to endometrial cancer seems to be tissue specific in our mouse model and in human datasets from TCGA and MSK-IMPACT.	('loss', 'Var', (6, 10))	('endometrial cancer', 'Phenotype', 'HP:0012114', (41, 59))	('leading to', 'Reg', (30, 40))	('endometrial cancer', 'Disease', 'MESH:D016889', (41, 59))	('endometrial cancer', 'Disease', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('human', 'Species', '9606', (114, 119))	('Pten', 'Gene', (14, 18))	('Dicer1', 'Gene', (23, 29))	('mouse', 'Species', '10090', (95, 100))
24897	32843721	Clinically, miR-16-5p and let-7-5p represent important molecular targets for cancer therapy.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('miR-16-5p', 'Var', (12, 21))	('let-7-5p', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miR-16-5p', 'Chemical', '-', (12, 21))
24898	32843721	Treatment with liposomal miR-16 is being tested for mesothelioma and is frequently considered a tumor suppressor.	('miR-16', 'Gene', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('liposomal', 'Var', (15, 24))	('tumor', 'Disease', (96, 101))	('mesothelioma', 'Disease', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
24900	32843721	Recent studies suggest that high expression of CDK6 may be a biomarker for poor prognosis endometrial cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CDK6', 'Gene', (47, 51))	('endometrial cancer', 'Phenotype', 'HP:0012114', (90, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('endometrial cancers', 'Disease', 'MESH:D016889', (90, 109))	('high', 'Var', (28, 32))	('endometrial cancers', 'Disease', (90, 109))
24905	32843721	Studies indicate that the use of T56-LIMKi, a LIM kinase inhibitor, leads to decreased proliferation and migration in cancer cells.	('cancer', 'Disease', (118, 124))	('T56-LIMKi', 'Var', (33, 42))	('proliferation', 'CPA', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('decreased', 'NegReg', (77, 86))
24909	32843721	Additional deletion of Pten in this background of Dicer1 deletion leads to poorly-differentiated adenocarcinoma.	('deletion', 'Var', (11, 19))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('deletion', 'Var', (57, 65))	('Pten', 'Gene', (23, 27))	('leads to', 'Reg', (66, 74))	('Dicer1', 'Gene', (50, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))
24910	32843721	While hyper-proliferation of endometrial epithelium from endogenous or exogenous estradiol with mutation of PTEN is a biologically plausible mechanism for the development of endometrial cancer, little is known about the mechanism of development of endometrial cancer from atrophic endometrium.	('endometrial cancer', 'Phenotype', 'HP:0012114', (174, 192))	('PTEN', 'Gene', (108, 112))	('endometrial cancer', 'Disease', (248, 266))	('endometrial cancer', 'Disease', 'MESH:D016889', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutation', 'Var', (96, 104))	('atrophic', 'Disease', 'MESH:D020966', (272, 280))	('endometrial cancer', 'Phenotype', 'HP:0012114', (248, 266))	('endometrial cancer', 'Disease', (174, 192))	('endometrial cancer', 'Disease', 'MESH:D016889', (248, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('estradiol', 'Chemical', 'MESH:D004958', (81, 90))	('atrophic', 'Disease', (272, 280))
24916	32843721	Moreover, activation of WNT/beta-catenin through deletion of adenomatous polyposis coli (Apc) with PgrCre/+ showed frequent endometrioid ovarian cancer that began in the epithelial cells of the oviduct.	('beta-catenin', 'Gene', (28, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('WNT', 'Gene', (24, 27))	('WNT', 'Gene', '22419', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Pgr', 'Gene', (99, 102))	('Apc', 'Gene', (89, 92))	('adenomatous polyposis coli', 'Gene', (61, 87))	('Apc', 'Gene', '11789', (89, 92))	('endometrioid ovarian cancer', 'Disease', 'MESH:D016889', (124, 151))	('beta-catenin', 'Gene', '12387', (28, 40))	('deletion', 'Var', (49, 57))	('adenomatous polyposis coli', 'Gene', '11789', (61, 87))	('Pgr', 'Gene', '18667', (99, 102))	('endometrioid ovarian cancer', 'Disease', (124, 151))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (61, 87))	('activation', 'PosReg', (10, 20))
24917	32843721	However, we believe that Pten cKO, Pten-Dicer het, and dcKO mice have metastatic endometrial cancer to the adnexa.	('endometrial cancer', 'Phenotype', 'HP:0012114', (81, 99))	('metastatic', 'CPA', (70, 80))	('endometrial cancer', 'Disease', 'MESH:D016889', (81, 99))	('Pten cKO', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Dicer', 'Gene', '23405', (40, 45))	('Dicer', 'Gene', (40, 45))	('endometrial cancer', 'Disease', (81, 99))	('dcKO', 'Chemical', '-', (55, 59))	('mice', 'Species', '10090', (60, 64))
25028	32015676	Serum CA125 and LDH for the diagnosis of uterine sarcomas are limited in present study, and the preoperative CA125 and LDH abnormalities were detected in 24 and 17 of 70 cases, respectively.	('CA125', 'Gene', '94025', (109, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('detected', 'Reg', (142, 150))	('CA125', 'Gene', '94025', (6, 11))	('sarcomas', 'Disease', (49, 57))	('CA125', 'Gene', (109, 114))	('CA125', 'Gene', (6, 11))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (41, 56))	('abnormalities', 'Var', (123, 136))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))	('LDH', 'Gene', (119, 122))
25134	31776037	On univariate analysis, myometrial invasion >=50% (HR: 3.69; 95% CI: 1.43, 9.58) and LVSI (HR: 3.54; 95% CI: 1.37, 9.18) were each associated with death, but neither was statistically significant when included together in a multivariable model.	('death', 'Disease', 'MESH:D003643', (147, 152))	('LVSI', 'Disease', (85, 89))	('myometrial', 'Disease', (24, 34))	('death', 'Disease', (147, 152))	('associated with', 'Reg', (131, 146))	('>=50%', 'Var', (44, 49))
25241	31789001	2) The decision on the operative method in laparoscopic surgery is made according to the basic policy described in CQ01, CQ03, and CQ04.	('CQ03', 'Var', (121, 125))	('CQ04', 'Var', (131, 135))	('CQ01', 'CellLine', 'CVCL:Z240', (115, 119))	('CQ01', 'Var', (115, 119))
25369	28566221	Despite equivalency in demographics and uterine tumor pathology risk factors for metastasis, the SLN group had more lymph node metastasis (30.3% vs. 14.7%, p<0.001), more stage IIIC disease (30.2% vs. 14.5%, p<0.001), more GOG high-risk cases (32.8% vs. 21.8%, p=0.013), and received more adjuvant therapy (28.6% vs. 16.3%, p<0.01).	('SLN', 'Var', (97, 100))	('tumor', 'Disease', (48, 53))	('stage IIIC', 'Disease', (171, 181))	('uterine tumor', 'Phenotype', 'HP:0010784', (40, 53))	('GOG', 'CPA', (223, 226))	('lymph node metastasis', 'CPA', (116, 137))	('more', 'PosReg', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('more', 'PosReg', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
25385	28566221	In a presentation at the 2016 IGCS biennial meeting, Soliman et al reported a SLN detection rate of 89% from a prospective study of high-grade or deeply invasive endometrial cancer for which SLN mapping was followed by completion pelvic and aortic lymphadenectomy.	('endometrial cancer', 'Disease', (162, 180))	('endometrial cancer', 'Phenotype', 'HP:0012114', (162, 180))	('endometrial cancer', 'Disease', 'MESH:D016889', (162, 180))	('SLN mapping', 'Var', (191, 202))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
25467	29617661	Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations.	('FBXW7', 'Gene', (88, 93))	('MDM2', 'Gene', '4193', (143, 147))	('MDM2', 'Gene', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutated', 'Var', (80, 87))	('cancer', 'Disease', (99, 105))	('FBXW7', 'Gene', '55294', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
25470	29617661	These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion.	('upregulation', 'PosReg', (51, 63))	('APC', 'Disease', (162, 165))	('MYC/TERT', 'Gene', (134, 142))	('PTEN', 'Gene', (166, 170))	('PTEN', 'Gene', '5728', (166, 170))	('TERT', 'CellLine', 'CVCL:C452', (138, 142))	('cell-cycle', 'Pathway', (67, 77))	('TP53', 'Protein', (128, 132))	('APC', 'Disease', 'MESH:D011125', (162, 165))	('DNA repair pathways', 'Pathway', (82, 101))	('mutated', 'Var', (120, 127))
25478	29617661	First, both basic and translational studies have shown extensive evidence connecting the malfunction of the ubiquitin pathway with tumor initiation and progression.	('tumor initiation', 'Disease', 'MESH:D009369', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ubiquitin pathway', 'Pathway', (108, 125))	('tumor initiation', 'Disease', (131, 147))	('malfunction', 'Var', (89, 100))
25486	29617661	Overall, across 8,811 non-hypermutated cancer samples, the mutation frequency was low for both UBQ and DUB genes, with an average mutation number per patient of 4.5 and 0.5, respectively.	('patient', 'Species', '9606', (150, 157))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('low', 'NegReg', (82, 85))	('UBQ', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutation', 'Var', (59, 67))
25488	29617661	First, we used a ratiometric method for nominating cancer driver genes based on the enrichment of hotspot or loss-of-function (LoF) mutations among all mutations observed in a gene (Figure 1A).	('loss-of-function', 'NegReg', (109, 125))	('mutations', 'Var', (152, 161))	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
25489	29617661	In this pan-cancer analysis, we identified 19 UBQ/DUB genes with >30% hotspot mutations and 29 genes with >30% LoF mutations (FBXW7 was identified by both criteria).	('UBQ/DUB genes', 'Gene', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('LoF', 'NegReg', (111, 114))	('FBXW7', 'Gene', '55294', (126, 131))	('cancer', 'Disease', (12, 18))	('FBXW7', 'Gene', (126, 131))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
25494	29617661	Among 15 driver genes identified by both methods, SPOP, KEAP1, and CHD4 were enriched with hotspot mutations, while BAP1, CDH1, CUL3, EP300, KDM5C, MAP3K1, NSD1, RNF43, TLE1, VHL, and LZTR1 contained excessive LoF mutations.	('BAP1', 'Gene', (116, 120))	('KDM5C', 'Gene', (141, 146))	('VHL', 'Disease', (175, 178))	('VHL', 'Disease', 'MESH:D006623', (175, 178))	('CDH1', 'Gene', (122, 126))	('LZTR1', 'Gene', (184, 189))	('TLE1', 'Gene', (169, 173))	('CHD4', 'Gene', (67, 71))	('NSD1', 'Gene', (156, 160))	('mutations', 'Var', (99, 108))	('SPOP', 'Gene', (50, 54))	('LoF', 'NegReg', (210, 213))	('RNF43', 'Gene', (162, 167))	('MAP3K1', 'Gene', (148, 154))
25495	29617661	Of particular interest, FBXW7 showed enrichment of both hotspot and LoF mutations (Figure 1A).	('mutations', 'Var', (72, 81))	('FBXW7', 'Gene', (24, 29))	('LoF', 'NegReg', (68, 71))	('FBXW7', 'Gene', '55294', (24, 29))
25498	29617661	To gain more insight into its mutational profile, we examined the mutation distributions of FBXW7 in different cancer types and found three distinct patterns (Figure 2A): (1) hotspot mutations were enriched in two uterine cancer types, uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS); (2) LoF mutations were enriched in skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), rectum adenocarcinoma (READ), and esophageal carcinoma (ESCA); and (3) the proportions of both hotspot and LoF mutations were high in head and neck squamous cell carcinoma (HNSC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), bladder urothelial carcinoma (BLCA), and colon adenocarcinoma (COAD).	('lung adenocarcinoma', 'Disease', (450, 469))	('skin cutaneous melanoma', 'Disease', (350, 373))	('mutations', 'Var', (589, 598))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('COAD', 'Disease', (794, 798))	('endometrial carcinoma', 'Disease', (251, 272))	('stomach adenocarcinoma', 'Disease', (382, 404))	('carcinosarcoma', 'Disease', 'MESH:D002296', (293, 307))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (413, 441))	('READ', 'Disease', (501, 505))	('bladder urothelial carcinoma', 'Disease', (731, 759))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (450, 469))	('melanoma', 'Phenotype', 'HP:0002861', (365, 373))	('rectum adenocarcinoma', 'Disease', (478, 499))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (355, 373))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (626, 649))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (731, 759))	('uterine cancer', 'Phenotype', 'HP:0010784', (214, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (418, 441))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (413, 441))	('lung squamous cell carcinoma', 'Disease', (413, 441))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (512, 532))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (772, 792))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (450, 469))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (285, 307))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (251, 272))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (382, 404))	('FBXW7', 'Gene', (92, 97))	('mutations', 'Var', (323, 332))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (251, 272))	('READ', 'Disease', 'None', (501, 505))	('esophageal carcinoma', 'Disease', (512, 532))	('cancer type', 'Disease', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (490, 499))	('COAD', 'Disease', 'MESH:D029424', (794, 798))	('cervical squamous cell carcinoma', 'Disease', (658, 690))	('endocervical adenocarcinoma', 'Disease', (695, 722))	('cancer type', 'Disease', (222, 233))	('cancer type', 'Disease', 'MESH:D009369', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (432, 441))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (478, 499))	('cancer type', 'Disease', 'MESH:D009369', (222, 233))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (512, 532))	('colon adenocarcinoma', 'Disease', (772, 792))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (350, 373))	('FBXW7', 'Gene', '55294', (92, 97))	('carcinosarcoma', 'Disease', (293, 307))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (667, 690))
25499	29617661	Consistent with previous studies, FBXW7 contains three notable missense mutation hotspots (R465, R479, and R505) in the second, third, and fourth WD40 domains that recognize the consensus phospho-motif located in its substrate (Figure 2B).	('FBXW7', 'Gene', '55294', (34, 39))	('R479', 'Var', (97, 101))	('FBXW7', 'Gene', (34, 39))	('R505', 'Var', (107, 111))	('R465', 'Var', (91, 95))
25500	29617661	Figure 2C shows the FBXW7 mutation distributions for the hotspot mutation-enriched cancer types and the LoF mutation-enriched cancer types.	('LoF', 'NegReg', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('FBXW7', 'Gene', '55294', (20, 25))	('mutation', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer type', 'Disease', (126, 137))	('FBXW7', 'Gene', (20, 25))	('cancer type', 'Disease', (83, 94))	('cancer type', 'Disease', 'MESH:D009369', (126, 137))	('cancer type', 'Disease', 'MESH:D009369', (83, 94))
25501	29617661	The three missense hotspots accounted for 49% (38 of 77) of the FBXW7 mutations observed in UCEC and UCS.	('FBXW7', 'Gene', '55294', (64, 69))	('mutations', 'Var', (70, 79))	('UCEC', 'Disease', (92, 96))	('FBXW7', 'Gene', (64, 69))	('observed in', 'Reg', (80, 91))	('UCS', 'Disease', (101, 104))
25502	29617661	The contrasting mutation patterns of FBXW7 mutations may reflect tissue-specific roles of FBXW7 substrates or different FBXW7-mediated oncogenic mechanisms in different tumor contexts.	('FBXW7', 'Gene', (37, 42))	('FBXW7', 'Gene', '55294', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('FBXW7', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('FBXW7', 'Gene', '55294', (90, 95))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (169, 174))	('FBXW7', 'Gene', '55294', (37, 42))	('FBXW7', 'Gene', (90, 95))
25503	29617661	We further assessed the occurrence of FBXW7 mutations with those in clinically actionable cancer genes and revealed that mutations in FBXW7 and PIK3CA showed mutual exclusivity in three cancer types: CESC, BLCA, and LUSC (Figure 2D), suggesting that mutations in these two genes confer similar functional consequences.	('cancer type', 'Disease', 'MESH:D009369', (186, 197))	('mutations', 'Var', (121, 130))	('CESC', 'Disease', (200, 204))	('PIK3CA', 'Gene', (144, 150))	('FBXW7', 'Gene', (134, 139))	('FBXW7', 'Gene', '55294', (38, 43))	('LUSC', 'Disease', (216, 220))	('PIK3CA', 'Gene', '5290', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('FBXW7', 'Gene', (38, 43))	('cancer type', 'Disease', (186, 197))	('BLCA', 'Disease', (206, 210))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('FBXW7', 'Gene', '55294', (134, 139))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
25504	29617661	Patients with FBXW7 or phosphatidylinositol 3-kinase (PI3K) pathway mutations (mutations found in PIK3CA, PTEN, and STK11) had higher PI3K pathway expression activity than patients without such mutations (Figure 2E).	('STK11', 'Gene', (116, 121))	('activity', 'MPA', (158, 166))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (23, 52))	('FBXW7', 'Gene', '55294', (14, 19))	('PIK3CA', 'Gene', (98, 104))	('phosphatidylinositol 3-kinase', 'Gene', (23, 52))	('STK11', 'Gene', '6794', (116, 121))	('PIK3CA', 'Gene', '5290', (98, 104))	('Patients', 'Species', '9606', (0, 8))	('PTEN', 'Gene', '5728', (106, 110))	('PTEN', 'Gene', (106, 110))	('FBXW7', 'Gene', (14, 19))	('higher', 'PosReg', (127, 133))	('PI3K pathway', 'Pathway', (134, 146))	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (79, 88))
25505	29617661	To infer somatic copy-number alteration (SCNA) drivers, we used GISTIC2 to identify significant focal deletion and amplification peaks in each of 33 cancer types.	('cancer type', 'Disease', 'MESH:D009369', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('deletion', 'Var', (102, 110))	('cancer type', 'Disease', (149, 160))	('amplification', 'MPA', (115, 128))
25506	29617661	UBQ and DUB genes showed similar overall SCNA profiles in terms of the amplification and deletion gene fractions across cancer types (Figures S3A and S3B).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer type', 'Disease', (120, 131))	('cancer type', 'Disease', 'MESH:D009369', (120, 131))	('deletion', 'Var', (89, 97))	('UBQ', 'Gene', (0, 3))
25508	29617661	Four cancer types (kidney renal clear cell carcinoma [KIRC], SKCM, cholangiocarcinoma [CHOL], and pancreatic adenocarcinoma [PAAD]) showed significant deletion peak enrichments, while no cancer types showed significant amplification peak enrichment (p < 0.01) (Figure 3A).	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (98, 123))	('pancreatic adenocarcinoma', 'Disease', (98, 123))	('cancer type', 'Disease', 'MESH:D009369', (187, 198))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('cancer type', 'Disease', 'MESH:D009369', (5, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('deletion', 'Var', (151, 159))	('cholangiocarcinoma', 'Disease', (67, 85))	('kidney renal clear cell carcinoma', 'Disease', (19, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (98, 123))	('SKCM', 'Disease', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (19, 52))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer type', 'Disease', (187, 198))	('cancer type', 'Disease', (5, 16))
25512	29617661	Among UBQ and DUB genes, we found a mutually exclusive pattern of MDM2 and SKP2 amplifications in LUAD (Figure S3E), suggesting convergence of their functions on the same downstream effectors.	('amplifications', 'Var', (80, 94))	('MDM2', 'Gene', '4193', (66, 70))	('MDM2', 'Gene', (66, 70))	('UBQ', 'Gene', (6, 9))	('SKP2', 'Gene', (75, 79))	('LUAD', 'Disease', (98, 102))
25514	29617661	For clinically actionable genes, we found that MDM2 amplifications were mutually exclusive to BRAF and ATM mutations in SKCM and BLCA, respectively (Figures 3C and S3F).	('MDM2', 'Gene', '4193', (47, 51))	('mutations', 'Var', (107, 116))	('SKCM', 'Gene', (120, 124))	('MDM2', 'Gene', (47, 51))
25515	29617661	BRAF kinase domain mutations, such as V600E, result in a constitutively activated form of the protein in around 50% of SKCM patients (45.1% in this study), which then leads to stimulated mitogen-activated protein kinase (MAPK) signaling and induces tumor cell proliferation.	('V600E', 'Var', (38, 43))	('induces', 'PosReg', (241, 248))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('SKCM', 'Disease', (119, 123))	('tumor', 'Disease', (249, 254))	('mitogen-activated', 'MPA', (187, 204))	('V600E', 'Mutation', 'rs113488022', (38, 43))	('constitutively', 'MPA', (57, 71))	('stimulated', 'PosReg', (176, 186))
25517	29617661	We observed MDM2 amplification in 4.1% of the SKCM samples in this study, in which p53 protein levels were significantly lower than in samples with BRAF mutations alone or with neither BRAF mutations nor MDM2 amplifications.	('MDM2', 'Gene', '4193', (12, 16))	('MDM2', 'Gene', '4193', (204, 208))	('MDM2', 'Gene', (12, 16))	('MDM2', 'Gene', (204, 208))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('SKCM', 'Disease', (46, 50))	('lower', 'NegReg', (121, 126))	('amplification', 'Var', (17, 30))
25519	29617661	Furthermore, the mutually exclusive pattern of MDM2 amplification and BRAF mutation suggests that a reduced p53 pathway or induced MAPK signaling can serve as an impetus for aberrant tumor cell proliferation (Figure 3E).	('MDM2', 'Gene', '4193', (47, 51))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('MDM2', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('reduced', 'NegReg', (100, 107))	('mutation', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('amplification', 'Var', (52, 65))	('MAPK signaling', 'MPA', (131, 145))	('BRAF', 'Gene', (70, 74))
25521	29617661	Studies have shown increased apoptosis and inhibition of melanoma growth by combining a BRAF inhibitor and p53 reactivation.	('apoptosis', 'CPA', (29, 38))	('combining', 'Interaction', (76, 85))	('reactivation', 'Var', (111, 123))	('inhibition', 'NegReg', (43, 53))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('BRAF', 'Protein', (88, 92))	('increased', 'PosReg', (19, 28))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))
25527	29617661	First, in 6 of the 7 cancer types, upregulated genes showed a significantly higher proportion of copy-number amplifications than did neutral genes (chi-square test, q < 0.01) (Figure 4C, top), highlighting the significant role of somatic copy-number gain in increasing UBQ/DUB gene expression in tumor samples.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('cancer type', 'Disease', (21, 32))	('tumor', 'Disease', (296, 301))	('expression', 'MPA', (282, 292))	('copy-number', 'Var', (238, 249))	('increasing', 'PosReg', (258, 268))	('upregulated', 'PosReg', (35, 46))	('copy-number', 'Var', (97, 108))	('UBQ/DUB', 'Gene', (269, 276))	('cancer type', 'Disease', 'MESH:D009369', (21, 32))	('gain', 'PosReg', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
25547	29617661	Then we examined SCNA drivers by focusing on known oncogenes and tumor suppressors residing in amplification or deletion peaks (identified by GISTIC2) in each cancer type.	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('deletion', 'Var', (112, 120))	('amplification', 'Var', (95, 108))	('cancer type', 'Disease', (159, 170))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer type', 'Disease', 'MESH:D009369', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
25548	29617661	We found that COCA2 was associated with the amplifications of MYC and TERT and the deletions of PTEN and APC in multiple cancer types (q < 0.001) (Figure 6D).	('PTEN', 'Gene', '5728', (96, 100))	('amplifications', 'Var', (44, 58))	('APC', 'Disease', (105, 108))	('MYC', 'Protein', (62, 65))	('multiple cancer', 'Disease', (112, 127))	('associated', 'Reg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('COCA', 'Species', '289672', (14, 18))	('cancer type', 'Disease', (121, 132))	('deletions', 'Var', (83, 92))	('multiple cancer', 'Disease', 'MESH:D009369', (112, 127))	('TERT', 'CellLine', 'CVCL:C452', (70, 74))	('TERT', 'Gene', (70, 74))	('cancer type', 'Disease', 'MESH:D009369', (121, 132))	('COCA2', 'Disease', (14, 19))	('APC', 'Disease', 'MESH:D011125', (105, 108))	('PTEN', 'Gene', (96, 100))
25550	29617661	Deletion or low expression of the tumor suppressor PTEN has been shown to drive cell-cycle progression, proliferation, and cell survival.	('drive', 'PosReg', (74, 79))	('cell survival', 'CPA', (123, 136))	('tumor', 'Disease', (34, 39))	('PTEN', 'Gene', '5728', (51, 55))	('proliferation', 'CPA', (104, 117))	('Deletion', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('expression', 'MPA', (16, 26))	('cell-cycle progression', 'CPA', (80, 102))	('PTEN', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('low', 'NegReg', (12, 15))
25553	29617661	Therefore, we put forward a model in which mutated TP53 and amplified MYC are closely associated with primarily an upregulation of key ubiquitin-related enzymes, leading to an uncontrolled cell cycle, elevated DNA damage response, and ultimately poor survival for COCA2 patients (Figure 7).	('elevated', 'PosReg', (201, 209))	('upregulation', 'PosReg', (115, 127))	('TP53', 'Gene', (51, 55))	('patients', 'Species', '9606', (270, 278))	('uncontrolled', 'MPA', (176, 188))	('COCA', 'Species', '289672', (264, 268))	('MYC', 'Protein', (70, 73))	('amplified', 'Gene', (60, 69))	('DNA damage response', 'MPA', (210, 229))	('mutated', 'Var', (43, 50))
25555	29617661	For example, substrates of FBXW7 are oncoproteins, such as cyclin E, c-Myc, and Notch, while substrates of SKP2 are tumor suppressors, such as p21, p27, and p57.	('SKP2', 'Gene', (107, 111))	('cyclin E', 'Protein', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('FBXW7', 'Gene', '55294', (27, 32))	('p27', 'Var', (148, 151))	('Notch', 'MPA', (80, 85))	('FBXW7', 'Gene', (27, 32))	('p21', 'Var', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p57', 'Var', (157, 160))	('tumor', 'Disease', (116, 121))	('c-Myc', 'MPA', (69, 74))
25558	29617661	For example, BAP1 and VHL are frequently mutated in mesothelioma (MESO) and KIRC, respectively, whereas FBXW7 is enriched with hotspot mutations in UCEC and UCS but enriched with LoF mutations in ESCA, LUAD, LUSC, READ, SKCM, and STAD.	('BAP1', 'Gene', (13, 17))	('ESCA', 'Disease', (196, 200))	('mutations', 'Var', (183, 192))	('READ', 'Disease', (214, 218))	('mutated', 'Reg', (41, 48))	('mutations', 'Var', (135, 144))	('VHL', 'Disease', 'MESH:D006623', (22, 25))	('mesothelioma', 'Disease', (52, 64))	('FBXW7', 'Gene', '55294', (104, 109))	('VHL', 'Disease', (22, 25))	('LoF', 'NegReg', (179, 182))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('READ', 'Disease', 'None', (214, 218))	('FBXW7', 'Gene', (104, 109))
25559	29617661	Second, we show that compared to matched normal tissues, genes in the ubiquitin pathway tend to be overexpressed in a range of cancer types, and collectively, 71% of the upregulated genes are contributed by one of three mechanisms: somatic copy-number gain, reduced methylation-mediated gene silencing, and reduced miRNA-mediated gene regulation in tumors.	('cancer type', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (349, 355))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('reduced', 'NegReg', (258, 265))	('copy-number', 'Var', (240, 251))	('miRNA-mediated', 'MPA', (315, 329))	('reduced', 'NegReg', (307, 314))	('methylation-mediated gene', 'MPA', (266, 291))	('cancer type', 'Disease', 'MESH:D009369', (127, 138))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('gain', 'PosReg', (252, 256))	('upregulated', 'PosReg', (170, 181))
25561	29617661	These tumor samples are associated with differential UBQ/DUB expression underlying the perturbation of many fundamental signaling pathways, notably cell-cycle progression and DNA damage repair, likely resulting from key molecular drivers such as TP53, MYC, TERT, PTEN, and APC.	('APC', 'Disease', 'MESH:D011125', (273, 276))	('TERT', 'Disease', (257, 261))	('APC', 'Disease', (273, 276))	('TERT', 'CellLine', 'CVCL:C452', (257, 261))	('MYC', 'Disease', (252, 255))	('DNA damage repair', 'MPA', (175, 192))	('PTEN', 'Gene', (263, 267))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('TP53', 'Var', (246, 250))	('PTEN', 'Gene', '5728', (263, 267))	('perturbation', 'NegReg', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('UBQ/DUB', 'Gene', (53, 60))	('cell-cycle progression', 'CPA', (148, 170))	('tumor', 'Disease', (6, 11))	('fundamental signaling pathways', 'Pathway', (108, 138))
25564	29617661	This could be largely due to the lack of systemic characterization of significant driver mutations, SCNA patterns, and dysregulated expression profiles in the ubiquitin pathway across cancer types through an integrated genomic analysis that would provide clinically relevant drug candidates to the pharmaceutical industry.	('cancer type', 'Disease', 'MESH:D009369', (184, 195))	('ubiquitin pathway', 'Pathway', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (89, 98))	('cancer type', 'Disease', (184, 195))	('expression', 'MPA', (132, 142))	('dysregulated', 'Var', (119, 131))
25566	29617661	Moreover, the deubiquitinase USP7 has been shown to deubiquitinate several key cancer proteins, and P5091, a highly specific inhibitor of USP7, induced apoptosis in multiple myeloma cells.	('multiple myeloma', 'Disease', (165, 181))	('multiple myeloma', 'Disease', 'MESH:D009101', (165, 181))	('induced', 'PosReg', (144, 151))	('USP7', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('apoptosis', 'CPA', (152, 161))	('multiple myeloma', 'Phenotype', 'HP:0006775', (165, 181))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('deubiquitinate', 'MPA', (52, 66))	('P5091', 'Var', (100, 105))
25574	29617661	Across the pan-cancer cohort, hotspot mutations were defined as missense or in-frame mutations at the same protein amino acid in > 2 patient samples.	('cancer', 'Disease', (15, 21))	('patient', 'Species', '9606', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('in-frame', 'Reg', (76, 84))	('missense', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
25575	29617661	Mutual exclusivity for FBXW7 mutations and mutations in clinically actionable genes (annotated as in OncoKB, http://oncokb.org) was performed with the R package "cometExactTest."	('mutations', 'Var', (29, 38))	('FBXW7', 'Gene', (23, 28))	('FBXW7', 'Gene', '55294', (23, 28))
25576	29617661	To study the effects of FBXW7 mutations, PI3K pathway expression was calculated from protein levels of the PI3K/Akt pathway components as measured by RPPA with the following formula where E means expression:   We obtained SCNA data of 9,125 patient samples from Genomic Data Commons and applied GISTIC2.	('FBXW7', 'Gene', '55294', (24, 29))	('FBXW7', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('patient', 'Species', '9606', (241, 248))
25673	28577359	Recently, Divine also reported that isolated BM from gynecologic malignancies was significantly associated with survival.	('survival', 'CPA', (112, 120))	('associated with', 'Reg', (96, 111))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('isolated BM', 'Var', (36, 47))	('malignancies', 'Disease', (65, 77))
25688	27499902	We identified non-synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations.	('alterations', 'Var', (110, 121))	('non-synonymous', 'Var', (14, 28))	('harbouring', 'Reg', (94, 104))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))
25689	27499902	The PI3K pathway was the most commonly mutated signalling pathway with mutations identified in PIK3CA, PTEN, PIK3R1, and/or PIK3R2 in two-thirds of the cases.	('PTEN', 'Gene', (103, 107))	('mutated', 'Reg', (39, 46))	('PIK3CA', 'Gene', (95, 101))	('PTEN', 'Gene', '5728', (103, 107))	('PIK3CA', 'Gene', '5290', (95, 101))	('PIK3R2', 'Gene', (124, 130))	('PIK3R2', 'Gene', '5296', (124, 130))	('mutations', 'Var', (71, 80))	('PI3K pathway', 'Pathway', (4, 16))	('PIK3R1', 'Gene', (109, 115))	('PIK3R1', 'Gene', '5295', (109, 115))
25690	27499902	Mutations in FBXW7, PPP2R1A, ARID1A and KRAS were demonstrated in a minority of cases.	('PPP2R1A', 'Gene', (20, 27))	('FBXW7', 'Gene', '55294', (13, 18))	('PPP2R1A', 'Gene', '5518', (20, 27))	('KRAS', 'Gene', (40, 44))	('FBXW7', 'Gene', (13, 18))	('ARID1A', 'Gene', '8289', (29, 35))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (40, 44))	('ARID1A', 'Gene', (29, 35))
25692	27499902	Furthermore, the same TP53 alterations and/or PI3K pathway mutations seen in the primary tumours were also identified in the metastatic sites.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('primary tumours', 'Disease', (81, 96))	('PI3K pathway', 'Pathway', (46, 58))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('TP53', 'Gene', '7157', (22, 26))	('mutations', 'Var', (59, 68))	('primary tumours', 'Disease', 'MESH:D009369', (81, 96))	('TP53', 'Gene', (22, 26))	('alterations', 'Var', (27, 38))
25695	27499902	Our results provide insights into the oncogenesis of uterine carcinosarcoma and identify targetable mutations that represent early oncogenic events.	('mutations', 'Var', (100, 109))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (53, 75))	('carcinosarcoma', 'Disease', (61, 75))	('carcinosarcoma', 'Disease', 'MESH:D002296', (61, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
25705	27499902	A number of prior studies compared patterns of X-chromosome inactivation, microsatellite instability (MSI), types of TP53 and KRAS mutations and loss of heterozygosity (LOH) status between the carcinoma and sarcoma elements and demonstrated shared molecular features in the majority of cases 12, 13, 14, 15.	('KRAS', 'Gene', '3845', (126, 130))	('mutations', 'Var', (131, 140))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (193, 214))	('MSI', 'Disease', (102, 105))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('loss', 'Var', (145, 149))	('microsatellite instability', 'MPA', (74, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('KRAS', 'Gene', (126, 130))	('MSI', 'Disease', 'None', (102, 105))
25720	27499902	All non-synonymous somatic mutations (except for CSMD3) underwent secondary validation using either Fluidigm 48X48 Access Arrays (Fluidigm, Markhma, ON, Canada), then barcoded and sequenced on a MiSeq, or by Sanger sequencing.	('mutations', 'Var', (27, 36))	('CSMD3', 'Gene', (49, 54))	('CSMD3', 'Gene', '114788', (49, 54))
25721	27499902	In brief, primer sets were designed using Primer 3 to amplify the specific mutations, tagged with CS1 (5'-ACACTGACGACATGGTTCTACA-3') and CS2 (5'-TACGGTAGCAGAGACTTGGTCT-3') sequencing tags, and synthesized by IDT Technologies (Coralville, IA, USA).	('CS2', 'Gene', (137, 140))	('CS1', 'Gene', '6744', (98, 101))	('CS1', 'Gene', (98, 101))	('mutations', 'Var', (75, 84))	('CS2', 'Gene', '1443', (137, 140))
25742	27499902	Overall, there appeared to be good concordance in the detection of mutations in FFPE tumour tissue.	('FFPE tumour', 'Disease', (80, 91))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('FFPE tumour', 'Disease', 'MESH:D009369', (80, 91))	('mutations', 'Var', (67, 76))
25743	27499902	TP53 mutations were present in the majority of carcinosarcoma (24 of 30) (80%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('carcinosarcoma', 'Disease', (47, 61))	('mutations', 'Var', (5, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('carcinosarcoma', 'Disease', 'MESH:D002296', (47, 61))
25744	27499902	Most of the tumours harbouring missense TP53 mutations showed diffuse nuclear p53 immunostaining, with the exception of two cases (7 and 21) that harboured TP53 deletions and showed diffuse nuclear p53 immunostaining (Table 2).	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('missense', 'Var', (31, 39))	('mutations', 'Var', (45, 54))	('tumours', 'Disease', (12, 19))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('TP53', 'Gene', '7157', (40, 44))	('p53', 'Gene', (78, 81))	('showed', 'Reg', (55, 61))	('p53', 'Gene', (198, 201))	('TP53', 'Gene', (40, 44))	('p53', 'Gene', '7157', (198, 201))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('p53', 'Gene', '7157', (78, 81))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))
25745	27499902	Cases 19 and 30 both demonstrated TP53 mutations (frameshift and nonsense) in the sarcoma component but not the carcinoma component of the tumour, and both displayed a wild-type pattern of p53 immunostaining in both components of the tumour.	('tumour', 'Disease', (139, 145))	('carcinoma component of the tumour', 'Disease', (112, 145))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('TP53', 'Gene', (34, 38))	('p53', 'Gene', '7157', (189, 192))	('tumour', 'Disease', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('frameshift', 'Var', (50, 60))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcoma component', 'Disease', 'MESH:D012509', (82, 99))	('carcinoma component of the tumour', 'Disease', 'MESH:D009369', (112, 145))	('nonsense', 'Var', (65, 73))	('TP53', 'Gene', '7157', (34, 38))	('sarcoma component', 'Disease', (82, 99))	('p53', 'Gene', (189, 192))
25746	27499902	Loss of nuclear p53 immunohistochemistry was detected in 5 cases with indel or nonsense mutations, and 3 additional tumours (cases 17, 18 and 29) displayed abnormal patterns of staining with no detectable mutations (Table 2 and supplementary material Table 2).	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('indel', 'Var', (70, 75))	('p53', 'Gene', (16, 19))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', '7157', (16, 19))	('additional tumours', 'Disease', 'MESH:D009369', (105, 123))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('nonsense mutations', 'Var', (79, 97))	('additional tumours', 'Disease', (105, 123))
25748	27499902	In the primary tumours, mutations involving genes that encode the kinase or regulatory proteins of the PI3K pathway were identified in 20 of 30 tumours (67%), where multiple PI3K pathway proteins were mutated in 6 tumours.	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('identified', 'Reg', (121, 131))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumours', 'Disease', (15, 22))	('primary tumours', 'Disease', (7, 22))	('tumours', 'Disease', 'MESH:D009369', (214, 221))	('tumours', 'Disease', (214, 221))	('primary tumours', 'Disease', 'MESH:D009369', (7, 22))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('mutations', 'Var', (24, 33))	('tumours', 'Disease', (144, 151))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
25749	27499902	PIK3CA mutations were found in 12 of 30 (40%) tumours, which were scattered throughout the different functional domains of PIK3CA (Figure 3).	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('PIK3CA', 'Gene', (123, 129))	('tumours', 'Disease', (46, 53))	('found', 'Reg', (22, 27))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (123, 129))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (7, 16))
25750	27499902	PTEN mutations, most commonly missense in type, were observed in eight tumours (27%).	('missense', 'Var', (30, 38))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('observed', 'Reg', (53, 61))	('tumours', 'Disease', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
25751	27499902	PIK3R1 mutations were found in five tumours (17%), while only one tumour demonstrated a PIK3R2 mutation.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('tumour', 'Disease', (36, 42))	('PIK3R1', 'Gene', '5295', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('PIK3R1', 'Gene', (0, 6))	('found', 'Reg', (22, 27))	('tumours', 'Disease', (36, 43))	('PIK3R2', 'Gene', (88, 94))	('PIK3R2', 'Gene', '5296', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', (66, 72))	('mutations', 'Var', (7, 16))
25752	27499902	Of note in this cohort, PIK3CA mutations were rarely found with concurrent PIK3R1 or PIK3R2 mutations.	('PIK3R1', 'Gene', (75, 81))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('mutations', 'Var', (92, 101))	('PIK3CA', 'Gene', '5290', (24, 30))	('PIK3R2', 'Gene', (85, 91))	('PIK3R1', 'Gene', '5295', (75, 81))	('PIK3R2', 'Gene', '5296', (85, 91))
25753	27499902	One tumour (case 20) with a PIK3CA mutation also harboured an AKT3 (E167D) mutation, while case 18 harboured an AKT3 (M336I) mutation at low frequency (5%) without concurrent PI3K pathway mutations.	('AKT3', 'Gene', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('PIK3CA', 'Gene', (28, 34))	('AKT3', 'Gene', '10000', (62, 66))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('AKT3', 'Gene', (112, 116))	('PIK3CA', 'Gene', '5290', (28, 34))	('M336I', 'Mutation', 'rs773792621', (118, 123))	('mutation', 'Var', (35, 43))	('tumour', 'Disease', (4, 10))	('E167D', 'Mutation', 'rs755369410', (68, 73))	('AKT3', 'Gene', '10000', (112, 116))
25756	27499902	By immunohistochemistry, only two cases showed loss of BAF250 (ARID1A), which corresponded to the presence of frameshift and nonsense mutations (Table 2).	('BAF250', 'Gene', (55, 61))	('frameshift', 'Var', (110, 120))	('nonsense mutations', 'Var', (125, 143))	('ARID1A', 'Gene', '8289', (63, 69))	('ARID1A', 'Gene', (63, 69))	('loss', 'NegReg', (47, 51))	('BAF250', 'Gene', '8289', (55, 61))
25758	27499902	A somatic MED12 mutation (D23Y) was identified in one tumour, which has been previously documented in a case of endometrial carcinoma 27; however, it was not the typical hotspot MED12 mutation found in uterine smooth muscle tumours 20, 21.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('D23Y', 'Var', (26, 30))	('muscle tumours', 'Disease', 'MESH:D009217', (217, 231))	('muscle tumours', 'Disease', (217, 231))	('MED12', 'Gene', (10, 15))	('MED12', 'Gene', (178, 183))	('tumours', 'Phenotype', 'HP:0002664', (224, 231))	('endometrial carcinoma', 'Disease', (112, 133))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('tumour', 'Disease', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (112, 133))	('D23Y', 'Mutation', 'p.D23Y', (26, 30))	('MED12', 'Gene', '9968', (178, 183))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (112, 133))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('MED12', 'Gene', '9968', (10, 15))
25761	27499902	A somatic POLE exonuclease domain mutation (M444K) was identified in one tumour (case 30), which was reported in an ultra-mutated endometrial carcinoma in a prior study 17.	('endometrial carcinoma', 'Disease', (130, 151))	('tumour', 'Disease', (73, 79))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (130, 151))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('M444K', 'Var', (44, 49))	('M444K', 'Mutation', 'p.M444K', (44, 49))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (130, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
25762	27499902	In keeping with the ultra-mutator phenotype, this tumour also possessed 11 point mutations involving eight other genes.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('point mutations', 'Var', (75, 90))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', (50, 56))
25767	27499902	Two cases exhibited additional mutation(s) in the sarcoma component compared to the carcinoma component: case 19 with a TP53 missense mutation, and case 27 with PIK3R2, CHD4 mutations, and a POLE non-exonuclease domain mutation.	('carcinoma component', 'Disease', (84, 103))	('CHD4', 'Gene', (169, 173))	('PIK3R2', 'Gene', '5296', (161, 167))	('missense mutation', 'Var', (125, 142))	('mutation', 'Var', (31, 39))	('sarcoma component', 'Disease', 'MESH:D012509', (50, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('carcinoma component', 'Disease', 'MESH:C562869', (84, 103))	('mutations', 'Var', (174, 183))	('CHD4', 'Gene', '1108', (169, 173))	('sarcoma component', 'Disease', (50, 67))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))	('PIK3R2', 'Gene', (161, 167))
25768	27499902	In contrast, two cases displayed additional mutation(s) in the carcinoma component compared to the sarcoma component: case 8 with an ARID1A mutation, and case 14 with PPP2R1A, FBXW7 and SPOP mutations.	('ARID1A', 'Gene', '8289', (133, 139))	('ARID1A', 'Gene', (133, 139))	('mutation', 'Var', (44, 52))	('sarcoma component', 'Disease', (99, 116))	('carcinoma component', 'Disease', 'MESH:C562869', (63, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('SPOP', 'Gene', '8405', (186, 190))	('mutation', 'Var', (140, 148))	('FBXW7', 'Gene', '55294', (176, 181))	('SPOP', 'Gene', (186, 190))	('carcinoma component', 'Disease', (63, 82))	('FBXW7', 'Gene', (176, 181))	('sarcoma component', 'Disease', 'MESH:D012509', (99, 116))	('PPP2R1A', 'Gene', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('PPP2R1A', 'Gene', '5518', (167, 174))
25769	27499902	Overall, there was complete concordance or partial overlap in mutations identified in the carcinoma and the sarcoma components in 11 of 12 cases, hence indicating clonal relatedness between the carcinoma and the sarcoma components.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcoma component', 'Disease', (212, 229))	('carcinoma', 'Disease', 'MESH:D002277', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Disease', 'MESH:D002277', (194, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma component', 'Disease', 'MESH:D012509', (108, 125))	('carcinoma', 'Disease', (90, 99))	('sarcoma component', 'Disease', (108, 125))	('carcinoma', 'Disease', (194, 203))	('sarcoma component', 'Disease', 'MESH:D012509', (212, 229))	('mutations', 'Var', (62, 71))
25773	27499902	For case 22, the carcinoma and the sarcoma components of the uterine primary all harboured the same PTEN, PIK3R1 and TP53 (frameshift) mutations with loss of p53 immunostaining.	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', '5728', (100, 104))	('sarcoma component', 'Disease', 'MESH:D012509', (35, 52))	('p53', 'Gene', '7157', (158, 161))	('carcinoma', 'Disease', (17, 26))	('PIK3R1', 'Gene', (106, 112))	('TP53', 'Gene', '7157', (117, 121))	('PIK3R1', 'Gene', '5295', (106, 112))	('TP53', 'Gene', (117, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mutations', 'Var', (135, 144))	('frameshift) mutations', 'Var', (123, 144))	('sarcoma components of the uterine', 'Phenotype', 'HP:0010784', (35, 68))	('sarcoma component', 'Disease', (35, 52))	('carcinoma', 'Disease', 'MESH:D002277', (17, 26))	('loss', 'NegReg', (150, 154))	('p53', 'Gene', (158, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
25774	27499902	In contrast, the metastatic tumour (bilateral ovaries and peritoneal deposits) displayed no evidence of PTEN, PIK3R1 mutations, and harboured a different TP53 missense mutation with diffuse nuclear p53 immunostaining (Figure 2E-F).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('TP53', 'Gene', (154, 158))	('missense mutation', 'Var', (159, 176))	('PIK3R1', 'Gene', (110, 116))	('bilateral ovaries', 'Disease', (36, 53))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('PIK3R1', 'Gene', '5295', (110, 116))	('p53', 'Gene', (198, 201))	('tumour', 'Disease', (28, 34))	('bilateral ovaries', 'Disease', 'MESH:D010051', (36, 53))	('p53', 'Gene', '7157', (198, 201))	('bilateral ovaries', 'Phenotype', 'HP:0010463', (36, 53))	('PTEN', 'Gene', (104, 108))	('TP53', 'Gene', '7157', (154, 158))	('PTEN', 'Gene', '5728', (104, 108))
25777	27499902	Additional immunohistochemistry analysis demonstrated nuclear WT1 positivity in the ovarian tumour but not the uterine tumour (Figure 2E-F) 28.	('uterine tumour', 'Phenotype', 'HP:0010784', (111, 125))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian tumour', 'Disease', (84, 98))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', (92, 98))	('WT1', 'Gene', '7490', (62, 65))	('WT1', 'Gene', (62, 65))	('ovarian tumour', 'Phenotype', 'HP:0100615', (84, 98))	('positivity', 'Var', (66, 76))	('tumour', 'Disease', (119, 125))	('ovarian tumour', 'Disease', 'MESH:D010051', (84, 98))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
25780	27499902	We have previously identified different molecular types of uterine carcinosarcomas with some tumours showing endometrial serous carcinoma-like mutation profiles (characterized by the presence of TP53 mutation with PPP2R1A and/or FBXW7 mutations and in the absence of PTEN, CTNNB1, KRAS or ARID1A mutations) and other tumours showing endometrioid carcinoma-like mutation profiles (characterized by the presence of PTEN, CTNNB1, KRAS and/or ARID1A mutations) 16.	('ARID1A', 'Gene', (439, 445))	('KRAS', 'Gene', (427, 431))	('CTNNB1', 'Gene', (419, 425))	('PTEN', 'Gene', (267, 271))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('ARID1A', 'Gene', (289, 295))	('KRAS', 'Gene', '3845', (281, 285))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (333, 355))	('CTNNB1', 'Gene', (273, 279))	('FBXW7', 'Gene', (229, 234))	('TP53', 'Gene', (195, 199))	('ARID1A', 'Gene', '8289', (439, 445))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('KRAS', 'Gene', (281, 285))	('ARID1A', 'Gene', '8289', (289, 295))	('PTEN', 'Gene', '5728', (267, 271))	('PPP2R1A', 'Gene', '5518', (214, 221))	('mutation', 'Var', (200, 208))	('carcinosarcomas', 'Disease', 'MESH:D002296', (67, 82))	('tumours', 'Disease', (317, 324))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (333, 355))	('PTEN', 'Gene', (413, 417))	('mutations', 'Var', (235, 244))	('endometrial serous carcinoma', 'Disease', (109, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('tumours', 'Phenotype', 'HP:0002664', (317, 324))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('FBXW7', 'Gene', '55294', (229, 234))	('PPP2R1A', 'Gene', (214, 221))	('TP53', 'Gene', '7157', (195, 199))	('tumours', 'Disease', 'MESH:D009369', (317, 324))	('CTNNB1', 'Gene', '1499', (419, 425))	('tumours', 'Disease', (93, 100))	('endometrioid carcinoma', 'Disease', (333, 355))	('PTEN', 'Gene', '5728', (413, 417))	('carcinosarcomas', 'Disease', (67, 82))	('CTNNB1', 'Gene', '1499', (273, 279))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (109, 137))	('tumour', 'Phenotype', 'HP:0002664', (317, 323))	('KRAS', 'Gene', '3845', (427, 431))	('mutations', 'Var', (446, 455))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
25789	27499902	This is evident in the cases where the two histologic components were separately analysed; all cases with detectable mutations shared at least one somatic mutation in common between the carcinoma and the sarcoma components.	('carcinoma', 'Disease', 'MESH:D002277', (186, 195))	('mutations', 'Var', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('sarcoma component', 'Disease', 'MESH:D012509', (204, 221))	('carcinoma', 'Disease', (186, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('sarcoma component', 'Disease', (204, 221))
25792	27499902	There were four tumours that showed differences in mutations in additional to shared mutations between the two components.	('mutations', 'Var', (51, 60))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
25793	27499902	These included two cases with additional mutations found in the sarcoma component and two cases with additional mutations found in the carcinoma component.	('mutations', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinoma component', 'Disease', 'MESH:C562869', (135, 154))	('sarcoma component', 'Disease', 'MESH:D012509', (64, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcoma component', 'Disease', (64, 81))	('carcinoma component', 'Disease', (135, 154))
25800	27499902	We have identified mutations involving PI3K pathway in two-thirds of uterine carcinosarcoma examined, most commonly involving PIK3CA and PTEN.	('PIK3CA', 'Gene', (126, 132))	('carcinosarcoma', 'Disease', (77, 91))	('mutations', 'Var', (19, 28))	('PI3K pathway', 'Pathway', (39, 51))	('PIK3CA', 'Gene', '5290', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('PTEN', 'Gene', (137, 141))	('carcinosarcoma', 'Disease', 'MESH:D002296', (77, 91))	('PTEN', 'Gene', '5728', (137, 141))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (69, 91))
25801	27499902	In contrast to prior studies on uterine carcinosarcomas 29, 30, our present analyses identified both traditional PIK3CA hotspots (exons 9 and 20) mutations as well as mutations in the adaptor binding domain, helical domain, and C2 domain which can also enhance kinase enzymatic activity 31, 32.	('mutations', 'Var', (146, 155))	('PIK3CA', 'Gene', (113, 119))	('carcinosarcomas', 'Disease', 'MESH:D002296', (40, 55))	('PIK3CA', 'Gene', '5290', (113, 119))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (32, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('mutations', 'Var', (167, 176))	('carcinosarcomas', 'Disease', (40, 55))	('enhance', 'PosReg', (253, 260))	('kinase enzymatic activity', 'MPA', (261, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
25802	27499902	When present, these PI3K pathway mutations were found in the carcinoma and sarcoma components of the primary tumour, as well as in the metastatic tumour.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (33, 42))	('tumour', 'Disease', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('found', 'Reg', (48, 53))	('PI3K pathway', 'Pathway', (20, 32))	('carcinoma and sarcoma components of the primary tumour', 'Disease', 'MESH:D012509', (61, 115))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
25803	27499902	This indicates that these PI3K pathway mutations occur relatively early in the tumourigenesis of carcinosarcoma and likely represent important oncogenic driver events that could be targeted with PIK3CA/mTOR inhibitors 33, 34, 35.	('carcinosarcoma', 'Disease', (97, 111))	('PIK3CA', 'Gene', (195, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('PIK3CA', 'Gene', '5290', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (39, 48))	('carcinosarcoma', 'Disease', 'MESH:D002296', (97, 111))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('mTOR', 'Gene', '2475', (202, 206))	('PI3K pathway', 'Pathway', (26, 38))	('mTOR', 'Gene', (202, 206))	('tumour', 'Disease', (79, 85))
25804	27499902	We also observed a very high frequency of TP53 alterations (90%) in this series of uterine carcinosarcomas, which is supported by previous literature 5, 12, 16.	('TP53', 'Gene', '7157', (42, 46))	('carcinosarcomas', 'Disease', 'MESH:D002296', (91, 106))	('TP53', 'Gene', (42, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('carcinosarcomas', 'Disease', (91, 106))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (83, 105))	('alterations', 'Var', (47, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
25806	27499902	In keeping with prior studies, MMR protein deficiency that suggests underlying microsatellite instability was rarely observed in our present series of uterine carcinosarcoma 12, 24.	('carcinosarcoma', 'Disease', (159, 173))	('carcinosarcoma', 'Disease', 'MESH:D002296', (159, 173))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (151, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('MMR protein deficiency', 'Disease', (31, 53))	('MMR protein deficiency', 'Disease', 'MESH:C536143', (31, 53))	('microsatellite', 'Var', (79, 93))
25807	27499902	A recent study demonstrated frequent mutations in chromatin remodelling genes (ARID1A, ARID1B, MLL3, SPOP) with the identification of 4 mismatch repair deficient tumour in a cohort of 17 uterine and five ovarian carcinosarcomas 36.	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('SPOP', 'Gene', '8405', (101, 105))	('MLL3', 'Gene', (95, 99))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (204, 227))	('deficient tumour', 'Disease', (152, 168))	('ARID1B', 'Gene', (87, 93))	('SPOP', 'Gene', (101, 105))	('mutations', 'Var', (37, 46))	('ARID1A', 'Gene', '8289', (79, 85))	('ARID1A', 'Gene', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('ovarian carcinosarcomas', 'Disease', (204, 227))	('MLL3', 'Gene', '58508', (95, 99))	('ARID1B', 'Gene', '57492', (87, 93))	('deficient tumour', 'Disease', 'MESH:D009369', (152, 168))	('mismatch repair', 'Var', (136, 151))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (204, 227))
25808	27499902	While these results are overall different from our present cohort, a closer examination reveals that nearly all of the identified ARID1A, ARID1B and MLL3 mutations were found in the four MMR-deficient uterine carcinosarcomas and in four of the five ovarian carcinosarcomas.	('ARID1A', 'Gene', (130, 136))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (249, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('MLL3', 'Gene', '58508', (149, 153))	('ARID1A', 'Gene', '8289', (130, 136))	('found', 'Reg', (169, 174))	('MLL3', 'Gene', (149, 153))	('carcinosarcomas', 'Disease', 'MESH:D002296', (209, 224))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (249, 272))	('carcinosarcomas', 'Disease', 'MESH:D002296', (257, 272))	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('deficient uterine', 'Phenotype', 'HP:0000013', (191, 208))	('ARID1B', 'Gene', (138, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (264, 272))	('carcinosarcomas', 'Disease', (209, 224))	('mutations', 'Var', (154, 163))	('ARID1B', 'Gene', '57492', (138, 144))	('carcinosarcomas', 'Disease', (257, 272))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (201, 223))	('ovarian carcinosarcomas', 'Disease', (249, 272))
25809	27499902	We did, however, identify a few cases in our cohort with ARID1A mutations and one with an SPOP mutation.	('SPOP', 'Gene', '8405', (90, 94))	('SPOP', 'Gene', (90, 94))	('mutations', 'Var', (64, 73))	('ARID1A', 'Gene', '8289', (57, 63))	('ARID1A', 'Gene', (57, 63))
25822	27499902	Further studies are needed to investigate whether there is increased propensity for POLE-mutated endometrioid carcinoma to display spindle cell elements.	('POLE-mutated', 'Var', (84, 96))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (97, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (97, 119))	('endometrioid carcinoma', 'Disease', (97, 119))
25850	23687522	Finally, monoclonal CEA staining tends to occur only in mucinous adenocarcinomas from the endocervix.	('monoclonal', 'Var', (9, 19))	('CEA', 'Gene', '1084', (20, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('mucinous adenocarcinomas', 'Disease', (56, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (56, 80))	('CEA', 'Gene', (20, 23))
25915	23687522	The authors interpreted this group to represent type I Bokhman tumors with transformation to higher grade tumors through accumulation of additional mutations.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('mutations', 'Var', (148, 157))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('type I Bokhman tumors', 'Disease', 'MESH:D005776', (48, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('type I Bokhman tumors', 'Disease', (48, 69))
25931	23687522	Mutations in these DNA mismatch repair genes result in high levels of microsatellite instability (MSI) in endometrial tumor DNA as compared to DNA from normal tissues.3Sporadic endometrial carcinoma can also have high levels of MSI due to methylation of the MLH1 gene promoter with subsequent transcriptional silencing.	('endometrial tumor', 'Disease', 'MESH:D016889', (106, 123))	('methylation', 'Var', (239, 250))	('transcriptional', 'MPA', (293, 308))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (177, 198))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('endometrial tumor', 'Disease', (106, 123))	('MLH1', 'Gene', '4292', (258, 262))	('MSI', 'MPA', (228, 231))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (177, 198))	('MLH1', 'Gene', (258, 262))	('endometrial carcinoma', 'Disease', (177, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
25939	23687522	A panel of 7 markers recommended by the NCI (BAT25, BAT26, BAT40, D2S123, D5S346, D173250, and TGF-betaR2) is used to detect changes in the number of microsatellite repeats in the tumor compared to normal tissue.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('D5S346', 'Var', (74, 80))	('D173250', 'Var', (82, 89))	('D2S123', 'Var', (66, 72))
25940	23687522	Tumors with allelic shift in 2 or more microsatellites in the panel are considered MSI-high (Figure 6).	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('allelic shift', 'Var', (12, 25))	('microsatellites', 'Var', (39, 54))
25942	23687522	Tumors with allelic shift in only 1 microsatellite are considered MSI-low.	('Tumors', 'Disease', (0, 6))	('allelic shift', 'Var', (12, 25))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))
25945	23687522	If methylation is present, it is much more likely that the patient has a sporadic endometrial carcinoma rather than a Lynch Syndrome-associated tumor.	('tumor', 'Disease', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (82, 103))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patient', 'Species', '9606', (59, 66))	('methylation', 'Var', (3, 14))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (118, 132))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (82, 103))	('endometrial carcinoma', 'Disease', (82, 103))	('Lynch Syndrome', 'Disease', (118, 132))
25947	23687522	Mutation of MLH1 or methylation of MLH1 typically results in loss of immunhistochemical expression of MLH1 and PMS2.	('MLH1', 'Gene', '4292', (12, 16))	('MLH1', 'Gene', (12, 16))	('MLH1', 'Gene', '4292', (102, 106))	('Mutation', 'Var', (0, 8))	('MLH1', 'Gene', (102, 106))	('PMS2', 'Gene', (111, 115))	('methylation', 'Var', (20, 31))	('PMS2', 'Gene', '5395', (111, 115))	('loss', 'NegReg', (61, 65))	('MLH1', 'Gene', (35, 39))	('immunhistochemical expression', 'MPA', (69, 98))	('MLH1', 'Gene', '4292', (35, 39))
25948	23687522	Mutation of MSH2 usually results in immunohistochemical loss of MSH2 and MSH6.	('MSH2', 'Gene', '4436', (12, 16))	('MSH2', 'Gene', (64, 68))	('MSH6', 'Gene', (73, 77))	('MSH2', 'Gene', '4436', (64, 68))	('loss', 'NegReg', (56, 60))	('Mutation', 'Var', (0, 8))	('MSH6', 'Gene', '2956', (73, 77))	('MSH2', 'Gene', (12, 16))
25949	23687522	However, mutation of MSH6 usually is associated with loss of MSH6 protein but retention of MSH2 by immunohistochemistry.	('mutation', 'Var', (9, 17))	('MSH6', 'Gene', '2956', (61, 65))	('MSH2', 'Gene', (91, 95))	('protein', 'Protein', (66, 73))	('MSH2', 'Gene', '4436', (91, 95))	('MSH6', 'Gene', '2956', (21, 25))	('loss', 'NegReg', (53, 57))	('MSH6', 'Gene', (61, 65))	('MSH6', 'Gene', (21, 25))
25950	23687522	Similarly, mutation of PMS2 is typically associated with loss of PMS2 protein but retained MLH1 immunohistochemical expression.	('PMS2', 'Gene', (23, 27))	('protein', 'Protein', (70, 77))	('PMS2', 'Gene', '5395', (23, 27))	('MLH1', 'Gene', '4292', (91, 95))	('PMS2', 'Gene', (65, 69))	('MLH1', 'Gene', (91, 95))	('PMS2', 'Gene', '5395', (65, 69))	('loss', 'NegReg', (57, 61))	('mutation', 'Var', (11, 19))
25951	23687522	Colon carcinomas with a defect in DNA mismatch repair, either due to mutation or MLH1 methylation, are typically associated with very high levels of tumor microsatellite instability, with 6 to 7 markers in the 7 marker panel demonstrating allelic shift.	('carcinomas', 'Phenotype', 'HP:0030731', (6, 16))	('defect', 'NegReg', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('MLH1', 'Gene', '4292', (81, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (6, 15))	('MLH1', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutation', 'Var', (69, 77))	('Colon carcinomas', 'Disease', (0, 16))	('methylation', 'Var', (86, 97))	('tumor', 'Disease', (149, 154))	('Colon carcinomas', 'Disease', 'MESH:D015179', (0, 16))	('to 7', 'Species', '1214577', (190, 194))	('associated', 'Reg', (113, 123))
25953	23687522	There are case reports of microsatellite stable thyroid anaplastic carcinoma and adrenal cortical carcinoma, both with loss of MSH2 expression by immunohistochemistry, from 2 different individuals with known pathogenic mutations in MSH2.	('MSH2', 'Gene', (232, 236))	('thyroid anaplastic carcinoma and adrenal cortical carcinoma', 'Disease', 'MESH:D065646', (48, 107))	('MSH2', 'Gene', (127, 131))	('MSH2', 'Gene', '4436', (232, 236))	('MSH2', 'Gene', '4436', (127, 131))	('thyroid anaplastic carcinoma', 'Phenotype', 'HP:0011779', (48, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('adrenal cortical carcinoma', 'Phenotype', 'HP:0006744', (81, 107))	('loss', 'NegReg', (119, 123))	('expression', 'MPA', (132, 142))	('microsatellite stable', 'Var', (26, 47))
25956	23687522	In addition, MSI analysis of paired synchronous ovarian and endometrial carcinomas revealed differing patterns of microsatellite allelic shift, despite the fact that the ovarian and endometrial tumor in each pair had lost expression of the same DNA mismatch repair protein by immunohistochemistry.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (60, 82))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('ovarian', 'Disease', 'MESH:D010051', (170, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('synchronous ovarian and endometrial carcinomas', 'Disease', 'MESH:D009378', (36, 82))	('endometrial tumor', 'Disease', 'MESH:D016889', (182, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('microsatellite', 'Var', (114, 128))	('ovarian', 'Disease', (48, 55))	('lost', 'NegReg', (217, 221))	('ovarian', 'Disease', 'MESH:D010051', (48, 55))	('ovarian', 'Disease', (170, 177))	('endometrial tumor', 'Disease', (182, 199))	('expression', 'MPA', (222, 232))
25959	23687522	Sporadic endometrial carcinomas that are MSI-high due to MLH1 methylation are known to be predominantly endometrioid, especially FIGO grades 2 and 3, with percentage endometrioid histotype reaching 96%.	('FIGO', 'Disease', (129, 133))	('Sporadic endometrial carcinomas', 'Disease', 'MESH:D016889', (0, 31))	('MLH1', 'Gene', '4292', (57, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('MLH1', 'Gene', (57, 61))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (9, 31))	('Sporadic endometrial carcinomas', 'Disease', (0, 31))	('methylation', 'Var', (62, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (9, 30))	('endometrioid', 'Disease', (104, 116))
25966	23687522	Interestingly, one study found that all of the non-endometrioid tumors arose in women with MSH2 mutations.	('women', 'Species', '9606', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('non-endometrioid tumors', 'Disease', (47, 70))	('MSH2', 'Gene', (91, 95))	('MSH2', 'Gene', '4436', (91, 95))	('arose', 'Reg', (71, 76))	('non-endometrioid tumors', 'Disease', 'MESH:D016889', (47, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutations', 'Var', (96, 105))
25967	23687522	In a population-based study of endometrial carcinoma with subsequent follow-up, two Lynch Syndrome-associated non-endometrioid endometrial carcinomas were identified, both in women with MSH6 mutations.	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (127, 149))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (31, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('mutations', 'Var', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('MSH6', 'Gene', (186, 190))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (84, 98))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (114, 149))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (127, 148))	('endometrial carcinoma', 'Disease', (31, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (127, 148))	('women', 'Species', '9606', (175, 180))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (31, 52))	('MSH6', 'Gene', '2956', (186, 190))	('Lynch Syndrome', 'Disease', (84, 98))	('endometrioid endometrial carcinomas', 'Disease', (114, 149))
25968	23687522	This suggests that there may be a genotype-phenotype relationship in which microsatellite instability due to loss of MLH1 by methylation of the promoter is almost exclusively associated with higher grade endometrioid tumors, while microsatellite instability due to defects in the MSH2/MSH6 pair can result in a more varied spectrum of endometrial carcinoma histology.	('associated', 'Reg', (175, 185))	('endometrioid tumors', 'Disease', 'MESH:D016889', (204, 223))	('MSH6', 'Gene', (285, 289))	('microsatellite instability', 'MPA', (231, 257))	('MSH6', 'Gene', '2956', (285, 289))	('MLH1', 'Gene', (117, 121))	('endometrioid tumors', 'Disease', (204, 223))	('MLH1', 'Gene', '4292', (117, 121))	('methylation', 'Var', (125, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('endometrial carcinoma', 'Disease', (335, 356))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('MSH2', 'Gene', (280, 284))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (335, 356))	('loss', 'NegReg', (109, 113))	('microsatellite instability', 'MPA', (75, 101))	('result in', 'Reg', (299, 308))	('MSH2', 'Gene', '4436', (280, 284))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (335, 356))
25971	23687522	Some of the microscopic features that have been associated with the presence of MSI-high include poor differentiation, mucinous features, signet ring cell differentiation, mixed tumor histology, tumor cells growing in a medullary-type pattern, increased tumor infiltrating lymphocytes, and a Crohn's like inflammatory infiltrate at the tumor periphery.	('tumor', 'Disease', (195, 200))	('poor differentiation', 'CPA', (97, 117))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('Crohn', 'Disease', (292, 297))	('tumor', 'Disease', (336, 341))	('tumor', 'Disease', (178, 183))	('increased', 'PosReg', (244, 253))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (254, 259))	("Crohn's like", 'Phenotype', 'HP:0100280', (292, 304))	('MSI-high', 'Gene', (80, 88))	('presence', 'Var', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mucinous', 'Disease', (119, 127))	('signet ring cell differentiation', 'CPA', (138, 170))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
25972	23687522	Most of these studies have not distinguished between sporadic MSI-high due to MLH1 methylation vs. MSI-high due to germline mutation of a DNA mismatch repair gene.	('MLH1', 'Gene', '4292', (78, 82))	('MSI-high', 'Disease', (62, 70))	('MLH1', 'Gene', (78, 82))	('due', 'Reg', (71, 74))	('methylation', 'Var', (83, 94))
25994	23687522	In our opinion, this approach seems too restrictive, as many MSH6 mutation carriers have uninformative family histories.	('MSH6', 'Gene', '2956', (61, 65))	('MSH6', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))
25997	23687522	Thus, PMS2 mutation may be phenotypically similar to MSH6 mutation, and the incidence of PMS2 mutation may be seriously underestimated using younger age and family history as determinants for further testing.	('PMS2', 'Gene', (89, 93))	('PMS2', 'Gene', (6, 10))	('PMS2', 'Gene', '5395', (89, 93))	('PMS2', 'Gene', '5395', (6, 10))	('MSH6', 'Gene', (53, 57))	('mutation', 'Var', (11, 19))	('MSH6', 'Gene', '2956', (53, 57))
25999	23687522	A number of different groups have demonstrated that immunohistochemistry alone has a high sensitivity and specificity in identifying endometrial carcinomas with high levels of microsatellite instability.	('microsatellite instability', 'Var', (176, 202))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (133, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (133, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('endometrial carcinomas', 'Disease', (133, 155))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (133, 155))
26002	23687522	It is possible that some of these patients have missense mutations of a DNA mismatch repair gene that result in translation of a non-functional protein.	('result in', 'Reg', (102, 111))	('DNA mismatch repair gene', 'Gene', (72, 96))	('missense mutations', 'Var', (48, 66))	('patients', 'Species', '9606', (34, 42))	('translation of a non-functional protein', 'MPA', (112, 151))
26003	23687522	Indeed, in our personal experiences with tissue testing, we have encountered several cases in which MLH1 mutations were identified in patients with MSI-high tumors with intact immunohistochemical expression of MLH1, MSH2, MSH6, and PMS2.	('PMS2', 'Gene', '5395', (232, 236))	('MSH2', 'Gene', (216, 220))	('MSH6', 'Gene', '2956', (222, 226))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('MSH2', 'Gene', '4436', (216, 220))	('MSI-high tumors', 'Disease', (148, 163))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('MLH1', 'Gene', '4292', (210, 214))	('MLH1', 'Gene', (210, 214))	('MSH6', 'Gene', (222, 226))	('mutations', 'Var', (105, 114))	('MLH1', 'Gene', (100, 104))	('MLH1', 'Gene', '4292', (100, 104))	('MSI-high tumors', 'Disease', 'MESH:D009369', (148, 163))	('identified', 'Reg', (120, 130))	('PMS2', 'Gene', (232, 236))
26013	23687522	Loss of PTEN tumor suppressor activity or activating mutations in the key molecules of the pathway lead to uncontrolled activation of mammalian target of rapamycin (mTOR) and, subsequently, protein S6 kinase, resulting in dysregulated control of protein translation and cell cycle progression.	('cell cycle progression', 'CPA', (270, 292))	('mammalian target of rapamycin', 'Gene', '2475', (134, 163))	('mTOR', 'Gene', (165, 169))	('Loss of PTEN tumor', 'Disease', 'MESH:D006223', (0, 18))	('activation', 'PosReg', (120, 130))	('mutations', 'Var', (53, 62))	('mammalian target of rapamycin', 'Gene', (134, 163))	('protein', 'Protein', (190, 197))	('Loss of PTEN tumor', 'Disease', (0, 18))	('dysregulated control of protein translation', 'MPA', (222, 265))	('mTOR', 'Gene', '2475', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
26014	23687522	AKT mutations are infrequent (2% to 4%) in endometrial carcinoma.	('AKT', 'Gene', (0, 3))	('endometrial carcinoma', 'Disease', (43, 64))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (43, 64))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (43, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('AKT', 'Gene', '207', (0, 3))	('mutations', 'Var', (4, 13))
26017	23687522	Furthermore, while AKT and PIK3CA are altered primarily by mutation and can be detected by targeted sequencing of mutational hotspots, loss of PTEN protein occurs from a variety of causes including somatic mutations, abnormalities in PTEN transcriptional and post-transcriptional regulation, actions of micro RNAs, as well as due to aberrant mechanisms of PTEN protein stability and degradation.	('mutations', 'Var', (206, 215))	('loss', 'NegReg', (135, 139))	('degradation', 'MPA', (383, 394))	('AKT', 'Gene', (19, 22))	('PIK3CA', 'Gene', (27, 33))	('AKT', 'Gene', '207', (19, 22))	('protein', 'Protein', (148, 155))	('PTEN', 'Gene', '5728', (143, 147))	('protein', 'Protein', (361, 368))	('mutation', 'Var', (59, 67))	('stability', 'MPA', (369, 378))	('PTEN', 'Gene', (143, 147))	('PIK3CA', 'Gene', '5290', (27, 33))	('PTEN', 'Gene', (356, 360))	('abnormalities', 'Var', (217, 230))	('PTEN', 'Gene', (234, 238))	('PTEN', 'Gene', '5728', (356, 360))	('PTEN', 'Gene', '5728', (234, 238))
26018	23687522	Therefore, clinically validated testing of endometrial tumors for aberrations in the PI3K -AKT-mTOR pathway will require the use of multimodal assays and an algorithmic approach.	('AKT', 'Gene', '207', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('endometrial tumors', 'Disease', (43, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('AKT', 'Gene', (91, 94))	('mTOR', 'Gene', (95, 99))	('endometrial tumors', 'Disease', 'MESH:D016889', (43, 61))	('mTOR', 'Gene', '2475', (95, 99))	('aberrations', 'Var', (66, 77))
26019	23687522	PTEN gene sequence abnormalities are highly variable in type (frameshifts, point mutations) and can occur throughout all 9 exons.	('point mutations', 'Var', (75, 90))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
26020	23687522	This necessitates the use of full length sequencing in order to detect PTEN mutations and subsequent loss of PTEN protein function.	('mutations', 'Var', (76, 85))	('loss', 'NegReg', (101, 105))	('function', 'MPA', (122, 130))	('PTEN', 'Gene', (109, 113))	('protein', 'Protein', (114, 121))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (109, 113))	('PTEN', 'Gene', '5728', (71, 75))
26030	23687522	In a recent study of patients with advanced solid tumors, including endometrial carcinomas, patients with PIK3CA tumor mutations had a better response to PI3K -AKT-mTOR inhibitors than patients with tumors with wild-type PIK3CA.	('tumors', 'Disease', (199, 205))	('PIK3CA', 'Gene', '5290', (106, 112))	('patients', 'Species', '9606', (21, 29))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mTOR', 'Gene', '2475', (164, 168))	('solid tumors', 'Disease', (44, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('AKT', 'Gene', '207', (160, 163))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('patients', 'Species', '9606', (92, 100))	('endometrial carcinomas', 'Disease', (68, 90))	('mutations', 'Var', (119, 128))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (113, 118))	('response', 'MPA', (142, 150))	('PIK3CA', 'Gene', '5290', (221, 227))	('solid tumors', 'Disease', 'MESH:D009369', (44, 56))	('PIK3CA', 'Gene', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('better', 'PosReg', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('AKT', 'Gene', (160, 163))	('patients', 'Species', '9606', (185, 193))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (68, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PIK3CA', 'Gene', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (50, 56))	('mTOR', 'Gene', (164, 168))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (68, 90))
26031	23687522	Interestingly, the presence of a KRAS mutation in the same tumor acted as a "dominant negative;" in other words, KRAS mutation is associated with resistance to pathway inhibition, no matter the PIK3CA mutation status.	('PIK3CA', 'Gene', '5290', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('resistance to', 'MPA', (146, 159))	('KRAS', 'Gene', (33, 37))	('KRAS', 'Gene', '3845', (33, 37))	('KRAS', 'Gene', (113, 117))	('mutation', 'Var', (118, 126))	('mutation', 'Var', (38, 46))	('KRAS', 'Gene', '3845', (113, 117))	('PIK3CA', 'Gene', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('associated with', 'Reg', (130, 145))
26034	23687522	The incidence of KRAS mutations in endometrial carcinoma is 14 to 36%.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (35, 56))	('endometrial carcinoma', 'Disease', (35, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (35, 56))	('KRAS', 'Gene', '3845', (17, 21))
26038	23687522	Activating mutations in BRAF have been shown to induce sensitivity to MEK inhibitors in cancer cells lines and early clinical trials of melanoma.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('MEK', 'Gene', '5609', (70, 73))	('induce', 'Reg', (48, 54))	('Activating mutations', 'Var', (0, 20))	('MEK', 'Gene', (70, 73))	('BRAF', 'Gene', (24, 28))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('BRAF', 'Gene', '673', (24, 28))	('melanoma', 'Disease', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
26039	23687522	However, BRAF mutations are rare in endometrial carcinoma (1 to 4%).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (36, 57))	('BRAF', 'Gene', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (36, 57))	('endometrial carcinoma', 'Disease', (36, 57))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
26046	23687522	Such assays include mutational analysis of BRAF, KRAS, and PIK3CA.	('KRAS', 'Gene', '3845', (49, 53))	('BRAF', 'Gene', '673', (43, 47))	('KRAS', 'Gene', (49, 53))	('BRAF', 'Gene', (43, 47))	('PIK3CA', 'Gene', (59, 65))	('PIK3CA', 'Gene', '5290', (59, 65))	('mutational', 'Var', (20, 30))
26052	23687522	Recently, it was reported that a small subset of colorectal cancer patients have discordant KRAS mutation results when comparing the primary tumor to the metastasis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('patients', 'Species', '9606', (67, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('KRAS', 'Gene', (92, 96))	('tumor', 'Disease', (141, 146))	('colorectal cancer', 'Disease', (49, 66))	('mutation', 'Var', (97, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('KRAS', 'Gene', '3845', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
26053	23687522	Furthermore, metastases may also be heterogeneous, harboring mutant and wild-type clones.	('metastases', 'Disease', (13, 23))	('mutant', 'Var', (61, 67))	('metastases', 'Disease', 'MESH:D009362', (13, 23))
26054	23687522	Therefore, if a mutation analysis from a metastasis/recurrence initially yields a negative result, does this mean the entire tumor lacks this mutation?	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutation', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('lacks', 'NegReg', (131, 136))	('negative', 'NegReg', (82, 90))
26126	32810311	These include an immune-inflamed phenotype, 15 ,  16  expression of T cell signaling pathway genes such as IFNgamma, 17  microsatellite instability, 18  somatic copy-number alterations, 19  human leukocyte antigen (HLA) class I diversity, 20  T cell repertoire clonality change, 21  WNT-beta-catenin signaling, 22  TGFbeta expression, 23  and even commensal microbiota.	('IFNgamma', 'Gene', '3458', (107, 115))	('beta-catenin', 'Gene', '1499', (287, 299))	('T cell signaling pathway genes', 'Gene', (68, 98))	('TGFbeta', 'Gene', (315, 322))	('alterations', 'Var', (173, 184))	('TGFbeta', 'Gene', '7039', (315, 322))	('beta-catenin', 'Gene', (287, 299))	('human', 'Species', '9606', (190, 195))	('IFNgamma', 'Gene', (107, 115))
26185	32810311	We analyzed RNA-Seq data of 28 pretreatment tumors from melanoma patients who received anti-PD-1 ICI.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('anti-PD-1', 'Var', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (65, 73))
26191	32810311	35  Axis 6 (Treg) and axis 7 (MDSC) were high in Pt25 and Pt16, respectively, suggesting that the strategies to deplete Treg or MDSC might be recommended to these patients.	('Treg', 'Chemical', '-', (12, 16))	('Pt16', 'Var', (58, 62))	('patients', 'Species', '9606', (163, 171))	('Pt25', 'Var', (49, 53))	('Treg', 'Chemical', '-', (120, 124))
26206	32810311	For example, immunograms for hallmarks of cancer could also be compiled by adopting gene sets for the eight hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.	('death', 'Disease', 'MESH:D003643', (198, 203))	('death', 'Disease', (198, 203))	('hallmarks of cancer', 'Disease', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('replicative immortality', 'CPA', (214, 237))	('immune destruction', 'CPA', (346, 364))	('invasion', 'CPA', (273, 281))	('activating', 'PosReg', (262, 272))	('enabling', 'PosReg', (205, 213))	('inducing', 'PosReg', (239, 247))	('reprogramming', 'Reg', (298, 311))	('angiogenesis', 'CPA', (248, 260))	('evading', 'Var', (155, 162))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (29, 48))	('proliferative signaling', 'MPA', (130, 153))	('sustaining', 'PosReg', (119, 129))
26216	32867127	ONC206 also synergized with paclitaxel in reducing USC cell viability.	('reducing', 'NegReg', (42, 50))	('ONC206', 'Var', (0, 6))	('USC cell viability', 'CPA', (51, 69))	('ONC206', 'Chemical', '-', (0, 6))	('paclitaxel', 'Chemical', 'MESH:D017239', (28, 38))
26232	32867127	Moreover, GPCR profiling with beta-arrestin recruitment revealed that although ONC206 selectively antagonized DRD2/3 like ONC201, it exhibited a much lower Ki value (~320 nM) than ONC201 for DRD2 with specificity across human GPCRs and complete antagonism.	('lower', 'NegReg', (150, 155))	('human', 'Species', '9606', (220, 225))	('DRD2/3', 'Gene', (110, 116))	('ONC206', 'Var', (79, 85))	('DRD2/3', 'Gene', '1813;1814', (110, 116))	('ONC206', 'Chemical', '-', (79, 85))	('antagonized', 'NegReg', (98, 109))
26234	32867127	Besides, shotgun mutagenesis across DRD2 identified seven residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites.	('mutagenesis', 'Var', (17, 28))	('ONC206', 'Chemical', '-', (80, 86))	('DRD2', 'Gene', (36, 40))
26236	32867127	These suggested that the tumor suppressing effect of ONC206 might be stronger than ONC201.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('ONC206', 'Chemical', '-', (53, 59))	('tumor', 'Disease', (25, 30))	('ONC206', 'Var', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
26242	32867127	The results showed that both ONC201 and ONC206 suppressed USC cell viability in a dose-dependent manner and the effect of ONC206 was markedly stronger than that of ONC201 (Figure 1B).	('ONC206', 'Var', (122, 128))	('suppressed', 'NegReg', (47, 57))	('ONC206', 'Chemical', '-', (122, 128))	('USC cell viability', 'CPA', (58, 76))	('ONC206', 'Chemical', '-', (40, 46))	('stronger', 'PosReg', (142, 150))	('ONC201', 'Var', (29, 35))	('ONC206', 'Var', (40, 46))
26243	32867127	IC50 values of ONC206 in ARK1, ARK2 and HEC50 cells were 4-to 10-fold lower than those of ONC201 (Table S1).	('HEC50', 'CellLine', 'CVCL:2929', (40, 45))	('ONC206', 'Chemical', '-', (15, 21))	('lower', 'NegReg', (70, 75))	('ARK2', 'Gene', (31, 35))	('ARK2', 'Gene', '9212', (31, 35))	('ONC206', 'Var', (15, 21))	('IC50', 'MPA', (0, 4))
26245	32867127	The results showed that ONC206 suppressed cell proliferation of ARK1, ARK2 and HEC50 cells in a dose-dependent manner (Figure 1C).	('ONC206', 'Var', (24, 30))	('cell proliferation', 'CPA', (42, 60))	('HEC50', 'CellLine', 'CVCL:2929', (79, 84))	('ARK2', 'Gene', (70, 74))	('ARK1', 'CPA', (64, 68))	('ONC206', 'Chemical', '-', (24, 30))	('suppressed', 'NegReg', (31, 41))	('ARK2', 'Gene', '9212', (70, 74))
26247	32867127	ARK1, ARK2 and HEC50 cells were exposed to 0.5, 10 and 100 muM ONC201 or ONC206 for 72 h and the number of apoptotic cells was detected using Annexin V and propidium iodide staining.	('ONC206', 'Chemical', '-', (73, 79))	('HEC50', 'CellLine', 'CVCL:2929', (15, 20))	('ARK2', 'Gene', (6, 10))	('propidium iodide', 'Chemical', 'MESH:D011419', (156, 172))	('Annexin V', 'Gene', '308', (142, 151))	('ARK2', 'Gene', '9212', (6, 10))	('Annexin V', 'Gene', (142, 151))	('ONC206', 'Var', (73, 79))
26248	32867127	The results showed that both ONC201 and ONC206 induced apoptosis in USC cells (Figure 1D).	('ONC206', 'Chemical', '-', (40, 46))	('apoptosis', 'CPA', (55, 64))	('ONC206', 'Var', (40, 46))	('ONC201', 'Var', (29, 35))
26250	32867127	The mice were then injected with 100 mg/kg ONC201 or ONC206 intraperitoneally twice per week for 6 weeks (Figure 2A).	('ONC206', 'Var', (53, 59))	('ONC201', 'Var', (43, 49))	('mice', 'Species', '10090', (4, 8))	('ONC206', 'Chemical', '-', (53, 59))
26251	32867127	The results showed that mice treated with ONC206 had significantly lower bioluminescent signals than those treated with PBS or ONC201 (Figure 2B,C).	('mice', 'Species', '10090', (24, 28))	('ONC206', 'Var', (42, 48))	('bioluminescent signals', 'MPA', (73, 95))	('PBS', 'Chemical', '-', (120, 123))	('ONC206', 'Chemical', '-', (42, 48))	('lower', 'NegReg', (67, 72))
26255	32867127	The results showed that tumor tissues from ONC206-treated mice had significantly fewer Ki-67-positive cells than those from ONC201-treated or control untreated mice (Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('Ki-67', 'Gene', (87, 92))	('ONC206', 'Chemical', '-', (43, 49))	('ONC206-treated', 'Var', (43, 57))	('mice', 'Species', '10090', (58, 62))	('fewer', 'NegReg', (81, 86))	('mice', 'Species', '10090', (160, 164))	('Ki-67', 'Gene', '17345', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
26256	32867127	The results showed that tumor tissues from ONC206-treated mice had significantly more apoptotic cells than those from ONC201-treated or control untreated mice (Figure 2E).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Disease', (24, 29))	('apoptotic cells', 'CPA', (86, 101))	('ONC206', 'Chemical', '-', (43, 49))	('more', 'PosReg', (81, 85))	('ONC206-treated', 'Var', (43, 57))	('mice', 'Species', '10090', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
26257	32867127	These findings suggested that ONC206 has higher efficacy in suppressing USC progression than ONC201 in vivo.	('ONC206', 'Var', (30, 36))	('USC', 'Disease', (72, 75))	('ONC206', 'Chemical', '-', (30, 36))	('suppressing', 'NegReg', (60, 71))
26260	32867127	The RPPA results were then validated using Western blot analyses on USC cells ARK1, ARK2 and HEC50 treated with ONC206 or the control buffer.	('ARK2', 'Gene', '9212', (84, 88))	('ONC206', 'Chemical', '-', (112, 118))	('HEC50', 'CellLine', 'CVCL:2929', (93, 98))	('ARK2', 'Gene', (84, 88))	('ONC206', 'Var', (112, 118))
26261	32867127	The results showed that ONC206-treated cells had markedly lower levels of phospho-p38MAPK, phospho-ERK, phospho-S6 and peroxisome proliferator activator receptor gamma coactivator 1 alpha (PGC-1alpha), suggesting that the p38MAPK/ERK/PGC-1alpha signaling pathways are inactivated in ONC206-treated cells (Figure 3B).	('ONC206', 'Chemical', '-', (283, 289))	('lower', 'NegReg', (58, 63))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', (99, 102))	('peroxisome', 'MPA', (119, 129))	('levels', 'MPA', (64, 70))	('ONC206-treated', 'Var', (24, 38))	('PGC-1alpha', 'Gene', (189, 199))	('PGC-1alpha', 'Gene', (234, 244))	('ONC206', 'Chemical', '-', (24, 30))	('ERK', 'Gene', '5594', (230, 233))	('phospho-S6', 'MPA', (104, 114))	('phospho-p38MAPK', 'MPA', (74, 89))	('PGC-1alpha', 'Gene', '10891', (234, 244))	('PGC-1alpha', 'Gene', '10891', (189, 199))	('ERK', 'Gene', (230, 233))
26263	32867127	In contrast, expression levels of pro-apoptotic cleaved caspase 3 were markedly higher in ONC206-treated cells than in control cells, suggesting that ONC206 plays a role in apoptosis, as we described above (Figure S2B).	('expression levels', 'MPA', (13, 30))	('higher', 'PosReg', (80, 86))	('ONC206', 'Chemical', '-', (150, 156))	('pro-apoptotic cleaved', 'MPA', (34, 55))	('ONC206', 'Chemical', '-', (90, 96))	('ONC206-treated', 'Var', (90, 104))
26264	32867127	We did not observe a significant induction of TRAIL expression in USC cells after treatment with ONC206, as previously reported in ONC201-treated USC cells (Figure S2C).	('TRAIL', 'Gene', (46, 51))	('ONC206', 'Var', (97, 103))	('TRAIL', 'Gene', '8743', (46, 51))	('ONC206', 'Chemical', '-', (97, 103))
26265	32867127	The RPPA and Western blot results indicated that ONC206 might induce metabolic reprogramming by altering the expression of proteins associated with glycolysis and the mitochondrial ETC.	('expression of', 'MPA', (109, 122))	('proteins', 'Protein', (123, 131))	('altering', 'Reg', (96, 104))	('induce', 'PosReg', (62, 68))	('ONC206', 'Var', (49, 55))	('metabolic reprogramming', 'CPA', (69, 92))	('ONC206', 'Chemical', '-', (49, 55))
26266	32867127	To further evaluate the effects of ONC206 on metabolic reprogramming, we determined ATP production, cytochrome c oxidase activity, ROS production and lactate production in USC cells after treatment with ONC206.	('ONC206', 'Var', (203, 209))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('ATP production', 'MPA', (84, 98))	('ROS production', 'MPA', (131, 145))	('cytochrome c oxidase activity', 'MPA', (100, 129))	('ONC206', 'Chemical', '-', (203, 209))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('lactate production', 'MPA', (150, 168))	('ONC206', 'Chemical', '-', (35, 41))	('ATP', 'Chemical', 'MESH:D000255', (84, 87))
26267	32867127	The results showed that ARK1, ARK2 and HEC50 cells treated with ONC206 had significantly lower levels of ATP and lactate production compared with control cells, suggesting that ONC206 suppresses both glycolysis and OXPHOS in USC cells (Figure 3D,E).	('glycolysis', 'MPA', (200, 210))	('ONC206', 'Var', (64, 70))	('ARK2', 'Gene', (30, 34))	('lower', 'NegReg', (89, 94))	('HEC50', 'CellLine', 'CVCL:2929', (39, 44))	('ONC206', 'Chemical', '-', (177, 183))	('ARK2', 'Gene', '9212', (30, 34))	('ONC206', 'Chemical', '-', (64, 70))	('lactate', 'Chemical', 'MESH:D019344', (113, 120))	('OXPHOS', 'MPA', (215, 221))	('ONC206', 'Var', (177, 183))	('ATP', 'Chemical', 'MESH:D000255', (105, 108))	('suppresses', 'NegReg', (184, 194))
26268	32867127	We also observed a decrease in cytochrome c oxidase activity and an increase in ROS production in ONC206-treated ARK1, ARK2 and HEC50 cells compared with control cells, suggesting a potential mechanism by which ONC206 induces apoptosis in USC cells (Figure 3F,G).	('ONC206', 'Var', (211, 217))	('HEC50', 'CellLine', 'CVCL:2929', (128, 133))	('ARK2', 'Gene', '9212', (119, 123))	('decrease', 'NegReg', (19, 27))	('ONC206-treated', 'Var', (98, 112))	('apoptosis', 'CPA', (226, 235))	('ONC206', 'Chemical', '-', (211, 217))	('increase in ROS production', 'Phenotype', 'HP:0025464', (68, 94))	('increase', 'PosReg', (68, 76))	('ROS production', 'MPA', (80, 94))	('ONC206', 'Chemical', '-', (98, 104))	('decrease in cytochrome c oxidase activity', 'Phenotype', 'HP:0003688', (19, 60))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('cytochrome c oxidase activity', 'MPA', (31, 60))	('ARK2', 'Gene', (119, 123))
26270	32867127	We first determined the effect of DRD2 silencing on the tumor-suppressor effect of ONC206.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('DRD2', 'Gene', (34, 38))	('silencing', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('ONC206', 'Chemical', '-', (83, 89))
26271	32867127	DRD2 was successfully knocked out in ARK2 cells using CRISPR/Cas9 technology (Figure S3A,B).	('ARK2', 'Gene', '9212', (37, 41))	('knocked out', 'Var', (22, 33))	('DRD2', 'Gene', (0, 4))	('ARK2', 'Gene', (37, 41))
26273	32867127	The results showed that the effect of ONC206 on cell viability was smaller in DRD2-KO ARK2 cells compared with Control-KO cells.	('ONC206', 'Gene', (38, 44))	('ONC206', 'Chemical', '-', (38, 44))	('cell viability', 'CPA', (48, 62))	('ARK2', 'Gene', (86, 90))	('DRD2-KO', 'Var', (78, 85))	('ARK2', 'Gene', '9212', (86, 90))	('smaller', 'NegReg', (67, 74))
26276	32867127	In addition, DRD2 knockout in ARK2 cells did not completely abrogate the tumor-suppressor effect of ONC206, suggesting that other D2-like receptors independent pathways may play a role in modulating the effect of ONC206 in USC cells.	('ARK2', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ARK2', 'Gene', '9212', (30, 34))	('abrogate', 'NegReg', (60, 68))	('ONC206', 'Chemical', '-', (213, 219))	('tumor', 'Disease', (73, 78))	('knockout', 'Var', (18, 26))	('ONC206', 'Chemical', '-', (100, 106))
26278	32867127	The results, again, showed that DRD2-KO cells had lower ATP and lactate production levels than those in the Control-KO cells, even without treatment with ONC206 (Figure S3E,F).	('lower', 'NegReg', (50, 55))	('DRD2-KO', 'Var', (32, 39))	('ONC206', 'Chemical', '-', (154, 160))	('lactate', 'Chemical', 'MESH:D019344', (64, 71))	('ATP', 'Chemical', 'MESH:D000255', (56, 59))
26279	32867127	Moreover, the decreases in ATP and lactate production levels following treatment with ONC206 were smaller in DRD2-KO cells than in Control-KO cells, suggesting that the effects of ONC206 on the mitochondrial ETC, OXPHOS, and glycolysis are disrupted in the absence of DRD2 (Figure 4B,C).	('smaller', 'NegReg', (98, 105))	('ONC206', 'Chemical', '-', (86, 92))	('decreases', 'NegReg', (14, 23))	('glycolysis', 'MPA', (225, 235))	('ONC206', 'Chemical', '-', (180, 186))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('DRD2-KO', 'Var', (109, 116))	('ONC206', 'Var', (86, 92))	('ONC206', 'Var', (180, 186))	('lactate', 'Chemical', 'MESH:D019344', (35, 42))	('OXPHOS', 'MPA', (213, 219))	('mitochondrial ETC', 'MPA', (194, 211))
26287	32867127	The results showed that ONC206 synergized with paclitaxel in reducing cell viability of USC cells, with combination index values <1.	('reducing', 'NegReg', (61, 69))	('ONC206', 'Var', (24, 30))	('cell viability of USC cells', 'CPA', (70, 97))	('ONC206', 'Chemical', '-', (24, 30))	('paclitaxel', 'Chemical', 'MESH:D017239', (47, 57))
26289	32867127	In the current study, we tested the novel orally bioavailable imipridone ONC206, a derivative of the first-in-class imipridone ONC201, for its anti-tumor effects and explored the underlying mechanism by which ONC206 suppresses the malignant phenotype of USC.	('malignant phenotype', 'CPA', (231, 250))	('ONC206', 'Chemical', '-', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ONC206', 'Var', (209, 215))	('tumor', 'Disease', (148, 153))	('imipridone', 'Chemical', '-', (116, 126))	('tested', 'Reg', (25, 31))	('suppresses', 'NegReg', (216, 226))	('ONC206', 'Chemical', '-', (209, 215))	('USC', 'Disease', (254, 257))	('imipridone', 'Chemical', '-', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
26290	32867127	Our findings demonstrated that ONC206 has a markedly higher potency compared to its parental compound ONC201 and exhibits significant induction of apoptosis in vitro.	('higher', 'PosReg', (53, 59))	('potency', 'MPA', (60, 67))	('ONC206', 'Var', (31, 37))	('apoptosis', 'CPA', (147, 156))	('ONC206', 'Chemical', '-', (31, 37))
26291	32867127	In an orthotopic mouse model for advanced USC, ONC206 treatment significantly reduced the tumor burden compared to either the control or ONC201 treatment, indicating ONC206 is more potent in suppressing the malignant phenotypes of USC.	('suppressing', 'NegReg', (191, 202))	('ONC206', 'Var', (47, 53))	('USC', 'Disease', (231, 234))	('ONC206', 'Chemical', '-', (166, 172))	('mouse', 'Species', '10090', (17, 22))	('malignant phenotypes', 'CPA', (207, 227))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('ONC206', 'Chemical', '-', (47, 53))	('reduced', 'NegReg', (78, 85))	('ONC206', 'Var', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
26292	32867127	We demonstrated that inhibiting p38MAPK/ERK signaling pathway, and suppressing both glycolysis and oxidative phosphorylation (OXPHOS) in USC through antagonizing DRD2 is one of the potential mechanisms for the anti-tumor effect of ONC206.	('glycolysis', 'MPA', (84, 94))	('ERK', 'Gene', '5594', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('inhibiting', 'NegReg', (21, 31))	('ONC206', 'Chemical', '-', (231, 237))	('ERK', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('DRD2', 'Gene', (162, 166))	('oxidative phosphorylation', 'MPA', (99, 124))	('tumor', 'Disease', (215, 220))	('suppressing', 'NegReg', (67, 78))	('antagonizing', 'Var', (149, 161))
26295	32867127	Our data revealed a similar but stronger effect of ONC206 on apoptosis induction compared to ONC201.	('ONC206', 'Var', (51, 57))	('apoptosis induction', 'CPA', (61, 80))	('ONC206', 'Chemical', '-', (51, 57))	('stronger', 'PosReg', (32, 40))
26301	32867127	Similarly, ONC206 was shown to be an antagonist for DRD2 and DRD3 as previously described.	('ONC206', 'Chemical', '-', (11, 17))	('DRD3', 'Gene', '1814', (61, 65))	('ONC206', 'Var', (11, 17))	('DRD3', 'Gene', (61, 65))
26305	32867127	Besides, our results demonstrated that PGC-1alpha expression levels were significantly lower in ONC206-treated cells.	('PGC-1alpha', 'Gene', (39, 49))	('PGC-1alpha', 'Gene', '10891', (39, 49))	('lower', 'NegReg', (87, 92))	('expression levels', 'MPA', (50, 67))	('ONC206-treated', 'Var', (96, 110))	('ONC206', 'Chemical', '-', (96, 102))
26308	32867127	ONC206 inactivates p38MAPK and subsequently destabilizes and down-regulates PGC-1alpha and TFAM.	('TFAM', 'Gene', '7019', (91, 95))	('TFAM', 'Gene', (91, 95))	('p38MAPK', 'Protein', (19, 26))	('destabilizes', 'NegReg', (44, 56))	('ONC206', 'Var', (0, 6))	('PGC-1alpha', 'Gene', (76, 86))	('PGC-1alpha', 'Gene', '10891', (76, 86))	('ONC206', 'Chemical', '-', (0, 6))	('down-regulates', 'NegReg', (61, 75))	('inactivates', 'NegReg', (7, 18))
26310	32867127	It is known that TFAM maintains the integrity of mitochondrial DNA (mtDNA) and therefore the loss of TFAM could cause mitochondrial damage and malfunction.	('cause', 'Reg', (112, 117))	('TFAM', 'Gene', '7019', (17, 21))	('TFAM', 'Gene', (17, 21))	('loss', 'Var', (93, 97))	('malfunction', 'MPA', (143, 154))	('TFAM', 'Gene', '7019', (101, 105))	('TFAM', 'Gene', (101, 105))	('mitochondrial damage', 'CPA', (118, 138))	('integrity', 'MPA', (36, 45))
26331	32867127	Immunolocalization of Ki-67 was performed using formalin-fixed, paraffin-embedded uterine tumor sections obtained from the uterine cancer-bearing athymic mice treated with ONC201, ONC206, or PBS.	('cancer', 'Disease', (131, 137))	('mice', 'Species', '10090', (154, 158))	('ONC206', 'Chemical', '-', (180, 186))	('uterine tumor', 'Phenotype', 'HP:0010784', (82, 95))	('PBS', 'Chemical', '-', (191, 194))	('Ki-67', 'Gene', '17345', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ONC201', 'Var', (172, 178))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ONC206', 'Var', (180, 186))	('paraffin', 'Chemical', 'MESH:D010232', (64, 72))	('uterine cancer', 'Phenotype', 'HP:0010784', (123, 137))	('formalin', 'Chemical', 'MESH:D005557', (48, 56))	('Ki-67', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
26336	32867127	In brief, formalin-fixed, paraffin-embedded uterine tumor sections obtained from the uterine cancer-bearing athymic mice treated with ONC201, ONC206, or PBS were first deparaffinized and dehydrated, and antigen retrieval was performed in sodium citrate buffer (pH 6.0) with a microwave at 95  C for 15 min.	('ONC206', 'Chemical', '-', (142, 148))	('mice', 'Species', '10090', (116, 120))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ONC201', 'Var', (134, 140))	('tumor', 'Disease', (52, 57))	('PBS', 'Chemical', '-', (153, 156))	('uterine tumor', 'Phenotype', 'HP:0010784', (44, 57))	('sodium citrate', 'Chemical', 'MESH:D000077559', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('paraffin', 'Chemical', 'MESH:D010232', (170, 178))	('PBS', 'Gene', (153, 156))	('uterine cancer', 'Phenotype', 'HP:0010784', (85, 99))	('ONC206', 'Var', (142, 148))	('formalin', 'Chemical', 'MESH:D005557', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('paraffin', 'Chemical', 'MESH:D010232', (26, 34))
26365	32867127	Pre-designed, FAM-labeled human DRD2 (Hs00241436_m1) and VIC-labeled human GAPDH TaqMan gene expression assays (Life Technologies Corp.) were used in the real-time PCR analysis.	('human', 'Species', '9606', (69, 74))	('Hs00241436_m1', 'Var', (38, 51))	('GAPDH', 'Gene', '2597', (75, 80))	('GAPDH', 'Gene', (75, 80))	('human', 'Species', '9606', (26, 31))
26367	32867127	In summary, our study reveals that ONC206 exhibits strong therapeutic efficacy in USC in vitro and in mouse models, and demonstrates the molecular mechanism by which ONC206 suppresses the malignant phenotype of USC.	('ONC206', 'Chemical', '-', (166, 172))	('suppresses', 'NegReg', (173, 183))	('malignant phenotype', 'CPA', (188, 207))	('USC', 'Disease', (82, 85))	('ONC206', 'Var', (166, 172))	('mouse', 'Species', '10090', (102, 107))	('ONC206', 'Chemical', '-', (35, 41))
26372	32867127	; writing:review and editing, C.-L.A.-Y., H.T.C., T-L.Y., P.T.S.	('C.-L.A.-Y.', 'Var', (30, 40))	('H.T', 'Disease', 'MESH:D000848', (42, 45))	('H.T', 'Disease', (42, 45))	('T-L.Y.', 'Var', (50, 56))
26387	30846786	The analyses using The Cancer Genome Atlas (TCGA) data have led to an integrated genomic classification of endometrioid endometrial carcinomas (EECs) and serous endometrial carcinomas (SECs) and the identification of the POLE (ultramutated), microsatellite instability (MSI) (hypermutated), copy-number low (endometrioid) and copy-number high (serous-like) subtypes, with distinct combinations of genomic and epigenetic alterations.	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (107, 142))	('copy-number low', 'Var', (291, 306))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (120, 142))	('endometrioid endometrial carcinomas', 'Disease', (107, 142))	('EECs', 'Phenotype', 'HP:0012114', (144, 148))	('serous endometrial carcinomas', 'Disease', (154, 183))	('serous endometrial carcinomas', 'Phenotype', 'HP:0012887', (154, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (161, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('serous endometrial carcinomas', 'Disease', 'MESH:D016889', (154, 183))	('MSI', 'Disease', 'None', (270, 273))	('MSI', 'Disease', (270, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (120, 141))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('copy-number high', 'Var', (326, 342))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('SECs', 'Phenotype', 'HP:0012887', (185, 189))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (161, 183))
26388	30846786	Mounting evidence suggests that some molecular alterations are preferentially found in endometrioid endometrial carcinomas (EECs), including mutations in PTEN and CTNNB1, whereas others such as TP53 mutations are more prevalent in serous endometrial carcinomas (SECs).	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('SECs', 'Phenotype', 'HP:0012887', (262, 266))	('CTNNB1', 'Gene', (163, 169))	('endometrioid endometrial carcinomas', 'Disease', (87, 122))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (238, 260))	('TP53', 'Gene', (194, 198))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (100, 121))	('PTEN', 'Gene', (154, 158))	('mutations', 'Var', (141, 150))	('serous endometrial carcinomas', 'Phenotype', 'HP:0012887', (231, 260))	('serous endometrial carcinomas', 'Disease', (231, 260))	('PTEN', 'Gene', '5728', (154, 158))	('CTNNB1', 'Gene', '1499', (163, 169))	('serous endometrial carcinomas', 'Disease', 'MESH:D016889', (231, 260))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (100, 122))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (87, 122))	('EECs', 'Phenotype', 'HP:0012114', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('TP53', 'Gene', '7157', (194, 198))	('carcinomas', 'Phenotype', 'HP:0030731', (250, 260))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (238, 259))
26453	30846786	The strict counts of genes after VP-treatment tended to be less than in their non-treated counterparts in both HEC-1-A and HEC-1-B (Supplementary Fig.	('VP', 'Chemical', 'MESH:D000077362', (33, 35))	('HEC-1-A', 'CellLine', 'CVCL:0293', (111, 118))	('VP-treatment', 'Var', (33, 45))	('less', 'NegReg', (59, 63))	('HEC-1-B', 'CellLine', 'CVCL:0294', (123, 130))	('strict counts', 'MPA', (4, 17))
26460	30846786	Of these, 3235 were downregulated and 5271 were upregulated in VP treated cells as compared to control cells.	('VP', 'Chemical', 'MESH:D000077362', (63, 65))	('VP treated', 'Var', (63, 73))	('downregulated', 'NegReg', (20, 33))	('upregulated', 'PosReg', (48, 59))
26497	30846786	Inhibition of the Hippo pathway leads to YAP activation, nuclear localization and cell proliferation in most cell types.	('YAP', 'Gene', (41, 44))	('nuclear localization', 'MPA', (57, 77))	('Inhibition', 'Var', (0, 10))	('Hippo pathway', 'Pathway', (18, 31))	('YAP', 'Gene', '10413', (41, 44))	('activation', 'PosReg', (45, 55))	('cell proliferation in', 'CPA', (82, 103))
26559	30268436	A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-beta Superfamily We present an integromic analysis of gene alterations that modulate transforming growth factor beta (TGF-beta)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA).	('transforming growth factor beta', 'Gene', (187, 218))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('cancer', 'Disease', (287, 293))	('TGF-beta', 'Gene', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('transforming growth factor beta', 'Gene', '7040', (187, 218))	('TGF-beta', 'Gene', '7040', (98, 106))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Disease', (263, 268))	('modulate', 'Reg', (178, 186))	('TGF-beta', 'Gene', '7040', (220, 228))	('TGF-beta', 'Gene', (98, 106))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))	('alterations', 'Var', (161, 172))
26560	30268436	Focusing on genes that encode mediators and regulators of TGF-beta signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('TGF-beta', 'Gene', (58, 66))	('mutation', 'Var', (120, 128))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (216, 240))	('amplification', 'Var', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('gastrointestinal cancers', 'Disease', (216, 240))	('frequencies', 'Reg', (201, 212))	('TGF-beta', 'Gene', '7040', (58, 66))
26562	30268436	Alterations in the TGF-beta superfamily correlated positively with expression of metastasis-associated genes and with decreased survival.	('Alterations', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (19, 27))	('metastasis-associated genes', 'Gene', (81, 108))	('decreased', 'NegReg', (118, 127))	('survival', 'CPA', (128, 136))	('expression', 'MPA', (67, 77))	('TGF-beta', 'Gene', (19, 27))
26563	30268436	Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-beta signaling in each cancer type.	('miR', 'Gene', (105, 108))	('TGF-beta', 'Gene', '7040', (153, 161))	('deletion', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mutation', 'Var', (49, 57))	('TGF-beta', 'Gene', (153, 161))	('transcriptional activity', 'MPA', (125, 149))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('amplification', 'Var', (59, 72))	('cancer', 'Disease', (180, 186))	('miR', 'Gene', '220972', (105, 108))
26579	30268436	We analyzed multiple data types: somatic copy number variation (CNV), point mutation, DNA methylation, mRNA expression (from mRNA-seq), miRNA expression (from miRNA-seq), and, for correlative analyses, protein expression (from reverse-phase protein arrays; RPPA).	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('point mutation', 'Var', (70, 84))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))	('mRNA expression', 'MPA', (103, 118))
26585	30268436	Using the cBioPortal definitions, genomic alterations were classified as gene amplifications, gains (low-level amplifications), deep deletions (equivalent to homozygous deletions for non-aneuploidy cases), shallow deletions (heterozygous loss), truncating mutations, inframe mutations, or missense mutations.	('non-aneuploidy', 'Disease', (183, 197))	('truncating', 'Disease', (245, 255))	('gains', 'Disease', (94, 99))	('deep', 'Disease', (128, 132))	('inframe mutations', 'Var', (267, 284))	('missense mutations', 'Var', (289, 307))	('shallow', 'Disease', (206, 213))	('non-aneuploidy', 'Disease', 'MESH:D000782', (183, 197))
26587	30268436	Although alteration frequencies were low, 39% of the tumors contained an alteration in at least one of the 43 genes.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('alteration', 'Var', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
26591	30268436	When excluding those six, cumulative mutation frequency (23%) in the TGF-beta core pathways was significantly higher than expected for a randomly selected set of 37 genes (Figure S1C, S1D).	('TGF-beta', 'Gene', '7040', (69, 77))	('higher', 'PosReg', (110, 116))	('mutation frequency', 'Var', (37, 55))	('TGF-beta', 'Gene', (69, 77))
26595	30268436	The frequency and type of genomic alteration varied widely across tumor types (Figure 2A and S2A), from no alterations in testicular germline tumors (TGCT) to all three types of alterations (mutation, deletion, and amplification) in urothelial bladder cancers (BLCA).	('deletion', 'Var', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('tumor', 'Disease', (66, 71))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('tumor', 'Disease', (142, 147))	('amplification', 'Var', (215, 228))	('urothelial bladder cancers', 'Disease', (233, 259))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('BLCA', 'Phenotype', 'HP:0009725', (261, 265))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
26596	30268436	There were genomic alterations of TGF-beta pathway genes in more than 50% of samples in 12 tumor types (Figure 2A, Tables S2-S4).	('TGF-beta', 'Gene', (34, 42))	('genomic alterations', 'Var', (11, 30))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TGF-beta', 'Gene', '7040', (34, 42))	('tumor', 'Disease', (91, 96))
26598	30268436	Without adjusting for background alteration burden, among the 39% of TCGA cases that carried TGF-beta pathway gene alterations, SKCM (70%), COAD (65%), and ESCA (65%) had the highest percentages of alterations; THCA (4%), KICH (6%), and TGCT (9%) had the lowest (Table S3).	('TGF-beta', 'Gene', '7040', (93, 101))	('COAD', 'Disease', (140, 144))	('TGF-beta', 'Gene', (93, 101))	('alterations', 'Reg', (198, 209))	('alterations', 'Var', (115, 126))	('KICH', 'Disease', 'None', (222, 226))	('ESCA', 'Phenotype', 'HP:0011459', (156, 160))	('COAD', 'Disease', 'MESH:D029424', (140, 144))	('KICH', 'Disease', (222, 226))
26599	30268436	We observed non-silent SMAD4 mutations in 24% and SMAD4 deletions in 13% of pancreatic adenocarcinoma (PAAD) samples (Figure 2A, 2C; Table S4).	('SMAD4', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutations', 'Var', (29, 38))	('SMAD4', 'Gene', (50, 55))	('pancreatic adenocarcinoma', 'Disease', (76, 101))	('deletions', 'Var', (56, 65))	('PAAD', 'Phenotype', 'HP:0006725', (103, 107))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (76, 101))	('SMAD4', 'Gene', '4089', (23, 28))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (76, 101))	('SMAD4', 'Gene', '4089', (50, 55))
26600	30268436	Because SMAD4 is the Co-Smad required for transducing the Smad signal to downstream effectors, loss of SMAD4 in PAAD by mutation or deletion suggests a tumor-suppressive role for TGF-beta signaling in PAAD, which is consistent with other reports.	('TGF-beta', 'Gene', (179, 187))	('deletion', 'Var', (132, 140))	('SMAD4', 'Gene', (8, 13))	('a tumor', 'Disease', 'MESH:D009369', (150, 157))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('SMAD4', 'Gene', '4089', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (120, 128))	('a tumor', 'Disease', (150, 157))	('SMAD4', 'Gene', '4089', (8, 13))	('TGF-beta', 'Gene', '7040', (179, 187))	('loss', 'NegReg', (95, 99))	('SMAD4', 'Gene', (103, 108))	('PAAD', 'Disease', (201, 205))	('PAAD', 'Phenotype', 'HP:0006725', (201, 205))
26604	30268436	Diffuse large B-cell lymphoma (DLBC) had a high frequency of deletions spanning different levels of the pathway:: ligands (TGFB2, INHBB, GDF1), receptors or receptor-associated proteins (BMPR1A, ACVR1, ACVR1C, ACV2A, ACVR2B, TGFBRAP1), and Smads (SMAD9):, indicative of a tumor-suppressive role for TGF-beta signaling in these early-stage DLBC cases in the TCGA cohort.	('deletions', 'Var', (61, 70))	('TGF-beta', 'Gene', (299, 307))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (14, 29))	('TGFB2', 'Gene', '7042', (123, 128))	('ACVR1C', 'Gene', (202, 208))	('ACVR1C', 'Gene', '130399', (202, 208))	('INHBB', 'Gene', (130, 135))	('BMPR1A', 'Gene', '657', (187, 193))	('ACV', 'Gene', (195, 198))	('ACV', 'Gene', (210, 213))	('ACV', 'Gene', (202, 205))	('ACVR1', 'Gene', (195, 200))	('a tumor', 'Disease', 'MESH:D009369', (270, 277))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (14, 29))	('TGFB2', 'Gene', (123, 128))	('TGFBRAP1', 'Gene', '9392', (225, 233))	('ACV', 'Gene', '83729', (202, 205))	('ACVR2B', 'Gene', '93', (217, 223))	('GDF1', 'Gene', (137, 141))	('ACV', 'Gene', '83729', (195, 198))	('ACV', 'Gene', '83729', (210, 213))	('ACVR1', 'Gene', '90', (202, 207))	('INHBB', 'Gene', '3625', (130, 135))	('B-cell lymphoma', 'Disease', (14, 29))	('early-stage DLBC', 'Disease', (327, 343))	('ACV', 'Gene', (217, 220))	('a tumor', 'Disease', (270, 277))	('BMPR1A', 'Gene', (187, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('ACVR1', 'Gene', (202, 207))	('ACVR1', 'Gene', '90', (195, 200))	('SMAD9', 'Gene', (247, 252))	('GDF1', 'Gene', '2657', (137, 141))	('TGF-beta', 'Gene', '7040', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('ACV', 'Gene', '83729', (217, 220))	('ACVR2B', 'Gene', (217, 223))	('SMAD9', 'Gene', '4093', (247, 252))	('TGFBRAP1', 'Gene', (225, 233))
26610	30268436	PAAD had deletions associated with 14 TGF-beta core genes, suggesting synergistic effects from ligands (BMP family), receptors (BMPR, TGFBR), and SMAD4.	('TGFBR', 'Gene', '7046;7048;7049', (134, 139))	('TGF-beta', 'Gene', (38, 46))	('BMP', 'Gene', (128, 131))	('BMP', 'Gene', (104, 107))	('TGFBR', 'Gene', (134, 139))	('SMAD4', 'Gene', '4089', (146, 151))	('PAAD', 'Phenotype', 'HP:0006725', (0, 4))	('TGF-beta', 'Gene', '7040', (38, 46))	('deletions', 'Var', (9, 18))	('BMP', 'Gene', '649', (104, 107))	('SMAD4', 'Gene', (146, 151))	('BMP', 'Gene', '649', (128, 131))
26611	30268436	Colorectal cancers (COAD and READ) were marked by SMAD4 and SMAD3 deletions.	('SMAD3', 'Gene', (60, 65))	('COAD', 'Disease', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Colorectal cancers', 'Disease', (0, 18))	('SMAD4', 'Gene', (50, 55))	('Colorectal cancers', 'Disease', 'MESH:D015179', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('COAD', 'Disease', 'MESH:D029424', (20, 24))	('deletions', 'Var', (66, 75))	('SMAD3', 'Gene', '4088', (60, 65))	('SMAD4', 'Gene', '4089', (50, 55))
26612	30268436	Deletions in genomic regions covering all ACVR genes except ACVR2B were identified as significant in DLBC.	('significant', 'Reg', (86, 97))	('ACV', 'Gene', '83729', (42, 45))	('ACVR2B', 'Gene', (60, 66))	('DLBC', 'Disease', (101, 105))	('ACV', 'Gene', (42, 45))	('ACV', 'Gene', '83729', (60, 63))	('ACVR2B', 'Gene', '93', (60, 66))	('ACV', 'Gene', (60, 63))	('Deletions', 'Var', (0, 9))
26613	30268436	To understand how gene alterations affect transcriptional output of the pathways, we analyzed the mRNA expression of 50 downstream targets of Smad signaling with defined roles as tumor promoters or tumor suppressors (Table S1).	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('alterations', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (179, 184))
26614	30268436	Surprisingly, the directionality of target-gene change was consistent for all mutations, even for mutations in the inhibitors SMAD6/7.	('SMAD6/7', 'Gene', '4091;4092', (126, 133))	('mutations', 'Var', (78, 87))	('SMAD6/7', 'Gene', (126, 133))
26615	30268436	An explanation is that mutations in pathway activators, like TGFB1/2/3 and TGFBR1/2/3, may result in gain of function, whereas mutations in the inhibitors SMAD6 and SMAD7 may result in loss of inhibitory function.	('TGFBR1/2/3', 'Gene', (75, 85))	('gain of function', 'PosReg', (101, 117))	('TGFBR1/2/3', 'Gene', '7046;7048;7049', (75, 85))	('TGFB1/2/3', 'Gene', (61, 70))	('SMAD7', 'Gene', (165, 170))	('mutations', 'Var', (23, 32))	('SMAD7', 'Gene', '4092', (165, 170))	('SMAD6', 'Gene', '4091', (155, 160))	('TGFB1/2/3', 'Gene', '7040;7042;7043', (61, 70))	('SMAD6', 'Gene', (155, 160))	('inhibitory function', 'MPA', (193, 212))
26617	30268436	Similarly, SMAD3 was generally co-amplified with SMAD6; both are in proximal cytogenetic bands, 15q22.33 and 15q22.31, respectively.	('SMAD3', 'Gene', '4088', (11, 16))	('SMAD3', 'Gene', (11, 16))	('SMAD6', 'Gene', '4091', (49, 54))	('15q22.33', 'Var', (96, 104))	('SMAD6', 'Gene', (49, 54))	('15q22.31', 'Var', (109, 117))
26618	30268436	In support of that hypothesis, both the amplification and deletion profiles (rows in Figure 2H-I) of those gene pairs were similar, and, consequently, SMAD2 and SMAD7 are co-clustered, whereas SMAD3 and SMAD6 clustered close to each other.	('SMAD7', 'Gene', (161, 166))	('SMAD7', 'Gene', '4092', (161, 166))	('SMAD2', 'Gene', (151, 156))	('SMAD2', 'Gene', '4087', (151, 156))	('SMAD6', 'Gene', '4091', (203, 208))	('deletion', 'Var', (58, 66))	('SMAD6', 'Gene', (203, 208))	('SMAD3', 'Gene', '4088', (193, 198))	('SMAD3', 'Gene', (193, 198))
26619	30268436	The effect of TGF-beta pathway amplification events on target gene mRNA expression was similar to that of mutations (Figure 2H), suggesting that most mutations in TGF-beta pathway activators are gain of function.	('TGF-beta', 'Gene', '7040', (163, 171))	('TGF-beta', 'Gene', (14, 22))	('gain of function', 'PosReg', (195, 211))	('TGF-beta', 'Gene', (163, 171))	('mutations', 'Var', (150, 159))	('TGF-beta', 'Gene', '7040', (14, 22))
26620	30268436	HMGA2 was overexpressed in samples with either mutations or amplifications in the TGF-beta pathway genes, with the exception of tumors with amplifications in TGFB2, TGFBR2, ACVR2B, SMAD4, SMAD5, or SMAD6.	('TGFBR2', 'Gene', (165, 171))	('SMAD6', 'Gene', (198, 203))	('ACVR2B', 'Gene', '93', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TGF-beta', 'Gene', '7040', (82, 90))	('SMAD4', 'Gene', (181, 186))	('tumors', 'Disease', (128, 134))	('overexpressed', 'PosReg', (10, 23))	('HMGA2', 'Gene', '8091', (0, 5))	('SMAD5', 'Gene', (188, 193))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('TGF-beta', 'Gene', (82, 90))	('ACVR2B', 'Gene', (173, 179))	('SMAD6', 'Gene', '4091', (198, 203))	('SMAD4', 'Gene', '4089', (181, 186))	('amplifications', 'Var', (140, 154))	('TGFB2', 'Gene', '7042', (158, 163))	('TGFBR2', 'Gene', '7048', (165, 171))	('SMAD5', 'Gene', '4090', (188, 193))	('amplifications', 'Var', (60, 74))	('TGFB2', 'Gene', (158, 163))	('HMGA2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
26625	30268436	SMAD5 amplification was associated with increased CDH2 expression; 36 other amplifications were associated with decreased CDH2 expression.	('CDH2', 'Gene', (50, 54))	('CDH2', 'Gene', '1000', (50, 54))	('SMAD5', 'Gene', (0, 5))	('expression', 'MPA', (127, 137))	('CDH2', 'Gene', (122, 126))	('expression', 'MPA', (55, 65))	('CDH2', 'Gene', '1000', (122, 126))	('SMAD5', 'Gene', '4090', (0, 5))	('increased', 'PosReg', (40, 49))	('amplification', 'Var', (6, 19))	('decreased', 'NegReg', (112, 121))
26627	30268436	Another exception was reduced HMGA2 expression in samples with amplifications of SMAD4 or TGFBR2, whereas HMGA2 expression increased in samples with mutations in SMAD4 or TGFBR2 (Figure 2G).	('increased', 'PosReg', (123, 132))	('mutations', 'Var', (149, 158))	('HMGA2', 'Gene', '8091', (30, 35))	('TGFBR2', 'Gene', (90, 96))	('SMAD4', 'Gene', '4089', (162, 167))	('TGFBR2', 'Gene', '7048', (171, 177))	('HMGA2', 'Gene', '8091', (106, 111))	('SMAD4', 'Gene', (81, 86))	('HMGA2', 'Gene', (30, 35))	('HMGA2', 'Gene', (106, 111))	('amplifications', 'Var', (63, 77))	('reduced', 'NegReg', (22, 29))	('TGFBR2', 'Gene', (171, 177))	('TGFBR2', 'Gene', '7048', (90, 96))	('SMAD4', 'Gene', (162, 167))	('expression', 'MPA', (36, 46))	('SMAD4', 'Gene', '4089', (81, 86))	('expression', 'MPA', (112, 122))
26629	30268436	The analysis identified 6genes with hotspot mutations, representing all levels of the TGF-beta pathway (Figure 3A-E).	('TGF-beta', 'Gene', '7040', (86, 94))	('TGF-beta', 'Gene', (86, 94))	('mutations', 'Var', (44, 53))
26631	30268436	Hotspot mutations of BMP5 occurred in 13 cases across 7 cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (8, 17))	('occurred', 'Reg', (26, 34))	('BMP5', 'Gene', (21, 25))	('BMP5', 'Gene', '653', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('Hotspot', 'PosReg', (0, 7))
26632	30268436	BMP5 is synthesized as a proprotein, and an R321 stop-codon mutation (4 cases) (Figure 3A) results in loss of the functional, secreted ligand.	('R321 stop-codon', 'Var', (44, 59))	('BMP5', 'Gene', '653', (0, 4))	('BMP5', 'Gene', (0, 4))	('loss', 'NegReg', (102, 106))
26633	30268436	Frameshift mutations in ACVR2A at the K437 hotspot generate the variants K437Efs*19 (7 cases in 2 cancers) and K437Rfs*5 (69 cases in 5 cancers), resulting in premature stop codons and deletion of two C-terminal helices of the 4-helix bundle (Figure 3A, 3D), which likely disrupt ACV signaling (; Yosef et al., 2017).	('ACV', 'Gene', '83729', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (98, 105))	('K437Efs*19', 'Var', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('K437Efs', 'Mutation', 'p.K437,FSE', (73, 80))	('ACV', 'Gene', (280, 283))	('disrupt', 'NegReg', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('ACV', 'Gene', '83729', (280, 283))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('K437Rfs*5', 'Var', (111, 120))	('stop codons', 'MPA', (169, 180))	('ACVR2A', 'Gene', '92', (24, 30))	('ACV', 'Gene', (24, 27))	('ACVR2A', 'Gene', (24, 30))	('deletion', 'Var', (185, 193))	('K437Rfs', 'Mutation', 'p.K437,FSR', (111, 118))	('Frameshift mutations', 'Var', (0, 20))
26634	30268436	Type I receptors ACVR1B and ACVR1C have similar C-terminal frameshift mutation hotspots at R485 (6 cases) and R441 (5 cases), respectively (Figure S3).	('ACVR1B', 'Gene', '91', (17, 23))	('ACVR1B', 'Gene', (17, 23))	('R441', 'Var', (110, 114))	('ACVR1C', 'Gene', (28, 34))	('ACVR1C', 'Gene', '130399', (28, 34))	('R485', 'Var', (91, 95))
26635	30268436	TGFBR2 R553 to C or H mutations and BMPR2 N583 frameshift might disrupt interaction with other receptor subunits or binding proteins.	('BMPR2', 'Gene', '659', (36, 41))	('binding', 'Interaction', (116, 123))	('N583 frameshift', 'Var', (42, 57))	('interaction', 'Interaction', (72, 83))	('TGFBR2', 'Gene', (0, 6))	('R553 to C or H mutations', 'Var', (7, 31))	('frameshift', 'Var', (47, 57))	('TGFBR2', 'Gene', '7048', (0, 6))	('disrupt', 'NegReg', (64, 71))	('BMPR2', 'Gene', (36, 41))
26636	30268436	Hotspots in SMAD4 at R361 and D537 (two conserved sites in R-Smads) normally stabilize homo- or heterotrimer oligomerization (Figure 3C).	('SMAD4', 'Gene', (12, 17))	('stabilize', 'Reg', (77, 86))	('D537', 'Var', (30, 34))	('homo- or heterotrimer oligomerization', 'MPA', (87, 124))	('SMAD4', 'Gene', '4089', (12, 17))
26637	30268436	Those mutations could have widespread effects, because SMAD4 is a binding partner for all Smad-dependent transcriptional regulation.	('mutations', 'Var', (6, 15))	('SMAD4', 'Gene', '4089', (55, 60))	('SMAD4', 'Gene', (55, 60))
26638	30268436	Mutation at either R361 or D537 in SMAD4 correlates with metastasis and decreased survival in colon cancer.	('survival', 'CPA', (82, 90))	('colon cancer', 'Disease', (94, 106))	('decreased', 'NegReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SMAD4', 'Gene', '4089', (35, 40))	('D537', 'Var', (27, 31))	('metastasis', 'CPA', (57, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('SMAD4', 'Gene', (35, 40))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
26639	30268436	SMAD2 exhibited 13 truncating mutations at S464 (Figure 3A).	('SMAD2', 'Gene', (0, 5))	('SMAD2', 'Gene', '4087', (0, 5))	('S464', 'Var', (43, 47))
26641	30268436	S464 is necessary for proper positioning of SMAD2 for phosphorylation at S465 and S467, both of which mediate interaction of SMAD2 with SMAD4 and dissociation of SMAD2 from TGFBR1 and the adaptor SARA (encoded by ZFYVE9).	('SARA', 'Gene', (196, 200))	('SMAD4', 'Gene', '4089', (136, 141))	('SARA', 'Gene', '9372', (196, 200))	('dissociation', 'MPA', (146, 158))	('ZFYVE9', 'Gene', '9372', (213, 219))	('TGFBR1', 'Gene', '7046', (173, 179))	('mediate', 'Reg', (102, 109))	('TGFBR1', 'Gene', (173, 179))	('SMAD4', 'Gene', (136, 141))	('interaction', 'Interaction', (110, 121))	('SMAD2', 'Gene', (162, 167))	('SMAD2', 'Gene', '4087', (162, 167))	('SMAD2', 'Gene', '4087', (125, 130))	('SMAD2', 'Gene', (125, 130))	('SMAD2', 'Gene', '4087', (44, 49))	('ZFYVE9', 'Gene', (213, 219))	('S467', 'Var', (82, 86))	('SMAD2', 'Gene', (44, 49))
26642	30268436	Hence, S464 mutations may prevent dissociation of SMAD2 from the receptor-adaptor complex, blocking the downstream signal (Figure 3E).	('S464 mutations', 'Var', (7, 21))	('SMAD2', 'Gene', (50, 55))	('downstream signal', 'MPA', (104, 121))	('blocking', 'NegReg', (91, 99))	('SMAD2', 'Gene', '4087', (50, 55))	('dissociation', 'MPA', (34, 46))	('prevent', 'NegReg', (26, 33))
26643	30268436	Of 176 mutations at hotspot sites across 6 genes, 115 (65%) were in cancers of the GI system (Figure S3): 60 in ESCA, 51 in COAD, 3 in PAAD, and 1 in LIHC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers of the GI system', 'Phenotype', 'HP:0007378', (68, 92))	('PAAD', 'Phenotype', 'HP:0006725', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('COAD', 'Disease', (124, 128))	('cancers of the GI system', 'Disease', 'MESH:D009369', (68, 92))	('cancers of the GI system', 'Disease', (68, 92))	('LIHC', 'Disease', (150, 154))	('ESCA', 'Phenotype', 'HP:0011459', (112, 116))	('LIHC', 'Disease', 'None', (150, 154))	('ESCA', 'Disease', (112, 116))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('mutations', 'Var', (7, 16))
26646	30268436	To determine if GI cancers possess a unique signature of altered TGF-beta pathway activity, we compared changes in the expression of 50 downstream genes related to mutations at hotspot sites (Figure 3B).	('TGF-beta', 'Gene', (65, 73))	('expression', 'MPA', (119, 129))	('GI cancers', 'Disease', (16, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('activity', 'MPA', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (164, 173))	('TGF-beta', 'Gene', '7040', (65, 73))
26648	30268436	Notably, CDH2 exhibited an overall reduction in expression except in the context of the BMP5 hotspot mutation.	('CDH2', 'Gene', (9, 13))	('CDH2', 'Gene', '1000', (9, 13))	('expression', 'MPA', (48, 58))	('BMP5', 'Gene', (88, 92))	('BMP5', 'Gene', '653', (88, 92))	('mutation', 'Var', (101, 109))	('reduction', 'NegReg', (35, 44))
26652	30268436	Guided by the enrichment of hotspot mutations in GI cancers, we tested for enrichment of TGF-beta pathway point mutations in GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (49, 59))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('GI cancers', 'Disease', 'MESH:D009369', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (49, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (125, 134))	('tested', 'Reg', (64, 70))	('point mutations', 'Var', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TGF-beta', 'Gene', '7040', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('GI cancers', 'Disease', (49, 59))	('GI cancers', 'Disease', (125, 135))	('TGF-beta', 'Gene', (89, 97))
26653	30268436	Non-silent mutations were significantly more common in GI cancers (596 of 1,511) than in the non-GI cancers (1,606 of 7,614).	('GI cancers', 'Disease', 'MESH:D009369', (55, 65))	('common', 'Reg', (45, 51))	('non-GI cancers', 'Disease', 'MESH:D009369', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (55, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('Non-silent mutations', 'Var', (0, 20))	('GI cancers', 'Disease', 'MESH:D009369', (97, 107))	('GI cancers', 'Disease', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('non-GI cancers', 'Disease', (93, 107))
26654	30268436	Deep deletions and amplifications were also significantly enriched in GI cancers.	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('Deep deletions', 'Var', (0, 14))	('amplifications', 'Var', (19, 33))
26655	30268436	COAD, READ, and STAD had recurrent aberrations in genes at each level of the pathway (ligands, receptors, and SMADs) and all axes (TGFBR, BMPR, ACVR), whereas PAAD had frequent mutations in only SMAD4 and TGFBR2 (Figure S4A).	('TGFBR', 'Gene', (205, 210))	('COAD', 'Disease', (0, 4))	('SMAD4', 'Gene', '4089', (195, 200))	('aberrations', 'Var', (35, 46))	('TGFBR2', 'Gene', '7048', (205, 211))	('ACV', 'Gene', (144, 147))	('BMP', 'Gene', (138, 141))	('mutations', 'Var', (177, 186))	('TGFBR', 'Gene', '7046;7048;7049', (131, 136))	('TGFBR2', 'Gene', (205, 211))	('SMAD4', 'Gene', (195, 200))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('TGFBR', 'Gene', '7046;7048;7049', (205, 210))	('PAAD', 'Phenotype', 'HP:0006725', (159, 163))	('BMP', 'Gene', '649', (138, 141))	('ACV', 'Gene', '83729', (144, 147))	('TGFBR', 'Gene', (131, 136))
26656	30268436	To compare the TGF-beta pathway transcriptional signatures in GI vs. other cancers, we calculated the target gene expression signatures associated with TGF-beta pathway mutations in both groups (Figure 4A-B).	('TGF-beta', 'Gene', '7040', (152, 160))	('mutations', 'Var', (169, 178))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('TGF-beta', 'Gene', '7040', (15, 23))	('cancers', 'Disease', (75, 82))	('TGF-beta', 'Gene', (15, 23))	('TGF-beta', 'Gene', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
26658	30268436	Whereas IL6 mRNA was increased in most non-GI cancers with TGF-beta pathway mutations, IL6 upregulation was significantly greater in GI cancers than non-GI cancers (Figure S4B), and within GI cancers IL6 expression was greater in samples with alterations in the TGF-beta pathway genes than those without alterations in the TGF-beta pathway genes.	('non-GI cancers', 'Disease', (39, 53))	('GI cancers than non-GI cancers', 'Disease', 'MESH:D009369', (133, 163))	('GI cancers', 'Disease', 'MESH:D009369', (189, 199))	('non-GI cancers', 'Disease', 'MESH:D009369', (39, 53))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('TGF-beta', 'Gene', (323, 331))	('GI cancers', 'Disease', 'MESH:D009369', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('IL6', 'Gene', '3569', (8, 11))	('alterations', 'Var', (243, 254))	('IL6', 'Gene', '3569', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('TGF-beta', 'Gene', (59, 67))	('increased', 'PosReg', (21, 30))	('non-GI cancers', 'Disease', 'MESH:D009369', (149, 163))	('GI cancers', 'Disease', 'MESH:D009369', (153, 163))	('IL6', 'Gene', '3569', (87, 90))	('GI cancer', 'Phenotype', 'HP:0007378', (43, 52))	('IL6', 'Gene', (8, 11))	('TGF-beta', 'Gene', '7040', (262, 270))	('IL6', 'Gene', (200, 203))	('GI cancers than non-GI cancers', 'Disease', (133, 163))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('GI cancer', 'Phenotype', 'HP:0007378', (153, 162))	('upregulation', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('IL6', 'Gene', (87, 90))	('expression', 'MPA', (204, 214))	('GI cancers', 'Disease', (189, 199))	('greater', 'PosReg', (122, 129))	('TGF-beta', 'Gene', '7040', (323, 331))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('mutations', 'Var', (76, 85))	('TGF-beta', 'Gene', (262, 270))	('GI cancer', 'Phenotype', 'HP:0007378', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('GI cancers', 'Disease', 'MESH:D009369', (133, 143))	('GI cancer', 'Phenotype', 'HP:0007378', (189, 198))	('TGF-beta', 'Gene', '7040', (59, 67))
26659	30268436	Notably, in non-GI cancers associated with GDF1 mutations, IL6 mRNA expression was markedly decreased, suggesting that GDF1 may play different roles in GI and non-GI cancers.	('non-GI cancers', 'Disease', 'MESH:D009369', (159, 173))	('GDF1', 'Gene', (43, 47))	('non-GI cancers', 'Disease', (159, 173))	('non-GI cancers', 'Disease', (12, 26))	('GDF1', 'Gene', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (163, 172))	('IL6', 'Gene', '3569', (59, 62))	('IL6', 'Gene', (59, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('decreased', 'NegReg', (92, 101))	('GDF1', 'Gene', '2657', (43, 47))	('mutations', 'Var', (48, 57))	('GDF1', 'Gene', '2657', (119, 123))
26661	30268436	In GI cancers, most TGF-beta pathway gene mutations were associated with increased FOS expression; exceptions were TGFBRAP1, SMAD7, SMAD5, GDF1, BMP5, and ACVRL1.	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('TGF-beta', 'Gene', (20, 28))	('ACVRL1', 'Gene', (155, 161))	('SMAD7', 'Gene', '4092', (125, 130))	('BMP5', 'Gene', (145, 149))	('BMP5', 'Gene', '653', (145, 149))	('TGFBRAP1', 'Gene', '9392', (115, 123))	('SMAD5', 'Gene', (132, 137))	('GDF1', 'Gene', (139, 143))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (73, 82))	('ACVRL1', 'Gene', '94', (155, 161))	('GDF1', 'Gene', '2657', (139, 143))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SMAD5', 'Gene', '4090', (132, 137))	('FOS', 'Gene', (83, 86))	('SMAD7', 'Gene', (125, 130))	('GI cancers', 'Disease', (3, 13))	('TGF-beta', 'Gene', '7040', (20, 28))	('FOS', 'Gene', '2353', (83, 86))	('TGFBRAP1', 'Gene', (115, 123))	('mutations', 'Var', (42, 51))
26662	30268436	In non-GI cancers, only mutations in TGFBR2 were associated with increased FOS expression; all other TGF-beta pathway gene mutations were associated with decreased FOS expression.	('decreased', 'NegReg', (154, 163))	('increased', 'PosReg', (65, 74))	('FOS', 'Gene', (164, 167))	('TGF-beta', 'Gene', '7040', (101, 109))	('TGFBR2', 'Gene', '7048', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('FOS', 'Gene', '2353', (164, 167))	('TGF-beta', 'Gene', (101, 109))	('non-GI cancers', 'Disease', (3, 17))	('FOS', 'Gene', (75, 78))	('TGFBR2', 'Gene', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('mutations', 'Var', (24, 33))	('non-GI cancers', 'Disease', 'MESH:D009369', (3, 17))	('GI cancer', 'Phenotype', 'HP:0007378', (7, 16))	('FOS', 'Gene', '2353', (75, 78))
26663	30268436	To compare the transcriptional output resulting from mutations in GI and non-GI cancers, we calculated differences in expression of the 50 target genes associated with mutations in the 43 genes (Figure 4C).	('non-GI cancers', 'Disease', 'MESH:D009369', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('differences', 'Reg', (103, 114))	('expression', 'MPA', (118, 128))	('non-GI cancers', 'Disease', (73, 87))	('mutations', 'Var', (168, 177))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
26664	30268436	The analysis revealed a shift toward repression of transcriptional output in GI cancers with the most significant shifts occurring with mutations in ACVR2B, INHBA, SMAD3, or GDF2.	('GDF2', 'Gene', (174, 178))	('repression', 'NegReg', (37, 47))	('GI cancers', 'Disease', (77, 87))	('SMAD3', 'Gene', '4088', (164, 169))	('INHBA', 'Gene', '3624', (157, 162))	('ACVR2B', 'Gene', '93', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('transcriptional output', 'MPA', (51, 73))	('SMAD3', 'Gene', (164, 169))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('INHBA', 'Gene', (157, 162))	('mutations', 'Var', (136, 145))	('GI cancers', 'Disease', 'MESH:D009369', (77, 87))	('ACVR2B', 'Gene', (149, 155))	('GDF2', 'Gene', '2658', (174, 178))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
26665	30268436	In GI cancers, mutations in GDF1 were associated with significantly increased target gene transcription.	('GDF1', 'Gene', '2657', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('GDF1', 'Gene', (28, 32))	('mutations', 'Var', (15, 24))	('target gene transcription', 'MPA', (78, 103))	('GI cancers', 'Disease', (3, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (68, 77))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))
26666	30268436	Mutations in any of the 43 genes were associated with reduced mRNA expression in GI cancers compared with non-GI cancers for most target genes with the largest reductions found for HMGA2 and TERT.	('GI cancer', 'Phenotype', 'HP:0007378', (110, 119))	('GI cancers', 'Disease', 'MESH:D009369', (110, 120))	('GI cancers', 'Disease', (81, 91))	('HMGA2', 'Gene', '8091', (181, 186))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('non-GI cancers', 'Disease', 'MESH:D009369', (106, 120))	('non-GI cancers', 'Disease', (106, 120))	('GI cancers', 'Disease', 'MESH:D009369', (81, 91))	('mRNA expression', 'MPA', (62, 77))	('Mutations', 'Var', (0, 9))	('HMGA2', 'Gene', (181, 186))	('reduced', 'NegReg', (54, 61))	('GI cancer', 'Phenotype', 'HP:0007378', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
26667	30268436	Compared to non-GI cancers, GI cancers had fewer genes with increased expression resulting from pathway mutations.	('non-GI cancers', 'Disease', (12, 26))	('mutations', 'Var', (104, 113))	('GI cancers', 'Disease', 'MESH:D009369', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('expression', 'MPA', (70, 80))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('GI cancers', 'Disease', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('GI cancer', 'Phenotype', 'HP:0007378', (28, 37))	('increased', 'PosReg', (60, 69))
26668	30268436	In GI cancers, mutations in any of the 43 genes were associated with a significantly increased expression of FOS, IL6, ZEB2, and ZEB1 compared to expression changes of the same genes resulting from pathway mutations in non-GI cancers.	('ZEB1', 'Gene', '6935', (129, 133))	('IL6', 'Gene', (114, 117))	('increased', 'PosReg', (85, 94))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('mutations', 'Var', (15, 24))	('non-GI cancers', 'Disease', (219, 233))	('non-GI cancers', 'Disease', 'MESH:D009369', (219, 233))	('FOS', 'Gene', (109, 112))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('GI cancers', 'Disease', 'MESH:D009369', (223, 233))	('expression', 'MPA', (95, 105))	('FOS', 'Gene', '2353', (109, 112))	('ZEB1', 'Gene', (129, 133))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ZEB2', 'Gene', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('IL6', 'Gene', '3569', (114, 117))	('GI cancers', 'Disease', (3, 13))	('ZEB2', 'Gene', '9839', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
26669	30268436	Finally, we probed for associations between transcriptional output and TGF-beta pathway gene alterations for all cancers and the GI and non-GI subsets (Figure 4E).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('alterations', 'Var', (93, 104))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('probed', 'Reg', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('TGF-beta', 'Gene', '7040', (71, 79))	('TGF-beta', 'Gene', (71, 79))
26672	30268436	To explore TGF-beta signaling pathway variation across the 33 cancers in the PanCancer cohort, we computed a "pathway activity score" based on mRNA expression of the 43 genes.	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('variation', 'Var', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
26694	30268436	We attribute this observation to co-occurring amplifications or deletions of SMAD7 and SMAD2 and co-occurring amplifications of SMAD6 and SMAD3 (Figure 1B).	('amplifications', 'Var', (46, 60))	('SMAD7', 'Gene', (77, 82))	('SMAD6', 'Gene', (128, 133))	('SMAD2', 'Gene', '4087', (87, 92))	('SMAD3', 'Gene', '4088', (138, 143))	('deletions', 'Var', (64, 73))	('SMAD7', 'Gene', '4092', (77, 82))	('SMAD2', 'Gene', (87, 92))	('SMAD3', 'Gene', (138, 143))	('SMAD6', 'Gene', '4091', (128, 133))
26701	30268436	We analyzed the combined impact of TGF-beta target gene expression and the 43 core gene alterations on patient survival across the PanCancer cohort.	('TGF-beta', 'Gene', (35, 43))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (88, 99))	('patient', 'Species', '9606', (103, 110))	('TGF-beta', 'Gene', '7040', (35, 43))
26702	30268436	We compared the survival of patients with 3 different cancer profiles: those with high expression of HMGA2 and alterations in any one of the 43 TGF-beta pathway genes (Figure 6C, High HMGA2/TGF-beta mutant), those with high HMGA2 expression and no alterations in any of the 43 genes (Figure 6C, High HMGA2/TGF-beta wild-type), and those with low expression of HMGA2 without considering alterations in TGF-beta pathway genes (Figure 6C, Low HMGA2 expression).	('TGF-beta', 'Gene', '7040', (306, 314))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('HMGA2', 'Gene', '8091', (360, 365))	('high', 'PosReg', (82, 86))	('HMGA2', 'Gene', '8091', (184, 189))	('HMGA2', 'Gene', '8091', (440, 445))	('HMGA2', 'Gene', (300, 305))	('TGF-beta', 'Gene', (401, 409))	('mutant', 'Var', (199, 205))	('HMGA2', 'Gene', (101, 106))	('TGF-beta', 'Gene', (306, 314))	('HMGA2', 'Gene', '8091', (224, 229))	('TGF-beta', 'Gene', '7040', (144, 152))	('patients', 'Species', '9606', (28, 36))	('TGF-beta', 'Gene', '7040', (190, 198))	('cancer', 'Disease', (54, 60))	('HMGA2', 'Gene', (360, 365))	('HMGA2', 'Gene', '8091', (300, 305))	('HMGA2', 'Gene', '8091', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TGF-beta', 'Gene', (144, 152))	('HMGA2', 'Gene', (440, 445))	('HMGA2', 'Gene', (184, 189))	('alterations', 'Var', (111, 122))	('TGF-beta', 'Gene', (190, 198))	('TGF-beta', 'Gene', '7040', (401, 409))	('HMGA2', 'Gene', (224, 229))
26706	30268436	We saw the opposite for cancers with downregulated CDH2; the worst outcome was associated with low CDH2 expression and mutations in 43 genes (Figure S6B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('low', 'NegReg', (95, 98))	('CDH2', 'Gene', (99, 103))	('CDH2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('expression', 'MPA', (104, 114))	('CDH2', 'Gene', '1000', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('mutations', 'Var', (119, 128))	('CDH2', 'Gene', '1000', (51, 55))	('cancers', 'Disease', (24, 31))
26707	30268436	Thus, the expression profile of specific target genes and alterations in the TGF-beta superfamily genes cooperated to increase tumor aggressiveness.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor aggressiveness', 'Disease', (127, 147))	('increase', 'PosReg', (118, 126))	('TGF-beta', 'Gene', '7040', (77, 85))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (127, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (133, 147))	('TGF-beta', 'Gene', (77, 85))	('alterations', 'Var', (58, 69))
26709	30268436	Because of the association of collagen overexpression and alterations in TGF-beta pathway genes with poor survival, we hypothesize that altered signaling through the TGF-beta superfamily pathways remodels the extracellular matrix to drive metastasis in multiple cancer contexts.	('cancer', 'Disease', (262, 268))	('overexpression', 'PosReg', (39, 53))	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', '7040', (166, 174))	('TGF-beta', 'Gene', (73, 81))	('remodels', 'Reg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('drive', 'PosReg', (233, 238))	('TGF-beta', 'Gene', (166, 174))	('metastasis', 'CPA', (239, 249))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('alterations', 'Var', (58, 69))
26711	30268436	In the GI cohort, only ZEB2 combined with TGF-beta pathway gene alteration yielded a significant difference, with low ZEB2 expression corresponding to a survival benefit.	('ZEB2', 'Gene', '9839', (23, 27))	('ZEB2', 'Gene', (118, 122))	('TGF-beta', 'Gene', (42, 50))	('expression', 'MPA', (123, 133))	('ZEB2', 'Gene', (23, 27))	('alteration', 'Var', (64, 74))	('benefit', 'PosReg', (162, 169))	('low', 'NegReg', (114, 117))	('TGF-beta', 'Gene', '7040', (42, 50))	('ZEB2', 'Gene', '9839', (118, 122))
26713	30268436	Thus, although TGF-beta pathway mutations may not occur as commonly in non-GI cancers, they may be important contributors to mortality.	('non-GI cancers', 'Disease', (71, 85))	('non-GI cancers', 'Disease', 'MESH:D009369', (71, 85))	('contributors', 'Reg', (109, 121))	('TGF-beta', 'Gene', '7040', (15, 23))	('TGF-beta', 'Gene', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('mutations', 'Var', (32, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
26731	30268436	We also identified BMPR2 and TGFBR2 as genes with hotspot sites of mutations that were common in STAD and COAD.	('COAD', 'Disease', (106, 110))	('STAD', 'Disease', (97, 101))	('COAD', 'Disease', 'MESH:D029424', (106, 110))	('mutations', 'Var', (67, 76))	('TGFBR2', 'Gene', (29, 35))	('BMPR2', 'Gene', (19, 24))	('BMPR2', 'Gene', '659', (19, 24))	('TGFBR2', 'Gene', '7048', (29, 35))
26732	30268436	The cancers with high frequencies of hotspot mutations in those two genes did not have high expression of miRNA 92a-3p, suggesting that there is little selective pressure for both mutation and downregulation by that miRNA.	('downregulation', 'NegReg', (193, 207))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', (216, 219))	('miR', 'Gene', '220972', (106, 109))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
26733	30268436	To examine the contribution of mutations, amplifications, deletions, DNA methylation and miRNAs to the pathway activity score across tumor types, we computed Pearson's correlations between the pathway activity score and (i) levels of DNA methylation or miRNA expression and (ii) percentages of mutations or CNVs in each tumor type and plotted the results in order of increasing pathway activity score (Figure 7F).	('miR', 'Gene', '220972', (253, 256))	('miR', 'Gene', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('CNVs', 'Var', (307, 311))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', (133, 138))	('mutations', 'Var', (294, 303))
26735	30268436	DNA methylation was dominant in DLBC, STAD, BRCA, and COAD.	('STAD', 'Disease', (38, 42))	('COAD', 'Disease', 'MESH:D029424', (54, 58))	('dominant', 'Reg', (20, 28))	('methylation', 'Var', (4, 15))	('DLBC', 'Disease', (32, 36))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))	('COAD', 'Disease', (54, 58))
26740	30268436	Some of the key findings of the study were that (i) 39% of the cancers carried TGF-beta pathway gene alterations; (ii) the genomic alterations appeared to affect expression of metastatic and EMT genes; (iii) six hotspot mutations were identified in six genes; (iv) the pathway was most frequently aberrant in GI cancers, which exhibited 115 of the 176 hotspot mutations identified; (iv) high expression of downstream target genes coupled with mutations in the TGF-beta pathway genes was associated with poor outcome, suggesting a net tumor-promoting role of the superfamily across the PanCancer cohort; (v) apparent gene silencing by DNA methylation and deletion of TGF-beta pathway genes were observed most frequently in DLBC, whereas miRNA silencing was seen most often in LAML.	('gene silencing', 'NegReg', (616, 630))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('cancers', 'Disease', (312, 319))	('GI cancers', 'Disease', (309, 319))	('tumor', 'Disease', (534, 539))	('miR', 'Gene', (736, 739))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumor', 'Disease', 'MESH:D009369', (534, 539))	('DLBC', 'Disease', (722, 726))	('TGF-beta', 'Gene', '7040', (460, 468))	('TGF-beta', 'Gene', '7040', (666, 674))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('GI cancers', 'Disease', 'MESH:D009369', (309, 319))	('TGF-beta', 'Gene', '7040', (79, 87))	('cancers', 'Disease', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (588, 594))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (638, 649))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('cancers', 'Disease', 'MESH:D009369', (312, 319))	('TGF-beta', 'Gene', (460, 468))	('TGF-beta', 'Gene', (79, 87))	('TGF-beta', 'Gene', (666, 674))	('GI cancer', 'Phenotype', 'HP:0007378', (309, 318))	('deletion', 'Var', (654, 662))	('DNA methylation', 'Var', (634, 649))	('miR', 'Gene', '220972', (736, 739))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
26742	30268436	Although 39% of the cancers had genomic alterations in at least one of the TGF-beta pathway genes, GI cancers were particularly enriched for them.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancers', 'Disease', (99, 109))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('GI cancers', 'Disease', 'MESH:D009369', (99, 109))	('genomic alterations', 'Var', (32, 51))	('TGF-beta', 'Gene', '7040', (75, 83))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TGF-beta', 'Gene', (75, 83))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('cancers', 'Disease', (20, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
26743	30268436	GI cancers were most influenced by recurrent hotspot mutations in 6 genes, SMAD4, SMAD2, BMPR2, BMP5, TGFBR2, and ACVR2A.	('BMP5', 'Gene', (96, 100))	('SMAD2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('BMP5', 'Gene', '653', (96, 100))	('BMPR2', 'Gene', (89, 94))	('GI cancers', 'Disease', (0, 10))	('SMAD4', 'Gene', (75, 80))	('TGFBR2', 'Gene', '7048', (102, 108))	('mutations', 'Var', (53, 62))	('hotspot', 'PosReg', (45, 52))	('ACVR2A', 'Gene', '92', (114, 120))	('GI cancer', 'Phenotype', 'HP:0007378', (0, 9))	('influenced', 'Reg', (21, 31))	('GI cancers', 'Disease', 'MESH:D009369', (0, 10))	('BMPR2', 'Gene', '659', (89, 94))	('ACVR2A', 'Gene', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('SMAD4', 'Gene', '4089', (75, 80))	('SMAD2', 'Gene', '4087', (82, 87))	('TGFBR2', 'Gene', (102, 108))
26744	30268436	The hotspot mutations in BMP5 and TGFBR2 had not been identified previously, and their function in GI cancer should be explored.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancer', 'Disease', (99, 108))	('mutations', 'Var', (12, 21))	('TGFBR2', 'Gene', '7048', (34, 40))	('GI cancer', 'Disease', 'MESH:D009369', (99, 108))	('BMP5', 'Gene', (25, 29))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('TGFBR2', 'Gene', (34, 40))	('BMP5', 'Gene', '653', (25, 29))
26764	30268436	We selected the list of core TGF-beta superfamily genes used in the paper by searching for the keyword "TGF-beta" in 4 databases: (i) BIOCARTA_TGFB_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/BIOCARTA_TGFB_PATHWAY), (ii) KEGG_TGF_BETA_SIGNALING_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/KEGG_TGF_BETA_SIGNALING_PATHWAY), (iii) GO_0007179 full gene set from BioMart, and (iv) subset of GO_0007179 (filtered by "experimental evidence") from AmiGo.	('AmiGo', 'Gene', '57463', (497, 502))	('TGF-beta', 'Gene', (104, 112))	('AmiGo', 'Gene', (497, 502))	('TGF-beta', 'Gene', '7040', (29, 37))	('TGF-beta', 'Gene', (29, 37))	('TGF-beta', 'Gene', '7040', (104, 112))	('GO_0007179', 'Var', (385, 395))
26765	30268436	(ii) We then performed extensive literature searches and kept only those genes that satisfied any of the following conditions: (a) the gene had previously been implicated in cancer, or (b) the gene was involved in direct binding to and regulation of Smad function, or (c) the gene was phenotypically associated with the TGF-beta superfamily, where mutations or deletions of the gene had resulted in phenotypes similar to those from loss of function of the TGF-beta superfamily pathways.	('TGF-beta', 'Gene', '7040', (320, 328))	('TGF-beta', 'Gene', (456, 464))	('mutations', 'Var', (348, 357))	('implicated', 'Reg', (160, 170))	('TGF-beta', 'Gene', (320, 328))	('involved', 'Reg', (202, 210))	('associated', 'Reg', (300, 310))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('resulted', 'Reg', (387, 395))	('binding', 'Interaction', (221, 228))	('deletions', 'Var', (361, 370))	('TGF-beta', 'Gene', '7040', (456, 464))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
26782	30268436	Copy-number alterations (CNA) were assessed as deviations in the tumor sample from the paired normal tissue sample, so they only reflected somatic changes.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Copy-number alterations', 'Var', (0, 23))
26790	30268436	This step realigns reads at sites that potentially harbor small insertions or deletions in either the tumor or the matched normal, to decrease the number of false positive single nucleotide variations caused by misaligned reads.	('insertions', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (78, 87))
26793	30268436	Firehose (http://www.broadinstitute.org/cancer/cga/Firehose) takes the BAM files for the tumor and patient- matched normal samples and performs analyses including quality control, local realignment, mutation calling, small insertion and deletion identification, rearrangement detection, coverage calculations and others as described briefly below.	('patient', 'Species', '9606', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('rearrangement', 'Var', (262, 275))	('deletion', 'Var', (237, 245))	('tumor', 'Disease', (89, 94))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cga', 'Gene', '1113', (47, 50))	('mutation calling', 'Var', (199, 215))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cga', 'Gene', (47, 50))	('small insertion', 'Var', (217, 232))
26796	30268436	Each oncoprint visualizes and quantifies the somatic mutation and copy number events in 9,125 patients with 33 cancer types for each gene family in the pathway.	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('copy number', 'Var', (66, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
26797	30268436	The hotspot mutations are extracted from MC3 MAF file first programmatically for any hotspot site with more than nine counts and validated through a systematic mining in the cBioPortal.	('MC3', 'Gene', '4159', (41, 44))	('mutations', 'Var', (12, 21))	('MAF', 'Gene', '4094', (45, 48))	('MAF', 'Gene', (45, 48))	('MC3', 'Gene', (41, 44))
26798	30268436	For ACVR2A and SMAD4 hotspot mutations are mapped onto the respective protein structures (pdb IDs: 4ASX for ACVR2A and 1DD1 for SMAD4) using the UCSF chimera software.	('SMAD4', 'Gene', (15, 20))	('ACVR2A', 'Gene', (108, 114))	('ACVR2A and 1DD1', 'Gene', '92', (108, 123))	('SMAD4', 'Gene', (128, 133))	('ACVR2A', 'Gene', '92', (4, 10))	('mutations', 'Var', (29, 38))	('ACVR2A', 'Gene', '92', (108, 114))	('SMAD4', 'Gene', '4089', (15, 20))	('SMAD4', 'Gene', '4089', (128, 133))	('ACVR2A', 'Gene', (4, 10))
26808	30268436	Tumor types for which few tumors have been profiled and that have infrequently occurring copy number alterations, GISTIC may fail to identify rare but important somatic events.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy number alterations', 'Var', (89, 112))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
26809	30268436	As more copy number profiles become available through large-scale tumor sequencing efforts, the ability to detect these rare but significant events will increase.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('copy number', 'Var', (8, 19))
26811	30268436	The genomic alteration frequencies for copy number gains or losses and mutations are extracted from the cBioPortal and programmatically form the MC3 MAF file.	('MC3', 'Gene', '4159', (145, 148))	('MC3', 'Gene', (145, 148))	('MAF', 'Gene', '4094', (149, 152))	('mutations', 'Var', (71, 80))	('losses', 'NegReg', (60, 66))	('MAF', 'Gene', (149, 152))	('copy number gains', 'Var', (39, 56))
26813	30268436	The samples with alterations in each core gene and wild type for all TGF-beta pathway genes are extracted from the MC3 MAF file.	('MAF', 'Gene', '4094', (119, 122))	('MAF', 'Gene', (119, 122))	('TGF-beta', 'Gene', (69, 77))	('MC3', 'Gene', '4159', (115, 118))	('MC3', 'Gene', (115, 118))	('TGF-beta', 'Gene', '7040', (69, 77))	('alterations', 'Var', (17, 28))
26814	30268436	The median fold change of transcriptional changes are calculated as the ratio of expression of downstream genes among all core pathway gene mutated, amplified and deleted samples to expression levels in TGF-beta pathway wild type samples.	('TGF-beta', 'Gene', (203, 211))	('deleted', 'Var', (163, 170))	('TGF-beta', 'Gene', '7040', (203, 211))	('expression', 'MPA', (81, 91))	('mutated', 'Var', (140, 147))
26818	30268436	The enrichment of genomic TGF-beta pathway genomic alterations in the GI cancers was statistically assessed using a one tailed Fisher's exact test, where the null hypothesis was the odds ratio of alterations in GI vs other cancers was not greater than 1.	('cancers', 'Disease', (223, 230))	('cancers', 'Disease', (73, 80))	('alterations', 'Var', (51, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('TGF-beta', 'Gene', '7040', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('TGF-beta', 'Gene', (26, 34))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
26819	30268436	The transcriptional outcome of GI cancers with TGF-beta pathway disruptions were quantified using the same method and downstream target gene list as we did in the analysis of transcriptional output from all cancers.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('GI cancer', 'Phenotype', 'HP:0007378', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('GI cancers', 'Disease', 'MESH:D009369', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('disruptions', 'Var', (64, 75))	('TGF-beta', 'Gene', '7040', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TGF-beta', 'Gene', (47, 55))	('cancers', 'Disease', (34, 41))	('GI cancers', 'Disease', (31, 41))
26843	30268436	We particularly focused on mRNA expression distribution of HMGA2, MMP9, collagens (COL1A1, COL1A2, COL3A1), TERT, FOXP3, CDH2 as the expression of these genes varied significantly between TGF-beta pathway mutated vs. wild type samples.	('mutated', 'Var', (205, 212))	('COL1A2', 'Gene', '1278', (91, 97))	('TERT', 'Gene', (108, 112))	('varied', 'Reg', (159, 165))	('TERT', 'Gene', '7015', (108, 112))	('CDH2', 'Gene', (121, 125))	('FOXP3', 'Gene', (114, 119))	('HMGA2', 'Gene', (59, 64))	('COL1A2', 'Gene', (91, 97))	('COL1A1', 'Gene', '1277', (83, 89))	('CDH2', 'Gene', '1000', (121, 125))	('COL3A1', 'Gene', '1281', (99, 105))	('TGF-beta', 'Gene', '7040', (188, 196))	('FOXP3', 'Gene', '50943', (114, 119))	('expression', 'MPA', (133, 143))	('COL1A1', 'Gene', (83, 89))	('MMP9', 'Gene', (66, 70))	('HMGA2', 'Gene', '8091', (59, 64))	('MMP9', 'Gene', '4318', (66, 70))	('TGF-beta', 'Gene', (188, 196))	('COL3A1', 'Gene', (99, 105))
26845	30268436	The resulting thresholds divided the cohorts into three groups as TGF-beta expression, TGF-beta mutant/high target expression, TGF-beta wt/high target expression and low target gene expression.	('TGF-beta', 'Gene', (87, 95))	('TGF-beta', 'Gene', (66, 74))	('TGF-beta', 'Gene', '7040', (127, 135))	('mutant/high', 'Var', (96, 107))	('TGF-beta', 'Gene', '7040', (87, 95))	('TGF-beta', 'Gene', (127, 135))	('TGF-beta', 'Gene', '7040', (66, 74))
26846	30268436	We merged the TGF-beta mutant/low target expression and TGF-beta wt/low expression cohorts as discriminating between these sets do not inform on the combined effect of TGF-beta mutations and target expression.	('TGF-beta', 'Gene', (168, 176))	('TGF-beta', 'Gene', '7040', (56, 64))	('TGF-beta', 'Gene', (14, 22))	('mutant/low', 'Var', (23, 33))	('mutant/low', 'NegReg', (23, 33))	('TGF-beta', 'Gene', (56, 64))	('TGF-beta', 'Gene', '7040', (14, 22))	('TGF-beta', 'Gene', '7040', (168, 176))
26907	29303935	Identification of ERbeta and/or GPER positivity, which has been associated with advanced disease and poorer outcomes in other gynecologic cancers, may potentially add prognostic information for patients with uterine AS.	('associated', 'Reg', (64, 74))	('ERbeta', 'Gene', (18, 24))	('patients', 'Species', '9606', (194, 202))	('uterine AS', 'Disease', (208, 218))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('GPER', 'Gene', '2852', (32, 36))	('advanced disease', 'Disease', (80, 96))	('ERbeta', 'Gene', '2100', (18, 24))	('advanced disease', 'Disease', 'MESH:D020178', (80, 96))	('positivity', 'Var', (37, 47))	('add', 'Reg', (163, 166))	('GPER', 'Gene', (32, 36))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
26974	29617664	Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2.	('BRCA1/2', 'Gene', (110, 117))	('TP53', 'Gene', '7157', (101, 105))	('BRCA1/2', 'Gene', '672;675', (110, 117))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (101, 105))	('DDR genes', 'Gene', (80, 89))
26975	29617664	Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ~20% of samples.	('MGMT', 'Gene', '4255', (91, 95))	('EXO5', 'Gene', (85, 89))	('epigenetic silencing', 'Var', (37, 57))	('MGMT', 'Gene', (91, 95))	('ALKBH3', 'Gene', (101, 107))	('ALKBH3', 'Gene', '221120', (101, 107))	('EXO5', 'Gene', '64789', (85, 89))
26978	29617664	A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations.	('mutations', 'Var', (143, 152))	('TP53', 'Gene', '7157', (138, 142))	('TP53', 'Gene', (138, 142))
26979	29617664	These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.	('human', 'Species', '9606', (44, 49))	('alterations', 'Var', (24, 35))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('DDR gene', 'Gene', (15, 23))	('determine', 'Reg', (96, 105))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
26981	29617664	They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('alterations', 'Var', (77, 88))	('DDR', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
26984	29617664	Homology-dependent recombination (HR), non-homologous end joining (NHEJ), the Fanconi anemia (FA) pathway, and translesion DNA synthesis (TLS) act alone or together to repair DNA strand breaks and complex events like interstrand crosslinks.	('anemia', 'Phenotype', 'HP:0001903', (86, 92))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (78, 92))	('Fanconi anemia', 'Disease', (78, 92))	('DNA', 'Var', (175, 178))	('Fanconi anemia', 'Disease', 'MESH:D005199', (78, 92))
26985	29617664	The consequences of DDR deficiency are becoming better understood through analyses of DDR gene alterations in cancer.	('cancer', 'Disease', (110, 116))	('DDR gene', 'Gene', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('alterations', 'Var', (95, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
26986	29617664	For example, frequent TP53 somatic mutations in many cancer types can disrupt the DNA damage response, apoptosis, or senescence pathways active in many early-stage cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('disrupt', 'NegReg', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('senescence pathways', 'Pathway', (117, 136))	('apoptosis', 'Pathway', (103, 112))	('DNA damage response', 'Pathway', (82, 101))	('cancers', 'Disease', (164, 171))	('somatic mutations', 'Var', (27, 44))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('TP53', 'Gene', '7157', (22, 26))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TP53', 'Gene', (22, 26))
26987	29617664	DDR deficiency may also lead to specific mutational "signatures," e.g., the short tandem repeat instability linked to the inactivation or silencing of DNA MMR in colorectal, ovarian, or endometrial cancer  The therapeutic implications of altered DDR function are becoming better known.	('silencing', 'NegReg', (138, 147))	('endometrial cancer', 'Disease', (186, 204))	('inactivation', 'Var', (122, 134))	('colorectal', 'Disease', 'MESH:D015179', (162, 172))	('short', 'MPA', (76, 81))	('deficiency', 'Var', (4, 14))	('endometrial cancer', 'Phenotype', 'HP:0012114', (186, 204))	('lead', 'Reg', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('endometrial cancer', 'Disease', 'MESH:D016889', (186, 204))	('ovarian', 'Disease', (174, 181))	('DNA MMR', 'Gene', (151, 158))	('colorectal', 'Disease', (162, 172))
26991	29617664	The loss of specific DDR pathways in cancer, in contrast to other cellular "hallmarks" of cancer, often generates stable:and thus more readily interpretable:"footprints" in cancer genomes, detected as an increased mutation burden, altered mutational signatures, or copy-number alterations including loss of heterozygosity (LOH).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('increased', 'PosReg', (204, 213))	('loss of heterozygosity', 'Var', (299, 321))	('cancer', 'Disease', (90, 96))	('altered', 'Reg', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('loss', 'NegReg', (4, 8))	('DDR pathways', 'Pathway', (21, 33))
26992	29617664	We provide below the most comprehensive analysis to date of DDR pathway gene alterations and their consequences in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (115, 120))	('alterations', 'Var', (77, 88))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('DDR pathway gene', 'Gene', (60, 76))	('cancer', 'Disease', (121, 127))
26995	29617664	We first determined the prevalence of DDR alterations across PanCanAtlas cancer types by integrating data on somatic truncating and missense mutations (Figures S1C and S1D), deep copy-number deletions defined by GISTIC, and epigenetic silencing events.	('deep copy-number deletions', 'Var', (174, 200))	('alterations', 'Var', (42, 53))	('epigenetic silencing events', 'Var', (224, 251))	('PanCanAtlas cancer', 'Disease', (61, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('DDR', 'Gene', (38, 41))	('PanCanAtlas cancer', 'Disease', 'MESH:D009369', (61, 79))	('missense mutations', 'Var', (132, 150))
26998	29617664	Similarly, cancer types with a large number of somatic copy-number alterations (SCNAs; e.g., OV [ovarian serous cystadenocarcinoma], SARC [sarcoma], ESCA [esophageal carcinoma], and STAD [stomach adenocarcinoma]) also had a larger number of SCNAs in DDR pathways.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (155, 175))	('ovarian serous cystadenocarcinoma', 'Disease', (97, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('esophageal carcinoma', 'Disease', (155, 175))	('DDR pathways', 'Pathway', (250, 262))	('copy-number alterations', 'Var', (55, 78))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (97, 130))	('stomach adenocarcinoma', 'Disease', (188, 210))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (155, 175))	('sarcoma', 'Disease', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('STAD', 'Disease', (182, 186))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (188, 210))	('cancer', 'Disease', (11, 17))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (97, 130))
27001	29617664	Some DDR genes were affected predominantly by one type of alteration, e.g., ALKBH3 and MGMT by epigenetic silencing.	('MGMT', 'Gene', (87, 91))	('MGMT', 'Gene', '4255', (87, 91))	('ALKBH3', 'Gene', (76, 82))	('affected', 'Reg', (20, 28))	('ALKBH3', 'Gene', '221120', (76, 82))	('epigenetic silencing', 'Var', (95, 115))	('DDR genes', 'Gene', (5, 14))
27002	29617664	Other genes were altered in two or more ways, e.g., mutations in TP53, PTEN, PER1, and BRCA1/2 were frequently accompanied by LOH (Figure 1D).	('mutations', 'Var', (52, 61))	('BRCA1/2', 'Gene', (87, 94))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('PER1', 'Gene', (77, 81))	('accompanied', 'Reg', (111, 122))	('BRCA1/2', 'Gene', '672;675', (87, 94))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('LOH', 'Disease', (126, 129))
27003	29617664	Gene-level mutation frequencies varied widely by cancer type and subtype.	('mutation', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
27004	29617664	For example, mutations in TP53, PTEN, ERCC5, and IDH1 were highly enriched, while other genes such as SOX4, SLX1A, and GTF2H2 were much less frequently mutated (Figure S1J).	('TP53', 'Gene', (26, 30))	('ERCC5', 'Gene', '2073', (38, 43))	('IDH1', 'Gene', '3417', (49, 53))	('GTF2H2', 'Gene', '2966', (119, 125))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('GTF2H2', 'Gene', (119, 125))	('SLX1A', 'Gene', (108, 113))	('SOX4', 'Gene', (102, 106))	('SOX4', 'Gene', '6659', (102, 106))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (13, 22))	('ERCC5', 'Gene', (38, 43))	('IDH1', 'Gene', (49, 53))	('SLX1A', 'Gene', '548593', (108, 113))
27005	29617664	It is already well established that cancers with somatic POLE and POLD1 mutations in their exonuclease domains or with microsatellite instability (MSI) exhibit a substantially higher mutation burden.	('mutations', 'Var', (72, 81))	('POLD1', 'Gene', (66, 71))	('microsatellite', 'MPA', (119, 133))	('mutation burden', 'MPA', (183, 198))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('MSI', 'Disease', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('higher', 'PosReg', (176, 182))	('POLD1', 'Gene', '5424', (66, 71))	('MSI', 'Disease', 'None', (147, 150))
27006	29617664	Here, we observed only two DDR genes (TP53 and POLE) that demonstrated a substantially different association between alterations and overall mutation burden when compared against a background of all other non-DDR genes (Figure S1K).	('alterations', 'Var', (117, 128))	('mutation', 'MPA', (141, 149))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (38, 42))
27012	29617664	In order to assess potential genomic consequences of DDR gene alterations, we performed a mutation signature correlation analysis focusing on loss-of-function alterations in the 48 genes we identified as putative cancer drivers (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alterations', 'Var', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('loss-of-function', 'NegReg', (142, 158))	('cancer', 'Disease', (213, 219))	('alterations', 'Var', (62, 73))
27014	29617664	We confirmed that mutational signature #19 (POLE signature, corresponding to COSMIC [Catalog of Somatic Mutations in Cancer] signature #10) is increased by over 4-fold in POLE-altered cancers (p = 1.0e-6) at the PanCanAtlas level, and in UCEC with greater significance (fold change = 10.1 and p = 4.8e-7, Figure S2B).	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('increased', 'PosReg', (143, 152))	('mutational', 'Var', (18, 28))	('POLE-altered cancers', 'Disease', 'MESH:D009369', (171, 191))	('POLE-altered cancers', 'Disease', (171, 191))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Disease', (117, 123))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))
27015	29617664	We also confirmed the association of signature #15 (temozolomide signature, corresponding to COSMIC signature #11) with MGMT alterations (Figure S2C).	('signature #', 'Var', (37, 48))	('temozolomide', 'Chemical', 'MESH:D000077204', (52, 64))	('MGMT', 'Gene', '4255', (120, 124))	('association', 'Interaction', (22, 33))	('MGMT', 'Gene', (120, 124))
27016	29617664	Epigenetic silencing was identified as an alternative prominent mechanism leading to recurrent gene deficiency.	('gene deficiency', 'Disease', (95, 110))	('Epigenetic silencing', 'Var', (0, 20))	('gene deficiency', 'Disease', 'MESH:D025063', (95, 110))
27018	29617664	Epigenetic silencing was less often observed for genes in the HR and FA pathways, e.g., BRCA1, RAD51C, NSMCE3, and FANCF.	('BRCA1', 'Gene', (88, 93))	('FANCF', 'Gene', '2188', (115, 120))	('NSMCE3', 'Gene', '56160', (103, 109))	('RAD51C', 'Gene', (95, 101))	('Epigenetic', 'Var', (0, 10))	('RAD51C', 'Gene', '5889', (95, 101))	('BRCA1', 'Gene', '672', (88, 93))	('FANCF', 'Gene', (115, 120))	('NSMCE3', 'Gene', (103, 109))	('FA pathways', 'Pathway', (69, 80))
27019	29617664	Methylation silencing was the dominant alteration in MGMT (92.4% of all alterations) and was significantly associated with signature #15 through mutation signature analysis (Figure S2C).	('Methylation', 'MPA', (0, 11))	('associated', 'Reg', (107, 117))	('signature #', 'Var', (123, 134))	('MGMT', 'Gene', (53, 57))	('MGMT', 'Gene', '4255', (53, 57))
27020	29617664	The high frequency of EXO5 silencing (94.5% of all EXO5 alterations) was both unexpected and intriguing.	('silencing', 'NegReg', (27, 36))	('EXO5', 'Gene', (22, 26))	('alterations', 'Var', (56, 67))	('EXO5', 'Gene', '64789', (22, 26))	('EXO5', 'Gene', (51, 55))	('EXO5', 'Gene', '64789', (51, 55))
27026	29617664	Furthermore, EXO5 deficiency was significantly linked to signature #1 (Figure S2E).	('linked', 'Reg', (47, 53))	('EXO5', 'Gene', (13, 17))	('EXO5', 'Gene', '64789', (13, 17))	('signature #1', 'Disease', (57, 69))	('deficiency', 'Var', (18, 28))
27031	29617664	We observed positive correlations among six different SCNA scores that were used to characterize the extent of aneuploidy, LOH, and homologous recombination deficiency in PanCancer Atlas samples (Figure 3A).	('LOH', 'Var', (123, 126))	('aneuploidy', 'Disease', (111, 121))	('deficiency in PanCancer Atlas', 'Disease', 'MESH:D007153', (157, 186))	('Cancer', 'Phenotype', 'HP:0002664', (174, 180))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('deficiency in PanCancer Atlas', 'Disease', (157, 186))
27032	29617664	We also found moderate, statistically significant positive correlations between mutation burden and SCNA scores, contrary to a previously reported inverse correlation between SCNA and mutation frequency in 12 cancer types.	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('mutation burden', 'Var', (80, 95))	('cancer', 'Disease', (209, 215))	('SCNA scores', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
27045	29617664	We identified additional contributions of DDR gene alterations to HRD scores by using a Bayesian ridge regression to model HRD scoring as a function of DDR gene alterations while controlling for cancer type as a covariate (Table S3).	('HRD', 'Disease', 'None', (123, 126))	('DDR gene', 'Gene', (152, 160))	('HRD', 'Disease', 'None', (66, 69))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('HRD', 'Disease', (123, 126))	('HRD', 'Disease', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('alterations', 'Var', (161, 172))
27048	29617664	BRCA1 alterations had the largest positive weight for predicting higher HRD scores.	('alterations', 'Var', (6, 17))	('BRCA1', 'Gene', (0, 5))	('HRD', 'Disease', (72, 75))	('BRCA1', 'Gene', '672', (0, 5))	('HRD', 'Disease', 'None', (72, 75))	('higher', 'PosReg', (65, 71))
27049	29617664	Alterations in either BRCA1 or RAD51B increased HRD score in most cancer types including the top two cancer types with the greatest number of alterations in either gene (Figure 3E).	('RAD51B', 'Gene', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RAD51B', 'Gene', '5890', (31, 37))	('HRD', 'Disease', 'None', (48, 51))	('BRCA1', 'Gene', '672', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('HRD', 'Disease', (48, 51))	('BRCA1', 'Gene', (22, 27))	('increased', 'PosReg', (38, 47))	('cancer', 'Disease', (66, 72))
27050	29617664	TP53 alterations were also associated with higher HRD scores, consistent with previous observations of a higher SCNA burden in TP53-mutated cancers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('higher', 'PosReg', (43, 49))	('HRD', 'Disease', (50, 53))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('alterations', 'Var', (5, 16))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('HRD', 'Disease', 'None', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TP53', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (127, 131))
27051	29617664	Other alterations in several MMR and NER genes had significant negative associations with HRD score, e.g., MLH1, TCEB3, and MSH2, suggesting a potential mutually exclusive relationship between HR and MMR or NER deficiencies.	('alterations', 'Var', (6, 17))	('negative', 'NegReg', (63, 71))	('MMR', 'Gene', (29, 32))	('NER genes', 'Gene', (37, 46))	('TCEB3', 'Gene', (113, 118))	('MSH2', 'Gene', (124, 128))	('HRD', 'Disease', 'None', (90, 93))	('MSH2', 'Gene', '4436', (124, 128))	('MLH1', 'Gene', '4292', (107, 111))	('MLH1', 'Gene', (107, 111))	('HRD', 'Disease', (90, 93))	('TCEB3', 'Gene', '6924', (113, 118))
27054	29617664	A majority of the fusions, including 18 in HR and 5 in MMR genes, had breakpoints in DDR functional domains that were predicted to disrupt function with readily predictable therapeutic consequences, e.g., for the HR gene fusions involving RAD51B and BRCA1 (Figure S4E).	('BRCA1', 'Gene', (250, 255))	('fusions', 'Var', (221, 228))	('RAD51B', 'Gene', (239, 245))	('disrupt', 'NegReg', (131, 138))	('RAD51B', 'Gene', '5890', (239, 245))	('BRCA1', 'Gene', '672', (250, 255))	('DDR', 'MPA', (85, 88))	('function', 'MPA', (139, 147))
27056	29617664	These included MGMT, PARP1, TOP3A, BLM, ERCC2, HFM1, POLE, POLD1, and POLQ, which collectively harbored 1,380 unique rare, recurrent non-synonymous mutations.	('PARP1', 'Gene', '142', (21, 26))	('BLM', 'Gene', (35, 38))	('TOP3A', 'Gene', '7156', (28, 33))	('HFM1', 'Gene', (47, 51))	('POLQ', 'Gene', (70, 74))	('MGMT', 'Gene', '4255', (15, 19))	('POLQ', 'Gene', '10721', (70, 74))	('MGMT', 'Gene', (15, 19))	('ERCC2', 'Gene', '2068', (40, 45))	('HFM1', 'Gene', '164045', (47, 51))	('TOP3A', 'Gene', (28, 33))	('BLM', 'Gene', '641', (35, 38))	('POLD1', 'Gene', (59, 64))	('POLD1', 'Gene', '5424', (59, 64))	('non-synonymous mutations', 'Var', (133, 157))	('ERCC2', 'Gene', (40, 45))	('PARP1', 'Gene', (21, 26))
27058	29617664	Molecular dynamics simulations of a subset of mutations (n = 86) in six proteins (POLE, POLD1, POLQ, ERCC2, HFM1, and BLM) revealed many additional mutations that were not predicted to be destabilizing but did alter protein dynamics (Figure S5).	('protein dynamics', 'MPA', (216, 232))	('POLQ', 'Gene', '10721', (95, 99))	('HFM1', 'Gene', '164045', (108, 112))	('mutations', 'Var', (148, 157))	('ERCC2', 'Gene', '2068', (101, 106))	('mutations', 'Var', (46, 55))	('BLM', 'Gene', (118, 121))	('POLD1', 'Gene', (88, 93))	('ERCC2', 'Gene', (101, 106))	('HFM1', 'Gene', (108, 112))	('POLD1', 'Gene', '5424', (88, 93))	('alter', 'Reg', (210, 215))	('BLM', 'Gene', '641', (118, 121))	('POLQ', 'Gene', (95, 99))
27059	29617664	Many genes displayed an inverse relationship between these two burden scores, with, e.g., destabilizing mutations in POLB associated with higher mutation and lower SCNA burden, whereas destabilizing PARP1 mutations were associated with lower mutation and higher SCNA burden (Figures 4D-4F).	('mutation', 'MPA', (145, 153))	('mutations', 'Var', (104, 113))	('lower', 'NegReg', (158, 163))	('POLB', 'Gene', '5423', (117, 121))	('SCNA burden', 'MPA', (262, 273))	('PARP1', 'Gene', '142', (199, 204))	('POLB', 'Gene', (117, 121))	('higher', 'PosReg', (138, 144))	('SCNA burden', 'MPA', (164, 175))	('PARP1', 'Gene', (199, 204))
27061	29617664	Cancer-associated TP53 mutations may promote these consequences through simple loss of function, as well as by altering transcription or through dominant-negative, gain-of-function mechanisms.	('transcription', 'MPA', (120, 133))	('TP53', 'Gene', '7157', (18, 22))	('loss of function', 'NegReg', (79, 95))	('TP53', 'Gene', (18, 22))	('Cancer', 'Disease', (0, 6))	('altering', 'Reg', (111, 119))	('mutations', 'Var', (23, 32))	('gain-of-function', 'PosReg', (164, 180))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
27065	29617664	The remaining gene, MPDU1, may have been identified by virtue of being located ~80 kb downstream of TP53 and thus sensitive to TP53 copy loss.	('TP53', 'Gene', '7157', (100, 104))	('MPDU1', 'Gene', '9526', (20, 25))	('TP53', 'Gene', (100, 104))	('MPDU1', 'Gene', (20, 25))	('copy loss', 'Var', (132, 141))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
27068	29617664	The classifier was also able to distinguish TP53 mutant from wild-type BRCA and UCEC, with nearly all basal-subtype BRCA cancers predicted to be TP53 deficient (Figures S6G and S6H).	('deficient', 'NegReg', (150, 159))	('mutant', 'Var', (49, 55))	('BRCA', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('TP53', 'Gene', '7157', (44, 48))	('basal-subtype BRCA cancers', 'Disease', 'MESH:D002280', (102, 128))	('basal-subtype BRCA cancers', 'Disease', (102, 128))	('BRCA', 'Gene', '672', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('BRCA', 'Gene', (71, 75))	('TP53', 'Gene', (44, 48))	('BRCA', 'Gene', '672', (116, 120))
27070	29617664	The classifier enabled the identification of phenocopying mutations both in TP53 and in other functionally related genes.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))
27071	29617664	Consistent with previous pan-cancer analyses, we observed that predicted TP53 loss-of-function samples, including cancers with synonymous TP53 c.375G>T mutation, had an increased SCNA burden when compared with wild-type samples (Figure 5C).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('TP53', 'Gene', '7157', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('TP53', 'Gene', '7157', (138, 142))	('cancers', 'Disease', (114, 121))	('SCNA burden', 'MPA', (179, 190))	('loss-of-function', 'NegReg', (78, 94))	('c.375G>T', 'Mutation', 'rs55863639', (143, 151))	('TP53', 'Gene', (73, 77))	('TP53', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('c.375G>T', 'Var', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
27072	29617664	This synonymous mutation may act by altering a splice donor to produce alternatively spliced transcripts that compromise TP53 function.	('mutation', 'Var', (16, 24))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('donor', 'Species', '9606', (54, 59))	('altering', 'Reg', (36, 44))	('compromise', 'NegReg', (110, 120))
27073	29617664	Samples with c.375G>T or c.375G>A mutations were also enriched for a 200 base pair truncation in exon 4 when compared with wild-type TP53 samples (OR [odds ratio] = 61.9, p < 2.2e-16).	('c.375G>A', 'Mutation', 'rs55863639', (25, 33))	('c.375G>T', 'Mutation', 'rs55863639', (13, 21))	('c.375G>T', 'Var', (13, 21))	('c.375G>A', 'Var', (25, 33))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))
27074	29617664	This mutation/truncation pairing was previously observed in a pancreatic cancer cell line and as a SNP (rs55863639) likely pathogenic for Li-Fraumeni syndrome.	('pancreatic cancer', 'Disease', 'MESH:D010190', (62, 79))	('pancreatic cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Li-Fraumeni syndrome', 'Disease', (138, 158))	('rs55863639', 'Var', (104, 114))	('pathogenic', 'Reg', (123, 133))	('rs55863639', 'Mutation', 'rs55863639', (104, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (138, 158))
27075	29617664	Significantly increased classifier scores were also noted for cancers with MDM2 copy-number amplification and CDK2NA copy-number deletion in an analysis including only non-hypermutated cancers without deleterious TP53 mutation (Figure 5D).	('increased', 'PosReg', (14, 23))	('copy-number amplification', 'Var', (80, 105))	('copy-number deletion', 'Var', (117, 137))	('TP53', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('MDM2', 'Gene', '4193', (75, 79))	('CDK2', 'Gene', (110, 114))	('MDM2', 'Gene', (75, 79))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('CDK2', 'Gene', '1017', (110, 114))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('cancers', 'Disease', (185, 192))	('TP53', 'Gene', '7157', (213, 217))
27076	29617664	We had observed a copy-number dosage effect for CDK2NA copy-number deletions, where loss of the CDKN2A-encoded P14ARF protein can phenocopy TP53 alterations.	('P14ARF', 'Gene', (111, 117))	('CDKN2A', 'Gene', '1029', (96, 102))	('deletions', 'Var', (67, 76))	('TP53', 'Gene', (140, 144))	('CDK2', 'Gene', (48, 52))	('protein', 'Protein', (118, 125))	('loss', 'Var', (84, 88))	('CDKN2A', 'Gene', (96, 102))	('P14ARF', 'Gene', '1029', (111, 117))	('CDK2', 'Gene', '1017', (48, 52))	('TP53', 'Gene', '7157', (140, 144))
27077	29617664	Among eight other tested genes, MDM4 and PPM1D copy-number amplification and ATM and CREBBP gene mutations were associated with increased TP53 classifier scores, while ATR, CHEK1/2, or RP6SKA3 mutations were not (Figure 5E).	('mutations', 'Var', (97, 106))	('TP53', 'Gene', '7157', (138, 142))	('CHEK1/2', 'Gene', '1111;11200', (173, 180))	('CREBBP', 'Gene', (85, 91))	('ATM', 'Gene', (77, 80))	('ATR', 'Gene', '545', (168, 171))	('ATR', 'Gene', (168, 171))	('increased', 'PosReg', (128, 137))	('CHEK1/2', 'Gene', (173, 180))	('TP53', 'Gene', (138, 142))	('ATM', 'Gene', '472', (77, 80))	('MDM4', 'Gene', '4194', (32, 36))	('CREBBP', 'Gene', '1387', (85, 91))	('PPM1D', 'Gene', (41, 46))	('MDM4', 'Gene', (32, 36))	('PPM1D', 'Gene', '8493', (41, 46))
27082	29617664	Fewer mutation-based associations with clinical outcomes were identified: e.g., a high mutation burden was associated with better prognosis in UCEC and STAD cancers, but worse prognosis in LGG and ACC cancers (Figure S7C).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('better', 'PosReg', (123, 129))	('STAD cancers', 'Disease', (152, 164))	('cancers', 'Disease', (201, 208))	('LGG', 'Disease', (189, 192))	('STAD cancers', 'Disease', 'MESH:D009369', (152, 164))	('UCEC', 'Disease', (143, 147))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('mutation burden', 'Var', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancers', 'Disease', (157, 164))
27086	29617664	We used TCGA PanCanAtlas data to systematically analyze the prevalence, nature, and consequences of DDR gene and pathway alterations across 9,125 samples representing 33 different cancer types.	('alterations', 'Var', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('DDR gene', 'Gene', (100, 108))
27087	29617664	DDR gene alterations were ubiquitous: approximately 1/3 of TCGA PanCanAtlas cancer types showed significant enrichment of somatic mutations in DDR genes, often accompanied by SCNA/LOH events.	('PanCanAtlas cancer', 'Disease', (64, 82))	('DDR genes', 'Gene', (143, 152))	('TCGA', 'Disease', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (130, 139))	('PanCanAtlas cancer', 'Disease', 'MESH:D009369', (64, 82))
27089	29617664	DNA methylation-dependent epigenetic silencing was also surprisingly frequent:though more variable:than mutation or deletion calls and encompassed one-third of TCGA cancer types.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('methylation-dependent', 'Var', (4, 25))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('epigenetic silencing', 'Var', (26, 46))
27091	29617664	Epigenetic silencing of DR pathway genes in gastrointestinal, central nervous, and lymphoid cancers were all associated with a high mutation burden.	('associated', 'Reg', (109, 119))	('DR pathway genes', 'Gene', (24, 40))	('lymphoid cancers', 'Disease', (83, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('gastrointestinal', 'Disease', (44, 60))	('Epigenetic silencing', 'Var', (0, 20))	('central nervous', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('gastrointestinal', 'Disease', 'MESH:D005767', (44, 60))	('lymphoid cancers', 'Disease', 'MESH:D009369', (83, 99))
27094	29617664	These findings highlight the role of epigenetics in shaping the DDR deficiency landscape in cancer and may provide useful biomarkers for enhanced response to, e.g., alkylating agent therapy.	('enhanced', 'PosReg', (137, 145))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('epigenetics', 'Var', (37, 48))	('DDR', 'MPA', (64, 67))
27096	29617664	Analyses of loss-of-function alterations within DDR pathways identified co-occurring alterations (largely consisting of mutations and epigenetic silencing) in the MMR pathway in UCEC and STAD cancers, though no pathway by cancer-type-specific, mutually exclusive combinations.	('epigenetic silencing', 'Var', (134, 154))	('STAD cancers', 'Disease', 'MESH:D009369', (187, 199))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('STAD cancers', 'Disease', (187, 199))	('cancer', 'Disease', (222, 228))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('alterations', 'Var', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (192, 198))	('MMR pathway', 'Pathway', (163, 174))	('loss-of-function', 'NegReg', (12, 28))	('DDR pathways', 'Gene', (48, 60))	('mutations', 'Var', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('UCEC', 'Disease', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
27097	29617664	Thus, the loss of both MMR and NER might markedly sensitize cancer cells to alkylating agent therapy and provide a starting point to identify effective treatment combinations.	('loss', 'Var', (10, 14))	('NER', 'Gene', (31, 34))	('sensitize', 'Reg', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('MMR', 'Gene', (23, 26))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
27099	29617664	EXO5 deficiency, identified here as an often epigenetically silenced DDR gene, was associated with signature 1 across multiple cancer types (Figure S2E) and has been associated with poor clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deficiency', 'Var', (5, 15))	('multiple cancer', 'Disease', 'MESH:D009369', (118, 133))	('EXO5', 'Gene', (0, 4))	('associated', 'Reg', (83, 93))	('multiple cancer', 'Disease', (118, 133))	('associated', 'Reg', (166, 176))	('EXO5', 'Gene', '64789', (0, 4))
27100	29617664	Co-occurrence plots of mutations and SCNA/LOH for the top 50 mutated DDR genes in TCGA samples (Figure 1D) and genome-wide DNA damage scores that further encompass LOH and aneuploidy (Figure 3A) suggest the potential for additional complex interactions among DDR gene alterations.	('DDR genes', 'Gene', (69, 78))	('interactions', 'Interaction', (240, 252))	('aneuploidy', 'Disease', 'MESH:D000782', (172, 182))	('mutations', 'Var', (23, 32))	('mutated', 'Var', (61, 68))	('aneuploidy', 'Disease', (172, 182))
27101	29617664	We extended the insights gained from analyzing the type and distribution of DDR gene alterations in cancer by using additional approaches.	('DDR gene', 'Gene', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (85, 96))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
27102	29617664	We found that POLD1 mutations, despite being less common than the POLE or POLQ mutations that contribute to hereditary colorectal cancer risk and the hypermutated phenotype, were as strongly associated with genomic instability.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('hereditary colorectal cancer', 'Disease', (108, 136))	('POLD1', 'Gene', '5424', (14, 19))	('hereditary colorectal cancer', 'Disease', 'MESH:D015179', (108, 136))	('POLQ', 'Gene', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('POLQ', 'Gene', '10721', (74, 78))	('associated', 'Reg', (191, 201))	('mutations', 'Var', (20, 29))	('POLD1', 'Gene', (14, 19))	('genomic instability', 'MPA', (207, 226))
27103	29617664	Molecular dynamics simulations further identified a subset of DDR gene mutations with the potential to alter protein conformational changes independent of effects on protein stability (Figure S5), raising the provocative question of whether destabilizing mutations alone contribute to genomic instability in cancer.	('DDR gene', 'Gene', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('protein conformational changes', 'MPA', (109, 139))	('cancer', 'Disease', (308, 314))	('mutations', 'Var', (71, 80))	('alter', 'Reg', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))
27105	29617664	This approach identified both TP53 mutant and TP53 mutant phenocopies, as well as potential TP53 tissue-specific roles in, e.g., ESCA and CESC cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TP53', 'Gene', (30, 34))	('mutant', 'Var', (51, 57))	('ESCA', 'Disease', (129, 133))	('mutant', 'Var', (35, 41))	('TP53', 'Gene', '7157', (46, 50))	('CESC cancers', 'Disease', (138, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('TP53', 'Gene', (46, 50))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (30, 34))	('CESC cancers', 'Disease', 'MESH:D009369', (138, 150))
27108	29617664	These associations were consistent in linking a high mutation burden or genomic instability with worse clinical outcomes across almost all cancer types.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('genomic instability', 'Var', (72, 91))	('mutation burden', 'Var', (53, 68))	('cancer', 'Disease', (139, 145))
27111	29617664	This extends the recognition of a bimodal distribution of HRD scores in breast and ovarian cancers and the enrichment of BRCA1/2 mutant or methylated cancers among HRD-high cancers that are more likely to respond to platinum-containing therapy.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('ovarian cancers', 'Phenotype', 'HP:0100615', (83, 98))	('platinum', 'Chemical', 'MESH:D010984', (216, 224))	('HRD-high cancers', 'Disease', (164, 180))	('mutant', 'Var', (129, 135))	('BRCA1/2', 'Gene', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (72, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('cancers', 'Disease', (150, 157))	('HRD', 'Disease', (164, 167))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('HRD', 'Disease', 'None', (164, 167))	('cancers', 'Disease', (173, 180))	('HRD-high cancers', 'Disease', 'MESH:D009369', (164, 180))	('HRD', 'Disease', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('BRCA1/2', 'Gene', '672;675', (121, 128))	('methylated', 'Var', (139, 149))	('HRD', 'Disease', 'None', (58, 61))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
27116	29617664	The many different cancer types that show epigenetic silencing of DR pathway genes such as MGMT and ALKBH3 may be especially vulnerable to types of DNA damage normally repaired by these proteins.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('ALKBH3', 'Gene', (100, 106))	('epigenetic silencing', 'Var', (42, 62))	('DR pathway genes', 'Gene', (66, 82))	('cancer', 'Disease', (19, 25))	('ALKBH3', 'Gene', '221120', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', '4255', (91, 95))
27126	29617664	For each combination of a cancer type and DDR pathway, we have three binary vectors that indicate for the samples of that cancer type whether at least one gene in a DDR pathway was mutated, deleted or silenced.	('silenced', 'NegReg', (201, 209))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('deleted', 'Var', (190, 197))	('mutated', 'Var', (181, 188))
27128	29617664	To estimate the probability of missense mutations being damaging, we further annotated these missense mutations using six commonly used functional prediction algorithms (Figure S1D): PolyPhen-2, SIFT, Mutation Taster, Mutation Assessor, LR and LRT.	('SIFT', 'Disease', 'None', (195, 199))	('missense', 'Var', (31, 39))	('SIFT', 'Disease', (195, 199))
27129	29617664	TP53 hotspot mutation substitutions such as R175H and R273H that didn't meet this threshold were manually rescued.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('R273H', 'Var', (54, 59))	('R273H', 'Mutation', 'rs28934576', (54, 59))	('R175H', 'Mutation', 'rs28934578', (44, 49))	('R175H', 'Var', (44, 49))
27136	29617664	However, probe cg14837411 on HM27 and probe cg27221688 on HM450 were only 100bp apart and both correlated with gene expression.	('HM27', 'CellLine', 'CVCL:8807', (29, 33))	('correlated', 'Reg', (95, 105))	('gene expression', 'MPA', (111, 126))	('cg14837411', 'Var', (15, 25))
27137	29617664	We manually added these back based on a beta value cutoff of 0.2 or above and combining both probes to call RAD51C epigenetic silencing.	('epigenetic silencing', 'Var', (115, 135))	('RAD51C', 'Gene', '5889', (108, 114))	('RAD51C', 'Gene', (108, 114))
27138	29617664	The aneuploidy score reports the total number of arm-level amplifications and deletions in each cancer and was computed using ABSOLUTE and an arm-level clustering algorithm, as described in.	('aneuploidy', 'Disease', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aneuploidy', 'Disease', 'MESH:D000782', (4, 14))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('deletions', 'Var', (78, 87))
27161	29617664	In order to provide a detailed assessment for the most recurrent variants in selected DDR proteins (n = 86; observed in at least 2 samples for POLQ or 3 samples for others), we utilized Generalized Born implicit solvent molecular dynamics (MD) simulations, which were carried out using NAMD and the CHARMM27 with CMAP force field.	('variants', 'Var', (65, 73))	('CMAP', 'Gene', (313, 317))	('POLQ', 'Gene', (143, 147))	('POLQ', 'Gene', '10721', (143, 147))	('CMAP', 'Gene', '8530', (313, 317))
27162	29617664	For POLE we studied in greater depth the recurrent V411A/D/I/L/M and P286R substitutions.	('V411A', 'Var', (51, 56))	('P286R', 'Var', (69, 74))	('P286R', 'Mutation', 'rs764973641', (69, 74))	('V411A', 'SUBSTITUTION', 'None', (51, 56))
27167	29617664	The labels (y) for the supervised task included samples with MC3 annotated deleterious TP53 mutations (samples with silent mutations were considered TP53 wild-type) and samples with TP53 deep copy number loss as predicted by the GISTIC2.0 algorithm.	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('deep copy number loss', 'Disease', (187, 208))	('TP53', 'Gene', '7157', (149, 153))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('TP53', 'Gene', (149, 153))	('MC3', 'Gene', (61, 64))	('deep copy number loss', 'Disease', 'MESH:D057887', (187, 208))
27172	29617664	We tested MDM2, MDM4, and PPM1D amplifications, CDKN2A deletions, and ATM, ATR, CHEK1, CHEK2, CREBBP, and RPS6KA3 mutations.	('ATR', 'Gene', '545', (75, 78))	('CREBBP', 'Gene', '1387', (94, 100))	('CHEK1', 'Gene', '1111', (80, 85))	('RPS6KA3', 'Gene', '6197', (106, 113))	('PPM1D', 'Gene', (26, 31))	('ATM', 'Gene', '472', (70, 73))	('RPS6KA3', 'Gene', (106, 113))	('CDKN2A', 'Gene', (48, 54))	('MDM2', 'Gene', (10, 14))	('CHEK1', 'Gene', (80, 85))	('MDM4', 'Gene', '4194', (16, 20))	('MDM4', 'Gene', (16, 20))	('ATR', 'Gene', (75, 78))	('CHEK2', 'Gene', (87, 92))	('MDM2', 'Gene', '4193', (10, 14))	('CDKN2A', 'Gene', '1029', (48, 54))	('CREBBP', 'Gene', (94, 100))	('ATM', 'Gene', (70, 73))	('CHEK2', 'Gene', '11200', (87, 92))	('PPM1D', 'Gene', '8493', (26, 31))	('deletions', 'Var', (55, 64))
27174	29617664	We removed tumors with deleterious TP53 mutations or deep copy number loss (n = 4,037).	('deep copy number loss', 'Disease', 'MESH:D057887', (53, 74))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('tumors', 'Disease', (11, 17))	('deep copy number loss', 'Disease', (53, 74))	('mutations', 'Var', (40, 49))	('tumors', 'Disease', 'MESH:D009369', (11, 17))
27179	29617664	DNA damage repair (DDR) gene alterations are prevalent in many human cancer types Homology-dependent recombination (HR) and direct repair were most frequently altered Loss of DDR function is linked to frequency and types of cancer genomic aberrations Altered HR function can be associated with better or worse outcomes by cancer type	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('human', 'Species', '9606', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (322, 328))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('alterations', 'Var', (29, 40))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', (69, 75))
27244	29533018	There were no events in 5-year OS in uterine leiomyosarcoma patients showing AR immune-reaction compared to the no expression group (100% vs. 54.8%; p=0.014), and patients having a co-expression of AR with ER and/or PR showed statistically significant better 5-year DFS and OS compared with ER and/or PR positive patients with negative AR expression.	('better', 'PosReg', (252, 258))	('ER', 'Gene', '2099', (206, 208))	('patients', 'Species', '9606', (163, 171))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (45, 59))	('co-expression', 'Var', (181, 194))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (37, 59))	('patients', 'Species', '9606', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('PR', 'Gene', '5241', (301, 303))	('DFS', 'CPA', (266, 269))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (45, 59))	('ER', 'Gene', '2099', (291, 293))	('leiomyosarcoma', 'Disease', (45, 59))	('patients', 'Species', '9606', (313, 321))	('PR', 'Gene', '5241', (216, 218))
27251	29533018	As with previous studies in endometrial cancer, the expression of AR was related to the lower rate of recurrence and death events in our study.	('endometrial cancer', 'Disease', (28, 46))	('endometrial cancer', 'Phenotype', 'HP:0012114', (28, 46))	('endometrial cancer', 'Disease', 'MESH:D016889', (28, 46))	('recurrence', 'CPA', (102, 112))	('death', 'Disease', 'MESH:D003643', (117, 122))	('death', 'Disease', (117, 122))	('expression', 'Var', (52, 62))	('lower', 'NegReg', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
27253	29533018	AR positivity in uterine leiomyosarcoma independently correlated with better DFS in this study as it did in Leitao et al..	('leiomyosarcoma', 'Disease', 'MESH:D007890', (25, 39))	('positivity', 'Var', (3, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('better', 'PosReg', (70, 76))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (17, 39))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (25, 39))	('leiomyosarcoma', 'Disease', (25, 39))	('DFS', 'Disease', (77, 80))
27255	29533018	In our series, uterine leiomyosarcoma having co-expression of AR with ER and/or PR showed significantly better DFS and OS than those with ER and/or PR positive patients with negative AR expression.	('leiomyosarcoma', 'Disease', (23, 37))	('patients', 'Species', '9606', (160, 168))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (15, 37))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (23, 37))	('PR', 'Gene', '5241', (80, 82))	('PR', 'Gene', '5241', (148, 150))	('ER', 'Gene', '2099', (70, 72))	('ER', 'Gene', '2099', (138, 140))	('co-expression', 'Var', (45, 58))	('better', 'PosReg', (104, 110))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (23, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('DFS', 'MPA', (111, 114))
27293	27867926	Biopsy under the hysteroscopy was done and showed uterine AS with histological high grade with stromal overgrowth, 30-40 brisk mitotic figures in 10 high power fields, no heterologous component, microscopically tumor cell necrosis present.	('stromal overgrowth', 'CPA', (95, 113))	('necrosis', 'Disease', 'MESH:D009336', (222, 230))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('overgrowth', 'Phenotype', 'HP:0001548', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('necrosis', 'Disease', (222, 230))	('30-40', 'Var', (115, 120))
27313	27867926	Unfavorable prognostic factors include presence of heterologous elements, necrosis, high mitotic rate, vascular invasion and extrauterine spread.	('necrosis', 'Disease', 'MESH:D009336', (74, 82))	('vascular invasion', 'CPA', (103, 120))	('high mitotic rate', 'CPA', (84, 101))	('necrosis', 'Disease', (74, 82))	('heterologous', 'Var', (51, 63))	('extrauterine spread', 'CPA', (125, 144))
27332	25933682	Women harboring a deleterious BRCA 1 or 2 mutation have a 40-65% lifetime risk of developing breast cancer and a 11-40% risk of developing ovarian cancer.	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ovarian cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('BRCA 1', 'Gene', '672', (30, 36))	('mutation', 'Var', (42, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (139, 153))	('BRCA 1', 'Gene', (30, 36))
27333	25933682	Approximately 5-10% of breast cancer patients and 13-16% of ovarian cancer patients harbor a germline BRCA 1 or 2 mutation.	('breast cancer', 'Disease', (23, 36))	('BRCA 1', 'Gene', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('patients', 'Species', '9606', (37, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('patients', 'Species', '9606', (75, 83))	('ovarian cancer', 'Disease', (60, 74))	('mutation', 'Var', (114, 122))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('BRCA 1', 'Gene', '672', (102, 108))
27343	25933682	BRCA mutation carriers may benefit from prophylactic surgery, utilization of chemoprevention, as well as increased surveillance.	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', (0, 4))	('BRCA', 'Gene', '672', (0, 4))
27346	25933682	In studies of women with BRCA1 or 2 mutations who underwent risk reduction salpingo-oophorectomy, occult gynecological carcinomas were identified in up to 9% of cases.	('carcinomas', 'Disease', (119, 129))	('to 9', 'Species', '1214577', (152, 156))	('BRCA1', 'Gene', '672', (25, 30))	('identified', 'Reg', (135, 145))	('mutations', 'Var', (36, 45))	('BRCA1', 'Gene', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('women', 'Species', '9606', (14, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('carcinomas', 'Disease', 'MESH:D002277', (119, 129))
27347	25933682	In addition, adherence to patient surveillance guidelines improves after genetic counseling and testing.	('patient', 'Species', '9606', (26, 33))	('genetic counseling', 'Var', (73, 91))	('improves', 'PosReg', (58, 66))	('adherence', 'MPA', (13, 22))
27362	25933682	Data collected included: age at diagnosis, year of diagnosis, race, tumor histology and stage, treatment, documented family history, insurance type, treating provider, parity, AshkenaziJewish heritage, referral to genetics, timing of referral, acceptance of genetic testing and identification of a mutation.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutation', 'Var', (298, 306))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
27376	25933682	A genetic mutation was detected in 46.7% of the uterine cancer patients, 44% of the ovarian cancer patients and 16.5% of the breast cancer patients.	('ovarian cancer', 'Disease', (84, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('uterine cancer', 'Phenotype', 'HP:0010784', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('cancer', 'Disease', (92, 98))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('genetic mutation', 'Var', (2, 18))	('detected', 'Reg', (23, 31))	('patients', 'Species', '9606', (63, 71))
27385	25933682	Referrals for genetic counseling and testing have been endorsed by The Society of Gynecologic Oncology (SGO), National Comprehensive Cancer Network (NCCN), and the American College of Obstetricians and Gynecologists (ACOG) highlighting the need for cancer risk assessments to be an integral part of office visits.	('Oncology', 'Phenotype', 'HP:0002664', (94, 102))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('Cancer', 'Disease', 'MESH:D009369', (133, 139))	('genetic', 'Var', (14, 21))	('cancer', 'Disease', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
27419	25933682	showing that patients were three times more likely to undergo genetic testing if referred by a provider.	('patients', 'Species', '9606', (13, 21))	('genetic testing', 'Var', (62, 77))	('undergo', 'Reg', (54, 61))
27425	25933682	found 44% ofwomen with aBRCA mutation did not have a positive family history in our study, 82% of the women with uterine cancer, 71% of women with breast cancer and 86% of women with ovarian cancer had a positive family history.	('mutation', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('BRCA', 'Gene', (24, 28))	('women', 'Species', '9606', (136, 141))	('uterine cancer', 'Phenotype', 'HP:0010784', (113, 127))	('cancer', 'Disease', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('women', 'Species', '9606', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian cancer', 'Disease', 'MESH:D010051', (183, 197))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Disease', (147, 160))	('women', 'Species', '9606', (172, 177))	('BRCA', 'Gene', '672', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('women', 'Species', '9606', (12, 17))	('ovarian cancer', 'Disease', (183, 197))	('cancer', 'Disease', (154, 160))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (121, 127))
27441	25933682	Genetic testing has the potential to reduce the morbidity and mortality from breast and gynecologic cancers.	('reduce', 'NegReg', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('Genetic testing', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
27459	26971567	Nevertheless, toxicity was also increased with combination therapy.	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('combination', 'Var', (47, 58))	('toxicity', 'Disease', (14, 22))	('increased', 'PosReg', (32, 41))
27547	24334674	Duplications of the spinal cord (often referred to as split cord malformations, diplomyelia or diastematomyelia) have long been recognized as congenital anomalies in humans, and usually occur with other abnormalities such as neural tube defects (; Pang et al.	('humans', 'Species', '9606', (166, 172))	('neural tube defects', 'Phenotype', 'HP:0045005', (225, 244))	('diplomyelia', 'Phenotype', 'HP:0100562', (80, 91))	('neural tube defects', 'Disease', 'MESH:D009436', (225, 244))	('congenital anomalies', 'Disease', (142, 162))	('Duplications', 'Var', (0, 12))	('cord malformations', 'Disease', (60, 78))	('neural tube defects', 'Disease', (225, 244))	('cord malformations', 'Disease', 'MESH:D000014', (60, 78))	('diplomyelia or diastematomyelia', 'Disease', (80, 111))	('diplomyelia or diastematomyelia', 'Disease', 'MESH:D009436', (80, 111))	('occur', 'Reg', (186, 191))	('congenital anomalies', 'Disease', 'MESH:D000013', (142, 162))
27550	24334674	Some human patients with segmental spinal cord/vertebral column duplications also exhibit soft tissue malformations and other defects which result in severe clinical disease (; Pathak et al.	('duplications', 'Var', (64, 76))	('result in', 'Reg', (140, 149))	('exhibit', 'Reg', (82, 89))	('patients', 'Species', '9606', (11, 19))	('malformations', 'Disease', 'MESH:D000014', (102, 115))	('human', 'Species', '9606', (5, 10))	('malformations', 'Disease', (102, 115))
27681	24334674	Dr. Crabbs explained that while it was not obvious in the previously projected photomicrographs, numerous pale yellow homogeneous droplets were present in many of the rats from the gavage studies Visibility of these droplets was enhanced by removing the condenser (Figure 4E).	('removing', 'Var', (241, 249))	('enhanced', 'PosReg', (229, 237))	('man', 'Species', '9606', (155, 158))	('rats', 'Species', '10116', (167, 171))
27706	24334674	In the NTP Pathology Group, Dr. Hiroaki Nagai studied 30 mice with hepatoblastoma arising within a hepatocellular carcinoma for mutations in H-ras or beta-catenin.	('mice', 'Species', '10090', (57, 61))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (67, 81))	('hepatoblastoma arising', 'Disease', (67, 89))	('mutations', 'Var', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('H-ras', 'Gene', '15461', (141, 146))	('hepatoblastoma arising', 'Disease', 'MESH:D018197', (67, 89))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('beta-catenin', 'Protein', (150, 162))	('hepatocellular carcinoma', 'Disease', (99, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))	('H-ras', 'Gene', (141, 146))	('NTP', 'Chemical', '-', (7, 10))
27711	24334674	Further, Principle Component Analysis (PCA) revealed that not only are hepatoblastomas genomically distinct from hepatocellular carcinomas but mouse hepatoblastomas are genetically similar to human hepatoblastomas based on marked dysregulation of genes involving Wnt/beta-catenin pathway, embryonic stem cell pluripotency, and embryonic imprinting (data not shown).	('hepatoblastomas', 'Disease', (149, 164))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (113, 138))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (198, 212))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (71, 85))	('hepatoblastomas', 'Disease', (198, 213))	('embryonic stem cell pluripotency', 'Disease', 'MESH:D020295', (289, 321))	('hepatocellular carcinomas', 'Disease', (113, 138))	('human', 'Species', '9606', (192, 197))	('mouse', 'Species', '10090', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (113, 137))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (149, 163))	('Wnt', 'Gene', '22416', (263, 266))	('hepatoblastomas', 'Disease', 'MESH:D018197', (71, 86))	('dysregulation', 'Var', (230, 243))	('hepatoblastomas', 'Disease', 'MESH:D018197', (149, 164))	('Wnt', 'Gene', (263, 266))	('hepatoblastomas', 'Disease', 'MESH:D018197', (198, 213))	('embryonic stem cell pluripotency', 'Disease', (289, 321))	('hepatoblastomas', 'Disease', (71, 86))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (113, 138))
27713	24334674	Conference participants were shown several tables including those conveying data regarding tumor development (tumors were increased in those animals harboring the AVY mutation), decreases in body weight gain (decreased in body weight gain were concomitant with treatment), and serum calcium analysis between groups (Table 5).	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('weight gain', 'Phenotype', 'HP:0004324', (196, 207))	('weight gain', 'Phenotype', 'HP:0004324', (227, 238))	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Disease', (110, 116))	('participants', 'Species', '9606', (11, 23))	('increased', 'PosReg', (122, 131))	('body weight gain', 'Disease', 'MESH:D015430', (191, 207))	('body weight gain', 'Disease', (191, 207))	('decreases', 'NegReg', (178, 187))	('mutation', 'Var', (167, 175))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('serum', 'MPA', (277, 282))	('AVY', 'Gene', (163, 166))	('calcium', 'Chemical', 'MESH:D002118', (283, 290))	('body weight gain', 'Disease', 'MESH:D015430', (222, 238))	('tumor', 'Disease', (110, 115))	('body weight gain', 'Disease', (222, 238))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
27719	24334674	There was a dose-related papillomagenesis at a rate more numerous in Avy x Tg.AC mice with concomitant loss of body weight (up to 40%).	('loss of body weight', 'Disease', 'MESH:D015431', (103, 122))	('mice', 'Species', '10090', (81, 85))	('papilloma', 'Disease', (25, 34))	('papilloma', 'Disease', 'MESH:D010212', (25, 34))	('rat', 'Species', '10116', (47, 50))	('loss of body weight', 'Disease', (103, 122))	('papilloma', 'Phenotype', 'HP:0012740', (25, 34))	('Avy x Tg.AC', 'Var', (69, 80))
27743	24334674	Deficiencies of protein 4.1 cause erythrocytic elliptocytosis, among other abnormal erythrocytic morphologies, but it does not result in intracellular inclusions.	('erythrocytic elliptocytosis', 'Disease', (34, 61))	('protein 4.1', 'Gene', '313052', (16, 27))	('Deficiencies', 'Var', (0, 12))	('protein 4.1', 'Gene', (16, 27))	('cause', 'Reg', (28, 33))	('elliptocytosis', 'Phenotype', 'HP:0004445', (47, 61))	('erythrocytic elliptocytosis', 'Disease', 'MESH:C567520', (34, 61))
27744	24334674	The formation of the inclusions is thought to be preanalytical artifact due to one or more of the following factors: location of blood collection (e.g., retro-orbital, submandibular, cardiac), type of ethylenediaminetetraacetic acid (EDTA) utilized (e.g., Na2EDTA, K2EDTA, K3EDTA), ratio of blood to EDTA, and potential constitutive differences in the blood vials.	('K2EDTA', 'Var', (265, 271))	('K3EDTA', 'Var', (273, 279))	('K3EDTA', 'Chemical', '-', (273, 279))	('Na2EDTA', 'Var', (256, 263))	('rat', 'Species', '10116', (282, 285))	('ethylenediaminetetraacetic acid', 'Chemical', 'MESH:D004492', (201, 232))	('Na2EDTA', 'Chemical', 'MESH:D004492', (256, 263))	('EDTA', 'Chemical', 'MESH:D004492', (300, 304))	('EDTA', 'Chemical', 'MESH:D004492', (259, 263))	('man', 'Species', '9606', (171, 174))	('EDTA', 'Chemical', 'MESH:D004492', (267, 271))	('K2EDTA', 'Chemical', '-', (265, 271))	('EDTA', 'Chemical', 'MESH:D004492', (275, 279))	('EDTA', 'Chemical', 'MESH:D004492', (234, 238))
27814	24334674	Dr. Molly Boyle (Integrated Laboratory Systems, Inc., RTP, NC) and Dr. Susan Elmore (NTP, NIEHS, RTP, NC) presented an unusual uterine lesion from an as yet unpublished NTP chronic gavage and carcinogenicity bioassay in Wistar Han rats.	('unusual uterine', 'Phenotype', 'HP:0000130', (119, 134))	('rat', 'Species', '10116', (32, 35))	('carcinogenic', 'Disease', 'MESH:D063646', (192, 204))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (231, 234))	('carcinogenic', 'Disease', (192, 204))	('NTP', 'Chemical', '-', (169, 172))	('Molly', 'Species', '69235', (4, 9))	('NTP', 'Chemical', '-', (85, 88))	('rats', 'Species', '10116', (231, 235))	('Dr.', 'Var', (67, 70))	('uterine lesion', 'CPA', (127, 141))
27888	24334674	The first in this series of three cases showed cyst like structures in the tunica muscularis of the glandular stomach and cecum of B6C3F1 and CD1-mice, which were lined by essentially normal mucosa (Figure 10A).	('B6C3F1', 'Var', (131, 137))	('mice', 'Species', '10090', (146, 150))	('CD1', 'Gene', '111334', (142, 145))	('CD1', 'Gene', (142, 145))
27939	23959089	In paraffin-embedded specimens, expression of the following molecular markers was detected: CD10 (27/36), vimentin (37/38), HHF35 (3/32), S-100 (0/25), desmin (2/29), CD117 (0/23), CD34 (2/24), alpha-inhibin (0/17), CK (1/34), CD99 (4/9), smooth muscle actin (5/25), EMA (0/7), estrogen receptor (13/16) and progesterone receptor (13/16).	('CD99', 'Gene', '4267', (227, 231))	('CD10', 'Gene', (92, 96))	('S-100', 'Var', (138, 143))	('CD34', 'Gene', '947', (181, 185))	('vimentin', 'Gene', '7431', (106, 114))	('CD117', 'Gene', (167, 172))	('vimentin', 'Gene', (106, 114))	('desmin', 'Gene', '1674', (152, 158))	('estrogen receptor', 'Gene', '2099', (278, 295))	('smooth muscle actin', 'Protein', (239, 258))	('alpha-inhibin', 'Protein', (194, 207))	('CD34', 'Gene', (181, 185))	('(13/16) and progesterone receptor', 'Gene', '5241', (296, 329))	('estrogen receptor', 'Gene', (278, 295))	('CD10', 'Gene', '4311', (92, 96))	('CD99', 'Gene', (227, 231))	('desmin', 'Gene', (152, 158))	('13/16) and progesterone receptor', 'Gene', (297, 329))	('CD117', 'Gene', '3815', (167, 172))	('HHF35', 'Gene', (124, 129))
27966	23959089	In our study, the group of ESS cases expressed CD10, vimentin, HHF35, desmin, CD34, CK, CD99, smooth muscle actin, estrogen receptor, and progesterone receptor.	('CD99', 'Gene', (88, 92))	('CD34', 'Protein', (78, 82))	('vimentin', 'Protein', (53, 61))	('HHF35', 'Gene', (63, 68))	('ESS', 'Disease', (27, 30))	('desmin', 'Protein', (70, 76))	('expressed', 'Reg', (37, 46))	('CD10', 'Var', (47, 51))	('smooth muscle actin, estrogen receptor, and progesterone receptor', 'Gene', '5241', (94, 159))
28027	24137385	The study clearly demonstrated that the components shared losses of chromosomes 9 and 17p, which were characteristic genetic alterations of urothelial carcinoma, and that the choriocarcinomatous components acquired additional chromosomal losses and gains, mostly associated with poorly-differentiated urothelial carcinoma.	('choriocarcinomatous components', 'Disease', (175, 205))	('choriocarcinomatous components', 'Disease', 'MESH:C562869', (175, 205))	('associated', 'Reg', (263, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (175, 190))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (140, 160))	('urothelial carcinoma', 'Disease', (301, 321))	('gains', 'PosReg', (249, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('urothelial carcinoma', 'Disease', (140, 160))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (301, 321))	('losses', 'NegReg', (58, 64))	('chromosomal losses', 'Var', (226, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
28048	32859123	A large-scale molecular analysis published in 2013 by the Cancer Genome Atlas (TCGA), defined four molecular categories of endometrial cancer: POLE mutated, hypermutated secondary to microsatellite instability (MSI), low copy number, and high copy number (serous-like).	('high copy number', 'Var', (238, 254))	('endometrial cancer', 'Disease', 'MESH:D016889', (123, 141))	('endometrial cancer', 'Phenotype', 'HP:0012114', (123, 141))	('hypermutated', 'Var', (157, 169))	('microsatellite instability', 'MPA', (183, 209))	('low copy number', 'Var', (217, 232))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))	('endometrial cancer', 'Disease', (123, 141))
28102	32859123	In an article by Miyoshi et al., a significantly lower disease-free survival rate was observed in breast cancer patients with high levels of WT1 mRNA compared to those with low levels.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('high levels', 'Var', (126, 137))	('breast cancer', 'Disease', (98, 111))	('WT1', 'Gene', '7490', (141, 144))	('disease-free survival rate', 'CPA', (55, 81))	('patients', 'Species', '9606', (112, 120))	('lower', 'NegReg', (49, 54))	('WT1', 'Gene', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
28111	32859123	In detail, we found that uterine carcinosarcoma with high WT1 expression showed the worst outcome, as also highlighted by Coosemans et al., especially regarding DFS/RFS/PFS.	('carcinosarcoma', 'Disease', (33, 47))	('high', 'Var', (53, 57))	('WT1', 'Gene', '7490', (58, 61))	('WT1', 'Gene', (58, 61))	('RFS', 'Disease', (165, 168))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (25, 47))	('carcinosarcoma', 'Disease', 'MESH:D002296', (33, 47))	('RFS', 'Disease', 'MESH:D005198', (165, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
28140	28215841	Within the extracted cases, presumed stage I endometrial cancer cases with known hysterectomy modality between 1983 and 2012 were included in the study (T1a, T1b, and T1NOS for tumor stage; N0 or Nx for nodal stage; and M0 or Mx for metastatic stage).	('endometrial cancer', 'Disease', (45, 63))	('T1b', 'Var', (158, 161))	('endometrial cancer', 'Disease', 'MESH:D016889', (45, 63))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('endometrial cancer', 'Phenotype', 'HP:0012114', (45, 63))	('T1NOS', 'Var', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('N0 or Nx', 'Var', (190, 198))	('tumor', 'Disease', (177, 182))
28163	28215841	On univariable analysis, women who had supracervical hysterectomy had a statistically significant lower 10-year endometrial cancer-specific survival rate compared to those who had total hysterectomy (91.1% versus 93.4%, P = 0.028; Fig.	('endometrial cancer', 'Disease', 'MESH:D016889', (112, 130))	('supracervical hysterectomy', 'Var', (39, 65))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('endometrial cancer', 'Disease', (112, 130))	('endometrial cancer', 'Phenotype', 'HP:0012114', (112, 130))	('women', 'Species', '9606', (25, 30))	('lower', 'NegReg', (98, 103))
28172	28215841	On multivariable analysis, supracervical hysterectomy remained an independent prognostic factor for decreased endometrial cancer-specific survival compared to total hysterectomy (adjusted-HR 1.72, 95%CI 1.20-2.47, P = 0.003; Table 3).	('supracervical hysterectomy', 'Var', (27, 53))	('endometrial cancer', 'Phenotype', 'HP:0012114', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('decreased endometrial cancer', 'Disease', (100, 128))	('decreased endometrial cancer', 'Disease', 'MESH:D016889', (100, 128))
28174	28215841	On univariable analysis, women who had supracervical hysterectomy had a statistically significant lower 10-year endometrial cancer-specific survival rate compared with those who had total hysterectomy (91.8% versus 94.5%, P = 0.013; Fig.	('endometrial cancer', 'Disease', 'MESH:D016889', (112, 130))	('supracervical hysterectomy', 'Var', (39, 65))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('endometrial cancer', 'Disease', (112, 130))	('endometrial cancer', 'Phenotype', 'HP:0012114', (112, 130))	('women', 'Species', '9606', (25, 30))	('lower', 'NegReg', (98, 103))
28205	28215841	For example, adjuvant radiotherapy was independently associated with decreased endometrial cancer-specific survival in a pre-matching model but this association was no longer independent in a post-matching model, implying that the statistical weight of adjuvant radiotherapy in a pre-matching model was likely affected by the total hysterectomy group where there were more stage IB disease and high grade tumors compared to the supracervical hysterectomy group.	('tumors', 'Disease', 'MESH:D009369', (405, 411))	('tumors', 'Disease', (405, 411))	('tumor', 'Phenotype', 'HP:0002664', (405, 410))	('endometrial cancer', 'Phenotype', 'HP:0012114', (79, 97))	('tumors', 'Phenotype', 'HP:0002664', (405, 411))	('adjuvant radiotherapy', 'Var', (13, 34))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('decreased endometrial cancer', 'Disease', (69, 97))	('decreased endometrial cancer', 'Disease', 'MESH:D016889', (69, 97))	('IB disease', 'Disease', (379, 389))	('IB disease', 'Disease', 'MESH:C567452', (379, 389))
28230	31645905	Biomarkers have been developed to predict patients' responsivity to immunotherapy treatments, such as genome-wide mutational load, PD-L1 protein expression in infiltrating immune cells, the number of cytotoxic T cells in a tumor microenvironment, or MSI status.	('men', 'Species', '9606', (241, 244))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('men', 'Species', '9606', (87, 90))	('PD-L1', 'Gene', '29126', (131, 136))	('MSI', 'Gene', '5928', (250, 253))	('MSI', 'Gene', (250, 253))	('mutational load', 'Var', (114, 129))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('patients', 'Species', '9606', (42, 50))	('protein', 'Protein', (137, 144))	('PD-L1', 'Gene', (131, 136))
28270	31645905	In head and neck squamous cell carcinoma (HNSC, P = 0.0044, adjusted) and skin cutaneous melanoma (SKCM, P = 0.0044, adjusted), patients with T3/4 had significantly lower immune response than those with T1/2, while kidney renal clear cell carcinoma (KIRC, P = 0.0044, adjusted) showed the opposite trend.	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (215, 248))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('KIRC', 'Disease', (250, 254))	('SKCM', 'Disease', 'MESH:C562393', (99, 103))	('kidney renal clear cell carcinoma', 'Disease', (215, 248))	('HNSC', 'Phenotype', 'HP:0012288', (42, 46))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('KIRC', 'Disease', 'MESH:D002292', (250, 254))	('immune response', 'MPA', (171, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (12, 40))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('T3/4', 'Var', (142, 146))	('patients', 'Species', '9606', (128, 136))	('lower', 'NegReg', (165, 170))	('lower immune response', 'Phenotype', 'HP:0002721', (165, 186))	('SKCM', 'Disease', (99, 103))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))
28288	31645905	It appears that the hypermutated (HM) colon adenocarcinoma (COAD) patients had the significantly highest immune response among the three different molecular subtypes (CIN, GS, HM) (P = 1.04 x 10-06, Figure 8C).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('immune response', 'MPA', (105, 120))	('hypermutated', 'Var', (20, 32))	('COAD', 'Disease', 'MESH:D015179', (60, 64))	('HM) colon adenocarcinoma', 'Disease', 'MESH:D015179', (34, 58))	('COAD', 'Disease', (60, 64))	('CIN', 'Phenotype', 'HP:0040012', (167, 170))	('highest', 'PosReg', (97, 104))	('patients', 'Species', '9606', (66, 74))
28305	31645905	Our results further demonstrated that the hypermutated (HM) subtype in colon adenocarcinoma (COAD) had a significantly higher immune response than either the chromosomal instability (CIN) or genome stable (GS) subtypes, making such patients potential candidates for immunotherapeutic treatments.	('COAD', 'Disease', 'MESH:D015179', (93, 97))	('chromosomal instability', 'Phenotype', 'HP:0040012', (158, 181))	('CIN', 'Phenotype', 'HP:0040012', (183, 186))	('patients', 'Species', '9606', (232, 240))	('immune', 'MPA', (126, 132))	('men', 'Species', '9606', (289, 292))	('colon adenocarcinoma', 'Disease', (71, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('higher', 'PosReg', (119, 125))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (71, 91))	('COAD', 'Disease', (93, 97))	('hypermutated', 'Var', (42, 54))
28332	31645905	For the same reason, the molecular subtypes investigated in detail in this study included: Basal/Her2/LumA/LumB in breast invasive carcinoma (BRCA) patients, CIN/GS/HM-indel/HM-SNV or /EBV in gastrointestinal cancer patients, IDH mutation status in glioma patients, and POLE/MSI/CN_Low/CN_High in uterine corpus endometrial carcinoma (UCEC) patients.	('patients', 'Species', '9606', (341, 349))	('IDH', 'Gene', '3417', (226, 229))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (192, 215))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (115, 140))	('gastrointestinal cancer', 'Disease', (192, 215))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (192, 215))	('CIN', 'Phenotype', 'HP:0040012', (158, 161))	('patients', 'Species', '9606', (148, 156))	('LumA', 'Gene', '79188', (102, 106))	('breast invasive carcinoma (BRCA', 'Gene', (115, 146))	('glioma', 'Disease', (249, 255))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (115, 147))	('MSI', 'Gene', (275, 278))	('MSI', 'Gene', '5928', (275, 278))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('BRCA', 'Phenotype', 'HP:0003002', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (312, 333))	('corpus endometrial carcinoma', 'Disease', (305, 333))	('patients', 'Species', '9606', (216, 224))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (305, 333))	('LumA', 'Gene', (102, 106))	('IDH', 'Gene', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Her2', 'Gene', '2064', (97, 101))	('patients', 'Species', '9606', (256, 264))	('CIN/GS/HM-indel/HM-SNV', 'Var', (158, 180))	('Her2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
28335	31645905	The Normal subtype in breast invasive carcinoma (BRCA) and IDH mutant group in glioblastoma multiforme (GBM) typically had a small number of patients, and as such were excluded from downstream analyses.	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (79, 102))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (22, 54))	('IDH', 'Gene', (59, 62))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (22, 47))	('mutant', 'Var', (63, 69))	('GBM', 'Disease', (104, 107))	('IDH', 'Gene', '3417', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('GBM', 'Disease', 'MESH:D005909', (104, 107))	('breast invasive carcinoma (BRCA', 'Gene', (22, 53))	('glioblastoma multiforme', 'Disease', (79, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('patients', 'Species', '9606', (141, 149))
28339	31645905	CIN Chromosomal instability GS genome stable HM hypermutated MSI microsatellite instability EBV Epstein-Barr virus SNV single-nucleotide variant HPV human papillomavirus	('single-nucleotide variant', 'Var', (119, 144))	('HPV', 'Species', '10566', (145, 148))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (96, 114))	('MSI', 'Gene', '5928', (61, 64))	('MSI', 'Gene', (61, 64))	('human papillomavirus', 'Species', '10566', (149, 169))	('Epstein-Barr virus', 'Disease', (96, 114))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (4, 27))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))
28349	31285650	Vascular displacement can mimic lymphovascular invasion (LVSI) histologically, which is among the factors considered during stratification of patients into risk groups for recurrence.	('lymphovascular invasion', 'Disease', (32, 55))	('Vascular displacement', 'Var', (0, 21))	('patients', 'Species', '9606', (142, 150))
28370	31285650	Positive LVSI was initially reported in 6 patients (10%) in the manipulator group and 9 (20%) in the no-manipulator group (P = .37).	('LVSI', 'Disease', (9, 13))	('patients', 'Species', '9606', (42, 50))	('manipulator', 'Var', (64, 75))	('Positive LVSI', 'Disease', (0, 13))
28383	31285650	LVSI have been shown to be an independent prognostic factor in early stage endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('LVSI', 'Var', (0, 4))	('endometrial cancer', 'Disease', (75, 93))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))
28392	30289582	LBGDx identified 11 pathogenic PTEN variants in 10 subjects, six PIK3CA variants in nine, three CTNNB1 variants in five, two KRAS variants in four, and three TP53 variants in three.	('TP53', 'Gene', '7157', (158, 162))	('PTEN', 'Gene', (31, 35))	('TP53', 'Gene', (158, 162))	('CTNNB1', 'Gene', '1499', (96, 102))	('PTEN', 'Gene', '5728', (31, 35))	('KRAS', 'Gene', (125, 129))	('KRAS', 'Gene', '3845', (125, 129))	('CTNNB1', 'Gene', (96, 102))	('PIK3CA', 'Gene', (65, 71))	('pathogenic', 'Reg', (20, 30))	('variants', 'Var', (36, 44))	('PIK3CA', 'Gene', '5290', (65, 71))
28393	30289582	Collectively, at least one pathogenic variant was identified in 19 subjects, which included 17 EC (15 endometrioid carcinoma and 2 endometrial carcinosarcomas), and one cervical adenocarcinoma.	('15 endometrioid carcinoma', 'Disease', 'MESH:D016889', (99, 124))	('EC', 'Phenotype', 'HP:0012114', (95, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('15 endometrioid carcinoma', 'Disease', (99, 124))	('endometrial carcinosarcomas', 'Disease', (131, 158))	('endometrial carcinosarcoma', 'Phenotype', 'HP:0012114', (131, 157))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (102, 124))	('endometrial carcinosarcomas', 'Phenotype', 'HP:0012114', (131, 158))	('endometrial carcinosarcomas', 'Disease', 'MESH:D002296', (131, 158))	('variant', 'Var', (38, 45))	('cervical adenocarcinoma', 'Disease', (169, 192))	('cervical adenocarcinoma', 'Disease', 'MESH:D002575', (169, 192))
28419	30289582	In the present study, we randomly selected 48 samples with an amount of DNA more than 5 mug and screened variants in the five genes including PTEN, PIK3CA, CTNNB1, KRAS, and TP53.	('PTEN', 'Gene', (142, 146))	('PIK3CA', 'Gene', '5290', (148, 154))	('PTEN', 'Gene', '5728', (142, 146))	('KRAS', 'Gene', '3845', (164, 168))	('TP53', 'Gene', (174, 178))	('CTNNB1', 'Gene', '1499', (156, 162))	('variants', 'Var', (105, 113))	('PIK3CA', 'Gene', (148, 154))	('KRAS', 'Gene', (164, 168))	('CTNNB1', 'Gene', (156, 162))	('TP53', 'Gene', '7157', (174, 178))
28421	30289582	Consequently, we identified a total of 11 PTEN variants in 10 women, six PIK3CA variants in nine, three CTNNB1 variants in five, two KRAS variants in four, and three TP53 variants in three (Table 2).	('PTEN', 'Gene', (42, 46))	('PIK3CA', 'Gene', '5290', (73, 79))	('variants', 'Var', (47, 55))	('PTEN', 'Gene', '5728', (42, 46))	('CTNNB1', 'Gene', '1499', (104, 110))	('TP53', 'Gene', '7157', (166, 170))	('CTNNB1', 'Gene', (104, 110))	('KRAS', 'Gene', (133, 137))	('TP53', 'Gene', (166, 170))	('PIK3CA', 'Gene', (73, 79))	('KRAS', 'Gene', '3845', (133, 137))	('women', 'Species', '9606', (62, 67))
28422	30289582	Regarding the PTEN mutations in the LBC samples, the allele frequencies of each mutation ranged from 8% to 56% with an average of 31.1%, suggesting a high proportion of tumor cells in the LBC samples.	('PTEN', 'Gene', (14, 18))	('PTEN', 'Gene', '5728', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', (169, 174))
28423	30289582	Although the average frequencies of pathogenic mutations in PIK3CA, CTNNB1, and TP53, were 32.1%, 25.8%, and 44.7%, respectively, the frequency of KRAS mutation ranged from 8% to 9% with an average of 8.5%.	('to 9', 'Species', '1214577', (176, 180))	('PIK3CA', 'Gene', (60, 66))	('PIK3CA', 'Gene', '5290', (60, 66))	('CTNNB1', 'Gene', (68, 74))	('TP53', 'Gene', '7157', (80, 84))	('mutations', 'Var', (47, 56))	('TP53', 'Gene', (80, 84))	('pathogenic', 'Reg', (36, 46))	('CTNNB1', 'Gene', '1499', (68, 74))	('KRAS', 'Gene', (147, 151))	('KRAS', 'Gene', '3845', (147, 151))
28426	30289582	The 11 PTEN variants comprised five nonsynonymous variants (p.D92G, p.R130G, p.R130P, p.R173C, and p.R173H), four nonsense variants (p.R130*, p.E157*, p.R233*, and p.E284*), and two deletions (c.568delC and c.800delA).	('p.D92G', 'Mutation', 'rs786204858', (60, 66))	('p.R130*', 'Mutation', 'p.R130*', (133, 140))	('p.E157*', 'Var', (142, 149))	('PTEN', 'Gene', '5728', (7, 11))	('c.800delA', 'Var', (207, 216))	('p.R173H', 'Mutation', 'rs121913294', (99, 106))	('p.R173H', 'Var', (99, 106))	('p.R130G', 'Var', (68, 75))	('p.R130*', 'Var', (133, 140))	('c.568delC', 'Mutation', 'c.568delC', (193, 202))	('p.D92G', 'Var', (60, 66))	('p.R233*', 'Var', (151, 158))	('p.E157*', 'Mutation', 'p.E157*', (142, 149))	('p.R130P', 'Mutation', 'rs121909229', (77, 84))	('c.800delA', 'Mutation', 'rs121913289', (207, 216))	('p.R173C', 'Mutation', 'rs121913293', (86, 93))	('c.568delC', 'Var', (193, 202))	('p.R173C', 'Var', (86, 93))	('p.R130P', 'Var', (77, 84))	('p.E284*', 'Mutation', 'p.E284*', (164, 171))	('p.E284*', 'Var', (164, 171))	('p.R130G', 'Mutation', 'rs121909224', (68, 75))	('PTEN', 'Gene', (7, 11))	('p.R233*', 'Mutation', 'p.R233*', (151, 158))
28427	30289582	Because the 10 individuals did not show clinical features associated with Cowden disease, a hereditary disease caused by germline mutations in PTEN, the 11 variants were considered somatic mutations.	('Cowden disease', 'Disease', 'MESH:D006223', (74, 88))	('Cowden disease', 'Disease', (74, 88))	('caused', 'Reg', (111, 117))	('hereditary disease', 'Disease', (92, 110))	('germline', 'Var', (121, 129))	('PTEN', 'Gene', (143, 147))	('hereditary disease', 'Disease', 'MESH:D030342', (92, 110))	('PTEN', 'Gene', '5728', (143, 147))
28428	30289582	Although eight of the 10 cases had one PTEN mutation, a case (LB-176) carried two (p.R130P and p.R173C) and the remaining case (LB-184) had three PTEN mutations (p.R130*, p.R173H, and p.R233*), suggesting that PTEN is a typical tumor suppressor gene that is inactivated by genetic alterations in both alleles.	('p.R130P', 'Mutation', 'rs121909229', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('PTEN', 'Gene', '5728', (39, 43))	('PTEN', 'Gene', (210, 214))	('p.R130P', 'Var', (83, 90))	('PTEN', 'Gene', (146, 150))	('p.R233*', 'Var', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('p.R173H', 'Mutation', 'rs121913294', (171, 178))	('p.R173H', 'Var', (171, 178))	('PTEN', 'Gene', '5728', (210, 214))	('p.R130*', 'Mutation', 'p.R130*', (162, 169))	('PTEN', 'Gene', '5728', (146, 150))	('p.R173C', 'Var', (95, 102))	('p.R173C', 'Mutation', 'rs121913293', (95, 102))	('p.R130*', 'Var', (162, 169))	('p.R233*', 'Mutation', 'p.R233*', (184, 191))	('PTEN', 'Gene', (39, 43))	('tumor', 'Disease', (228, 233))
28431	30289582	Mutations of CTNNB1, KRAS, and TP53 were found in five, four, and three cases, respectively, and all were regarded as pathogenic mutations.	('found', 'Reg', (41, 46))	('KRAS', 'Gene', '3845', (21, 25))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('CTNNB1', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('CTNNB1', 'Gene', '1499', (13, 19))	('KRAS', 'Gene', (21, 25))
28432	30289582	Among the 19 subjects with at least one pathogenic mutation, 15 were diagnosed as endometrioid carcinoma, two as endometrial carcinosarcoma, and one as cervical adenocarcinoma.	('cervical adenocarcinoma', 'Disease', (152, 175))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (82, 104))	('endometrial carcinosarcoma', 'Phenotype', 'HP:0012114', (113, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('endometrial carcinosarcoma', 'Disease', 'MESH:D002296', (113, 139))	('endometrioid carcinoma', 'Disease', (82, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (82, 104))	('mutation', 'Var', (51, 59))	('endometrial carcinosarcoma', 'Disease', (113, 139))	('cervical adenocarcinoma', 'Disease', 'MESH:D002575', (152, 175))
28433	30289582	Although the remaining case carried a KRAS mutation, no cytological or ultrasound abnormalities were identified in the patient who suffered from familial adenomatous (FAP) polyposis of the colon.	('carried', 'Reg', (28, 35))	('KRAS', 'Gene', '3845', (38, 42))	('patient', 'Species', '9606', (119, 126))	('mutation', 'Var', (43, 51))	('familial adenomatous (FAP) polyposis of the colon', 'Disease', 'MESH:D011125', (145, 194))	('KRAS', 'Gene', (38, 42))
28438	30289582	In the present study, we identified frequent mutations in PTEN (10/20), PIK3CA (7/20), CTNNB1 (5/20), KRAS (2/20), and TP53 (3/20) in EC by amplicon sequencing of the five genes and showed that LBGDx contributes to enhanced sensitivity of cytological screening for endometrial cancer.	('PTEN', 'Gene', '5728', (58, 62))	('mutations', 'Var', (45, 54))	('endometrial cancer', 'Disease', (265, 283))	('CTNNB1', 'Gene', '1499', (87, 93))	('sensitivity', 'MPA', (224, 235))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('endometrial cancer', 'Phenotype', 'HP:0012114', (265, 283))	('PIK3CA', 'Gene', (72, 78))	('KRAS (2/20', 'Gene', '3845', (102, 112))	('EC', 'Phenotype', 'HP:0012114', (134, 136))	('endometrial cancer', 'Disease', 'MESH:D016889', (265, 283))	('CTNNB1', 'Gene', (87, 93))	('PIK3CA', 'Gene', '5290', (72, 78))	('enhanced', 'PosReg', (215, 223))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('PTEN', 'Gene', (58, 62))
28439	30289582	Although the number of samples analyzed in this study is limited, the frequencies of mutations in the five genes are in good agreement with previous reports.13, 14 It is of note that frequent mutations of TP53 have been found in aggressive endometrial carcinomas including high-grade serous types and carcinosarcomas.15 In addition, TP53 (75.5%) and PIK3CA (34.0%) mutations are most frequently observed in uterine carcinosarcoma.16 Consistent with these reports, we identified TP53 mutations in the two patients with carcinosarcomas and in a patient with endometrioid carcinoma at stage IIIc2.	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (240, 262))	('TP53', 'Gene', '7157', (478, 482))	('carcinosarcomas', 'Disease', 'MESH:D002296', (301, 316))	('TP53', 'Gene', (333, 337))	('PIK3CA', 'Gene', '5290', (350, 356))	('carcinosarcomas', 'Disease', (518, 533))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (556, 578))	('aggressive endometrial carcinomas', 'Disease', 'MESH:D016889', (229, 262))	('patients', 'Species', '9606', (504, 512))	('aggressive endometrial carcinomas', 'Disease', (229, 262))	('TP53', 'Gene', '7157', (205, 209))	('carcinosarcomas', 'Disease', (301, 316))	('carcinosarcoma', 'Disease', (415, 429))	('mutations', 'Var', (483, 492))	('carcinosarcoma', 'Disease', 'MESH:D002296', (415, 429))	('TP53', 'Gene', '7157', (333, 337))	('endometrioid carcinoma', 'Disease', (556, 578))	('PIK3CA', 'Gene', (350, 356))	('TP53', 'Gene', (478, 482))	('carcinosarcoma', 'Disease', (518, 532))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (569, 578))	('carcinosarcoma', 'Disease', 'MESH:D002296', (518, 532))	('carcinosarcoma', 'Disease', (301, 315))	('patient', 'Species', '9606', (504, 511))	('carcinosarcomas', 'Disease', 'MESH:D002296', (518, 533))	('TP53', 'Gene', (205, 209))	('patient', 'Species', '9606', (543, 550))	('carcinosarcoma', 'Disease', 'MESH:D002296', (301, 315))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (556, 578))
28440	30289582	Additionally, PIK3CA and KRAS mutations were identified in one of the two cases with cervical adenocarcinoma.	('cervical adenocarcinoma', 'Disease', (85, 108))	('identified', 'Reg', (45, 55))	('cervical adenocarcinoma', 'Disease', 'MESH:D002575', (85, 108))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('PIK3CA', 'Gene', (14, 20))	('PIK3CA', 'Gene', '5290', (14, 20))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
28450	30289582	As a result, they identified mutations in all five EC patients.	('EC', 'Phenotype', 'HP:0012114', (51, 53))	('identified', 'Reg', (18, 28))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (29, 38))
28454	30289582	Wang Y. and colleagues reported that somatic mutations were detected in nine Pap brush samples from 714 control women without cancer.12 However, Maritschnegg et al documented that they determined somatic mutations in eight of 27 patients with benign disease, and that six of the eight mutations were detected in KRAS.17 Surprisingly, Nair et al.	('patients', 'Species', '9606', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (204, 213))	('women', 'Species', '9606', (112, 117))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('benign disease', 'Disease', (243, 257))	('benign disease', 'Disease', 'MESH:D009369', (243, 257))	('KRAS', 'Gene', (312, 316))	('KRAS', 'Gene', '3845', (312, 316))
28455	30289582	disclosed that uterine lavage fluid from 51 of 95 women without histopathological evidence of cancer carried mutations in cancer-associated genes.18 The mutations included KRAS G12S (10 cases), KRAS G12C (eight cases), and PIK3CA H1047R (eight cases), and their allele fractions were relatively high ranging from 1.0% to 30.4% (average: 3.0%).	('KRAS', 'Gene', (172, 176))	('KRAS', 'Gene', '3845', (172, 176))	('G12C', 'Mutation', 'rs121913530', (199, 203))	('G12S', 'Mutation', 'rs121913530', (177, 181))	('cancer', 'Disease', (122, 128))	('KRAS', 'Gene', (194, 198))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('women', 'Species', '9606', (50, 55))	('PIK3CA', 'Gene', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PIK3CA', 'Gene', '5290', (223, 229))	('H1047R', 'Var', (230, 236))	('KRAS', 'Gene', '3845', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('H1047R', 'SUBSTITUTION', 'None', (230, 236))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
28457	30289582	These data may imply that the KRAS mutation found in the FAP patient may be derived from non-pathogenic or premalignant lesion(s).	('patient', 'Species', '9606', (61, 68))	('FAP', 'Disease', 'MESH:C567782', (57, 60))	('mutation', 'Var', (35, 43))	('FAP', 'Disease', (57, 60))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (30, 34))
28460	30289582	Germline mutations in PTEN are responsible for Cowden syndrome.	('Germline mutations', 'Var', (0, 18))	('Cowden syndrome', 'Disease', 'MESH:D006223', (47, 62))	('Cowden syndrome', 'Disease', (47, 62))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('responsible', 'Reg', (31, 42))
28461	30289582	In the present study, we found 11 PTEN variants at a frequency ranging from 8% to 56%, and five cases showed more than 40%.	('PTEN', 'Gene', (34, 38))	('variants', 'Var', (39, 47))	('PTEN', 'Gene', '5728', (34, 38))
28462	30289582	However, Cowden syndrome is a rare autosomal dominant disorder and the frequency of this disease is considered to be approximately one in 200 000 individuals.22 In addition, no abnormality was found in 240 patients with endometrial cancer in the screening of PTEN mutations.23 Therefore, we assumed that the PTEN variants were somatic mutations.	('endometrial cancer', 'Disease', (220, 238))	('Cowden syndrome', 'Disease', (9, 24))	('autosomal dominant disorder', 'Disease', (35, 62))	('variants', 'Var', (313, 321))	('PTEN', 'Gene', (259, 263))	('endometrial cancer', 'Phenotype', 'HP:0012114', (220, 238))	('PTEN', 'Gene', '5728', (259, 263))	('PTEN', 'Gene', (308, 312))	('endometrial cancer', 'Disease', 'MESH:D016889', (220, 238))	('patients', 'Species', '9606', (206, 214))	('PTEN', 'Gene', '5728', (308, 312))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (35, 62))	('Cowden syndrome', 'Disease', 'MESH:D006223', (9, 24))
28466	30289582	Furthermore, identification of pathogenic mutations at endometrial screening may lead to the selection of anticancer drugs for neoadjuvant chemotherapy prior to surgical intervention.	('cancer', 'Disease', (110, 116))	('lead to', 'Reg', (81, 88))	('endometrial', 'Gene', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
28473	30347759	Of note, ZFPM1/FOG1 mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region.	('ZFPM1/FOG1', 'Gene', (9, 19))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (49, 73))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (49, 73))	('patients', 'Species', '9606', (74, 82))	('adrenocortical carcinoma', 'Disease', (49, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('occurred', 'Reg', (30, 38))	('mutations', 'Var', (20, 29))
28483	30347759	The imbalance in favor of the PR-minus is found in many human malignancies and it can be due to inactivating mutations or silencing of the complete form and/or to increased expression of the PR-minus form.	('inactivating mutations', 'Var', (96, 118))	('increased', 'PosReg', (163, 172))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('human', 'Species', '9606', (56, 61))	('expression', 'MPA', (173, 183))	('silencing', 'Var', (122, 131))	('malignancies', 'Disease', (62, 74))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
28488	30347759	For instance, frameshift mutations of microsatellite repeats within the PRDM2 coding region are frequent events in various cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('frameshift mutations', 'Var', (14, 34))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('PRDM2', 'Gene', '7799', (72, 77))	('PRDM2', 'Gene', (72, 77))	('cancers', 'Disease', (123, 130))	('microsatellite repeats', 'Var', (38, 60))
28489	30347759	A recent study has described a frameshift mutation in the C-terminal region of PRDM2, affecting the (A)9 repeat within exon 8, as a microsatellite indel driver hotspot and as a driver mutation in microsatellite instability (MSI) colorectal cancer.	('colorectal cancer', 'Disease', (229, 246))	('frameshift mutation', 'Var', (31, 50))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('colorectal cancer', 'Disease', 'MESH:D015179', (229, 246))	('MSI', 'Disease', 'None', (224, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (229, 246))	('PRDM2', 'Gene', (79, 84))	('PRDM2', 'Gene', '7799', (79, 84))	('MSI', 'Disease', (224, 227))	('affecting', 'Reg', (86, 95))	('microsatellite instability', 'Disease', (196, 222))
28490	30347759	Notably, a similar frameshift mutation was found to occur in a mononucleotide repeat (A7) of PRDM3/MECOM gene in this cancer type.	('cancer', 'Disease', (118, 124))	('PRDM3', 'Gene', (93, 98))	('occur', 'Reg', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MECOM', 'Gene', (99, 104))	('PRDM3', 'Gene', '2122', (93, 98))	('frameshift', 'Var', (19, 29))	('mononucleotide', 'Chemical', '-', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MECOM', 'Gene', '2122', (99, 104))
28496	30347759	This evidence suggests that PRDMs are involved in human cancer through modulation of several processes, such as epigenetic modifications, genetic reprogramming, inflammation, and metabolic homeostasis.	('epigenetic modifications', 'Var', (112, 136))	('modulation', 'Reg', (71, 81))	('involved', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('metabolic homeostasis', 'CPA', (179, 200))	('genetic reprogramming', 'CPA', (138, 159))	('inflammation', 'Disease', 'MESH:D007249', (161, 173))	('human', 'Species', '9606', (50, 55))	('inflammation', 'Disease', (161, 173))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
28497	30347759	To date, both mutations and altered expression have been reported for some PRDMs in specific cancer entities.	('PRDMs', 'Disease', (75, 80))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('reported', 'Reg', (57, 65))	('mutations', 'Var', (14, 23))	('expression', 'MPA', (36, 46))
28503	30347759	Silent or synonymous mutations were 1531 (26.7% of total mutations) and ranged between 11% (PRDM6) and 41% (PRDM8) of the total mutations for each gene (Figure 1).	('PRDM6', 'Gene', '93166', (92, 97))	('PRDM6', 'Gene', (92, 97))	('PRDM8', 'Gene', '56978', (108, 113))	('PRDM8', 'Gene', (108, 113))	('Silent or synonymous mutations', 'Var', (0, 30))
28505	30347759	Non-sense mutations were more recurrent in PRDM5 (23), PRDM9 (60), and ZFPM2/FOG2 (34), whereas splice sites disrupting mutations were more frequently detected in PRDM3/MECOM (13), PRDM9 (19), PRDM10 (14) and PRDM12 (13) (Figure 1).	('MECOM', 'Gene', (169, 174))	('PRDM9', 'Gene', (55, 60))	('PRDM9', 'Gene', '56979', (55, 60))	('PRDM5', 'Gene', '11107', (43, 48))	('PRDM10', 'Gene', '56980', (193, 199))	('MECOM', 'Gene', '2122', (169, 174))	('ZFPM2', 'Gene', '23414', (71, 76))	('ZFPM2', 'Gene', (71, 76))	('PRDM12', 'Gene', '59335', (209, 215))	('FOG2', 'Gene', '23414', (77, 81))	('FOG2', 'Gene', (77, 81))	('PRDM5', 'Gene', (43, 48))	('PRDM3', 'Gene', (163, 168))	('PRDM3', 'Gene', '2122', (163, 168))	('PRDM12', 'Gene', (209, 215))	('Non-sense mutations', 'Var', (0, 19))	('PRDM10', 'Gene', (193, 199))	('PRDM9', 'Gene', (181, 186))	('PRDM9', 'Gene', '56979', (181, 186))
28509	30347759	In detail, PRDM8 and PRDM15 were mutated at low rates in most of the analyzed cancer types except PAAD where they were both frequently mutated (16.0% and 11.2%, respectively).	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutated', 'Var', (33, 40))	('PRDM8', 'Gene', (11, 16))	('PRDM8', 'Gene', '56978', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PRDM15', 'Gene', '63977', (21, 27))	('PRDM15', 'Gene', (21, 27))
28515	30347759	Through this approach, we evaluated the percentage of samples with at least one mutated PRDM gene in each tumor type ranging from 1.02% (2/196) in LAML samples to 55.43% (51/92) in ACC samples.	('PRDM', 'Gene', (88, 92))	('mutated', 'Var', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
28517	30347759	Specifically, we found 11/18 (61%) multi-hit mutations in COAD, 10/11 (90%) in READ, and 23/47 (48%) in ACC (see Supplementary file S1).	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (45, 54))	('COAD', 'Disease', (58, 62))
28518	30347759	Missense mutations with a SIFT score ranging in the interval 0.0-0.05 and/or with a PolyPhen score in the interval 0.5-1 were considered as deleterious or probably damaging, respectively.	('SIFT', 'Disease', (26, 30))	('SIFT', 'Disease', 'None', (26, 30))	('Missense mutations', 'Var', (0, 18))
28521	30347759	Interestingly, a random sampling weighted on the size of the annotated protein domains demonstrated that somatic deleterious mutations were significantly enriched in the PR domain of PRDM1, PRDM5, PRDM6, PRDM8, PRDM9, PRDM12 and PRDM13 (p < 0.005).	('PRDM13', 'Gene', '59336', (229, 235))	('PRDM12', 'Gene', '59335', (218, 224))	('PRDM8', 'Gene', (204, 209))	('PRDM13', 'Gene', (229, 235))	('PRDM1', 'Gene', '639', (229, 234))	('PRDM1', 'Gene', '639', (183, 188))	('PRDM9', 'Gene', (211, 216))	('PRDM6', 'Gene', '93166', (197, 202))	('PRDM9', 'Gene', '56979', (211, 216))	('PRDM1', 'Gene', (229, 234))	('PRDM1', 'Gene', (183, 188))	('mutations', 'Var', (125, 134))	('PRDM5', 'Gene', '11107', (190, 195))	('PRDM6', 'Gene', (197, 202))	('PRDM12', 'Gene', (218, 224))	('PRDM5', 'Gene', (190, 195))	('PRDM1', 'Gene', '639', (218, 223))	('PRDM8', 'Gene', '56978', (204, 209))	('PRDM1', 'Gene', (218, 223))
28522	30347759	Another important aspect of cancer genetic studies is the presence of possible recurrent and hotspot mutations.	('cancer', 'Disease', (28, 34))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
28523	30347759	Figure 3 illustrates mutations in PRDM genes recurring in more than three tumor types.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PRDM genes', 'Gene', (34, 44))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (21, 30))
28524	30347759	Interestingly, the frameshift mutation T/- K678X, despite affecting PRDM3/MECOM in a region not containing known domains, was recurrent in different tumor types; similarly, also the missense mutation G/A S237L occurred in a region without known domains but in many tumors.	('G/A S237L', 'Var', (200, 209))	('MECOM', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (265, 270))	('PRDM3', 'Gene', '2122', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('affecting', 'Reg', (58, 67))	('tumors', 'Disease', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('S237L', 'Mutation', 'rs748747672', (204, 209))	('MECOM', 'Gene', '2122', (74, 79))	('tumor', 'Disease', (149, 154))	('K678X', 'Mutation', 'p.K678X', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('T/- K678X', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('PRDM3', 'Gene', (68, 73))
28525	30347759	Otherwise, missense mutations affecting a Zn-finger domain and occurring in different tumors were observed for PRDM9, PRDM14, and PRDM16.	('PRDM16', 'Gene', '63976', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Zn-finger domain', 'MPA', (42, 58))	('PRDM9', 'Gene', (111, 116))	('affecting', 'Reg', (30, 39))	('PRDM9', 'Gene', '56979', (111, 116))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('missense mutations', 'Var', (11, 29))	('PRDM16', 'Gene', (130, 136))	('PRDM14', 'Gene', (118, 124))	('PRDM14', 'Gene', '63978', (118, 124))
28526	30347759	Likewise, PRDM12 was frequently mutated in a splice donor site in a region coding for the PR domain whereas in different tumor types, ZFPM2/FOG2 was affected by the missense mutation C/T R734C in a region without known domains.	('donor', 'Species', '9606', (52, 57))	('ZFPM2', 'Gene', '23414', (134, 139))	('R734C', 'Mutation', 'rs781567366', (187, 192))	('ZFPM2', 'Gene', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('PRDM12', 'Gene', '59335', (10, 16))	('PRDM12', 'Gene', (10, 16))	('FOG2', 'Gene', '23414', (140, 144))	('FOG2', 'Gene', (140, 144))	('C/T R734C', 'Var', (183, 192))	('affected', 'Reg', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
28527	30347759	In addition, PRDM2 and PRDM15 revealed an in-frame deletion in various cancers and PRDM11 a frameshift mutation.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('in-frame deletion', 'Var', (42, 59))	('cancers', 'Disease', (71, 78))	('PRDM11', 'Gene', '56981', (83, 89))	('PRDM2', 'Gene', (13, 18))	('PRDM2', 'Gene', '7799', (13, 18))	('frameshift mutation', 'Var', (92, 111))	('PRDM15', 'Gene', '63977', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PRDM15', 'Gene', (23, 29))	('PRDM11', 'Gene', (83, 89))
28528	30347759	Interestingly, all these mutations were particularly recurrent in ACC patients.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (25, 34))	('ACC', 'Disease', (66, 69))
28529	30347759	Otherwise, the frameshift mutations E444X and P445X led to premature stop codons at the residues 669 and 796, respectively; both of the mutated proteins shared only the first 443 residues with the canonical protein whereas they changed in the 444-669 and 444-796 regions and missed respectively 337 and 210 residues at the C-terminal, which contains the last five zinc fingers of ZFPM1/FOG1.	('P445X', 'Var', (46, 51))	('E444X', 'Mutation', 'p.E444X', (36, 41))	('ZFPM1/FOG1', 'Gene', (380, 390))	('P445X', 'Mutation', 'p.P445X', (46, 51))	('E444X', 'Var', (36, 41))
28531	30347759	This method is based on the feature that cancer gene mutations frequently cluster in particular positions of the protein.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (53, 62))	('cluster', 'Reg', (74, 81))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
28532	30347759	Based on the scores of this analysis, ZFPM1/FOG1 can be considered as a cancer driver for ACC (Figure 4f) and PRDM8 for PAAD (Figure S2).	('ACC', 'Disease', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ZFPM1/FOG1', 'Var', (38, 48))	('PAAD', 'Disease', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('PRDM8', 'Gene', (110, 115))	('PRDM8', 'Gene', '56978', (110, 115))	('cancer', 'Disease', (72, 78))
28557	30347759	Remarkably, VEP analysis indicated that the percentage of total deleterious mutations across the tumor samples was high for most genes.	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (76, 85))
28558	30347759	More interestingly, a random sampling weighted on the size of the annotated protein domains demonstrated that deleterious mutations were significantly enriched in the PR domain of PRDM1, PRDM5, PRDM6, PRDM8, PRDM9, PRDM12 and PRDM13.	('PRDM5', 'Gene', '11107', (187, 192))	('PRDM12', 'Gene', (215, 221))	('PRDM5', 'Gene', (187, 192))	('PRDM1', 'Gene', '639', (215, 220))	('PRDM1', 'Gene', (215, 220))	('PRDM8', 'Gene', '56978', (201, 206))	('PRDM13', 'Gene', '59336', (226, 232))	('PRDM1', 'Gene', '639', (180, 185))	('PRDM9', 'Gene', (208, 213))	('PRDM6', 'Gene', '93166', (194, 199))	('PRDM13', 'Gene', (226, 232))	('PRDM1', 'Gene', (180, 185))	('PRDM9', 'Gene', '56979', (208, 213))	('PRDM1', 'Gene', '639', (226, 231))	('PRDM8', 'Gene', (201, 206))	('PRDM12', 'Gene', '59335', (215, 221))	('PRDM1', 'Gene', (226, 231))	('PRDM6', 'Gene', (194, 199))	('mutations', 'Var', (122, 131))
28559	30347759	Frequent mutations disrupting the PR domain in tumor samples would be a mechanism for removing the tumor suppressor function of the PR-plus isoform in favor of the oncogenic PR-minus form.	('tumor', 'Disease', (99, 104))	('removing', 'NegReg', (86, 94))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (47, 52))
28560	30347759	A big challenge in cancer biology studies is distinguishing between mutations conferring a selective growth advantage to cancer cells (drivers) and those randomly accumulating and without significant effects on the oncogenic process (passengers).	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('growth advantage', 'CPA', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (68, 77))	('cancer', 'Disease', (121, 127))
28561	30347759	Moreover, recent studies have highlighted the existence of "mini-driver" genes with weaker tumor-promoting effects, thus expanding the previous driver-passenger dichotomy to a continuous model.	('genes', 'Var', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
28564	30347759	Notably, these hotspot mutations recurred also in other malignancies, such as COAD, KIRP, READ, STAD, and UCS, supporting an important role of this gene in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('STAD', 'Disease', (96, 100))	('READ', 'Disease', (90, 94))	('carcinogenesis', 'Disease', (156, 170))	('KIRP', 'Disease', (84, 88))	('COAD', 'Disease', 'MESH:D029424', (78, 82))	('UCS', 'Disease', (106, 109))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('mutations', 'Var', (23, 32))	('malignancies', 'Disease', (56, 68))	('COAD', 'Disease', (78, 82))
28572	30347759	Additionally, a recent study identified a driver PRDM2 mutation in MSI colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MSI colorectal cancer', 'Disease', 'MESH:D015179', (67, 88))	('MSI colorectal cancer', 'Disease', (67, 88))	('PRDM2', 'Gene', '7799', (49, 54))	('mutation', 'Var', (55, 63))	('PRDM2', 'Gene', (49, 54))
28579	30347759	Moreover, it would be interesting to investigate whether these mutations contribute to cancer progression and metastasis, as well as whether they correlate with prognosis and/or with drug response and resistance.	('mutations', 'Var', (63, 72))	('cancer', 'Disease', (87, 93))	('contribute', 'Reg', (73, 83))	('metastasis', 'CPA', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('correlate', 'Reg', (146, 155))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
28582	30347759	To assess whether one or more PRDM proteins could be considered as cancer driver genes based on the positional clustering of the variants in the selected human cancers, we used a re-implementation of the software OncodriveCLUST within the maftools package.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('human', 'Species', '9606', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancer', 'Disease', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancer', 'Disease', (160, 166))	('cancers', 'Disease', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('variants', 'Var', (129, 137))
28583	30347759	Three-dimensional (3D) modeling of the human canonical and mutant ZFPM1/FOG1 proteins was carried out using I-TASSER.	('ZFPM1/FOG1', 'Gene', (66, 76))	('mutant', 'Var', (59, 65))	('human', 'Species', '9606', (39, 44))
28644	30410774	published a decision analysis comparing surgical risks of laparotomy with risks of disseminated occult malignancy during laparoscopy for women with large leiomyoma, and predicted that laparoscopic hysterectomy was associated with slightly better 5-year overall survival and improved quality-adjusted life years.	('better', 'PosReg', (239, 245))	('occult malignancy', 'Disease', 'MESH:D009369', (96, 113))	('leiomyoma', 'Disease', 'MESH:D007889', (154, 163))	('occult malignancy', 'Disease', (96, 113))	('overall survival', 'MPA', (253, 269))	('laparoscopic', 'Var', (184, 196))	('improved', 'PosReg', (274, 282))	('women', 'Species', '9606', (137, 142))	('leiomyoma', 'Disease', (154, 163))	('quality-adjusted life years', 'CPA', (283, 310))
28645	30410774	Thus, on a population level, the benefits of MIS for the large majority of patients may outweigh the very small risk of disseminating occult malignancy in very few patients.	('patients', 'Species', '9606', (75, 83))	('MIS', 'Var', (45, 48))	('patients', 'Species', '9606', (164, 172))	('occult malignancy', 'Disease', (134, 151))	('occult malignancy', 'Disease', 'MESH:D009369', (134, 151))
28694	28940304	Overall, among 53 UCSs in this study, the most frequently mutated of these 15 genes were TP53 (75.5%), PIK3CA (34.0%), PPP2R1A (18.9%), FBXW7 (18.9%), CHD4 (17.0%), and FOXA2 (15.1%).	('FBXW7', 'Gene', '55294', (136, 141))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('CHD4', 'Gene', '1108', (151, 155))	('FOXA2', 'Gene', '3170', (169, 174))	('FBXW7', 'Gene', (136, 141))	('PIK3CA', 'Gene', (103, 109))	('FOXA2', 'Gene', (169, 174))	('CHD4', 'Gene', (151, 155))	('PIK3CA', 'Gene', '5290', (103, 109))	('PPP2R1A', 'Gene', (119, 126))	('mutated', 'Var', (58, 65))	('PPP2R1A', 'Gene', '5518', (119, 126))
28695	28940304	FOXA2 has not previously been implicated in UCSs and was predominated by frameshift and nonsense mutations.	('FOXA2', 'Gene', '3170', (0, 5))	('nonsense mutations', 'Var', (88, 106))	('frameshift', 'Var', (73, 83))	('FOXA2', 'Gene', (0, 5))
28696	28940304	One UCS with a FOXA2 frameshift mutation expressed truncated FOXA2 protein by immunoblotting.	('FOXA2', 'Gene', '3170', (15, 20))	('FOXA2', 'Gene', '3170', (61, 66))	('truncated', 'MPA', (51, 60))	('FOXA2', 'Gene', (15, 20))	('protein', 'Protein', (67, 74))	('FOXA2', 'Gene', (61, 66))	('frameshift mutation', 'Var', (21, 40))
28697	28940304	Sequencing of FOXA2 in 160 primary ECs revealed somatic mutations in 5.7% of serous, 22.7% of clear cell, 9% of endometrioid and 11.1% of mixed ECs, most of which were frameshift mutations.	('frameshift mutations', 'Var', (168, 188))	('mutations', 'Var', (56, 65))	('FOXA2', 'Gene', (14, 19))	('EC', 'Phenotype', 'HP:0012114', (144, 146))	('EC', 'Phenotype', 'HP:0012114', (35, 37))	('serous', 'Disease', (77, 83))	('endometrioid', 'Disease', (112, 124))	('clear cell', 'Disease', (94, 104))	('FOXA2', 'Gene', '3170', (14, 19))
28706	28940304	Targeted gene sequencing and whole exome sequencing of UCSs have uncovered frequent somatic mutations in genes involved in the DNA damage response (TP53, MLH1), the PI3-kinase pathway (PIK3CA, PTEN, PIK3R1), chromatin remodeling (ARID1A, MLL3/KMT2C, ARID1B, BAZ1A), ubiquitin-mediated protein degradation (FBXW7, SPOP), signal transduction (KRAS, NRAS, JAK2, ERBB2), WNT signaling (CTNNB1) and protein dephosphorylation (PPP2R1A) , .	('protein dephosphorylation', 'MPA', (394, 419))	('TP53', 'Gene', (148, 152))	('FBXW7', 'Gene', '55294', (306, 311))	('KMT2C', 'Gene', '58508', (243, 248))	('KMT2C', 'Gene', (243, 248))	('PPP2R1A', 'Gene', '5518', (421, 428))	('PIK3CA', 'Gene', '5290', (185, 191))	('ERBB2', 'Gene', '2064', (359, 364))	('MLL3', 'Gene', (238, 242))	('NRAS', 'Gene', '4893', (347, 351))	('PTEN', 'Gene', (193, 197))	('CTNNB1', 'Gene', '1499', (382, 388))	('DNA', 'MPA', (127, 130))	('PPP2R1A', 'Gene', (421, 428))	('JAK2', 'Gene', '3717', (353, 357))	('PIK3R1', 'Gene', (199, 205))	('PI3-kinase', 'Pathway', (165, 175))	('TP53', 'Gene', '7157', (148, 152))	('PTEN', 'Gene', '5728', (193, 197))	('ARID1A', 'Gene', (230, 236))	('ARID1B', 'Gene', (250, 256))	('mutations', 'Var', (92, 101))	('PIK3CA', 'Gene', (185, 191))	('MLH1', 'Gene', (154, 158))	('KRAS', 'Gene', '3845', (341, 345))	('FBXW7', 'Gene', (306, 311))	('BAZ1A', 'Gene', (258, 263))	('CTNNB1', 'Gene', (382, 388))	('NRAS', 'Gene', (347, 351))	('ARID1B', 'Gene', '57492', (250, 256))	('KRAS', 'Gene', (341, 345))	('signal transduction', 'MPA', (320, 339))	('JAK2', 'Gene', (353, 357))	('ARID1A', 'Gene', '8289', (230, 236))	('MLH1', 'Gene', '4292', (154, 158))	('MLL3', 'Gene', '58508', (238, 242))	('BAZ1A', 'Gene', '11177', (258, 263))	('ERBB2', 'Gene', (359, 364))	('ubiquitin-mediated protein degradation', 'MPA', (266, 304))	('PIK3R1', 'Gene', '5295', (199, 205))
28708	28940304	The recent integrated genomic analysis of 57 UCSs by The Cancer Genome Atlas (TCGA) further implicated the mutational disruption of ARHGAP35, RB1, U2AF1, and ZBTB7B in the molecular pathogenesis of UCS .	('UCS', 'Disease', (198, 201))	('U2AF1', 'Gene', (147, 152))	('Cancer Genome Atlas', 'Disease', (57, 76))	('ZBTB7B', 'Gene', (158, 164))	('ARHGAP35', 'Gene', (132, 140))	('RB1', 'Gene', (142, 145))	('ZBTB7B', 'Gene', '51043', (158, 164))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (57, 76))	('RB1', 'Gene', '5925', (142, 145))	('mutational disruption', 'Var', (107, 128))	('U2AF1', 'Gene', '7307', (147, 152))	('ARHGAP35', 'Gene', '2909', (132, 140))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
28711	28940304	We also report frequent FOXA2 mutations in other histological subtypes of EC, further supporting FOXA2 as a driver of uterine carcinomas.	('FOXA2', 'Gene', (24, 29))	('FOXA2', 'Gene', '3170', (97, 102))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (118, 136))	('FOXA2', 'Gene', (97, 102))	('EC', 'Phenotype', 'HP:0012114', (74, 76))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('FOXA2', 'Gene', '3170', (24, 29))	('carcinomas', 'Disease', (126, 136))	('carcinomas', 'Disease', 'MESH:D002277', (126, 136))
28724	28940304	Exonic variants were discriminated as somatic or germline by sequencing independent PCR products generated from relevant tumor and matched normal DNAs.	('Exonic variants', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
28738	28940304	There was a mean of 33 validated nonsynonymous/splice junction somatic mutations per tumor (range 13-71 mutations/tumor); validated mutations were distributed among 426 protein-encoding genes.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('nonsynonymous/splice junction', 'Var', (33, 62))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
28743	28940304	Given the high frequency of frameshift FOXA2 mutations in the prevalence screen tumors (described below), and the known challenges in calling insertions and deletions by next generation sequencing , we subsequently also Sanger sequenced FOXA2 in the 14 discovery screen tumors.	('tumors', 'Disease', (270, 276))	('mutations', 'Var', (45, 54))	('FOXA2', 'Gene', (237, 242))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('FOXA2', 'Gene', '3170', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('FOXA2', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('frameshift', 'Var', (28, 38))	('FOXA2', 'Gene', '3170', (237, 242))
28744	28940304	Among the 53 tumors in the combined discovery and prevalence screens, the most frequently mutated of the 15 genes were TP53 (75.5% of UCSs somatically mutated), PIK3CA (34.0%), PPP2R1A (18.9%), FBXW7 (18.9%), CHD4 (17.0%), and FOXA2 (15.1%) (Figure 1, Table 1, Supplementary Table 5, and Supplementary Figure 1).	('CHD4', 'Gene', '1108', (209, 213))	('tumors', 'Disease', (13, 19))	('FOXA2', 'Gene', (227, 232))	('mutated', 'Var', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('PIK3CA', 'Gene', (161, 167))	('PIK3CA', 'Gene', '5290', (161, 167))	('PPP2R1A', 'Gene', (177, 184))	('CHD4', 'Gene', (209, 213))	('FBXW7', 'Gene', '55294', (194, 199))	('PPP2R1A', 'Gene', '5518', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('TP53', 'Gene', '7157', (119, 123))	('FOXA2', 'Gene', '3170', (227, 232))	('TP53', 'Gene', (119, 123))	('FBXW7', 'Gene', (194, 199))
28746	28940304	Most FOXA2 mutations were frameshift or nonsense mutations predicted to encode truncated proteins that would disrupt one or more functional domains, including the carboxy-terminal transactivation domain (Figure 2a, and Table 1).	('mutations', 'Var', (11, 20))	('FOXA2', 'Gene', '3170', (5, 10))	('carboxy-terminal', 'MPA', (163, 179))	('frameshift', 'Var', (26, 36))	('FOXA2', 'Gene', (5, 10))	('disrupt', 'NegReg', (109, 116))
28747	28940304	Two missense mutations in FOXA2 localized to the central DNA binding (Winged helix) domain (Figure 2a), which is highly conserved across proteins in the forkhead box family .	('FOXA2', 'Gene', (26, 31))	('FOXA2', 'Gene', '3170', (26, 31))	('localized', 'Reg', (32, 41))	('missense mutations', 'Var', (4, 22))
28748	28940304	Both missense mutations are predicted to impact protein function by three in silico algorithms (Mutation Assessor, PolyPhen, and SIFT).	('SIFT', 'Disease', 'None', (129, 133))	('missense mutations', 'Var', (5, 23))	('protein', 'Protein', (48, 55))	('SIFT', 'Disease', (129, 133))	('impact', 'Reg', (41, 47))
28749	28940304	Only one of eight FOXA2-mutated tumors (1241T; FOXA2-Met142Profs*8) was MSI+ and none were MSH6- or POLE-mutated (Figure 1).	('MSH6', 'Gene', '2956', (91, 95))	('FOXA2', 'Gene', (18, 23))	('1241T;', 'Var', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('FOXA2', 'Gene', '3170', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('MSH6', 'Gene', (91, 95))	('FOXA2', 'Gene', '3170', (18, 23))	('FOXA2', 'Gene', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
28750	28940304	In terms of histology, FOXA2 mutations were identified in UCSs for which the sequenced DNA was isolated from admixed carcinoma/sarcoma (three cases) or from predominantly carcinoma (five cases) (Supplementary Table 1 and Supplementary Table 2).	('carcinoma', 'Disease', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('mutations', 'Var', (29, 38))	('carcinoma', 'Disease', (117, 126))	('FOXA2', 'Gene', '3170', (23, 28))	('carcinoma/sarcoma', 'Disease', 'MESH:D012509', (117, 134))	('FOXA2', 'Gene', (23, 28))	('carcinoma', 'Disease', 'MESH:D002277', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinoma/sarcoma', 'Disease', (117, 134))	('carcinoma', 'Disease', 'MESH:D002277', (117, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
28752	28940304	We uncovered somatic FOXA2 mutations in 5.7% of serous ECs, 22.7% of clear cell ECs, 9.0% of endometrioid ECs, and 11.1% of mixed histology ECs (Table 1).	('mutations', 'Var', (27, 36))	('clear cell ECs', 'Disease', (69, 83))	('endometrioid', 'Disease', (93, 105))	('EC', 'Phenotype', 'HP:0012114', (140, 142))	('FOXA2', 'Gene', (21, 26))	('serous ECs', 'Disease', (48, 58))	('EC', 'Phenotype', 'HP:0012114', (106, 108))	('EC', 'Phenotype', 'HP:0012114', (55, 57))	('EC', 'Phenotype', 'HP:0012114', (80, 82))	('FOXA2', 'Gene', '3170', (21, 26))
28754	28940304	Five frameshift mutations in ECs and one frameshift mutation in a UCS formed a FOXA2 mutation cluster, resulting from overlapping genomic deletions in which the first positions of the frameshift were located within amino acids 346-349 (Figure 2b).	('FOXA2', 'Gene', '3170', (79, 84))	('frameshift', 'Var', (5, 15))	('FOXA2', 'Gene', (79, 84))	('EC', 'Phenotype', 'HP:0012114', (29, 31))
28755	28940304	All but one of 16 FOXA2 mutations in ECs are predicted to prematurely truncate FOXA2 (Figure 2a), and most FOXA2-mutated ECs (13 of 16 cases) were microsatellite stable (Supplementary Table 6) consistent with our observations in UCSs (Figure 1).	('FOXA2', 'Gene', '3170', (107, 112))	('FOXA2', 'Gene', (107, 112))	('FOXA2', 'Gene', (18, 23))	('EC', 'Phenotype', 'HP:0012114', (121, 123))	('truncate', 'NegReg', (70, 78))	('mutations', 'Var', (24, 33))	('FOXA2', 'Gene', '3170', (79, 84))	('FOXA2', 'Gene', '3170', (18, 23))	('EC', 'Phenotype', 'HP:0012114', (37, 39))	('FOXA2', 'Gene', (79, 84))
28761	28940304	Strikingly, one tumor (UCS-5) exhibited a shorter form of FOXA2 than expected (Figure 3b); sequencing all coding exons of FOXA2 from the genomic DNA of this tumor revealed that it harbored the A346Gfs*11 variant (Figure 3c).	('tumor', 'Disease', (157, 162))	('FOXA2', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('FOXA2', 'Gene', '3170', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('A346Gfs', 'Mutation', 'c.346,FSA>G', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('A346Gfs*11', 'Var', (193, 203))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('FOXA2', 'Gene', (122, 127))	('FOXA2', 'Gene', '3170', (58, 63))
28762	28940304	Matched normal DNA for UCS-5 was not available for sequencing but we predict that the A346Gfs*11 variant in this tumor is more likely to be somatic than germline because this alteration also occurred as a somatic mutation in a serous EC in our study (Table 1), and because it occurred within the recurrently mutated N-terminal region of FOXA2 (Figure 2).	('tumor', 'Disease', (113, 118))	('A346Gfs', 'Mutation', 'c.346,FSA>G', (86, 93))	('A346Gfs*11', 'Var', (86, 96))	('FOXA2', 'Gene', (337, 342))	('EC', 'Phenotype', 'HP:0012114', (234, 236))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('FOXA2', 'Gene', '3170', (337, 342))
28763	28940304	Although the A346Gfs*11 variant in UCS-5 appeared to be heterozygous at the genomic level, only the variant allele was detectable in cDNA generated from this tumor (Figure 3c).	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('UCS-5', 'Gene', (35, 40))	('A346Gfs', 'Mutation', 'c.346,FSA>G', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('A346Gfs*11', 'Var', (13, 23))
28766	28940304	The occurrence of FOXA2 mutations in 15.1% of UCSs in our study coupled with the fact that they are predominated by frameshift mutations predicted to prematurely truncate FOXA2 strongly suggests they are pathogenic driver mutations in some UCSs.	('FOXA2', 'Gene', (18, 23))	('pathogenic', 'Reg', (204, 214))	('frameshift', 'Var', (116, 126))	('FOXA2', 'Gene', '3170', (171, 176))	('FOXA2', 'Gene', (171, 176))	('mutations', 'Var', (24, 33))	('FOXA2', 'Gene', '3170', (18, 23))	('UCSs', 'Disease', (240, 244))
28768	28940304	Our observation of FOXA2 mutations in 9% of endometrioid ECs corroborates the recent report of FOXA2 mutations in 9.4% of such tumors .	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutations', 'Var', (25, 34))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('FOXA2', 'Gene', '3170', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('endometrioid ECs', 'Disease', (44, 60))	('FOXA2', 'Gene', '3170', (95, 100))	('FOXA2', 'Gene', (19, 24))	('FOXA2', 'Gene', (95, 100))	('EC', 'Phenotype', 'HP:0012114', (57, 59))
28769	28940304	We extend these observations to further implicate FOXA2 as a candidate driver gene in other EC histological subtypes: within our cohort, 22.7% of clear cell, 11.1% of mixed histology and 5.7% of serous ECs harbored FOXA2 mutations.	('EC', 'Phenotype', 'HP:0012114', (92, 94))	('mutations', 'Var', (221, 230))	('harbored', 'Reg', (206, 214))	('EC', 'Phenotype', 'HP:0012114', (202, 204))	('FOXA2', 'Gene', '3170', (50, 55))	('FOXA2', 'Gene', '3170', (215, 220))	('FOXA2', 'Gene', (50, 55))	('FOXA2', 'Gene', (215, 220))
28772	28940304	One UCS that exhibited wildtype and mutated FOXA2 in genomic DNA had only the mutated allele in the cDNA and exhibited only a truncated protein by immunoblotting.	('mutated', 'Var', (36, 43))	('FOXA2', 'Gene', '3170', (44, 49))	('FOXA2', 'Gene', (44, 49))
28773	28940304	These observations suggest that this tumor is either homozygous for the mutated allele with the wildtype allele in the genomic DNA being contributed by admixed normal cells that do not express the FOXA2 protein, or that the tumor is heterozygous at the genomic level but expresses FOXA2 exclusively from the mutant allele.	('mutated', 'Var', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (224, 229))	('FOXA2', 'Gene', '3170', (197, 202))	('FOXA2', 'Gene', '3170', (281, 286))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('FOXA2', 'Gene', (197, 202))	('FOXA2', 'Gene', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
28774	28940304	Further studies are required to determine whether other FOXA2-mutated UCSs and ECs exclusively express the mutant allele.	('EC', 'Phenotype', 'HP:0012114', (79, 81))	('FOXA2', 'Gene', (56, 61))	('mutant', 'Var', (107, 113))	('FOXA2', 'Gene', '3170', (56, 61))
28776	28940304	Our combined whole exome sequencing and targeted gene sequencing of UCSs also revealed frequent somatic mutations in FBXW7 and CHD4.	('CHD4', 'Gene', '1108', (127, 131))	('mutations', 'Var', (104, 113))	('FBXW7', 'Gene', '55294', (117, 122))	('CHD4', 'Gene', (127, 131))	('FBXW7', 'Gene', (117, 122))
28777	28940304	The incidence of somatic FBXW7 mutations among the UCSs in our study (18.9%) is in keeping with the frequency at which this tumor suppressor gene is mutated in other UCS cohorts (10.7% to 39%) .	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('FBXW7', 'Gene', '55294', (25, 30))	('FBXW7', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
28778	28940304	All FBXW7 mutations in the UCSs within our study localized to the substrate-binding WD repeats (Supplementary Figure 1), consistent with the FBXW7 mutation spectrum in other cancers , including endometrial cancers.	('WD', 'Disease', 'MESH:D006527', (84, 86))	('endometrial cancers', 'Disease', (194, 213))	('FBXW7', 'Gene', '55294', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('localized', 'Reg', (49, 58))	('FBXW7', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('FBXW7', 'Gene', '55294', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('mutations', 'Var', (10, 19))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('endometrial cancer', 'Phenotype', 'HP:0012114', (194, 212))	('FBXW7', 'Gene', (141, 146))	('cancers', 'Disease', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('endometrial cancers', 'Disease', 'MESH:D016889', (194, 213))
28780	28940304	Our finding that 17% of UCSs had somatically mutated CHD4, which encodes a catalytic subunit of the NuRD chromatin remodeling complex, is in line with recent reports of CHD4 mutations in 5.9%-18% of UCS cohorts .	('UCSs', 'Disease', (24, 28))	('CHD4', 'Gene', (169, 173))	('CHD4', 'Gene', (53, 57))	('CHD4', 'Gene', '1108', (169, 173))	('CHD4', 'Gene', '1108', (53, 57))	('mutated', 'Var', (45, 52))
28781	28940304	Most (6 of 10) CHD4 mutations in our study localized to the catalytic ATPase-helicase and helicase domains (Supplementary Figure 1), and two of these mutations involved arginine-975 and arginine-1162, which are two prominent pan-cancer mutation hotspots in CHD4 .	('arginine', 'Chemical', 'MESH:D001120', (169, 177))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('arginine-1162', 'Var', (186, 199))	('CHD4', 'Gene', (15, 19))	('CHD4', 'Gene', '1108', (257, 261))	('arginine-975', 'Var', (169, 181))	('helicase', 'Protein', (90, 98))	('localized', 'Reg', (43, 52))	('CHD4', 'Gene', (257, 261))	('CHD4', 'Gene', '1108', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('arginine', 'Chemical', 'MESH:D001120', (186, 194))	('mutations', 'Var', (20, 29))
28782	28940304	In conclusion, using a combination of whole exome sequencing and targeted gene sequencing we have identified a high frequency of FOXA2 frameshift mutations in UCSs.	('FOXA2', 'Gene', (129, 134))	('frameshift mutations', 'Var', (135, 155))	('UCSs', 'Disease', (159, 163))	('FOXA2', 'Gene', '3170', (129, 134))
28783	28940304	In addition, we also find frequent FOXA2 frameshift mutations in uterine carcinomas including serous ECs and clear cell ECs.	('FOXA2', 'Gene', '3170', (35, 40))	('EC', 'Phenotype', 'HP:0012114', (120, 122))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (65, 83))	('FOXA2', 'Gene', (35, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('carcinomas', 'Disease', (73, 83))	('clear cell ECs', 'Disease', (109, 123))	('serous ECs', 'Disease', (94, 104))	('carcinomas', 'Disease', 'MESH:D002277', (73, 83))	('EC', 'Phenotype', 'HP:0012114', (101, 103))	('frameshift mutations', 'Var', (41, 61))
28795	26463439	The distinctions in both clinicopathological and prognostic characteristics between UCS and G3EC suggest that this subtype should be treated separately from high-risk epithelial endometrial carcinoma.	('G3EC', 'Var', (92, 96))	('UCS', 'Chemical', '-', (84, 87))	('UCS', 'Disease', (84, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('epithelial endometrial carcinoma', 'Disease', 'MESH:D016889', (167, 199))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (178, 199))	('epithelial endometrial carcinoma', 'Disease', (167, 199))	('EC', 'Phenotype', 'HP:0012114', (94, 96))	('UCS', 'Phenotype', 'HP:0002891', (84, 87))
28835	26463439	The average diameter of the largest tumors observed in UCS and G3EC patients were 4.6 cm (range, 0.3 to 14.0 cm) and 4.0 cm (range, 0.3 to 11.0 cm), respectively, and these values showed significant statistical differences (p=0.046).	('UCS', 'Phenotype', 'HP:0002891', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('patients', 'Species', '9606', (68, 76))	('G3EC', 'Var', (63, 67))	('UCS', 'Chemical', '-', (55, 58))	('EC', 'Phenotype', 'HP:0012114', (65, 67))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
28851	26463439	G3EC patients with ascites fluid (p=0.003), advanced disease (p<0.001), adnexal involvement (p=0.043), vaginal involvement (p=0.027), LVSI and nerve invasion (p<0.001), and lymph node metastases (p<0.001) were correlated with worse OS (Table 3).	('worse OS', 'Disease', (226, 234))	('patients', 'Species', '9606', (5, 13))	('ascites', 'Phenotype', 'HP:0001541', (19, 26))	('lymph node metastases', 'Disease', 'MESH:D009362', (173, 194))	('ascites fluid', 'Disease', (19, 32))	('lymph node metastases', 'Disease', (173, 194))	('G3EC', 'Var', (0, 4))	('ascites fluid', 'Disease', 'MESH:D001201', (19, 32))	('OS', 'Chemical', '-', (232, 234))	('EC', 'Phenotype', 'HP:0012114', (2, 4))
28861	26463439	A SEER (Surveillance, Epidemiology and End Results) study reported that high-grade EM cases had significantly better OS than UCS cases after adjusting for age, race, lymph node dissection, stage, and postoperative RT.	('OS', 'Chemical', '-', (117, 119))	('high-grade', 'Var', (72, 82))	('UCS', 'Phenotype', 'HP:0002891', (125, 128))	('better', 'PosReg', (110, 116))	('UCS', 'Chemical', '-', (125, 128))
28890	26463439	Several studies have shown favorable outcomes in carcinosarcoma patients treated with carboplatin-paclitaxel and recommended this regimen as a first-line treatment.	('patients', 'Species', '9606', (64, 72))	('carcinosarcoma', 'Disease', 'MESH:D002296', (49, 63))	('carboplatin', 'Chemical', 'MESH:D016190', (86, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('carboplatin-paclitaxel', 'Var', (86, 108))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('carcinosarcoma', 'Disease', (49, 63))
28941	26425710	Following surgical staging, the patient completed systemic treatment with carboplatin (AUC 5) and paclitaxel (175 mg/m2) dosed every 21 days, followed by whole pelvic radiotherapy (5040 cGy) and vaginal brachytherapy (2283 cGy).	('2283 cGy', 'Var', (218, 226))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('patient', 'Species', '9606', (32, 39))	('5040 cGy', 'Var', (181, 189))	('carboplatin', 'Chemical', 'MESH:D016190', (74, 85))
28988	26161390	Our review emphasizes on the strengths, pitfalls, and limitations of microscopic features as well as immunohistochemical and polymerase chain reaction- (PCR-) based tests used by laboratories to screen for DNA mismatch repair (MMR) and PTEN gene mutations in patients to enable a more targeted and cost effective approach in the use of confirmatory gene mutational analysis tests.	('mutations', 'Var', (246, 255))	('PTEN', 'Gene', (236, 240))	('PTEN', 'Gene', '5728', (236, 240))	('patients', 'Species', '9606', (259, 267))
28990	26161390	We also review the evidence postulating on the possible inclusion of uterine serous carcinoma as part of the spectrum of malignancies seen in hereditary breast and ovarian carcinoma syndrome, driven by mutations in BRCA1/2.	('hereditary breast and ovarian carcinoma syndrome', 'Disease', 'MESH:D061325', (142, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('BRCA1/2', 'Gene', (215, 222))	('malignancies', 'Disease', 'MESH:D009369', (121, 133))	('serous carcinoma', 'Disease', (77, 93))	('serous carcinoma', 'Disease', 'MESH:D018284', (77, 93))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (164, 181))	('BRCA1/2', 'Gene', '672;675', (215, 222))	('malignancies', 'Disease', (121, 133))	('mutations', 'Var', (202, 211))
28993	26161390	Since then, other mutations in molecular pathways such as DNA mismatch repair (MMR) and PTEN have shown to result in syndromes causing endometrial carcinomas, the most common gynecological carcinoma to afflict women worldwide.	('causing', 'Reg', (127, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinoma', 'Disease', (189, 198))	('carcinoma', 'Disease', (147, 156))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (135, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('PTEN', 'Gene', (88, 92))	('endometrial carcinomas', 'Disease', (135, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))	('PTEN', 'Gene', '5728', (88, 92))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (135, 157))	('women', 'Species', '9606', (210, 215))	('result in', 'Reg', (107, 116))	('carcinoma', 'Disease', 'MESH:D002277', (147, 156))	('carcinoma', 'Disease', 'MESH:D002277', (189, 198))	('syndromes', 'Disease', (117, 126))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (135, 156))	('mutations', 'Var', (18, 27))
28997	26161390	With the advent of immunohistochemical (IHC) markers and molecular testing for specific gene mutations, anatomic pathologists now play a bigger role than ever aiding oncologists and geneticists towards a more directed approach towards confirmatory genetic testing.	('aid', 'Gene', '57379', (159, 162))	('aid', 'Gene', (159, 162))	('mutations', 'Var', (93, 102))
29005	26161390	Microsatellite instability (MSI) can be seen in patients harboring either germline or somatic DNA MMR gene mutations.	('DNA MMR', 'Gene', (94, 101))	('Microsatellite instability', 'MPA', (0, 26))	('patients', 'Species', '9606', (48, 56))	('mutations', 'Var', (107, 116))
29006	26161390	LS is a result of germline mutations in the DNA MMR genes MLH1, MSH2, MSH6, and PSM2.	('germline mutations', 'Var', (18, 36))	('MSH2', 'Gene', (64, 68))	('MSH2', 'Gene', '4436', (64, 68))	('MSH6', 'Gene', (70, 74))	('PSM2', 'Gene', (80, 84))	('DNA MMR', 'Gene', (44, 51))	('MLH1', 'Gene', '4292', (58, 62))	('MSH6', 'Gene', '2956', (70, 74))	('MLH1', 'Gene', (58, 62))	('result', 'Reg', (8, 14))
29007	26161390	Nonhereditary somatic mutation is due to promoter hypermethylation of the MLH1 gene resulting in silencing of the gene causing similar MSI levels in the genome seen in 10% to 25% of sporadic tumors, especially colorectal and endometrial carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('MLH1', 'Gene', '4292', (74, 78))	('MLH1', 'Gene', (74, 78))	('sporadic tumors', 'Disease', 'MESH:D009369', (182, 197))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (225, 247))	('silencing', 'MPA', (97, 106))	('colorectal and endometrial carcinomas', 'Disease', 'MESH:D016889', (210, 247))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('sporadic tumors', 'Disease', (182, 197))	('promoter hypermethylation', 'Var', (41, 66))	('MSI levels', 'MPA', (135, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (225, 246))
29011	26161390	Approximately 2% to 6% of all endometrial carcinomas can be attributed to germline mutations in the DNA MMR genes.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('DNA MMR', 'Gene', (100, 107))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (30, 52))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (30, 51))	('attributed', 'Reg', (60, 70))	('germline mutations', 'Var', (74, 92))	('endometrial carcinomas', 'Disease', (30, 52))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (30, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
29013	26161390	Germline mutation in the MSH6 gene is associated with the highest risk for developing endometrial carcinomas.	('associated', 'Reg', (38, 48))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (86, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('MSH6', 'Gene', '2956', (25, 29))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (86, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (86, 107))	('Germline mutation', 'Var', (0, 17))	('endometrial carcinomas', 'Disease', (86, 108))	('MSH6', 'Gene', (25, 29))
29014	26161390	Mutations in MLH1 and MSH6 genes result in a higher risk of developing colorectal carcinoma.	('MSH6', 'Gene', '2956', (22, 26))	('colorectal carcinoma', 'Disease', (71, 91))	('MLH1', 'Gene', (13, 17))	('MLH1', 'Gene', '4292', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Mutations', 'Var', (0, 9))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (71, 91))	('MSH6', 'Gene', (22, 26))
29015	26161390	Individuals with germline mutations in PMS2 have the lowest overall risk of developing LS-associated tumors.	('PMS2', 'Gene', '5395', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('germline mutations', 'Var', (17, 35))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('PMS2', 'Gene', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
29021	26161390	Mutations in MSH6 and PSM2 are more likely to result in failure to meet either of the guidelines.	('result', 'Reg', (46, 52))	('MSH6', 'Gene', '2956', (13, 17))	('Mutations', 'Var', (0, 9))	('PSM2', 'Gene', (22, 26))	('MSH6', 'Gene', (13, 17))
29022	26161390	Clinical predictive tools relying on personal and family history such as PREMM1,2,6, MMRpredict, and MMRpro have been developed to quantify the risk of harboring germline DNA MMR mutations in colorectal patients.	('colorectal', 'Disease', 'MESH:D015179', (192, 202))	('patients', 'Species', '9606', (203, 211))	('germline DNA', 'Var', (162, 174))	('colorectal', 'Disease', (192, 202))
29039	26161390	Undifferentiated and dedifferentiated endometrioid carcinomas have been associated with MSI, in particular MLH1/PMS2 gene mutation, due to either promoter methylation or germline mutation.	('MSI', 'Disease', (88, 91))	('PMS2', 'Gene', '5395', (112, 116))	('germline mutation', 'Var', (170, 187))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (38, 61))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (38, 60))	('Undifferentiated', 'Disease', (0, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('mutation', 'Var', (122, 130))	('associated', 'Reg', (72, 82))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (38, 61))	('MLH1', 'Gene', '4292', (107, 111))	('MLH1', 'Gene', (107, 111))	('endometrioid carcinomas', 'Disease', (38, 61))	('PMS2', 'Gene', (112, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
29050	26161390	Cost effective and readily available screening tools available in most laboratories are (1) IHC to look for abnormal loss of DNA MMR proteins, (2) MSI analysis by PCR to detect for increased microsatellite repeats in specific loci and when required, and (3) MLH1 promoter methylation also utilizing PCR.	('loss', 'NegReg', (117, 121))	('microsatellite repeats', 'Var', (191, 213))	('DNA MMR proteins', 'Protein', (125, 141))	('MLH1', 'Gene', '4292', (258, 262))	('MLH1', 'Gene', (258, 262))	('increased', 'PosReg', (181, 190))
29055	26161390	In contrast to patients with colorectal cancers, patients with sporadic MSI MLH1 methylated endometrial carcinomas do not benefit from additional testing for V600E mutation of the BRAF gene as less than 1% display this mutation.	('patients', 'Species', '9606', (15, 23))	('endometrial carcinomas', 'Disease', (92, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('colorectal cancers', 'Disease', (29, 47))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (92, 113))	('V600E', 'Var', (158, 163))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BRAF', 'Gene', '673', (180, 184))	('MLH1', 'Gene', (76, 80))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (92, 114))	('BRAF', 'Gene', (180, 184))	('colorectal cancers', 'Disease', 'MESH:D015179', (29, 47))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (92, 114))	('patients', 'Species', '9606', (49, 57))	('MLH1', 'Gene', '4292', (76, 80))	('V600E', 'Mutation', 'rs113488022', (158, 163))
29058	26161390	Somatic mutation via epigenetic methylation silencing of the MLH1 promoter gene results in loss of PMS2 IHC staining.	('PMS2', 'Gene', (99, 103))	('epigenetic methylation silencing', 'Var', (21, 53))	('PMS2', 'Gene', '5395', (99, 103))	('MLH1', 'Gene', '4292', (61, 65))	('MLH1', 'Gene', (61, 65))	('loss', 'NegReg', (91, 95))
29059	26161390	Epigenetic silencing can also occur in the MSH2 gene following deletions in the EPCAM gene leading to loss of IHC staining in the partner protein, MSH6.	('EPCAM', 'Gene', '4072', (80, 85))	('MSH2', 'Gene', '4436', (43, 47))	('MSH6', 'Gene', '2956', (147, 151))	('deletions', 'Var', (63, 72))	('IHC staining in', 'MPA', (110, 125))	('MSH6', 'Gene', (147, 151))	('loss', 'NegReg', (102, 106))	('EPCAM', 'Gene', (80, 85))	('Epigenetic', 'MPA', (0, 10))	('MSH2', 'Gene', (43, 47))
29060	26161390	Germline mutations in MSH6 or PMS2 genes do not result in loss of IHC staining in its obligatory partner.	('PMS2', 'Gene', (30, 34))	('loss', 'NegReg', (58, 62))	('MSH6', 'Gene', '2956', (22, 26))	('IHC staining', 'MPA', (66, 78))	('PMS2', 'Gene', '5395', (30, 34))	('Germline', 'Var', (0, 8))	('MSH6', 'Gene', (22, 26))
29068	26161390	The Bethesda MSI panel consists of two mononucleotides and three dinucleotides (BAT25, BAT26, D2S123, D5S346, and D17S250) and is still widely used despite two well-known pitfalls caused by the dinucleotides.	('BAT25', 'Var', (80, 85))	('dinucleotides', 'Chemical', 'MESH:D015226', (65, 78))	('BAT26', 'Var', (87, 92))	('dinucleotides', 'Chemical', 'MESH:D015226', (194, 207))	('D5S346', 'Var', (102, 108))	('mononucleotides', 'Chemical', '-', (39, 54))	('D2S123', 'Var', (94, 100))	('D17S250', 'Var', (114, 121))
29072	26161390	Although MSI-H is seen when germline mutation occurs in any of the four DNA MMR genes, mutations in MSH6 more frequently results in MSI-L or even MSS status.	('MSH6', 'Gene', (100, 104))	('MSS status', 'Disease', (146, 156))	('MSI-H', 'Disease', 'MESH:D000848', (9, 14))	('MSI-H', 'Disease', (9, 14))	('MSH6', 'Gene', '2956', (100, 104))	('results in', 'Reg', (121, 131))	('MSI-L', 'Disease', (132, 137))	('mutations', 'Var', (87, 96))
29073	26161390	MSS MSH6 mutated cases are more commonly seen with the use of the Bethesda panel.	('MSH6', 'Gene', '2956', (4, 8))	('mutated', 'Var', (9, 16))	('MSH6', 'Gene', (4, 8))
29078	26161390	MLPA is also used to detect deletions in the EPCAM gene, which results in somatic methylation of the MSH2 gene.	('EPCAM', 'Gene', '4072', (45, 50))	('deletions', 'Var', (28, 37))	('EPCAM', 'Gene', (45, 50))	('MSH2', 'Gene', (101, 105))	('results in', 'Reg', (63, 73))	('MSH2', 'Gene', '4436', (101, 105))
29079	26161390	A certain proportion of patients with IHC and/or MSI analysis results suggestive of LS will have no mutations in DNA MMR genes.	('DNA MMR genes', 'Gene', (113, 126))	('mutations', 'Var', (100, 109))	('patients', 'Species', '9606', (24, 32))
29082	26161390	Female relatives of LS proband patients who are suspected or confirmed to be DNA MMR mutation carriers should be offered the option to undergo surveillance in the effort to prevent endometrial carcinomas.	('endometrial carcinomas', 'Disease', 'MESH:D016889', (181, 203))	('DNA MMR', 'Gene', (77, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (181, 202))	('mutation', 'Var', (85, 93))	('patients', 'Species', '9606', (31, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('endometrial carcinomas', 'Disease', (181, 203))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (181, 203))
29086	26161390	in mind, it is prudent that if it is decided that no active surveillance is to be carried out, female carriers of the DNA MMR gene mutations must be educated on the need to seek immediate medical attention for further investigation if they have any abnormal uterine bleeding.	('bleeding', 'Disease', 'MESH:D006470', (266, 274))	('mutations', 'Var', (131, 140))	('DNA MMR', 'Gene', (118, 125))	('bleeding', 'Disease', (266, 274))	('abnormal uterine', 'Phenotype', 'HP:0000130', (249, 265))	('abnormal uterine bleeding', 'Phenotype', 'HP:0100608', (249, 274))
29088	26161390	MTS is mostly due to germline mutations in MSH2 and MLH1.	('MSH2', 'Gene', '4436', (43, 47))	('MTS', 'Disease', 'MESH:C535808', (0, 3))	('germline mutations', 'Var', (21, 39))	('MLH1', 'Gene', (52, 56))	('MLH1', 'Gene', '4292', (52, 56))	('MTS', 'Disease', (0, 3))	('due', 'Reg', (14, 17))	('MSH2', 'Gene', (43, 47))
29102	26161390	Individuals with germline MSH6 mutations are associated with higher risk of developing endometrial carcinomas and generally do not conform to the classic LS presentation with personal and family histories of young-onset colorectal cancer.	('MSH6', 'Gene', '2956', (26, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('mutations', 'Var', (31, 40))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (87, 109))	('germline', 'Var', (17, 25))	('colorectal cancer', 'Disease', (220, 237))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (87, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (220, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (87, 108))	('endometrial carcinomas', 'Disease', (87, 109))	('MSH6', 'Gene', (26, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
29104	26161390	Selected IHC testing prompted by clinical history may potentially result in the missed the opportunity of identifying MTS patients harboring mutations in the MSH6 gene.	('MTS', 'Disease', 'MESH:C535808', (118, 121))	('mutations', 'Var', (141, 150))	('MSH6', 'Gene', '2956', (158, 162))	('MTS', 'Disease', (118, 121))	('patients', 'Species', '9606', (122, 130))	('MSH6', 'Gene', (158, 162))
29106	26161390	CS is due to germline mutations in the phosphatase and tensin homologue (PTEN) gene located on chromosome 10q23.3.	('PTEN', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (73, 77))	('due to', 'Reg', (6, 12))	('phosphatase and tensin homologue', 'Gene', '5728', (39, 71))	('germline mutations', 'Var', (13, 31))
29108	26161390	A clinical epidemiological study utilizing confirmatory PTEN gene mutation analysis suggests a prevalence of between 1 in 200,000 and 1 in 250,000 but is likely an underestimation.	('PTEN', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (56, 60))	('mutation', 'Var', (66, 74))
29115	26161390	In two separate studies, between 16% and 17% of women with endometrial carcinomas who fulfill the clinical diagnostic criteria for CS have been shown to carry the deleterious germline PTEN mutations.	('PTEN', 'Gene', (184, 188))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (59, 81))	('PTEN', 'Gene', '5728', (184, 188))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (59, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (59, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('women', 'Species', '9606', (48, 53))	('mutations', 'Var', (189, 198))	('endometrial carcinomas', 'Disease', (59, 81))
29117	26161390	The lifetime risk of CS patients with PTEN germline mutation developing endometrial carcinomas is between 13% and 19%, which is a substantially higher lifetime risk of the general population estimated to be between 2% and 4%.	('PTEN', 'Gene', '5728', (38, 42))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (72, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('germline mutation', 'Var', (43, 60))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (72, 94))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (72, 93))	('patients', 'Species', '9606', (24, 32))	('endometrial carcinomas', 'Disease', (72, 94))	('PTEN', 'Gene', (38, 42))
29122	26161390	In a recent study, CS and CS-like patients with endometrial carcinoma were shown to be linked to mutations other than the PTEN gene.	('mutations', 'Var', (97, 106))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (48, 69))	('linked', 'Reg', (87, 93))	('endometrial carcinoma', 'Disease', (48, 69))	('patients', 'Species', '9606', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (48, 69))	('PTEN', 'Gene', (122, 126))	('PTEN', 'Gene', '5728', (122, 126))
29132	26161390	Unfortunately, the study was limited by the lack of central pathology review and we are therefore unable to use the reported histology subtypes to help guide clinical risk assessment for germline PTEN mutations.	('PTEN', 'Gene', '5728', (196, 200))	('mutations', 'Var', (201, 210))	('PTEN', 'Gene', (196, 200))
29134	26161390	Validated pediatric and adult risk calculators to determine the risk of an individual harboring PTEN gene mutations have been made freely available online (http://www.lerner.ccf.org/gmi/ccscore/).	('PTEN', 'Gene', '5728', (96, 100))	('PTEN', 'Gene', (96, 100))	('mutations', 'Var', (106, 115))
29154	26161390	The majority of patients meeting the guidelines for the diagnosis of CS have a mutation of the PTEN gene (up to 80%) but the figure is lower when patients are referred from the community (approximately 25%).	('patients', 'Species', '9606', (16, 24))	('PTEN', 'Gene', (95, 99))	('mutation', 'Var', (79, 87))	('PTEN', 'Gene', '5728', (95, 99))	('patients', 'Species', '9606', (146, 154))
29156	26161390	It has been shown that de novo PTEN mutations are found in approximately 40% of proband patients who fulfill the criteria of possibly harboring the PTEN gene mutation.	('PTEN', 'Gene', (148, 152))	('PTEN', 'Gene', (31, 35))	('PTEN', 'Gene', '5728', (31, 35))	('PTEN', 'Gene', '5728', (148, 152))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (36, 45))
29157	26161390	Mutations in genes such as SDBH-D and KLLN which can result in similar disruption to the PTEN gene are also seen in some CS patients.	('patients', 'Species', '9606', (124, 132))	('KLLN', 'Gene', (38, 42))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (89, 93))	('PTEN', 'Gene', (89, 93))	('SDBH-D', 'Gene', (27, 33))	('KLLN', 'Gene', '100144748', (38, 42))
29161	26161390	Women with germline mutations in BRCA1 and BRCA2 genes have an increased lifetime risk of developing breast (40%-85%) and ovarian (10-39%) carcinomas.	('Women', 'Species', '9606', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('carcinomas', 'Disease', 'MESH:D002277', (139, 149))	('BRCA2', 'Gene', (43, 48))	('BRCA1', 'Gene', '672', (33, 38))	('carcinomas', 'Disease', (139, 149))	('germline mutations', 'Var', (11, 29))	('BRCA2', 'Gene', '675', (43, 48))	('breast', 'Disease', (101, 107))	('BRCA1', 'Gene', (33, 38))	('ovarian', 'Disease', (122, 129))
29162	26161390	Additionally, germline BRCA1/2 mutations have also been associated with carcinomas of the fallopian tube, colon, melanoma, and pancreas.	('mutations', 'Var', (31, 40))	('colon', 'Disease', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('pancreas', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('associated', 'Reg', (56, 66))	('melanoma', 'Disease', (113, 121))	('BRCA1/2', 'Gene', (23, 30))	('carcinomas of the fallopian tube', 'Disease', (72, 104))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('carcinomas of the fallopian tube', 'Disease', 'MESH:D005185', (72, 104))	('pancreas', 'Disease', 'MESH:D010190', (127, 135))	('BRCA1/2', 'Gene', '672;675', (23, 30))
29165	26161390	Cells with mutations in either BRCA gene result in hypersensitivity to crosslinkage agents such as cisplatin or poly (ADP-ribose) polymerase (PARP) inhibitors which produce double stranded breaks.	('mutations', 'Var', (11, 20))	('PARP', 'Gene', '142', (142, 146))	('BRCA', 'Gene', '672', (31, 35))	('hypersensitivity', 'Disease', 'MESH:D004342', (51, 67))	('BRCA', 'Gene', (31, 35))	('poly (ADP-ribose) polymerase', 'Gene', '142', (112, 140))	('PARP', 'Gene', (142, 146))	('poly (ADP-ribose) polymerase', 'Gene', (112, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('hypersensitivity', 'Disease', (51, 67))
29170	26161390	Further evidence suggesting a possible underlying difference in biology special to USC was the finding of a higher incidence of subsequent breast cancer in women with USC compared to endometrioid endometrial carcinoma (25% versus 3.2%, resp., P < 0.001).	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('women', 'Species', '9606', (156, 161))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (196, 217))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('USC', 'Var', (167, 170))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (183, 217))	('endometrioid endometrial carcinoma', 'Disease', (183, 217))
29177	26161390	Both were later found to harbor one of the BRCA1 founder mutations.	('BRCA1', 'Gene', (43, 48))	('mutations', 'Var', (57, 66))	('BRCA1', 'Gene', '672', (43, 48))
29179	26161390	A large Israeli study of 199 endometrial carcinoma Ashkenazi Jewish patients, mostly with endometrioid carcinoma, was negative for BRCA1/2 mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('BRCA1/2', 'Gene', (131, 138))	('mutations', 'Var', (139, 148))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (90, 112))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (90, 112))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (29, 50))	('patients', 'Species', '9606', (68, 76))	('BRCA1/2', 'Gene', '672;675', (131, 138))	('endometrioid carcinoma', 'Disease', (90, 112))	('endometrial carcinoma', 'Disease', (29, 50))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (29, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
29181	26161390	Subsequent to this, four other studies involving only Jewish patients with USC found an increased mutation rate in BRCA1 between 14% and 27% which is significantly higher than the 2.3% mutation rate in Israeli population.	('BRCA1', 'Gene', '672', (115, 120))	('BRCA1', 'Gene', (115, 120))	('patients', 'Species', '9606', (61, 69))	('mutation', 'Var', (98, 106))
29182	26161390	Between 50% and 100% of these patients with BRCA1/2 mutations either had a personal history of breast carcinoma or at least a first degree relative with breast carcinoma or ovarian carcinoma.	('mutations', 'Var', (52, 61))	('breast carcinoma', 'Disease', 'MESH:D001943', (153, 169))	('breast carcinoma', 'Disease', 'MESH:D001943', (95, 111))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (173, 190))	('breast carcinoma', 'Phenotype', 'HP:0003002', (153, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('BRCA1/2', 'Gene', (44, 51))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('breast carcinoma or ovarian carcinoma', 'Disease', 'MESH:D001943', (153, 190))	('patients', 'Species', '9606', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('breast carcinoma or ovarian carcinoma', 'Disease', (153, 190))	('breast carcinoma', 'Disease', (95, 111))	('BRCA1/2', 'Gene', '672;675', (44, 51))
29183	26161390	However, a Canadian study involving 56 non-Jewish women with USC failed to detect any of the four commonest BRCA1 or BRCA2 mutations, of which three are founder mutations in Ashkenazi Jews.	('BRCA2', 'Gene', '675', (117, 122))	('BRCA1', 'Gene', '672', (108, 113))	('women', 'Species', '9606', (50, 55))	('BRCA1', 'Gene', (108, 113))	('BRCA2', 'Gene', (117, 122))	('mutations', 'Var', (123, 132))
29185	26161390	A comprehensive search for all classes of BRCA1/2 mutations was performed using the BROCA panel.	('mutations', 'Var', (50, 59))	('BRCA1/2', 'Gene', (42, 49))	('BRCA1/2', 'Gene', '672;675', (42, 49))
29186	26161390	Interestingly, 36 other patients had nondeleterious or variants of unknown significant mutations, 12 of which are reported as benign on the Breast Cancer Information Core database (BIC).	('Breast Cancer', 'Phenotype', 'HP:0003002', (140, 153))	('Breast Cancer', 'Disease', (140, 153))	('variants', 'Var', (55, 63))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Breast Cancer', 'Disease', 'MESH:D001943', (140, 153))	('patients', 'Species', '9606', (24, 32))
29187	26161390	It would be important that as longitudinal studies of patients with BRCA mutations mature it will help clarify if USC is truly a BRCA-related tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('BRCA', 'Gene', '672', (129, 133))	('BRCA', 'Gene', '672', (68, 72))	('BRCA', 'Gene', (129, 133))	('BRCA', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
29190	26161390	However, other more crucial issues as indicated by the recent findings in the GOG-0199 study suggest postmenopausal age, abnormal transvaginal ovarian ultrasound findings and elevated serum CA-125 are associated with elevated risk of harboring invasive serous carcinoma in fallopian tube, ovary, and peritoneum or serous tubal intraepithelial carcinoma (STIC) in the fallopian tube of asymptomatic patients with deleterious BRCA1/2 gene mutations.	('BRCA1/2', 'Gene', '672;675', (424, 431))	('serous tubal intraepithelial carcinoma', 'Disease', (314, 352))	('mutations', 'Var', (437, 446))	('invasive serous carcinoma in fallopian tube', 'Disease', 'MESH:D005185', (244, 287))	('BRCA1/2', 'Gene', (424, 431))	('serous tubal intraepithelial carcinoma', 'Disease', 'MESH:D002278', (314, 352))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('abnormal transvaginal ovarian', 'Disease', (121, 150))	('invasive serous carcinoma in fallopian tube', 'Disease', (244, 287))	('abnormal transvaginal ovarian', 'Disease', 'MESH:D010049', (121, 150))	('postmenopausal age', 'Phenotype', 'HP:0008209', (101, 119))	('patients', 'Species', '9606', (398, 406))
29227	25874175	The multivariate analysis showed that mitotic count was a significant prognostic factor for OS, but other factors, such as age, stage, histology, tumor size, WPRT and chemotherapy, did not affect OS (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('OS', 'Chemical', '-', (196, 198))	('mitotic', 'Var', (38, 45))	('tumor', 'Disease', (146, 151))	('OS', 'Chemical', '-', (92, 94))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
29273	25874175	The disease-free survival (DFS) was significantly better in the chemotherapy arm than in the RT alone arm (3-yr DFS: 55% vs. 41%, p = 0.048), but the OS was not different (3-yr OS: 81% vs. 69%, p = 0.41).	('OS', 'Chemical', '-', (177, 179))	('disease-free survival', 'CPA', (4, 25))	('OS', 'Chemical', '-', (150, 152))	('better', 'PosReg', (50, 56))	('chemotherapy', 'Var', (64, 76))
29315	25520907	On preoperative endometrial cytology examination, abnormalities of class III or greater were considered positive for uterine sarcoma.	('abnormalities of class III', 'Phenotype', 'HP:0001976', (50, 76))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('abnormalities', 'Var', (50, 63))	('sarcoma', 'Disease', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (117, 132))
29362	25520907	In addition, hyperintense signal on T1-weighted images is thought to indicate intratumoral hemorrhage and coagulative necrosis.	('hemorrhage', 'Disease', 'MESH:D006470', (91, 101))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('necrosis', 'Disease', (118, 126))	('necrosis', 'Disease', 'MESH:D009336', (118, 126))	('hemorrhage', 'Disease', (91, 101))	('hyperintense signal', 'Var', (13, 32))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
29370	25520907	Thus far, numerous studies have reported on the usefulness of FDG-PET in uterine sarcomas; however, most of them consisted of reports on the usefulness of FDG-PET in the diagnosis of recurrence of uterine sarcomas; few reports have focused on its usefulness as a means for preoperative diagnosis of uterine sarcomas.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (197, 212))	('sarcomas', 'Disease', (81, 89))	('FDG-PET', 'Var', (155, 162))	('sarcomas', 'Disease', 'MESH:D012509', (307, 315))	('sarcomas', 'Disease', 'MESH:D012509', (205, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (307, 315))	('sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('sarcomas', 'Phenotype', 'HP:0100242', (205, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('sarcomas', 'Disease', (307, 315))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (299, 314))	('sarcomas', 'Disease', (205, 213))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (73, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
29510	19787091	Molecular Mechanisms of Uterine Leiomyosarcomas: Involvement of Defect in LMP2 Expression Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass.	('pain', 'Disease', 'MESH:D010146', (174, 178))	('pelvic mass', 'Phenotype', 'HP:0031501', (186, 197))	('Involvement', 'Reg', (49, 60))	('Leiomyosarcomas', 'Phenotype', 'HP:0100243', (32, 47))	('pelvic', 'Disease', (186, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('LMP2', 'Gene', (74, 78))	('Patients', 'Species', '9606', (90, 98))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (112, 126))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (112, 126))	('Leiomyosarcomas', 'Disease', 'MESH:D007890', (32, 47))	('pain', 'Disease', (174, 178))	('vaginal bleeding', 'Disease', 'MESH:D014592', (156, 172))	('LMS', 'Phenotype', 'HP:0100243', (128, 131))	('Uterine Leiomyosarcomas', 'Phenotype', 'HP:0002891', (24, 47))	('pain', 'Phenotype', 'HP:0012531', (174, 178))	('Defect', 'Var', (64, 70))	('LMP2', 'Gene', '5698', (74, 78))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (104, 126))	('vaginal bleeding', 'Disease', (156, 172))	('leiomyosarcoma', 'Disease', (112, 126))	('Leiomyosarcomas', 'Disease', (32, 47))
29516	19787091	Analysis of human uterine LMS shows somatic mutations in the IFNgamma signalling pathway, thus the loss of LMP2 induction is attributable to a defect in the earliest steps of the IFN-gamma signalling pathway.	('defect', 'NegReg', (143, 149))	('IFNgamma', 'Gene', '3458', (61, 69))	('IFNgamma', 'Gene', (61, 69))	('mutations', 'Var', (44, 53))	('loss', 'NegReg', (99, 103))	('human', 'Species', '9606', (12, 17))	('LMS', 'Phenotype', 'HP:0100243', (26, 29))	('LMP2', 'Gene', (107, 111))	('IFN-gamma', 'Gene', '3458', (179, 188))	('IFN-gamma', 'Gene', (179, 188))
29527	19787091	Defective LMP2 expression may initiate the development of spontaneous human uterine LMS.	('LMP2', 'Gene', (10, 14))	('human', 'Species', '9606', (70, 75))	('LMS', 'Phenotype', 'HP:0100243', (84, 87))	('Defective', 'Var', (0, 9))	('spontaneous human uterine LMS', 'Disease', (58, 87))	('initiate', 'Reg', (30, 38))
29533	19787091	LMS was observed in LMP2-/- female mice but not in their parental mice, C57BL/6 mice (Fig.	('LMS', 'Phenotype', 'HP:0100243', (0, 3))	('LMP2-/-', 'Var', (20, 27))	('mice', 'Species', '10090', (66, 70))	('mice', 'Species', '10090', (35, 39))	('mice', 'Species', '10090', (80, 84))	('LMS', 'Disease', (0, 3))
29546	19787091	Sequence analysis demonstrated that the loss of IFN-gamma responsiveness in the human uterine LMS cell line was attributable to the inadequate kinase activity of JAK1 due to a G781E mutation in the ATP-binding region.	('IFN-gamma', 'Gene', '3458', (48, 57))	('IFN-gamma', 'Gene', (48, 57))	('inadequate', 'NegReg', (132, 142))	('LMS', 'Phenotype', 'HP:0100243', (94, 97))	('loss', 'NegReg', (40, 44))	('G781E', 'Mutation', 'p.G781E', (176, 181))	('human', 'Species', '9606', (80, 85))	('G781E', 'Var', (176, 181))	('kinase activity', 'MPA', (143, 158))	('JAK1', 'Gene', (162, 166))	('JAK1', 'Gene', '3716', (162, 166))	('ATP', 'Chemical', 'MESH:D000255', (198, 201))
29550	19787091	Genetic alterations in tyrosine kinases have previously been firmly implicated in tumorgenesis, but only a few serine/threonine kinases are known to be mutated in human cancers.	('Genetic alterations', 'Var', (0, 19))	('cancers', 'Disease', (169, 176))	('tyrosine kinases', 'Enzyme', (23, 39))	('serine', 'Chemical', 'MESH:D012694', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('human', 'Species', '9606', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tyrosine', 'Chemical', 'MESH:D014443', (23, 31))	('implicated', 'Reg', (68, 78))	('tumor', 'Disease', (82, 87))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
29551	19787091	For instance, mice carring homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, and JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas.	('muscle cell hyperplasia', 'Disease', 'MESH:D006965', (91, 114))	('sarcomas', 'Disease', (250, 258))	('Pten', 'Gene', (50, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))	('Pten', 'Gene', '19211', (50, 54))	('abdominal leiomyosarcomas', 'Disease', (119, 144))	('abdominal leiomyosarcomas', 'Disease', 'MESH:D007890', (119, 144))	('sarcomas', 'Disease', (136, 144))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (129, 144))	('mice', 'Species', '10090', (14, 18))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (129, 143))	('sarcomas', 'Disease', 'MESH:D012509', (250, 258))	('muscle cell hyperplasia', 'Disease', (91, 114))	('deletion', 'Var', (38, 46))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (250, 258))	('overexpression block adipocytic', 'Disease', (181, 212))	('overexpression block adipocytic', 'Disease', 'MESH:D006327', (181, 212))
29553	19787091	Therefore, the examination of human uterine LMS tissues (32 LMS tissue sections and normal tissue sections located in the same tissue) was performed to detect somatic (tumor-specific) mutations in the IFN-gamma signal cascade.	('human', 'Species', '9606', (30, 35))	('tumor', 'Disease', (168, 173))	('mutations', 'Var', (184, 193))	('IFN-gamma', 'Gene', (201, 210))	('IFN-gamma', 'Gene', '3458', (201, 210))	('LMS', 'Phenotype', 'HP:0100243', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('LMS', 'Phenotype', 'HP:0100243', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
29554	19787091	The genetic approach has already addressed that somatic mutations in JAK1 molecule correlate to the initiation of several cancer progressions and other disorders.	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('JAK1', 'Gene', (69, 73))	('JAK1', 'Gene', '3716', (69, 73))
29555	19787091	Overall, nearly 42.9% (6/14) of uterine LMS tissues had mutations in the ATP-binding region or kinase-active site of JAK1.	('mutations in', 'Var', (56, 68))	('JAK1', 'Gene', '3716', (117, 121))	('uterine LMS', 'Disease', (32, 43))	('ATP', 'Chemical', 'MESH:D000255', (73, 76))	('LMS', 'Phenotype', 'HP:0100243', (40, 43))	('JAK1', 'Gene', (117, 121))
29556	19787091	Furthermore the genetic approach has already revealed that somatic mutations in the LMP2 molecule or its enhancer region correlate to the initiation of several cancer progressions and other disorders, 35.7% (5/14) of uterine LMS tissues had somatic mutations in the Lmp2 promoter region, which is required for transcriptional activation.	('LMP2', 'Gene', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('mutations', 'Var', (249, 258))	('mutations', 'Var', (67, 76))	('uterine LMS', 'Disease', (217, 228))	('Lmp2', 'Gene', '5698', (266, 270))	('LMS', 'Phenotype', 'HP:0100243', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('Lmp2', 'Gene', (266, 270))
29558	19787091	Nearly 35.7% (5/14) of uterine LMS tissues had mutations in the STAT1 intermolecular region.	('STAT1', 'Gene', '6772', (64, 69))	('LMS', 'Phenotype', 'HP:0100243', (31, 34))	('uterine LMS', 'Disease', (23, 34))	('mutations', 'Var', (47, 56))	('STAT1', 'Gene', (64, 69))
29562	19787091	The discovery of these mutational defects in a key cell-signalling pathway may be an important development in the pathogenesis of human uterine LMS.	('mutational defects', 'Var', (23, 41))	('LMS', 'Phenotype', 'HP:0100243', (144, 147))	('key cell-signalling pathway', 'Pathway', (47, 74))	('human', 'Species', '9606', (130, 135))
29571	19787091	In SKN-Lmp2 transfectants, there is a correlation between the levels of exogenous LMP2 expression and the degree of suppression of the transformed phenotype.	('LMP2', 'Gene', (82, 86))	('Lmp2', 'Gene', '5698', (7, 11))	('Lmp2', 'Gene', (7, 11))	('SKN', 'Gene', (3, 6))	('SKN', 'Gene', '55733', (3, 6))	('transfectants', 'Var', (12, 25))
29574	19787091	Microarray analysis has elucidated that LMP2 expression dramatically influences the expression pattern of cell-cycle regulators, especially anti-oncogenic factor interferon regulatory factor 1 (IRF-1), which directly correlate to progressively worsen with the increasing stage and grade of the tumor (Fig.	('interferon regulatory factor 1', 'Gene', '3659', (162, 192))	('tumor', 'Disease', (294, 299))	('IRF-1', 'Gene', (194, 199))	('influences', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('interferon regulatory factor 1', 'Gene', (162, 192))	('expression pattern', 'MPA', (84, 102))	('IRF-1', 'Gene', '3659', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('expression', 'Var', (45, 55))	('worsen', 'NegReg', (244, 250))	('LMP2', 'Gene', (40, 44))
29577	19787091	Defective LMP2 expression is likely to be a risk factor for the development of human uterine LMS, as it is in LMP2-deficient mice.	('human', 'Species', '9606', (79, 84))	('risk', 'Reg', (44, 48))	('LMS', 'Phenotype', 'HP:0100243', (93, 96))	('LMP2', 'Gene', (10, 14))	('mice', 'Species', '10090', (125, 129))	('Defective', 'Var', (0, 9))
29581	19787091	For almost all types of cancer studied to date, it seems as if the transition from a normal, healthy cell to a cancer cell is a step-wise progression that requires genetic changes in several different oncogenes and tumor suppressors.	('genetic changes', 'Var', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
29588	19787091	It is clear that mutations in key regulatory genes (tumor suppressors and proto-oncogenes) alter the behavior of cells and can potentially lead to the unregulated growth seen in cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lead to', 'Reg', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('alter', 'Reg', (91, 96))	('tumor', 'Disease', (52, 57))	('behavior of cells', 'MPA', (101, 118))	('unregulated growth', 'MPA', (151, 169))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('mutations', 'Var', (17, 26))
29603	33489157	Immunohistochemical analysis of the biopsy specimen showed positivity for p16, p53, and p63, leading to the diagnosis of squamous cell carcinoma.	('p16', 'Gene', (74, 77))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('p63', 'Gene', '8626', (88, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('positivity', 'Var', (59, 69))	('p16', 'Gene', '1029', (74, 77))	('p63', 'Gene', (88, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
29605	33489157	Genotyping of the biopsy specimen showed positivity for human papillomavirus (HPV) type 31.	('HPV', 'Species', '10566', (78, 81))	('HPV', 'Gene', (78, 81))	('human papillomavirus', 'Species', '10566', (56, 76))	('positivity', 'Var', (41, 51))
29631	33489157	The mutation spectrum in a three-base context did not represent the APOBEC signature (ie, enrichment of substitution of a C preceded by a T into either T, G, or A) typical of HPV-associated cancers 15  (Figure 8).	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('substitution', 'Var', (104, 116))	('HPV-associated', 'Disease', (175, 189))	('HPV', 'Species', '10566', (175, 178))
29632	33489157	Of the 16 nonsynonymous mutations identified, PIK3C2B (T879N), KDR (V297I), and TET2 (P29R) were registered in the Catalogue of Somatic Mutations in Cancer 16  as recurrent mutations.	('V297I', 'Mutation', 'rs2305948', (68, 73))	('T879N', 'Mutation', 'rs748210384', (55, 60))	('KDR', 'Gene', (63, 66))	('PIK3C2B', 'Gene', (46, 53))	('T879N', 'Var', (55, 60))	('PIK3C2B', 'Gene', '5287', (46, 53))	('TET2', 'Gene', (80, 84))	('V297I', 'Var', (68, 73))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('KDR', 'Gene', '3791', (63, 66))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('TET2', 'Gene', '54790', (80, 84))	('P29R', 'Mutation', 'rs12498609', (86, 90))
29645	33489157	15  None of the mutations in PIK3C2B, KDR, and TET2 identified in the present case were reported in two previous large-scale landmark studies of UCC-mutation profiles.	('PIK3C2B', 'Gene', (29, 36))	('KDR', 'Gene', (38, 41))	('PIK3C2B', 'Gene', '5287', (29, 36))	('TET2', 'Gene', '54790', (47, 51))	('mutations', 'Var', (16, 25))	('TET2', 'Gene', (47, 51))	('KDR', 'Gene', '3791', (38, 41))
29664	33378353	DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('DACH1', 'Gene', '1602', (0, 5))	('prostate cancer', 'Disease', 'MESH:D011471', (201, 216))	('prostate cancer', 'Phenotype', 'HP:0012125', (201, 216))	('DACH1', 'Gene', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('bladder', 'Disease', (188, 195))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('prostate cancer', 'Disease', (201, 216))	('endometrial cancer', 'Phenotype', 'HP:0012114', (28, 46))	('DACH1', 'Gene', '1602', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('endometrial cancer', 'Disease', (28, 46))	('endometrial cancer', 'Disease', 'MESH:D016889', (28, 46))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (134, 139))	('DACH1', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (134, 139))
29666	33378353	In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population.	('DACH1', 'Gene', '1602', (132, 137))	('endometrial cancer', 'Disease', (165, 183))	('endometrial cancer', 'Phenotype', 'HP:0012114', (165, 183))	('endometrial cancer', 'Disease', 'MESH:D016889', (165, 183))	('patients', 'Species', '9606', (151, 159))	('Oncology', 'Phenotype', 'HP:0002664', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('DACH1', 'Gene', (132, 137))	('mutations', 'Var', (138, 147))
29669	33378353	Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05.	('women', 'Species', '9606', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('endometrial cancer', 'Disease', 'MESH:D016889', (20, 38))	('endometrial cancer', 'Phenotype', 'HP:0012114', (20, 38))	('patients', 'Species', '9606', (190, 198))	('patients', 'Species', '9606', (92, 100))	('Cancer', 'Disease', (125, 131))	('endometrial cancer', 'Disease', (152, 170))	('DACH1', 'Gene', (69, 74))	('mutations', 'Var', (75, 84))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('DACH1', 'Gene', '1602', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('endometrial cancer', 'Phenotype', 'HP:0012114', (152, 170))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('endometrial cancer', 'Disease', (20, 38))	('endometrial cancer', 'Disease', 'MESH:D016889', (152, 170))
29670	33378353	DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04).	('DACH1', 'Gene', (0, 5))	('DACH1', 'Gene', '1602', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('increased', 'PosReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('mutations', 'Var', (6, 15))
29671	33378353	DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('DACH1', 'Gene', (71, 76))	('DACH1', 'Gene', (0, 5))	('higher', 'PosReg', (30, 36))	('DACH1', 'Gene', '1602', (71, 76))	('DACH1', 'Gene', '1602', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('patients', 'Species', '9606', (14, 22))	('mutated', 'Var', (6, 13))
29672	33378353	DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2.	('MLH1', 'Gene', '4292', (74, 78))	('MLH1', 'Gene', (74, 78))	('DACH1', 'Gene', (0, 5))	('DACH1', 'Gene', '1602', (0, 5))	('PMS2', 'Gene', (84, 88))	('PMS2', 'Gene', '5395', (84, 88))	('mutations', 'Var', (6, 15))
29673	33378353	DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342).	('microsatellite instability', 'MPA', (56, 82))	('DACH1', 'Gene', '1602', (0, 5))	('DACH1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
29674	33378353	DACH1 mutations are prevalent in Kentucky patients with endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('endometrial cancer', 'Disease', (56, 74))	('DACH1', 'Gene', (0, 5))	('DACH1', 'Gene', '1602', (0, 5))	('endometrial cancer', 'Phenotype', 'HP:0012114', (56, 74))	('endometrial cancer', 'Disease', 'MESH:D016889', (56, 74))	('patients', 'Species', '9606', (42, 50))	('prevalent', 'Reg', (20, 29))	('mutations', 'Var', (6, 15))
29675	33378353	These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('high tumor', 'Disease', 'MESH:D009369', (36, 46))	('high tumor', 'Disease', (36, 46))	('mutations', 'Var', (6, 15))
29684	33378353	They were able to classify these cancers into POLE ultramutated, microsatellite instability hypermutated (MSI-H), copy number low, and copy number high.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('copy number low', 'Var', (114, 129))	('copy number high', 'Var', (135, 151))
29685	33378353	Uterine serous cancers and approximately 25% of high-grade endometrioid tumors were in the copy number high group and had frequent TP53 mutations and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('serous cancers', 'Disease', 'MESH:D009369', (8, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('endometrioid tumors', 'Disease', (59, 78))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('mutations', 'Var', (136, 145))	('endometrioid tumors', 'Disease', 'MESH:D016889', (59, 78))	('serous cancers', 'Disease', (8, 22))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
29686	33378353	The majority of endometrioid cancers were in the copy number low group and were TP53 wild-type with PTEN and PIK3CA commonly mutated.	('PTEN', 'Gene', (100, 104))	('PIK3CA', 'Gene', (109, 115))	('PTEN', 'Gene', '5728', (100, 104))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('PIK3CA', 'Gene', '5290', (109, 115))	('TP53', 'Gene', '7157', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TP53', 'Gene', (80, 84))	('endometrioid cancers', 'Disease', 'MESH:D009369', (16, 36))	('copy number low', 'Var', (49, 64))	('endometrioid cancers', 'Disease', (16, 36))
29699	33378353	DACH1 is also an endogenous regulator of cyclin D1, with loss of DACH1 resulting in increased cyclin D1, which is required for the G1/S transition.	('cyclin D1', 'Gene', (41, 50))	('cyclin D1', 'Gene', (94, 103))	('DACH1', 'Gene', (0, 5))	('DACH1', 'Gene', '1602', (0, 5))	('DACH1', 'Gene', (65, 70))	('increased', 'PosReg', (84, 93))	('DACH1', 'Gene', '1602', (65, 70))	('loss', 'Var', (57, 61))	('cyclin D1', 'Gene', '595', (41, 50))	('cyclin D1', 'Gene', '595', (94, 103))
29701	33378353	Our primary objective was to determine the frequency of DACH1 mutations in our population and their association with other tumor suppressor genes, tumor mutation burden, microsatellite instability, and clinical risk factors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (123, 128))	('association', 'Interaction', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('DACH1', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('DACH1', 'Gene', '1602', (56, 61))	('mutations', 'Var', (62, 71))
29728	33378353	Preparation of M2GEN Whole Exome Sequencing (WES) libraries involves hybrid capture using an enhanced Integrated DNA Technology (IDT) WES kit (38.7 Mb) with additional custom-designed probes for double coverage of 440 cancer genes.	('cancer', 'Disease', (218, 224))	('hybrid', 'Var', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (218, 224))
29737	33378353	TMB was calculated using the count of non-synonymous somatic mutations (single nucleotide variants and small insertions/deletions, including missense, stop gain, stop loss and start loss mutations) per mega-case in the coding region of the specific capture kit.	('TMB', 'Chemical', '-', (0, 3))	('missense', 'Var', (141, 149))	('stop gain', 'Disease', (151, 160))	('stop', 'Disease', (162, 166))
29738	33378353	Out of 65 patients, 12 had DACH1 gene mutations as shown in Table 1.	('mutations', 'Var', (38, 47))	('DACH1', 'Gene', (27, 32))	('DACH1', 'Gene', '1602', (27, 32))	('patients', 'Species', '9606', (10, 18))
29747	33378353	There were no significant associations between DACH1 mutation and clinical covariates, including grade, stage, or histology.	('DACH1', 'Gene', (47, 52))	('DACH1', 'Gene', '1602', (47, 52))	('mutation', 'Var', (53, 61))
29748	33378353	Age is approaching significance with a p-value of 0.053, with DACH1 mutations trending towards occurring more frequently in older patients, as shown in Table 3.	('mutations', 'Var', (68, 77))	('DACH1', 'Gene', (62, 67))	('DACH1', 'Gene', '1602', (62, 67))	('patients', 'Species', '9606', (130, 138))
29749	33378353	Though not reaching statistical significance, 7/12 (58%) of the patients with DACH1 mutations also had high-grade disease, compared to 26/53 (49%) of those who were wild-type.	('DACH1', 'Gene', (78, 83))	('DACH1', 'Gene', '1602', (78, 83))	('patients', 'Species', '9606', (64, 72))	('high-grade disease', 'Disease', (103, 121))	('mutations', 'Var', (84, 93))
29751	33378353	DACH1 gene mutations were not statistically associated with a microsatellite unstable genome in either the MCC cohort (p-value = 0.1342) or in the TCGA analysis through cBioPortal using the MSIsensor Score (p-value = 0.142) as shown in Table 4.	('associated', 'Reg', (44, 54))	('mutations', 'Var', (11, 20))	('DACH1', 'Gene', (0, 5))	('microsatellite unstable genome', 'MPA', (62, 92))	('DACH1', 'Gene', '1602', (0, 5))
29752	33378353	Other commonly occurring driver mutations associated with microsatellite instability and genome instability were frequent in the DACH1 patients.	('patients', 'Species', '9606', (135, 143))	('DACH1', 'Gene', (129, 134))	('DACH1', 'Gene', '1602', (129, 134))	('associated', 'Reg', (42, 52))	('mutations', 'Var', (32, 41))	('genome instability', 'MPA', (89, 107))	('microsatellite instability', 'MPA', (58, 84))
29753	33378353	We compared frequencies of commonly found driver mutations including PTEN, PIK3CA, TP53, POLE, and the Lynch Syndrome-associated genes (MLH1, MSH2, MSH6, PMS2) using the enrichment test to determine whether the frequency of gene mutations in the MCC cohort was similar to that of the TCGA PanCancer Atlas (PCA) endometrial carcinoma and carcinosarcoma datasets.	('MLH1', 'Gene', '4292', (136, 140))	('PMS2', 'Gene', '5395', (154, 158))	('Lynch Syndrome', 'Disease', (103, 117))	('MSH2', 'Gene', (142, 146))	('carcinosarcoma', 'Disease', (337, 351))	('PIK3CA', 'Gene', (75, 81))	('PTEN', 'Gene', '5728', (69, 73))	('TP53', 'Gene', (83, 87))	('MSH6', 'Gene', (148, 152))	('mutations', 'Var', (229, 238))	('carcinosarcoma', 'Disease', 'MESH:D002296', (337, 351))	('MSH6', 'Gene', '2956', (148, 152))	('MSH2', 'Gene', '4436', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('PMS2', 'Gene', (154, 158))	('PanCancer Atlas (PCA) endometrial carcinoma', 'Disease', 'MESH:D016889', (289, 332))	('Cancer', 'Phenotype', 'HP:0002664', (292, 298))	('TP53', 'Gene', '7157', (83, 87))	('PIK3CA', 'Gene', '5290', (75, 81))	('MLH1', 'Gene', (136, 140))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (103, 117))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (311, 332))	('PTEN', 'Gene', (69, 73))
29754	33378353	We identified 3.8% (25/586 patients) DACH1 gene mutations in uterine cancer somatic samples in the TCGA PCA of endometrial and carcinosarcoma patients, which was significantly lower than the 18.5% (12/65, p = 1.05E-05) seen in the MCC patient cohort.	('DACH1', 'Gene', '1602', (37, 42))	('patient', 'Species', '9606', (235, 242))	('carcinosarcoma', 'Disease', 'MESH:D002296', (127, 141))	('endometrial', 'Disease', (111, 122))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('patient', 'Species', '9606', (27, 34))	('uterine cancer', 'Phenotype', 'HP:0010784', (61, 75))	('patients', 'Species', '9606', (27, 35))	('carcinosarcoma', 'Disease', (127, 141))	('patient', 'Species', '9606', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('patients', 'Species', '9606', (142, 150))	('DACH1', 'Gene', (37, 42))	('cancer', 'Disease', (69, 75))
29755	33378353	In addition, MLH1 (22/65, 33.85%, p = 2.63E-13), MSH2 (25/65, 38.46%, p = 2.87E-07), MSH6 (28/65, 43.1%, p = 1.01E-11), PMS2 (12/65, 18.5%, p = 3.79E-03), and POLE (28/65, 43.08%, 5.39E-08) mutations were more common in the MCC cohort than the TCGA PCA, while mutation frequency in PTEN, PIK3CA, and TP53 were not statistically difference in the two datasets.	('PTEN', 'Gene', (282, 286))	('common', 'Reg', (210, 216))	('PIK3CA', 'Gene', (288, 294))	('PTEN', 'Gene', '5728', (282, 286))	('MLH1', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (300, 304))	('PIK3CA', 'Gene', '5290', (288, 294))	('mutations', 'Var', (190, 199))	('MLH1', 'Gene', '4292', (13, 17))	('MSH2', 'Gene', (49, 53))	('MCC', 'Disease', (224, 227))	('PMS2', 'Gene', '5395', (120, 124))	('TP53', 'Gene', (300, 304))	('MSH6', 'Gene', '2956', (85, 89))	('MSH2', 'Gene', '4436', (49, 53))	('MSH6', 'Gene', (85, 89))	('PMS2', 'Gene', (120, 124))
29756	33378353	We performed a co-occurrence analysis using the Fisher's exact test to determine whether DACH1 mutations are mutually exclusive or tend to co-occur with other gene mutations, with a significant co-occurrence pattern noted between DACH1 and two of the four Lynch Syndrome associated genes, MLH1 (p = 2.39E-04) and PMS2 (p = 3.67E-07) as well as DACH1 and POLE (p = 5.78E-08), shown in Table 5.	('DACH1', 'Gene', (89, 94))	('DACH1', 'Gene', '1602', (89, 94))	('DACH1', 'Gene', (230, 235))	('PMS2', 'Gene', (313, 317))	('DACH1', 'Gene', '1602', (230, 235))	('PMS2', 'Gene', '5395', (313, 317))	('MLH1', 'Gene', '4292', (289, 293))	('DACH1', 'Gene', '1602', (344, 349))	('MLH1', 'Gene', (289, 293))	('mutations', 'Var', (95, 104))	('DACH1', 'Gene', (344, 349))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (256, 270))	('Lynch Syndrome', 'Disease', (256, 270))
29761	33378353	A total of 2,599 genes were significantly differentially expressed (FDR values < 0.05) between the DACH1 mutated patients and wild-type (Fig 3), with a large proportion of these being upregulated in the setting of mutated DACH1.	('DACH1', 'Gene', (222, 227))	('DACH1', 'Gene', '1602', (222, 227))	('patients', 'Species', '9606', (113, 121))	('differentially', 'Reg', (42, 56))	('DACH1', 'Gene', (99, 104))	('DACH1', 'Gene', '1602', (99, 104))	('mutated', 'Var', (105, 112))	('mutated', 'Var', (214, 221))	('upregulated', 'PosReg', (184, 195))
29762	33378353	The top ten upregulated and downregulated differentially expressed genes comparing DACH1 mutated patients to wild-type are displayed in Table 6a and 6b.	('downregulated', 'NegReg', (28, 41))	('DACH1', 'Gene', '1602', (83, 88))	('DACH1', 'Gene', (83, 88))	('differentially expressed', 'MPA', (42, 66))	('mutated', 'Var', (89, 96))	('upregulated', 'PosReg', (12, 23))	('patients', 'Species', '9606', (97, 105))
29763	33378353	We performed an in-depth pathway analysis utilizing the RNA sequencing data to determine cell-specific pathways impacted by DACH1 mutations, shown in Table 7 and Fig 4A and 4B.	('DACH1', 'Gene', (124, 129))	('mutations', 'Var', (130, 139))	('DACH1', 'Gene', '1602', (124, 129))	('impacted', 'Reg', (112, 120))
29765	33378353	Pathways related to cellular injury and cancer predominated, suggesting DACH1 mutations lead to disease processes resulting in cellular injury and cancer (Fig 5A).	('disease', 'Disease', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lead to', 'Reg', (88, 95))	('cellular injury', 'Disease', (127, 142))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cellular injury', 'Disease', (20, 35))	('cellular injury', 'Disease', 'MESH:D004806', (127, 142))	('cancer', 'Disease', (40, 46))	('mutations', 'Var', (78, 87))	('cellular injury', 'Disease', 'MESH:D004806', (20, 35))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('DACH1', 'Gene', (72, 77))	('DACH1', 'Gene', '1602', (72, 77))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
29768	33378353	Multiple pathways involved in cell cycle control, signaling, and development were also significantly differentially expressed between DACH1 mutated and wild-type as assessed by RNA sequencing.	('DACH1', 'Gene', (134, 139))	('DACH1', 'Gene', '1602', (134, 139))	('differentially expressed', 'Reg', (101, 125))	('mutated', 'Var', (140, 147))
29769	33378353	We performed network mapping using IPA with Global Network Overlay to determine the interplay of DACH1 on genes found to be significantly altered between DACH1 mutated patients and wild-type (Fig 6A).	('DACH1', 'Gene', (154, 159))	('altered', 'Reg', (138, 145))	('mutated', 'Var', (160, 167))	('DACH1', 'Gene', '1602', (154, 159))	('patients', 'Species', '9606', (168, 176))	('DACH1', 'Gene', (97, 102))	('DACH1', 'Gene', '1602', (97, 102))
29770	33378353	This revealed an interplay between three genes including ASCL1 (3.070 expression fold change, p-value = 2.08E-03), SOX2 (expression fold change 3.470, p-value = 1.84E-02), and LHX1 (4.090 expression fold change, p-value = 1.58E-02) when comparing DACH1 mutated patients to wild-type.	('LHX1', 'Gene', (176, 180))	('LHX1', 'Gene', '3975', (176, 180))	('DACH1', 'Gene', (247, 252))	('SOX2', 'Gene', (115, 119))	('SOX2', 'Gene', '6657', (115, 119))	('mutated', 'Var', (253, 260))	('DACH1', 'Gene', '1602', (247, 252))	('patients', 'Species', '9606', (261, 269))	('ASCL1', 'Gene', (57, 62))	('ASCL1', 'Gene', '429', (57, 62))
29773	33378353	We first compared tumor mutation counts in the TCGA PCA endometrial cancer and carcinosarcoma cohorts between DACH1 mutated patients and wild-type and found clinically significant differences with a median of 8972 in DACH1 mutants vs. 65 in DACH1 wild-type (p-value = 7.35e-09).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (18, 23))	('carcinosarcoma', 'Disease', 'MESH:D002296', (79, 93))	('DACH1', 'Gene', '1602', (110, 115))	('mutants', 'Var', (223, 230))	('endometrial cancer', 'Phenotype', 'HP:0012114', (56, 74))	('DACH1', 'Gene', (217, 222))	('carcinosarcoma', 'Disease', (79, 93))	('DACH1', 'Gene', (241, 246))	('DACH1', 'Gene', '1602', (217, 222))	('PCA endometrial cancer', 'Disease', 'MESH:D016889', (52, 74))	('DACH1', 'Gene', '1602', (241, 246))	('DACH1', 'Gene', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mutated', 'Var', (116, 123))	('PCA endometrial cancer', 'Disease', (52, 74))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
29774	33378353	We repeated this analysis in our MCC population with a median of 2160 in DACH1 mutated patients vs. 490 in DACH1 wild-type (p-value = 6E-04).	('DACH1', 'Gene', '1602', (73, 78))	('mutated', 'Var', (79, 86))	('DACH1', 'Gene', (107, 112))	('DACH1', 'Gene', '1602', (107, 112))	('patients', 'Species', '9606', (87, 95))	('DACH1', 'Gene', (73, 78))
29775	33378353	We then compared TMB between DACH1 wild-type and mutated patients in the MCC cohort.	('mutated', 'Var', (49, 56))	('TMB', 'Chemical', '-', (17, 20))	('DACH1', 'Gene', '1602', (29, 34))	('patients', 'Species', '9606', (57, 65))	('DACH1', 'Gene', (29, 34))
29776	33378353	As expected, given the marked difference in tumor mutation counts in both TCGA PCA and MCC, DACH1 wild-type patients had a median TMB of 6.02 and DACH1 mutated patients had a significantly higher median TMB of 24.0 (p-value = 4.29E-05) compared by the Wilcoxon rank sum test (Fig 7).	('DACH1', 'Gene', (92, 97))	('patients', 'Species', '9606', (160, 168))	('DACH1', 'Gene', '1602', (92, 97))	('patients', 'Species', '9606', (108, 116))	('mutated', 'Var', (152, 159))	('TMB', 'Chemical', '-', (203, 206))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('higher', 'PosReg', (189, 195))	('TMB', 'MPA', (130, 133))	('DACH1', 'Gene', (146, 151))	('DACH1', 'Gene', '1602', (146, 151))	('tumor', 'Disease', (44, 49))	('TMB', 'MPA', (203, 206))	('TMB', 'Chemical', '-', (130, 133))
29777	33378353	Given the co-occurrence of mutations found in DACH1 with MLH1, POLE, and PMS2, we then compared microsatellite instability between DACH1 mutated patients and DACH1 wild-type in the MCC cohort using the chi-square test, and no significance was found between the two groups (p-value = 0.2659) as shown in Table 8, with 3/12 DACH1 mutated patients being MSI-H, and 8/12 being MSS, and one patient with MSI unavailable.	('mutations', 'Var', (27, 36))	('MLH1', 'Gene', '4292', (57, 61))	('patient', 'Species', '9606', (336, 343))	('DACH1', 'Gene', (158, 163))	('PMS2', 'Gene', '5395', (73, 77))	('DACH1', 'Gene', '1602', (46, 51))	('DACH1', 'Gene', (322, 327))	('DACH1', 'Gene', '1602', (158, 163))	('DACH1', 'Gene', (131, 136))	('DACH1', 'Gene', '1602', (322, 327))	('PMS2', 'Gene', (73, 77))	('patients', 'Species', '9606', (336, 344))	('mutated', 'Var', (328, 335))	('patient', 'Species', '9606', (386, 393))	('DACH1', 'Gene', '1602', (131, 136))	('patients', 'Species', '9606', (145, 153))	('MLH1', 'Gene', (57, 61))	('patient', 'Species', '9606', (145, 152))	('DACH1', 'Gene', (46, 51))
29778	33378353	We assessed overall survival analysis between MCC DACH1 mutated patients and wild-type given prior studies suggesting an increase in stage, lymph node status, and metastasis with reduced DACH1 expression using the Cox model, correcting for stage and grade.	('patients', 'Species', '9606', (64, 72))	('increase', 'PosReg', (121, 129))	('DACH1', 'Gene', (50, 55))	('metastasis', 'CPA', (163, 173))	('lymph node status', 'CPA', (140, 157))	('mutated', 'Var', (56, 63))	('DACH1', 'Gene', '1602', (50, 55))	('stage', 'CPA', (133, 138))	('expression', 'MPA', (193, 203))	('DACH1', 'Gene', (187, 192))	('reduced', 'NegReg', (179, 186))	('DACH1', 'Gene', '1602', (187, 192))
29779	33378353	No significant difference was noted between DACH1 wild-type and mutated patients (p-value = 0.803), with 80% of patients still alive at five years in both groups (Fig 8A).	('DACH1', 'Gene', (44, 49))	('DACH1', 'Gene', '1602', (44, 49))	('patients', 'Species', '9606', (112, 120))	('mutated', 'Var', (64, 71))	('patients', 'Species', '9606', (72, 80))
29780	33378353	In TCGA PCA, at five years, 90.48% of the patients with the DACH1 mutation were still alive, while 70.47% of patients who were DACH1 wild-type group were still alive.	('DACH1', 'Gene', (60, 65))	('patients', 'Species', '9606', (109, 117))	('DACH1', 'Gene', '1602', (60, 65))	('DACH1', 'Gene', (127, 132))	('DACH1', 'Gene', '1602', (127, 132))	('mutation', 'Var', (66, 74))	('patients', 'Species', '9606', (42, 50))
29782	33378353	Our network analysis further supports this role in endometrial cancer by revealing three essential upregulated genes and their pathways with significant differences in expression between DACH1 mutated patients and wild-type, ASCL1, SOX2, LHX1.	('patients', 'Species', '9606', (201, 209))	('expression', 'MPA', (168, 178))	('LHX1', 'Gene', (238, 242))	('upregulated', 'PosReg', (99, 110))	('endometrial cancer', 'Disease', (51, 69))	('LHX1', 'Gene', '3975', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutated', 'Var', (193, 200))	('endometrial cancer', 'Phenotype', 'HP:0012114', (51, 69))	('ASCL1', 'Gene', (225, 230))	('ASCL1', 'Gene', '429', (225, 230))	('endometrial cancer', 'Disease', 'MESH:D016889', (51, 69))	('SOX2', 'Gene', '6657', (232, 236))	('differences', 'Reg', (153, 164))	('SOX2', 'Gene', (232, 236))	('DACH1', 'Gene', (187, 192))	('DACH1', 'Gene', '1602', (187, 192))
29784	33378353	We anticipate that DACH1 mutations result in loss of transcriptional repression of these regulators resulting in uncontrolled cell cycle progression in endometrial cancer, similar to DACH1's control of the cell cycle via cyclin D1 in breast cancer.	('DACH1', 'Gene', (183, 188))	('DACH1', 'Gene', (19, 24))	('mutations', 'Var', (25, 34))	('DACH1', 'Gene', '1602', (183, 188))	('DACH1', 'Gene', '1602', (19, 24))	('transcriptional repression', 'MPA', (53, 79))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('cyclin D1', 'Gene', (221, 230))	('cyclin D1', 'Gene', '595', (221, 230))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Disease', (234, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('endometrial cancer', 'Disease', (152, 170))	('endometrial cancer', 'Phenotype', 'HP:0012114', (152, 170))	('uncontrolled', 'MPA', (113, 125))	('loss', 'NegReg', (45, 49))	('endometrial cancer', 'Disease', 'MESH:D016889', (152, 170))
29786	33378353	In our population, we identified a high frequency of both DACH1 and POLE mutations when compared to the TCGA PCA, and that POLE and DACH1 are significantly co-mutated.	('DACH1', 'Gene', '1602', (132, 137))	('DACH1', 'Gene', (58, 63))	('DACH1', 'Gene', '1602', (58, 63))	('POLE', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('DACH1', 'Gene', (132, 137))
29789	33378353	Of these, the majority (~85%) are explained by hypermethylation of the MLH1 promoter, approximately 5% by germline mutations in Lynch-associated genes (MLH1, MSH2, MSH6, PMS2) and the remaining 10% by somatic mutations, unusual germline mutations not covered by clinical panels, or POLE mutations.	('MLH1', 'Gene', (152, 156))	('MLH1', 'Gene', '4292', (71, 75))	('mutations', 'Var', (115, 124))	('MLH1', 'Gene', (71, 75))	('MSH2', 'Gene', (158, 162))	('explained by', 'Reg', (34, 46))	('MSH6', 'Gene', '2956', (164, 168))	('hypermethylation', 'MPA', (47, 63))	('PMS2', 'Gene', (170, 174))	('MSH2', 'Gene', '4436', (158, 162))	('MSH6', 'Gene', (164, 168))	('PMS2', 'Gene', '5395', (170, 174))	('MLH1', 'Gene', '4292', (152, 156))
29790	33378353	In our Kentucky population, mutation frequency in MLH1, MSH2, MSH6, and PMS2 was approximately 34%, 38%, 43%, and 19%, respectively, all significantly higher than reported by TCGA and with significant co-occurrence between DACH1 and MLH1 and PMS2, despite similar rates seen in TP53, PTEN, and PIK3CA.	('PMS2', 'Gene', '5395', (242, 246))	('PTEN', 'Gene', '5728', (284, 288))	('mutation', 'Var', (28, 36))	('higher', 'PosReg', (151, 157))	('DACH1', 'Gene', '1602', (223, 228))	('MSH2', 'Gene', (56, 60))	('MSH6', 'Gene', (62, 66))	('TP53', 'Gene', '7157', (278, 282))	('PIK3CA', 'Gene', '5290', (294, 300))	('MSH6', 'Gene', '2956', (62, 66))	('PMS2', 'Gene', '5395', (72, 76))	('PMS2', 'Gene', (242, 246))	('MSH2', 'Gene', '4436', (56, 60))	('MLH1', 'Gene', (50, 54))	('MLH1', 'Gene', (233, 237))	('MLH1', 'Gene', '4292', (50, 54))	('PIK3CA', 'Gene', (294, 300))	('TP53', 'Gene', (278, 282))	('PTEN', 'Gene', (284, 288))	('PMS2', 'Gene', (72, 76))	('DACH1', 'Gene', (223, 228))	('MLH1', 'Gene', '4292', (233, 237))
29791	33378353	Since co-occurrence of mutations typically occurs among functionally related genes that work together to promote tumorigenesis, we hypothesize that DACH1 and DNA repair genes like POLE partner to halt the cell cycle and repair DNA and that concurrent mutation of these tumor suppressors drives oncogenesis in a subset of patients with endometrial cancer.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('halt', 'NegReg', (196, 200))	('promote', 'PosReg', (105, 112))	('endometrial cancer', 'Disease', 'MESH:D016889', (335, 353))	('DACH1', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('patients', 'Species', '9606', (321, 329))	('mutations', 'Var', (23, 32))	('DACH1', 'Gene', '1602', (148, 153))	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cell cycle', 'CPA', (205, 215))	('endometrial cancer', 'Phenotype', 'HP:0012114', (335, 353))	('oncogenesis', 'CPA', (294, 305))	('mutation', 'Var', (251, 259))	('tumor', 'Disease', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('drives', 'PosReg', (287, 293))	('endometrial cancer', 'Disease', (335, 353))
29794	33378353	At MCC, DACH1 mutated patients had a median TMB of 24.0, significantly higher than DACH1 wild-type patients.	('higher', 'PosReg', (71, 77))	('DACH1', 'Gene', (8, 13))	('mutated', 'Var', (14, 21))	('DACH1', 'Gene', '1602', (8, 13))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (99, 107))	('TMB', 'MPA', (44, 47))	('DACH1', 'Gene', (83, 88))	('DACH1', 'Gene', '1602', (83, 88))	('TMB', 'Chemical', '-', (44, 47))
29800	33378353	In addition, the availability of paired RNA Seq and whole exome sequencing allowed for an extensive assessment of differentially altered pathways in those with DACH1 mutations.	('mutations', 'Var', (166, 175))	('DACH1', 'Gene', '1602', (160, 165))	('altered', 'Reg', (129, 136))	('DACH1', 'Gene', (160, 165))
29801	33378353	Finally, to our knowledge, we are the first to identify the significant co-occurrence of DACH1 mutations with both POLE and Lynch associated genes and an over-representation of these mutations in our Kentucky population.	('DACH1', 'Gene', (89, 94))	('DACH1', 'Gene', '1602', (89, 94))	('mutations', 'Var', (95, 104))
29802	33378353	The study sample size is small, with 65 patients total and 12 with DACH1 mutations, and may be too small to detect possible clinical variables associated with DACH1 gene mutations.	('DACH1', 'Gene', (67, 72))	('DACH1', 'Gene', '1602', (67, 72))	('patients', 'Species', '9606', (40, 48))	('DACH1', 'Gene', (159, 164))	('DACH1', 'Gene', '1602', (159, 164))	('mutations', 'Var', (73, 82))
29808	33378353	In part, DACH1 mutations and enrichments in other co-occurring pathogenic genes may explain these differences.	('DACH1', 'Gene', '1602', (9, 14))	('mutations', 'Var', (15, 24))	('DACH1', 'Gene', (9, 14))
29810	33378353	22 Oct 2020  PONE-D-20-31424 DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden PLOS ONE Dear Dr. Kolesar, Thank you for submitting your manuscript to PLOS ONE.	('DACH1', 'Gene', '1602', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high tumor', 'Disease', 'MESH:D009369', (95, 105))	('endometrial cancer', 'Disease', (57, 75))	('high tumor', 'Disease', (95, 105))	('PONE-D-20-31424', 'Chemical', '-', (13, 28))	('mutation', 'Var', (35, 43))	('endometrial cancer', 'Disease', 'MESH:D016889', (57, 75))	('endometrial cancer', 'Phenotype', 'HP:0012114', (57, 75))	('DACH1', 'Gene', (29, 34))
29818	33378353	(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The title of this paper is DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutation', 'Var', (123, 131))	('endometrial cancer', 'Disease', (145, 163))	('high tumor', 'Disease', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('high tumor', 'Disease', 'MESH:D009369', (183, 193))	('endometrial cancer', 'Phenotype', 'HP:0012114', (145, 163))	('DACH1', 'Gene', (117, 122))	('DACH1', 'Gene', '1602', (117, 122))	('endometrial cancer', 'Disease', 'MESH:D016889', (145, 163))
29821	33378353	the mutations in DACH1 or TMB by DACH1 status and also analyzed within subgroups).	('DACH1', 'Gene', (33, 38))	('DACH1', 'Gene', '1602', (33, 38))	('DACH1', 'Gene', (17, 22))	('TMB', 'Gene', (26, 29))	('DACH1', 'Gene', '1602', (17, 22))	('TMB', 'Chemical', '-', (26, 29))	('mutations', 'Var', (4, 13))
29822	33378353	Then what fraction of POLE, MSI-H and other is DACH1 mutated.	('DACH1', 'Gene', (47, 52))	('mutated', 'Var', (53, 60))	('DACH1', 'Gene', '1602', (47, 52))
29824	33378353	5) There are few enough DACH1 mutations that they should all be listed with protein effects.	('DACH1', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('DACH1', 'Gene', '1602', (24, 29))
29825	33378353	10.1371/journal.pone.0244558.r002  8 Dec 2020  Reviewer #1: The title of this paper is DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('high tumor', 'Disease', (153, 163))	('endometrial cancer', 'Disease', (115, 133))	('endometrial cancer', 'Phenotype', 'HP:0012114', (115, 133))	('DACH1', 'Gene', (87, 92))	('DACH1', 'Gene', '1602', (87, 92))	('endometrial cancer', 'Disease', 'MESH:D016889', (115, 133))	('high tumor', 'Disease', 'MESH:D009369', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutation frequency', 'Var', (93, 111))
29827	33378353	14 Dec 2020  DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden PONE-D-20-31424R1 Dear Dr. Kolesar, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.	('high tumor', 'Disease', 'MESH:D009369', (79, 89))	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('endometrial cancer', 'Phenotype', 'HP:0012114', (41, 59))	('DACH1', 'Gene', (13, 18))	('DACH1', 'Gene', '1602', (13, 18))	('endometrial cancer', 'Disease', 'MESH:D016889', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PONE-D-20-31424', 'Chemical', '-', (106, 121))	('high tumor', 'Disease', (79, 89))	('endometrial cancer', 'Disease', (41, 59))
29829	33378353	17 Dec 2020  PONE-D-20-31424R1  DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden  Dear Dr. Kolesar: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('endometrial cancer', 'Disease', 'MESH:D016889', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('endometrial cancer', 'Phenotype', 'HP:0012114', (60, 78))	('DACH1', 'Gene', '1602', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('high tumor', 'Disease', (98, 108))	('endometrial cancer', 'Disease', (60, 78))	('PONE-D-20-31424', 'Chemical', '-', (13, 28))	('mutation', 'Var', (38, 46))	('high tumor', 'Disease', 'MESH:D009369', (98, 108))	('DACH1', 'Gene', (32, 37))
29833	33265910	The role of postoperative radiotherapy delivered as external-beam radiotherapy (EBRT), vaginal brachytherapy (VBT) or a combination of both, in the management of carcinosarcoma of the uterus is not clearly defined, as only limited randomized trial data are available, indicating a reduction in locoregional recurrences after EBRT.	('VBT', 'Chemical', '-', (110, 113))	('EBRT', 'Chemical', '-', (325, 329))	('locoregional recurrences', 'CPA', (294, 318))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('reduction', 'NegReg', (281, 290))	('carcinosarcoma of the uterus', 'Disease', 'MESH:D002296', (162, 190))	('carcinosarcoma of the uterus', 'Phenotype', 'HP:0010784', (162, 190))	('EBRT', 'Chemical', '-', (80, 84))	('carcinosarcoma of the uterus', 'Disease', (162, 190))	('EBRT', 'Var', (325, 329))
29870	33265910	found in their matched analysis of NCDB data (2004-2012, stages I-III) an improvement of overall survival by the combination of EBRT + VBT with a hazard ratio of 0.74.	('VBT', 'Gene', (135, 138))	('VBT', 'Chemical', '-', (135, 138))	('improvement', 'PosReg', (74, 85))	('overall survival', 'MPA', (89, 105))	('EBRT', 'Chemical', '-', (128, 132))	('EBRT +', 'Var', (128, 134))
29882	33265910	For the remaining stage I patients, i.e., stage IB, the most relevant data may be from Seagle et al., showing a significant improvement of overall survival with VBT, but only a trend for EBRT.	('improvement', 'PosReg', (124, 135))	('overall survival', 'MPA', (139, 155))	('patients', 'Species', '9606', (26, 34))	('VBT', 'Var', (161, 164))	('VBT', 'Chemical', '-', (161, 164))	('EBRT', 'Chemical', '-', (187, 191))
29896	31844128	Given the established pathogenic behavior of P. somerae and accompanying network in tissue infections and ulcers, future investigation into their role in EC is warranted.	('ulcers', 'Disease', 'MESH:D014456', (106, 112))	('EC', 'Phenotype', 'HP:0012114', (154, 156))	('infections', 'Disease', 'MESH:D007239', (91, 101))	('P. somerae', 'Species', '322095', (45, 55))	('P. somerae', 'Var', (45, 55))	('infections', 'Disease', (91, 101))	('ulcers', 'Disease', (106, 112))
29901	31844128	In contrast, type II tumors are not sensitive to estrogen, generally contain mutations in the p53 gene, and tend to be aggressive with a poor prognosis.	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('contain', 'Reg', (69, 76))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('type II tumors', 'Disease', (13, 27))	('mutations', 'Var', (77, 86))	('type II tumors', 'Disease', 'MESH:D009369', (13, 27))
29929	31844128	In summary, all parameters analyzed (menopause status, BMI, and vaginal pH) showed a significant impact on the microbiome composition, with postmenopause, obesity, and high vaginal pH significantly increasing the microbiome diversity.	('increasing', 'PosReg', (198, 208))	('microbiome diversity', 'CPA', (213, 233))	('obesity', 'Phenotype', 'HP:0001513', (155, 162))	('high vaginal pH', 'Var', (168, 183))	('obesity', 'Disease', 'MESH:D009765', (155, 162))	('microbiome composition', 'MPA', (111, 133))	('obesity', 'Disease', (155, 162))	('impact', 'Reg', (97, 103))
29935	31844128	The network displays a complex net of relationships, and identifies P. somerae as the microbe with the strongest association with EC.	('P. somerae', 'Species', '322095', (68, 78))	('association', 'Interaction', (113, 124))	('P. somerae', 'Var', (68, 78))	('EC', 'Phenotype', 'HP:0012114', (130, 132))
29944	31844128	The microbiome of the lower tract and uterus was significantly different for patients with (p = 0.027, Supplemental Table S4) and without (p = 0.02, Supplemental Table S5) EC.	('different', 'Reg', (63, 72))	('Supplemental Table S4', 'Var', (103, 124))	('EC', 'Phenotype', 'HP:0012114', (172, 174))	('patients', 'Species', '9606', (77, 85))
29957	31844128	Among all samples with positive qPCR results for P. somerae, the frequency of distribution between patients with and without cancer was significantly different, with more EC patients showing P. somerae detection in both sequencing and qPCR results (Supplemental Fig.	('EC', 'Phenotype', 'HP:0012114', (171, 173))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('patients', 'Species', '9606', (174, 182))	('P. somerae', 'Species', '322095', (49, 59))	('P. somerae', 'Var', (49, 59))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('P. somerae', 'Species', '322095', (191, 201))	('P. somerae', 'Var', (191, 201))
29958	31844128	Among all patients, the sensitivity of P. somerae as a predictive marker of EC was 74%, with a specificity of 63% (Supplemental Table S10).	('S10', 'Gene', (134, 137))	('EC', 'Phenotype', 'HP:0012114', (76, 78))	('S10', 'Gene', '6204', (134, 137))	('patients', 'Species', '9606', (10, 18))	('P. somerae', 'Species', '322095', (39, 49))	('P. somerae', 'Var', (39, 49))
29964	31844128	Of particular notice is that P. somerae was detected in all (100%) Type II EC patients, and 57% of the hyperplasia patients Supplemental Table S11.	('EC', 'Phenotype', 'HP:0012114', (75, 77))	('Type II EC', 'Disease', (67, 77))	('patients', 'Species', '9606', (115, 123))	('hyperplasia', 'Disease', (103, 114))	('patients', 'Species', '9606', (78, 86))	('S11', 'Gene', '6267', (143, 146))	('hyperplasia', 'Disease', 'MESH:D006965', (103, 114))	('P. somerae', 'Var', (29, 39))	('S11', 'Gene', (143, 146))	('P. somerae', 'Species', '322095', (29, 39))	('Type II EC', 'Disease', 'MESH:D016532', (67, 77))
29985	31844128	P. somerae has been isolated from diabetic foot ulcers, bacterial vaginosis, chronic otitis media, and chronic bone and soft tissue infections, suggesting that it may act as a pathogen.	('soft tissue infections', 'Disease', 'MESH:D018461', (120, 142))	('bacterial vaginosis', 'Phenotype', 'HP:0030683', (56, 75))	('bacterial vaginosis', 'Disease', (56, 75))	('P. somerae', 'Species', '322095', (0, 10))	('P. somerae', 'Var', (0, 10))	('chronic otitis', 'Phenotype', 'HP:0000389', (77, 91))	('diabetic foot ulcers', 'Disease', (34, 54))	('otitis', 'Disease', (85, 91))	('diabetic foot ulcers', 'Disease', 'MESH:D017719', (34, 54))	('otitis media', 'Phenotype', 'HP:0000388', (85, 97))	('bacterial vaginosis', 'Disease', 'MESH:D016585', (56, 75))	('otitis', 'Disease', 'MESH:D010031', (85, 91))	('soft tissue infections', 'Disease', (120, 142))
29986	31844128	Further, P. gingivalis, which is closely related to P. somerae, has been implicated in esophageal cancer and Alzheimer's disease, implying that the Porphyromonas genus contains species with the ability to cause serious disease in humans.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('implicated', 'Reg', (73, 83))	("Alzheimer's disease", 'Disease', (109, 128))	('Porphyromonas', 'Species', '322095', (148, 161))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('P. somerae', 'Species', '322095', (52, 62))	('cancer', 'Disease', (98, 104))	('P. gingivalis', 'Species', '837', (9, 22))	('humans', 'Species', '9606', (230, 236))	('P. gingivalis', 'Var', (9, 22))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (109, 128))
29995	31844128	This becomes of particular interest to pursue given that P. somerae was detected in all Type II EC cases in our study, which is more prevalent in black women.	('women', 'Species', '9606', (152, 157))	('EC', 'Phenotype', 'HP:0012114', (96, 98))	('detected', 'Reg', (72, 80))	('Type II EC', 'Disease', 'MESH:D016532', (88, 98))	('P. somerae', 'Species', '322095', (57, 67))	('P. somerae', 'Var', (57, 67))	('Type II EC', 'Disease', (88, 98))
30121	31831737	In particular, proteome-based versus mRNA-based subtyping associations, respectively, included (proteome-based) k1 to (mRNA-based) c1, k2 to both c3 and c10, k3 to c3, k4 to c5, k5 to c6, k6 to c7, and k7 to c8.	('k4 to c5', 'Var', (168, 176))	('k3 to c3', 'Var', (158, 166))	('c10', 'Gene', (153, 156))	('k5 to c6', 'Var', (178, 186))	('c10', 'Gene', '3226', (153, 156))
30136	31831737	2e), other tumors that were not breast could also manifest a k4-associated signature pattern.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('k4-associated', 'Var', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))
30246	28800945	Mutation status for TP53 or PTEN, or with the aggressive integrative, transcript-based, or somatic copy number alteration-based molecular subtype were acquired from the Cancer Genome Atlas.	('PTEN', 'Gene', (28, 32))	('Cancer', 'Phenotype', 'HP:0002664', (169, 175))	('PTEN', 'Gene', '5728', (28, 32))	('TP53', 'Gene', (20, 24))	('Mutation', 'Var', (0, 8))	('TP53', 'Gene', '7157', (20, 24))
30252	28800945	Mutations in TP53, PTEN and the three aggressive molecular subtypes each varied by race, age and histology.	('TP53', 'Gene', (13, 17))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('varied', 'Reg', (73, 79))
30256	28800945	Impact of age of diagnosis on the proportion of the high-risk histology (upper left), adjusted risk of death (upper right), survival (lower left), and the proportion with a TP53 mutation, wildtype PTEN, copy number variant (CNV) high subtype, mitotic transcript-based subtype and the cluster 4 subtype in black compared with white endometrial cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('white endometrial cancer', 'Disease', (325, 349))	('mutation', 'Var', (178, 186))	('patients', 'Species', '9606', (350, 358))	('PTEN', 'Gene', (197, 201))	('death', 'Disease', 'MESH:D003643', (103, 108))	('endometrial cancer', 'Phenotype', 'HP:0012114', (331, 349))	('death', 'Disease', (103, 108))	('TP53', 'Gene', '7157', (173, 177))	('PTEN', 'Gene', '5728', (197, 201))	('TP53', 'Gene', (173, 177))	('white endometrial cancer', 'Disease', 'MESH:D016889', (325, 349))
30262	28800945	Racial differences have also been reported in prevalence of prognostic transcripts including PSPHL, SERPINA4, ITGA3, BET1L, FAM228B and HEATR6, the aggressive copy number variant (CNV) high, somatic copy number alteration (SCNA) cluster 4 and transcript-based mitotic molecular subtypes, mutations in TP53 and PTEN, oncoproteins such as HER2 or copy number alterations in 1q23 in EC.	('SERPINA4', 'Gene', '5267', (100, 108))	('ITGA3', 'Gene', (110, 115))	('PTEN', 'Gene', '5728', (310, 314))	('BET1L', 'Gene', (117, 122))	('mutations', 'Var', (288, 297))	('SERPINA4', 'Gene', (100, 108))	('HER2', 'Gene', (337, 341))	('1q23', 'Gene', (372, 376))	('HEATR6', 'Gene', '63897', (136, 142))	('EC', 'Disease', 'MESH:D016889', (380, 382))	('TP53', 'Gene', '7157', (301, 305))	('copy number alterations in', 'Var', (345, 371))	('BET1L', 'Gene', '51272', (117, 122))	('ITGA3', 'Gene', '3675', (110, 115))	('FAM228B', 'Gene', (124, 131))	('HEATR6', 'Gene', (136, 142))	('PSPHL', 'Gene', (93, 98))	('PSPHL', 'Gene', '8781', (93, 98))	('HER2', 'Gene', '2064', (337, 341))	('PTEN', 'Gene', (310, 314))	('FAM228B', 'Gene', '375190', (124, 131))	('EC', 'Phenotype', 'HP:0012114', (380, 382))	('TP53', 'Gene', (301, 305))
30294	28800945	TCGA data were analyzed to determine if the odds of presenting with a mutation in TP53 or PTEN, or with an aggressive molecular subtype varied by race and/or age of diagnosis.	('TP53', 'Gene', (82, 86))	('PTEN', 'Gene', (90, 94))	('PTEN', 'Gene', '5728', (90, 94))	('TP53', 'Gene', '7157', (82, 86))	('mutation', 'Var', (70, 78))
30315	28800945	The racial disparity in survival was larger in EEC patients with G1/G2 vs. G3 disease (Fig.	('EEC', 'Disease', 'MESH:D016889', (47, 50))	('EC', 'Phenotype', 'HP:0012114', (48, 50))	('G1/G2', 'Var', (65, 70))	('EEC', 'Phenotype', 'HP:0012114', (47, 50))	('patients', 'Species', '9606', (51, 59))	('EEC', 'Disease', (47, 50))
30321	28800945	Mutations in TP53, wild-type PTEN and the three aggressive molecular subtypes have previously been shown to be associated with the high-risk histology.	('TP53', 'Gene', (13, 17))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('associated', 'Reg', (111, 121))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))
30324	28800945	The odds ratio for presenting with the following aggressive molecular features in black vs. white patients diagnosed at >=65 and <65 years old was 9.8 vs. 2.9 for a TP53 mutation, 15.6 vs. 2.0 for wild-type PTEN, 10.0 vs. 4.3 for CNV high subtype, 7.8 vs. 2.7 for the mitotic subtype, and 7.2 vs. 4.6 for the SNCA cluster 4 subtype, but all the interaction tests did not reach the level of statistical significance (P > 0.05 for all).	('TP53', 'Gene', (165, 169))	('PTEN', 'Gene', (207, 211))	('PTEN', 'Gene', '5728', (207, 211))	('patients', 'Species', '9606', (98, 106))	('SNCA', 'Gene', '6622', (309, 313))	('SNCA', 'Gene', (309, 313))	('TP53', 'Gene', '7157', (165, 169))	('mutation', 'Var', (170, 178))
30335	28800945	Molecular alterations may also explain at least some of the disparities reported between older vs. younger black and white EC patients.	('EC', 'Phenotype', 'HP:0012114', (123, 125))	('white EC', 'Disease', (117, 125))	('white EC', 'Disease', 'MESH:D016889', (117, 125))	('patients', 'Species', '9606', (126, 134))	('Molecular alterations', 'Var', (0, 21))
30336	28800945	Prior studies have documented molecular alterations between black and white EC patients including racial differences in prevalence of prognostic transcripts, molecular subtypes, mutations, proteins or copy number alterations.	('proteins', 'Protein', (189, 197))	('white EC', 'Disease', (70, 78))	('EC', 'Phenotype', 'HP:0012114', (76, 78))	('patients', 'Species', '9606', (79, 87))	('white EC', 'Disease', 'MESH:D016889', (70, 78))	('copy number alterations', 'Var', (201, 224))	('mutations', 'Var', (178, 187))
30337	28800945	For example, TP53 mutations and the aggressive molecular subtypes defined by TCGA were more common in black vs. white EC patients and associated with poor outcomes.	('associated', 'Reg', (134, 144))	('TP53', 'Gene', (13, 17))	('white EC', 'Disease', 'MESH:D016889', (112, 120))	('common', 'Reg', (92, 98))	('EC', 'Phenotype', 'HP:0012114', (118, 120))	('TP53', 'Gene', '7157', (13, 17))	('patients', 'Species', '9606', (121, 129))	('white EC', 'Disease', (112, 120))	('mutations', 'Var', (18, 27))
30338	28800945	In contrast, PTEN mutations and certain transcripts were more common in white vs. black patients and associated with a more favorable outcome.	('PTEN', 'Gene', (13, 17))	('patients', 'Species', '9606', (88, 96))	('PTEN', 'Gene', '5728', (13, 17))	('mutations', 'Var', (18, 27))
30339	28800945	We not only confirmed that mutations in TP53 and wild-type PTEN were significantly more common in black vs. white EC patients, but also showed that they were also more common in older vs. younger patients regardless of race.	('mutations', 'Var', (27, 36))	('common', 'Reg', (88, 94))	('white EC', 'Disease', (108, 116))	('patients', 'Species', '9606', (196, 204))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('white EC', 'Disease', 'MESH:D016889', (108, 116))	('EC', 'Phenotype', 'HP:0012114', (114, 116))	('patients', 'Species', '9606', (117, 125))	('PTEN', 'Gene', (59, 63))	('common', 'Reg', (168, 174))	('PTEN', 'Gene', '5728', (59, 63))
30363	28800945	TP53 mutation, wild-type PTEN, and the aggressive molecular subtypes (CNV high, mitotic and SCNA cluster 4) were significantly more common in black patients, though increased in all patients diagnosed at >=65.	('mitotic', 'CPA', (80, 87))	('TP53', 'Gene', '7157', (0, 4))	('patients', 'Species', '9606', (148, 156))	('TP53', 'Gene', (0, 4))	('common', 'Reg', (132, 138))	('PTEN', 'Gene', '5728', (25, 29))	('patients', 'Species', '9606', (182, 190))	('PTEN', 'Gene', (25, 29))	('mutation', 'Var', (5, 13))
30369	28800945	Mutations in TP53 and PTEN, and molecular subtypes vary by age of diagnosis and race.	('TP53', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('TP53', 'Gene', '7157', (13, 17))
30386	31174566	MLAs harbor recurrent mutations in KRAS and PIK3CA but lack PTEN mutations, demonstrating biological overlap with both mesonephric and endometrioid carcinomas.	('PIK3CA', 'Gene', (44, 50))	('MLAs', 'Gene', (0, 4))	('KRAS', 'Gene', (35, 39))	('MLAs', 'Gene', '81893', (0, 4))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (135, 157))	('PIK3CA', 'Gene', '5290', (44, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('endometrioid carcinomas', 'Disease', (135, 158))	('PTEN', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (35, 39))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (135, 158))	('PTEN', 'Gene', '5728', (60, 64))	('mutations', 'Var', (22, 31))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
30403	31174566	On molecular testing, KRAS mutation (c.35G > C, p.G12A; Gly12Ala) was detected in this endometrial cancer.	('endometrial cancer', 'Disease', (87, 105))	('Gly12Ala', 'Var', (56, 64))	('detected', 'Reg', (70, 78))	('Gly12Ala', 'SUBSTITUTION', 'None', (56, 64))	('c.35G > C', 'Var', (37, 46))	('endometrial cancer', 'Disease', 'MESH:D016889', (87, 105))	('p.G12A', 'Mutation', 'rs121913529', (48, 54))	('endometrial cancer', 'Phenotype', 'HP:0012114', (87, 105))	('KRAS', 'Gene', '3845', (22, 26))	('KRAS', 'Gene', (22, 26))	('c.35G > C', 'Mutation', 'rs121913529', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
30407	31174566	On molecular testing, same KRAS mutation (c.35G > C, p.G12A; Gly12Ala) was detected in the initial biopsy.	('KRAS', 'Gene', '3845', (27, 31))	('c.35G > C', 'Mutation', 'rs121913529', (42, 51))	('Gly12Ala', 'Var', (61, 69))	('Gly12Ala', 'SUBSTITUTION', 'None', (61, 69))	('c.35G > C', 'Var', (42, 51))	('p.G12A', 'Mutation', 'rs121913529', (53, 59))	('KRAS', 'Gene', (27, 31))
30438	29765148	As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis.	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (67, 76))
30441	29765148	We show that, for most cancer types, de-sparsified mutation data associate with phenotypic data.	('de-sparsified mutation', 'Var', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
30442	29765148	We identify poor prognostic subtypes in three cancer types, which are associated with mutations in signal transduction pathways for which targeted treatment options are available.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('signal transduction pathways', 'Pathway', (99, 127))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
30443	29765148	Finally, we perform a pan-cancer subtyping analysis and identify nine pan-cancer subtypes, which associate with mutations in four overarching sets of biological pathways.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
30450	29765148	Since the onset of large-scale genomic experiments, cancer subtypes have been identified in multiple cancers, using mRNA and microRNA expression levels, methylation data, copy number alterations and combinations of different 'omics data types, but few studies have subtyped patients based on somatic mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('multiple cancers', 'Disease', 'MESH:D009369', (92, 108))	('cancer', 'Disease', (101, 107))	('patients', 'Species', '9606', (274, 282))	('multiple cancers', 'Disease', (92, 108))	('copy', 'Var', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
30453	29765148	However, subtype classification using somatic mutations in cancer is challenging, mainly because the data are very sparse: many tumours only have a handful of mutations in coding regions yet the total number of mutations within a population is typically substantial.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('mutations', 'Var', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
30454	29765148	Often, frequent cancer drivers:such as TP53:are mutated, as well as so-called "passenger" events that are considered mutational noise yet which may still influence tumour properties.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('mutated', 'Var', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('influence', 'Reg', (154, 163))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', (39, 43))
30464	29765148	While these studies have improved our understanding of the genes and pathways that are recurrently mutated in cancer, data are now available for many more samples and cancer types, increasing the power to detect new mutational patterns and cancer subtypes.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('increasing', 'PosReg', (181, 191))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (240, 246))	('mutational', 'Var', (216, 226))
30485	29765148	For each cancer type, we clustered the pathway mutation scores using hierarchical clustering with binomial distance.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutation', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
30500	29765148	We divided the cell lines into two groups: those that had mutations in all 94 "Set 1" pathways (n = 156), and those that did not (n = 845), and performed a t-test to identify significant differences in response to drugs targeting phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/MTOR) signalling (Benjamini-Hochberg adjusted p-values <0.05).	('mutations', 'Var', (58, 67))	('MTOR', 'Gene', '2475', (292, 296))	('Set 1"', 'Gene', '9739', (79, 85))	('Set 1"', 'Gene', (79, 85))	('mammalian', 'Species', '9606', (256, 265))	('MTOR', 'Gene', (292, 296))
30502	29765148	We repeated this analysis on cell lines that had mutations in all 38 "Set 2" pathways (n = 681) and those that did not (n = 320) and drugs targeting DNA replication.	('Set 2"', 'Gene', (70, 76))	('Set 2"', 'Gene', '29072', (70, 76))	('mutations', 'Var', (49, 58))
30503	29765148	We note that we identified a relatively high number of cell lines with mutations in all "Set 2" pathways compared to the number we identified in primary tumours.	('Set 2"', 'Gene', (89, 95))	('primary tumours', 'Disease', 'MESH:D009369', (145, 160))	('Set 2"', 'Gene', '29072', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (71, 80))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('primary tumours', 'Disease', (145, 160))
30514	29765148	As expected, we observed a larger number of mutated pathways than of mutated cancer-associated genes across all samples (median = 103).	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutated', 'Var', (44, 51))
30518	29765148	These percentages were lower for mutations in cancer-associated genes, with an average of 54.8% of all cancer-associated genes being mutated in a cancer type (minimum of 6.1% for KICH, maximum of 95.1% for UCEC).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (46, 52))	('UCEC', 'Disease', (206, 210))	('mutated', 'Var', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
30529	29765148	Additionally, technical variability (batch number) appears to associate with pathway mutation scores in a number of cancers.	('associate', 'Reg', (62, 71))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('pathway', 'PosReg', (77, 84))	('mutation scores', 'Var', (85, 100))
30538	29765148	In addition to these known cancer-driver pathways, we identified mutations in neurotrophin signalling, which plays a role in neuron development and differentiation, in the poor prognosis subtype.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('neurotrophin signalling', 'Gene', (78, 101))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (65, 74))
30542	29765148	In addition to these pathways, DNA damage response pathways, which included p53 and ATM signalling, were mutated in the poor prognostic subtype of LAML.	('ATM', 'Gene', (84, 87))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('ATM', 'Gene', '472', (84, 87))	('mutated', 'Var', (105, 112))	('DNA damage response pathways', 'Pathway', (31, 59))
30544	29765148	Tumours assigned to this subtype had higher mutation scores in multiple epidermal growth factor receptor (EGFR) family pathways, in cell-cell contact and cellular structure ("adherens junction", "gap junction"), the immune system ("cytokine-cytokine receptor interaction") and in brain tissue-associated pathways (including "gonadotropin-releasing hormone signalling").	('mutation', 'Var', (44, 52))	('higher', 'PosReg', (37, 43))	('epidermal growth factor receptor', 'Gene', (72, 104))	('EGFR', 'Gene', '1956', (106, 110))	('gonadotropin-releasing hormone', 'Gene', (325, 355))	('epidermal growth factor receptor', 'Gene', '1956', (72, 104))	('gonadotropin-releasing hormone', 'Gene', '2796', (325, 355))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('EGFR', 'Gene', (106, 110))
30545	29765148	Mutations in cell-cell contact genes could be important for metastasis, and immune cells are known to play a critical role into transforming low-grade glioma into glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('Mutations', 'Var', (0, 9))	('glioblastoma', 'Disease', (163, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))	('glioma', 'Disease', (151, 157))
30547	29765148	However, while this gene was mutated in 15/17 patients, other genes belonging to EGFR family pathways, including EGF, GNAS and PTRB, were also mutated in tumours belonging to this subtype and might not have been detected if we had focussed on EGFR alone.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('patients', 'Species', '9606', (46, 54))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('PTRB', 'Gene', (127, 131))	('EGF', 'Gene', (113, 116))	('tumours belonging', 'Disease', 'MESH:D009369', (154, 171))	('EGFR', 'Gene', '1956', (81, 85))	('GNAS', 'Gene', '2778', (118, 122))	('tumours belonging', 'Disease', (154, 171))	('EGFR', 'Gene', '1956', (243, 247))	('mutated', 'Var', (143, 150))	('EGFR', 'Gene', (243, 247))	('GNAS', 'Gene', (118, 122))	('EGFR', 'Gene', (81, 85))
30549	29765148	For each of the significant cancer types, we performed 10,000 sample label permutations and found that the original log-rank tests were more significant than those on the permuted null background (Benjamini-Hochberg adjusted p-values p < 0.01), indicating that the poor prognostic subtypes were not identified by chance but were detected based on mutations in specific biological pathways (see Supplemental Fig.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (347, 356))
30556	29765148	This was not unexpected, as we found specific mutations in p53 pathways in this subtype.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('mutations', 'Var', (46, 55))
30563	29765148	In total, the subtypes that were enriched for mutations in drug targets from CMap account for 12% (689/5805) of all primary tumours from TCGA.	('mutations', 'Var', (46, 55))	('primary tumours', 'Disease', 'MESH:D009369', (116, 131))	('primary tumours', 'Disease', (116, 131))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('CMap', 'Gene', (77, 81))
30579	29765148	All of the subtypes, except S5, which had no subtype-specific pathway mutations, had frequent mutations in Kyoto Encyclopedia of Genes and Genomes "pathways in cancer".	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', (160, 166))	('Kyoto Encyclopedia of Genes', 'Gene', (107, 134))	('Genomes "pathways', 'Pathway', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
30581	29765148	Using hierarchical clustering (binomial distance) on average mutation scores in these 202 pathways, we identified four overarching "sets" of pathways that were differentially mutated in the pan-cancer subtypes (see Fig.	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutation', 'Var', (61, 69))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
30587	29765148	Most of the sets are either mutated alone (such as Set 2 in pan-cancer subtypes S4 and S6) or in combination with other sets (for example, Sets 2-4 in pan-cancer subtype S8).	('mutated', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Set 2', 'Gene', (51, 56))	('Set 2', 'Gene', '29072', (51, 56))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
30594	29765148	We identified significantly higher protein activation scores in tumours from patients belonging to the subtypes that had higher levels of mutations in these pathways.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('protein activation scores', 'MPA', (35, 60))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('higher', 'PosReg', (28, 34))	('patients', 'Species', '9606', (77, 85))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (138, 147))
30596	29765148	This indicates that the pan-cancer subtypes we had identified based on pathway mutation scores also corresponded to higher protein levels in these pathways.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('higher', 'PosReg', (116, 122))	('mutation scores', 'Var', (79, 94))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('protein levels', 'MPA', (123, 137))
30597	29765148	Second, we wanted to determine whether cell lines with mutations in the overarching sets of pathways we had identified in the pan-cancer subtypes were more sensitive to drugs targeting those pathways.	('sensitive', 'MPA', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
30598	29765148	We identified which cell lines had mutations in all "Set 1" pathways and compared how these cells responded to PI3K/MTOR inhibitors compared to other cell lines (Methods).	('MTOR', 'Gene', (116, 120))	('Set 1"', 'Gene', '9739', (53, 59))	('Set 1"', 'Gene', (53, 59))	('MTOR', 'Gene', '2475', (116, 120))	('mutations', 'Var', (35, 44))
30601	29765148	We repeated this analysis for cell lines with mutations in all "Set 2" pathways and compared how these cell lines responded to drugs interfering with DNA replication.	('Set 2"', 'Gene', '29072', (64, 70))	('Set 2"', 'Gene', (64, 70))	('mutations', 'Var', (46, 55))
30607	29765148	We showed that SAMBAR helps identifying mutational patterns associated with clinical phenotypes and prognosis and potential targeted treatment options for cancer-specific subtypes, as well as mutational patterns that are manifested across multiple cancer types.	('cancer', 'Disease', (248, 254))	('SAMBAR', 'Species', '662561', (15, 21))	('multiple cancer', 'Disease', (239, 254))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('multiple cancer', 'Disease', 'MESH:D009369', (239, 254))	('mutational', 'Var', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', (155, 161))	('associated', 'Reg', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
30610	29765148	For example, we identified MDM2 inhibitors as potential targets for treatment of the poor prognosis subtype in ACC by integrating subtype-specific mutations with a drug-targeting database.	('mutations', 'Var', (147, 156))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('ACC', 'Disease', (111, 114))	('MDM2', 'Gene', '4193', (27, 31))	('MDM2', 'Gene', (27, 31))
30614	29765148	By generating patient-specific "pathway mutation profiles", we may not only identify patients who could benefit from specific targeted therapeutics but we will also obtain a clearer picture of the cellular processes that are altered through mutation in a specific tumour.	('tumour', 'Disease', (264, 270))	('mutation', 'Var', (40, 48))	('patient', 'Species', '9606', (85, 92))	('patients', 'Species', '9606', (85, 93))	('patient', 'Species', '9606', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('mutation', 'Var', (241, 249))
30619	29765148	In addition, one of the pan-cancer mutational patterns we identified was enriched for several growth factor pathways, including EGF receptor family genes, and FGFR and nerve growth factor signalling.	('mutational', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('growth factor pathways', 'Pathway', (94, 116))	('EGF receptor family genes', 'Gene', (128, 153))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FGFR', 'Gene', (159, 163))	('cancer', 'Disease', (28, 34))	('nerve growth factor signalling', 'Pathway', (168, 198))
30620	29765148	Because these pathways are mutated in a large set of the primary tumours we analysed, we believe that these treatment options are worthy of further investigation and may lead to better treatment options for a large numbers of patients.	('mutated', 'Var', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('patients', 'Species', '9606', (226, 234))	('primary tumours', 'Disease', 'MESH:D009369', (57, 72))	('primary tumours', 'Disease', (57, 72))
30622	29765148	Our framework to classify cancers based on mutational patterns in biological pathways could help expand precision medicine applications both by identifying groups of patients who may or may not respond to particular therapies and by identifying pathways that might be useful targets for therapeutic intervention.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('mutational', 'Var', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('patients', 'Species', '9606', (166, 174))
30735	27980218	These defects may be inherited, as with Lynch syndrome/hereditary nonpolyposis colorectal cancer, or may be somatically acquired, most commonly due to promoter hypermethylation of the MMR gene MLH1.	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (55, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('due to', 'Reg', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('inherited', 'Reg', (21, 30))	('hereditary nonpolyposis colorectal cancer', 'Disease', (55, 96))	('Lynch syndrome', 'Disease', (40, 54))	('promoter hypermethylation', 'Var', (151, 176))	('Lynch syndrome', 'Disease', 'MESH:D003123', (40, 54))	('MLH1', 'Gene', '4292', (193, 197))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (55, 96))	('MLH1', 'Gene', (193, 197))
30741	27980218	As NGS increases in both cost-effectiveness and prevalence, NGS-based methods may permit identification of MSI status without requiring additional clinical testing or patient sample processing.	('MSI', 'Disease', (107, 110))	('NGS', 'Var', (3, 6))	('patient', 'Species', '9606', (167, 174))
30742	27980218	Lastly, NGS data is becoming increasingly available in tumor types that are not routinely tested for MSI, with potential opportunities to identify microsatellite instability in previously uncharacterized cancers.	('microsatellite', 'Var', (147, 161))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', (55, 60))
30762	27980218	Previous studies have suggested that different MSI positive cancers may have specific microsatellite loci that are most commonly unstable.	('MSI positive cancers', 'Disease', 'MESH:D009369', (47, 67))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('MSI positive cancers', 'Disease', (47, 67))	('microsatellite loci', 'Var', (86, 105))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
30792	27980218	MANTIS is a tool for identifying microsatellite instability in paired tumor-normal patient samples (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('microsatellite instability', 'Var', (33, 59))	('patient', 'Species', '9606', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
30808	27980218	This bias towards monomer repeats was expected since intronic mononucleotide repeats outnumber other repeat regions in the human genome.	('intronic mononucleotide repeats', 'Var', (53, 84))	('outnumber', 'NegReg', (85, 94))	('human', 'Species', '9606', (123, 128))	('mononucleotide', 'Chemical', '-', (62, 76))
30916	28226030	In conclusion, patients without deep myometrial invasion and LVSI on the final uterine pathological examination, low Ca-125 values (<21 U/mL) and normal radiological images of the LNs have an extremely low risk of LN metastasis (2.7%) that does not justify the performance of a second surgery for nodal dissection.	('patients', 'Species', '9606', (15, 23))	('low', 'Var', (113, 116))	('Ca-125', 'Gene', '94025', (117, 123))	('Ca-125', 'Gene', (117, 123))	('LN metastasis', 'CPA', (214, 227))
30929	27130238	High-risk histology (aRR 1.14, 95%CI: 1.04-1.25) was positively associated with referral, while Medicaid insurance was negatively associated with referral (aRR 0.64, 95%CI: 0.42-0.96).	('referral', 'Disease', (80, 88))	('aRR 1', 'Gene', '408', (21, 26))	('aRR 1', 'Gene', (21, 26))	('High-risk', 'Var', (0, 9))
30968	27130238	Those with scores >= 1 represent patients with a comorbidity profile that is associated with greater hospitalization and health care utilization and/or greater mortality risk.	('greater', 'PosReg', (93, 100))	('hospitalization', 'CPA', (101, 116))	('patients', 'Species', '9606', (33, 41))	('scores >= 1', 'Var', (11, 22))
30988	27130238	For all patients who received chemotherapy, the site of surgery and site of chemotherapy were used to create 3 referral care model groups: High-Volume-All (HV-All), High-Volume-Hybrid (HV-Hybrid), and High-Volume-None (HV-None) (Table 4).	('High-Volume-All', 'Var', (139, 154))	('High-Volume-Hybrid', 'Var', (165, 183))	('patients', 'Species', '9606', (8, 16))
31034	26356327	We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex.	('BRG1', 'Gene', (186, 190))	('loss', 'NegReg', (149, 153))	('SMARCA4', 'Gene', (124, 131))	('BRG1', 'Gene', '6597', (186, 190))	('ATPase', 'Gene', (223, 229))	('inactivating mutations', 'Var', (67, 89))	('SMARCA4', 'Gene', (177, 184))	('SMARCA4', 'Gene', '6597', (124, 131))	('SMARCA4', 'Gene', '6597', (177, 184))	('ATPase', 'Gene', '1769', (223, 229))
31042	26356327	Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.	('SMARCA4', 'Gene', '6597', (26, 33))	('SWI/SNF', 'Gene', (145, 152))	('ATPase', 'Gene', '1769', (153, 159))	('SCCOHT', 'Disease', (107, 113))	('inhibit', 'NegReg', (164, 171))	('growth of SCCOHT cell lines', 'CPA', (176, 203))	('SMARCA4', 'Gene', (26, 33))	('loss', 'NegReg', (34, 38))	('ATPase', 'Gene', (153, 159))	('restoration', 'Var', (123, 134))
31050	26356327	Recently, four groups independently identified inactivating SMARCA4 mutations in the majority of SCCOHTs, resulting in loss of SMARCA4 protein 2, 3, 4, 5.	('SMARCA4', 'Gene', (127, 134))	('SMARCA4', 'Gene', '6597', (60, 67))	('SMARCA4', 'Gene', '6597', (127, 134))	('inactivating', 'Var', (47, 59))	('loss', 'NegReg', (119, 123))	('mutations', 'Var', (68, 77))	('SMARCA4', 'Gene', (60, 67))
31052	26356327	SWI/SNF subunits have been frequently implicated as tumour suppressors, with approximately 20% of cancers bearing mutations in these genes 9, 10.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (114, 123))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('tumour', 'Disease', (52, 58))
31056	26356327	Indeed, loss of SMARCA4 has been shown to lead to dependence on SMARCA2-containing SWI/SNF complexes for survival in some cell lines 11, 12, 13, raising the possibility of targeting SMARCA2 in SCCOHT using inhibitors of its ATPase or bromodomain.	('ATPase', 'Gene', '1769', (224, 230))	('dependence', 'MPA', (50, 60))	('ATPase', 'Gene', (224, 230))	('SMARCA4', 'Gene', (16, 23))	('loss', 'Var', (8, 12))	('SMARCA4', 'Gene', '6597', (16, 23))
31057	26356327	The establishment of SMARCA4 mutation with accompanying loss of protein as the pathognomonic mutation in SCCOHT raises the need to explore the spectrum of tumours that share SMARCA4 (and perhaps SMARCA2) loss to understand the diagnostic utility of SMARCA4 immunohistochemistry (IHC).	('tumours', 'Disease', (155, 162))	('mutation', 'Var', (29, 37))	('SMARCA4', 'Gene', '6597', (249, 256))	('SMARCA4', 'Gene', (21, 28))	('loss', 'NegReg', (56, 60))	('SMARCA4', 'Gene', '6597', (21, 28))	('SMARCA4', 'Gene', '6597', (174, 181))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('SMARCA4', 'Gene', (249, 256))	('protein', 'Protein', (64, 71))	('SMARCA4', 'Gene', (174, 181))
31066	26356327	Tumours were scored as negative if tumour cell nuclei showed no staining only if adequate staining was detected in internal positive control cells (endothelium, lymphocytes or fibroblasts); absence of staining has previously been shown to correlate with the presence of inactivating mutations in SMARCA4 2, 3, 4, 5, 15.	('absence', 'NegReg', (190, 197))	('SMARCA4', 'Gene', (296, 303))	('SMARCA4', 'Gene', '6597', (296, 303))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('inactivating mutations', 'Var', (270, 292))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('tumour', 'Disease', (35, 41))
31077	26356327	To produce lentiviruses expressing SMARCA4 or SMARCA2, pLDpuro-SMARCA4 or pLDpuro-SMARCA2 was co-transfected with packaging plasmids psPAX2 and pMD2.G into HEK293T cells.	('HEK293T', 'CellLine', 'CVCL:0063', (156, 163))	('pLDpuro-SMARCA2', 'Var', (74, 89))	('SMARCA4', 'Gene', (35, 42))	('SMARCA4', 'Gene', (63, 70))	('SMARCA4', 'Gene', '6597', (63, 70))	('SMARCA4', 'Gene', '6597', (35, 42))
31087	26356327	Cells were infected with lentivirus containing pLDpuro-GFP, -SMARCA4 or -SMARCA2.	('SMARCA4', 'Gene', (61, 68))	('pLDpuro-GFP', 'Var', (47, 58))	('SMARCA4', 'Gene', '6597', (61, 68))
31107	26356327	These data demonstrate that the lack of SMARCA4 in ovarian tumours is a highly sensitive and almost completely specific IHC marker of SCCOHT.	('lack', 'Var', (32, 36))	('SMARCA4', 'Gene', '6597', (40, 47))	('ovarian tumour', 'Phenotype', 'HP:0100615', (51, 65))	('ovarian tumours', 'Disease', (51, 66))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('SMARCA4', 'Gene', (40, 47))	('ovarian tumours', 'Disease', 'MESH:D010051', (51, 66))
31117	26356327	The lack of mutations or deletions involving SMARCA2 in SCCOHT and the expression of SMARCA2 protein in rare tumour cells suggest that the absence of SMARCA2 protein in most tumour cells arises from epigenetic silencing or mRNA degradation, as reported in other SMARCA2-deficient cell lines 17, 18, 19, 20, 21.	('protein', 'Protein', (158, 165))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('SMARCA2', 'Gene', (150, 157))	('absence', 'NegReg', (139, 146))	('epigenetic silencing', 'Var', (199, 219))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('mRNA degradation', 'MPA', (223, 239))	('SMARCA2', 'Gene', (85, 92))	('tumour', 'Disease', (109, 115))	('deletions', 'Var', (25, 34))	('SMARCA2', 'Gene', (45, 52))	('tumour', 'Disease', (174, 180))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
31120	26356327	SMARCA2 mRNA levels were significantly lower in BIN67 and SCCOHT1 cells than in NOY1 (a yolk sac tumour cell line), SVOG3e (an immortalized primary granulosa cell line) or KGN cells (an adult granulosa cell tumour cell line) (Figure 4B), suggesting epigenetically silencing of the SMARCA2 gene or degradation of SMARCA2 mRNA as the mechanism underlying the lack of SMARCA2 protein in SCCOHT cells.	('tumour', 'Disease', (97, 103))	('adult granulosa cell tumour', 'Phenotype', 'HP:0031919', (186, 213))	('tumour', 'Disease', (207, 213))	('granulosa cell tumour', 'Disease', (192, 213))	('SMARCA2', 'Gene', (281, 288))	('degradation', 'MPA', (297, 308))	('granulosa cell tumour', 'Disease', 'MESH:D006106', (192, 213))	('SMARCA2 mRNA levels', 'MPA', (0, 19))	('NOY1', 'CellLine', 'CVCL:0P30', (80, 84))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('epigenetically silencing', 'Var', (249, 273))	('lower', 'NegReg', (39, 44))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
31124	26356327	These data implicate HDAC-mediated epigenetic silencing of the SMARCA2 gene in SCCOHT or, alternatively, an indirect inhibitory effect on SMARCA2 mRNA degradation.	('HDAC', 'Gene', '9734', (21, 25))	('epigenetic silencing', 'Var', (35, 55))	('implicate', 'Reg', (11, 20))	('SCCOHT', 'Disease', (79, 85))	('inhibitory effect', 'NegReg', (117, 134))	('SMARCA2', 'Gene', (63, 70))	('SMARCA2 mRNA degradation', 'MPA', (138, 162))	('HDAC', 'Gene', (21, 25))
31128	26356327	Therefore, the rapid growth arrest that SMARCA4 or SMARCA2 expression induced in SCCOHT cells is consistent with the absence of detectable RB1 gene mutations in all tumour samples and the presence of intact, full length RB1 protein (both hypo- and hyper-phosphorylated forms) in the BIN67 cells (data not shown).	('RB1', 'Gene', (220, 223))	('SMARCA4', 'Gene', '6597', (40, 47))	('mutations', 'Var', (148, 157))	('growth arrest', 'Phenotype', 'HP:0001510', (21, 34))	('RB1', 'Gene', '5925', (220, 223))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('absence', 'NegReg', (117, 124))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('SMARCA2', 'Gene', (51, 58))	('RB1', 'Gene', (139, 142))	('growth arrest', 'Disease', 'MESH:D006323', (21, 34))	('tumour', 'Disease', (165, 171))	('growth arrest', 'Disease', (21, 34))	('SMARCA4', 'Gene', (40, 47))	('RB1', 'Gene', '5925', (139, 142))
31129	26356327	Almost all SCCOHTs contain inactivating somatic and germline mutations in SMARCA4 that result in loss of the SMARCA4 (BRG1) protein.	('SMARCA4', 'Gene', (74, 81))	('SMARCA4', 'Gene', '6597', (74, 81))	('loss', 'NegReg', (97, 101))	('BRG1', 'Gene', (118, 122))	('protein', 'Protein', (124, 131))	('BRG1', 'Gene', '6597', (118, 122))	('germline mutations', 'Var', (52, 70))	('inactivating', 'Var', (27, 39))	('SMARCA4', 'Gene', (109, 116))	('SMARCA4', 'Gene', '6597', (109, 116))
31133	26356327	Therefore, the absence of SMARCA4 is highly sensitive and essentially completely specific for SCCOHT.	('SMARCA4', 'Gene', (26, 33))	('SMARCA4', 'Gene', '6597', (26, 33))	('absence', 'Var', (15, 22))	('SCCOHT', 'Disease', (94, 100))
31134	26356327	Though we only studied small numbers of germ cell tumours in the differential diagnosis of SCCOHT, our results are consistent with those of Witkowski et al, who found no SMARCA4 mutations in 106 germ cell tumours, including 25 dysgerminomas and seminomas 27.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('dysgerminoma', 'Phenotype', 'HP:0100621', (227, 239))	('germ cell tumours', 'Disease', (40, 57))	('germ cell tumours', 'Disease', 'MESH:D009373', (40, 57))	('germ cell tumours', 'Disease', (195, 212))	('seminomas', 'Disease', 'MESH:D018239', (245, 254))	('seminomas', 'Disease', (245, 254))	('germ cell tumours', 'Disease', 'MESH:D009373', (195, 212))	('dysgerminomas', 'Disease', 'MESH:D004407', (227, 240))	('SMARCA4', 'Gene', (170, 177))	('dysgerminomas', 'Disease', (227, 240))	('SMARCA4', 'Gene', '6597', (170, 177))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('mutations', 'Var', (178, 187))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
31138	26356327	The near universal expression of SMARCA4 as determined by IHC contrasts with the presence of SMARCA4 point mutations or deletions reported in several tumours in our study such as high-grade serous carcinomas 9, 10, 31, 32, 33.	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('deletions', 'Var', (120, 129))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('SMARCA4', 'Gene', (93, 100))	('serous carcinomas', 'Disease', 'MESH:D018284', (190, 207))	('SMARCA4', 'Gene', '6597', (93, 100))	('SMARCA4', 'Gene', (33, 40))	('SMARCA4', 'Gene', '6597', (33, 40))	('serous carcinomas', 'Disease', (190, 207))	('point mutations', 'Var', (101, 116))
31140	26356327	Of almost 100 SMARCA4 mutations reported in SCCOHT, all but three are destructive to the protein (truncating, frameshift, spice site or deletions) 15 with common bi-allelic inactivation due to mutation or loss of heterozygosity of the second allele 3, 5.	('frameshift', 'Var', (110, 120))	('SMARCA4', 'Gene', (14, 21))	('deletions', 'Var', (136, 145))	('SMARCA4', 'Gene', '6597', (14, 21))	('mutations', 'Var', (22, 31))
31141	26356327	In contrast, approximately 80% of SMARCA4 mutations found in more than 500 other tumour samples are missense and do not typically involve inactivation of the second allele 9, 10, 31, 32.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('missense', 'Var', (100, 108))	('SMARCA4', 'Gene', (34, 41))	('SMARCA4', 'Gene', '6597', (34, 41))	('tumour', 'Disease', (81, 87))	('mutations', 'Var', (42, 51))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
31142	26356327	Therefore, several tumours in our study may harbour missense mutations in SMARCA4 that, by their nature, were not suggested by IHC.	('SMARCA4', 'Gene', (74, 81))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('SMARCA4', 'Gene', '6597', (74, 81))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('missense mutations', 'Var', (52, 70))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
31143	26356327	Interestingly, although ovarian high-grade serous carcinomas reportedly show mutually exclusive homozygous deletions in SMARCA4 and SMARCA2 31, 32, we did not observe SMARCA4 protein loss in any of our samples.	('SMARCA4', 'Gene', (167, 174))	('SMARCA4', 'Gene', (120, 127))	('SMARCA4', 'Gene', '6597', (167, 174))	('SMARCA4', 'Gene', '6597', (120, 127))	('serous carcinomas', 'Disease', (43, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('deletions', 'Var', (107, 116))	('SMARCA2', 'Gene', (132, 139))	('serous carcinomas', 'Disease', 'MESH:D018284', (43, 60))	('ovarian high', 'Phenotype', 'HP:0008209', (24, 36))
31145	26356327	Accordingly, it seems unlikely that random selection of two different areas of a tumour for inclusion in a TMA would result in all tumour cells in both regions having homozygous deletions in SMARCA4.	('tumour', 'Disease', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('TMA', 'Disease', 'MESH:D000783', (107, 110))	('deletions', 'Var', (178, 187))	('tumour', 'Disease', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('TMA', 'Disease', (107, 110))	('SMARCA4', 'Gene', (191, 198))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('SMARCA4', 'Gene', '6597', (191, 198))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
31160	26356327	The conspicuous lack of SMARCA2 mutations in three papers that identified the SMARCA4 mutation in SCCOHT by next-generation sequencing 2, 3, 5, together with the up-regulation of SMARCA2 mRNA and translated protein by the histone deacetylase inhibitor trichostatin A, indicates that the lack of SMARCA2 protein expression is due to either epigenetic or post-transcriptional silencing.	('expression', 'MPA', (311, 321))	('up-regulation', 'PosReg', (162, 175))	('SMARCA4', 'Gene', '6597', (78, 85))	('histone deacetylase', 'Gene', (222, 241))	('trichostatin A', 'Chemical', 'MESH:C012589', (252, 266))	('SMARCA2', 'Gene', (295, 302))	('protein', 'Protein', (303, 310))	('epigenetic', 'Var', (339, 349))	('mutation', 'Var', (86, 94))	('SMARCA4', 'Gene', (78, 85))	('histone deacetylase', 'Gene', '9734', (222, 241))
31168	26356327	Similar to our findings in SCCOHT, malignant rhabdoid tumours also show dual deficiency for core SWI/SNF members: SMARCB1 by mutation and SMARCA2 by non-mutational silencing 41, 42, 43.	('SMARCB1', 'Gene', '6598', (114, 121))	('SMARCB1', 'Gene', (114, 121))	('deficiency', 'NegReg', (77, 87))	('malignant rhabdoid tumours', 'Disease', 'MESH:C563738', (35, 61))	('malignant rhabdoid tumours', 'Disease', (35, 61))	('SMARCA2', 'Gene', (138, 145))	('non-mutational silencing', 'Var', (149, 173))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('mutation', 'Var', (125, 133))
31176	26852677	Therefore, we focused on the biological effects and the enhancement of drug effects brought by this low-intensity ultrasound energy and reported on the efficacy against a uterine sarcoma model, by implementing the basic studies, for the first time, including the concomitant use of low-intensity ultrasound irradiation, as an expected new antiangiogenic therapy for cancer treatment.	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('low-intensity', 'Var', (100, 113))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Disease', (366, 372))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (171, 186))	('enhancement of drug effects', 'Phenotype', 'HP:0020173', (56, 83))	('sarcoma', 'Disease', 'MESH:D012509', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('sarcoma', 'Disease', (179, 186))
31230	26852677	Although surgical resection or panhysterectomy using a laser scalpel is currently common for in situ carcinomas and microinvasive cancer, modifying the current vaginal probe for diagnosis may make it possible to irradiate the uterine cervix within the scope of sufficient ultrasound.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('situ carcinomas', 'Disease', 'MESH:D002278', (96, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('situ carcinomas', 'Disease', (96, 111))	('modifying', 'Var', (138, 147))	('uterine cervix', 'Phenotype', 'HP:0030160', (226, 240))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
31246	25449308	In patients with uterine adenosarcoma, the presence of SO or LVSI confers a higher risk of recurrence.	('LVSI', 'Gene', (61, 65))	('adenosarcoma', 'Disease', (25, 37))	('adenosarcoma', 'Disease', 'MESH:D018195', (25, 37))	('patients', 'Species', '9606', (3, 11))	('presence', 'Var', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
31381	25449308	Pathologic analyses of uterine adenosarcoma have identified estrogen receptor positivity in approximately 80% of cases and progesterone receptor positivity in 65% to 80% of cases; however, the incidence of hormone receptor positivity is lower in patients with sarcomatous overgrowth.	('progesterone receptor', 'Gene', (123, 144))	('progesterone receptor', 'Gene', '5241', (123, 144))	('positivity', 'Var', (78, 88))	('sarcomatous overgrowth', 'Disease', (260, 282))	('estrogen', 'MPA', (60, 68))	('hormone receptor', 'Gene', '3164', (206, 222))	('patients', 'Species', '9606', (246, 254))	('hormone receptor', 'Gene', (206, 222))	('overgrowth', 'Phenotype', 'HP:0001548', (272, 282))	('adenosarcoma', 'Disease', (31, 43))	('adenosarcoma', 'Disease', 'MESH:D018195', (31, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('sarcomatous overgrowth', 'Disease', 'MESH:D018316', (260, 282))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))
31412	25229768	Lynch Syndrome Screening Should Be Considered for All Patients With Newly Diagnosed Endometrial Cancer Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes.	('Lynch syndrome', 'Disease', (103, 117))	('Endometrial Cancer', 'Disease', 'MESH:D016889', (84, 102))	('Endometrial Cancer', 'Disease', (84, 102))	('germline mutations', 'Var', (177, 195))	('Lynch Syndrome', 'Disease', (0, 14))	('Patients', 'Species', '9606', (54, 62))	('Lynch syndrome', 'Disease', 'MESH:D003123', (103, 117))	('autosomal dominant inherited disorder', 'Disease', 'MESH:D030342', (129, 166))	('caused by', 'Reg', (167, 176))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Endometrial Cancer', 'Phenotype', 'HP:0012114', (84, 102))	('MMR', 'Gene', (220, 223))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (0, 14))	('autosomal dominant inherited disorder', 'Disease', (129, 166))
31413	25229768	Mutation carriers are at substantially increased risk of developing cancers of the colorectum and endometrium, among others.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('Mutation', 'Var', (0, 8))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('endometrium', 'Disease', (98, 109))
31423	25229768	Of the tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated tumor morphology, or location in the lower uterine segment).	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('tumor', 'Disease', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('mutation', 'Var', (77, 85))	('tumors', 'Disease', (7, 13))	('cancer', 'Disease', (231, 237))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Disease', (314, 319))	('LS-associated', 'Disease', (54, 67))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('MMR-associated', 'Gene', (299, 313))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
31425	25229768	Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer syndrome, is caused by germline defects in DNA mismatch repair (MMR) genes and is characterized by a predilection for oncogenesis at a variety of sites including the colon, rectum, small bowel, endometrium, ovary, stomach, pancreas, renal pelvis and ureter, and brain.	('ovary', 'Disease', 'MESH:D010051', (273, 278))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('small bowel', 'Disease', (247, 258))	('hereditary nonpolyposis colorectal cancer syndrome', 'Disease', 'MESH:D003123', (24, 74))	('pancreas, renal pelvis and ureter', 'Disease', 'MESH:D014516', (289, 322))	('renal pelvis', 'Phenotype', 'HP:0000125', (299, 311))	('hereditary nonpolyposis colorectal cancer syndrome', 'Disease', (24, 74))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('small bowel', 'Disease', 'MESH:D015212', (247, 258))	('Lynch syndrome', 'Disease', (0, 14))	('defects', 'Var', (98, 105))	('MMR', 'Gene', (130, 133))	('caused by', 'Reg', (79, 88))	('DNA', 'Gene', (109, 112))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (24, 65))	('ovary', 'Disease', (273, 278))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
31431	25229768	In a small subset of patients, mutations in the gene EPCAM can also lead to an LS phenotype by causing hypermethylation and inactivation of the MSH2 promoter.	('LS phenotype', 'Disease', (79, 91))	('EPCAM', 'Gene', (53, 58))	('mutations', 'Var', (31, 40))	('inactivation', 'NegReg', (124, 136))	('lead to', 'Reg', (68, 75))	('MSH2', 'Gene', (144, 148))	('EPCAM', 'Gene', '4072', (53, 58))	('patients', 'Species', '9606', (21, 29))	('MSH2', 'Gene', '4436', (144, 148))	('causing', 'Reg', (95, 102))	('hypermethylation', 'MPA', (103, 119))
31432	25229768	Immunohistochemical (IHC) staining to identify the loss of MSH2, MSH6, MLH1, and PMS2 protein expression serves as a more cost-effective screening approach and has been shown to be sensitive and, in the absence of sporadic MLH1 promoter methylation, specific for underlying germline defects.	('MLH1', 'Gene', '4292', (71, 75))	('loss', 'Var', (51, 55))	('MSH6', 'Gene', (65, 69))	('protein', 'Protein', (86, 93))	('MLH1', 'Gene', (71, 75))	('MSH2', 'Gene', (59, 63))	('PMS2', 'Gene', '5395', (81, 85))	('MSH2', 'Gene', '4436', (59, 63))	('MSH6', 'Gene', '2956', (65, 69))	('MLH1', 'Gene', '4292', (223, 227))	('MLH1', 'Gene', (223, 227))	('PMS2', 'Gene', (81, 85))
31433	25229768	Microsatellite instability testing also serves as a surrogate for abnormalities in the MMR system, but this test has been shown to be less sensitive than IHC, in large part due to failure to detect many MSH6 germline mutation carriers.	('Microsatellite', 'MPA', (0, 14))	('germline mutation', 'Var', (208, 225))	('MSH6', 'Gene', '2956', (203, 207))	('MSH6', 'Gene', (203, 207))
31437	25229768	Regardless of the testing approach utilized, it is incumbent upon gynecologic oncologists and pathologists to appropriately screen endometrial cancer patients for defects in the DNA MMR system.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('defects', 'Var', (163, 170))	('endometrial cancer', 'Disease', (131, 149))	('DNA MMR system', 'Gene', (178, 192))	('patients', 'Species', '9606', (150, 158))	('endometrial cancer', 'Phenotype', 'HP:0012114', (131, 149))	('endometrial cancer', 'Disease', 'MESH:D016889', (131, 149))
31445	25229768	MSH6 mutations, in particular, have been implicated in endometrial cancers arising in LS patients above 50 years of age and are known to be missed using current clinical screening criteria.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('MSH6', 'Gene', '2956', (0, 4))	('mutations', 'Var', (5, 14))	('endometrial cancer', 'Phenotype', 'HP:0012114', (55, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (89, 97))	('endometrial cancers', 'Disease', (55, 74))	('implicated', 'Reg', (41, 51))	('endometrial cancers', 'Disease', 'MESH:D016889', (55, 74))	('MSH6', 'Gene', (0, 4))
31446	25229768	Buchanan et al recently demonstrated that restricting MMR testing to women under 50 years of age misses a significant proportion of MMR mutation-positive cases and proposed expanding testing recommendations to endometrial cancers arising in women below 60 years of age.	('MMR', 'Gene', (132, 135))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('endometrial cancer', 'Phenotype', 'HP:0012114', (210, 228))	('mutation-positive', 'Var', (136, 153))	('endometrial cancers', 'Disease', 'MESH:D016889', (210, 229))	('endometrial cancers', 'Disease', (210, 229))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('women', 'Species', '9606', (241, 246))	('women', 'Species', '9606', (69, 74))
31455	25229768	Mutational analysis for BRAF V600E was performed on an early, initial subset of 30 cases but discontinued due to absence of detectable BRAF mutation in the tumors tested.	('BRAF', 'Gene', '673', (135, 139))	('V600E', 'Mutation', 'rs113488022', (29, 34))	('BRAF', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('V600E', 'Var', (29, 34))	('BRAF', 'Gene', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('BRAF', 'Gene', '673', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))
31465	25229768	Microsatellite instability testing, when performed, was conducted by Stanford Clinical Laboratories using a commercially available primer set (Promega MSI Analysis System; Promega BioSciences, San Luis Obispo, CA) that includes 5 mononucleotide (BAT25, BAT26, NR21, NR24, and MONO27) and 2 pentanucleotide (Penta C and Penta D) repeats on both tumor and normal tissue for each patient.	('mononucleotide', 'Chemical', '-', (230, 244))	('Penta C', 'Chemical', 'MESH:C005406', (307, 314))	('BAT25', 'Var', (246, 251))	('tumor', 'Disease', (344, 349))	('patient', 'Species', '9606', (377, 384))	('MONO27', 'Var', (276, 282))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('BAT26', 'Var', (253, 258))	('pentanucleotide', 'Chemical', '-', (290, 305))	('tumor', 'Disease', 'MESH:D009369', (344, 349))
31472	25229768	Loss of MLH1/PMS2 was initially identified in 97 cases, which showed methylation of the MLH1 gene promoter; although some of the patients with these tumors may have LS not detected by the current protocol, these cancers were considered to be sporadic for the purposes of this study and were excluded from further analysis.	('PMS2', 'Gene', (13, 17))	('MLH1', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('MLH1', 'Gene', '4292', (88, 92))	('PMS2', 'Gene', '5395', (13, 17))	('MLH1', 'Gene', (88, 92))	('patients', 'Species', '9606', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('methylation', 'Var', (69, 80))	('cancers', 'Disease', (212, 219))	('MLH1', 'Gene', '4292', (8, 12))
31485	25229768	Most had germline mutations in MSH2 (n = 12), followed by MSH6 (n = 3) and MLH1 (n = 2).	('MSH6', 'Gene', (58, 62))	('MLH1', 'Gene', '4292', (75, 79))	('MLH1', 'Gene', (75, 79))	('MSH6', 'Gene', '2956', (58, 62))	('MSH2', 'Gene', (31, 35))	('MSH2', 'Gene', '4436', (31, 35))	('germline mutations', 'Var', (9, 27))
31486	25229768	One tumor with loss of MLH1/PMS2 was associated with an MLH1 germline mutation variant of uncertain significance, whereas another tumor with loss of MSH6 was associated with an MSH6 germline mutation variant of uncertain significance.	('tumor', 'Disease', (4, 9))	('MLH1', 'Gene', '4292', (23, 27))	('MLH1', 'Gene', (23, 27))	('MSH6', 'Gene', '2956', (149, 153))	('variant', 'Var', (79, 86))	('PMS2', 'Gene', (28, 32))	('MSH6', 'Gene', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PMS2', 'Gene', '5395', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('MSH6', 'Gene', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('associated', 'Reg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (130, 135))	('MSH6', 'Gene', '2956', (177, 181))	('MLH1', 'Gene', '4292', (56, 60))	('MLH1', 'Gene', (56, 60))
31491	25229768	Although clinical confirmation and/or germline testing was not performed on all patients in this study, prior work has shown that loss of MMR protein expression is a reasonably reliable proxy for identifying potential LS patients.	('loss', 'Var', (130, 134))	('patients', 'Species', '9606', (221, 229))	('MMR protein', 'Protein', (138, 149))	('patients', 'Species', '9606', (80, 88))
31492	25229768	In addition (and based predominantly on colorectal cancer studies), although MLH1 promoter hypermethylation may rarely occur in LS, the presence of MLH1 hypermethylation in tumors with loss of MLH1 and PMS2 expression can be used as a surrogate marker for sporadic carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('hypermethylation', 'Var', (153, 169))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('MLH1', 'Gene', (148, 152))	('PMS2', 'Gene', (202, 206))	('MLH1', 'Gene', (77, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('MLH1', 'Gene', '4292', (148, 152))	('tumors', 'Disease', (173, 179))	('loss', 'NegReg', (185, 189))	('MLH1', 'Gene', (193, 197))	('MLH1', 'Gene', '4292', (77, 81))	('colorectal cancer', 'Disease', (40, 57))	('sporadic carcinoma', 'Disease', (256, 274))	('sporadic carcinoma', 'Disease', 'MESH:C538614', (256, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('MLH1', 'Gene', '4292', (193, 197))	('PMS2', 'Gene', '5395', (202, 206))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
31497	25229768	It has been demonstrated that IHC is a highly sensitive technique to identify mutations in MMR genes in colorectal cancer, therefore one would predict that an IHC-based screening approach would not miss significant numbers of LS patients.	('patients', 'Species', '9606', (229, 237))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('MMR', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (78, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('colorectal cancer', 'Disease', (104, 121))
31500	25229768	Thus, loss of MSH6 expression can detect both defects in MSH6 and MSH2, whereas PMS2 loss is a stand-in for both PMS2 and MLH1 defects.	('MSH6', 'Gene', '2956', (57, 61))	('MSH6', 'Gene', (14, 18))	('loss', 'Var', (6, 10))	('MLH1 defects', 'Disease', 'MESH:D005128', (122, 134))	('MLH1 defects', 'Disease', (122, 134))	('defects', 'Var', (46, 53))	('MSH6', 'Gene', '2956', (14, 18))	('PMS2', 'Gene', '5395', (80, 84))	('PMS2', 'Gene', (80, 84))	('MSH6', 'Gene', (57, 61))	('MSH2', 'Gene', (66, 70))	('MSH2', 'Gene', '4436', (66, 70))	('PMS2', 'Gene', (113, 117))	('PMS2', 'Gene', '5395', (113, 117))
31501	25229768	Loss of both MSH2 and MSH6 protein expression with preservation of both these genes on germline testing may indicate an underlying EPCAM deletion, therefore IHC for EPCAM and/or germline testing of EPCAM should be considered in this setting.	('EPCAM', 'Gene', (198, 203))	('MSH6', 'Gene', '2956', (22, 26))	('protein', 'Protein', (27, 34))	('MSH2', 'Gene', (13, 17))	('MSH2', 'Gene', '4436', (13, 17))	('EPCAM', 'Gene', '4072', (131, 136))	('deletion', 'Var', (137, 145))	('expression', 'MPA', (35, 45))	('EPCAM', 'Gene', (165, 170))	('Loss', 'NegReg', (0, 4))	('EPCAM', 'Gene', '4072', (198, 203))	('MSH6', 'Gene', (22, 26))	('EPCAM', 'Gene', '4072', (165, 170))	('EPCAM', 'Gene', (131, 136))
31503	25229768	Unlike colorectal cancer, BRAF mutations do not generally occur in association with sporadic methylation of MLH1 in endometrial cancer.	('mutations', 'Var', (31, 40))	('endometrial cancer', 'Disease', 'MESH:D016889', (116, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (7, 24))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (26, 30))	('colorectal cancer', 'Disease', (7, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('endometrial cancer', 'Disease', (116, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('MLH1', 'Gene', (108, 112))	('MLH1', 'Gene', '4292', (108, 112))	('endometrial cancer', 'Phenotype', 'HP:0012114', (116, 134))	('colorectal cancer', 'Disease', 'MESH:D015179', (7, 24))
31520	25229768	A secondary function of MMR testing in colorectal cancers is the identification of sporadic carcinomas with MLH1 promoter methylation.	('sporadic carcinomas', 'Disease', 'MESH:C538614', (83, 102))	('colorectal cancers', 'Disease', (39, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('methylation', 'Var', (122, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('MLH1', 'Gene', (108, 112))	('colorectal cancers', 'Disease', 'MESH:D015179', (39, 57))	('sporadic carcinomas', 'Disease', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MLH1', 'Gene', '4292', (108, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))
31521	25229768	Although not associated with familial cancer syndromes, this defect nonetheless leads to microsatellite instability indistinguishable from what is seen with germline MMR gene mutations.	('familial cancer syndromes', 'Disease', 'MESH:D009386', (29, 54))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('familial cancer syndromes', 'Disease', (29, 54))	('leads to', 'Reg', (80, 88))	('mutations', 'Var', (175, 184))	('microsatellite instability', 'MPA', (89, 115))
31522	25229768	In the colon, microsatellite instability is associated with improved overall prognosis but decreased response to fluorouracil.	('microsatellite instability', 'Var', (14, 40))	('fluorouracil', 'Chemical', 'MESH:D005472', (113, 125))	('improved', 'PosReg', (60, 68))	('response to fluorouracil', 'MPA', (101, 125))	('decreased', 'NegReg', (91, 100))
31523	25229768	The prognostic implications of sporadic MLH1 methylation have not been well characterized, but as we learn more about the behavior of sporadic endometrial cancer with MLH1 methylation, it is possible that this information may have independent value for guiding clinical treatment.	('endometrial cancer', 'Phenotype', 'HP:0012114', (143, 161))	('MLH1', 'Gene', '4292', (40, 44))	('MLH1', 'Gene', '4292', (167, 171))	('endometrial cancer', 'Disease', 'MESH:D016889', (143, 161))	('MLH1', 'Gene', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('methylation', 'Var', (172, 183))	('endometrial cancer', 'Disease', (143, 161))	('MLH1', 'Gene', (40, 44))
31526	25229768	Although it has been suggested that the benefit is lower for those diagnosed at older ages and with lesspenetrant MSH6 mutations, data are limited.	('MSH6', 'Gene', '2956', (114, 118))	('lower', 'NegReg', (51, 56))	('mutations', 'Var', (119, 128))	('MSH6', 'Gene', (114, 118))
31536	24951283	Lynch Syndrome occurs due to a germline mutation in one of a family of DNA MMR genes, with subsequent loss of associated protein expression.	('Lynch Syndrome', 'Disease', (0, 14))	('protein expression', 'MPA', (121, 139))	('DNA MMR', 'Gene', (71, 78))	('loss', 'NegReg', (102, 106))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (0, 14))	('germline mutation', 'Var', (31, 48))
31537	24951283	Mutation of MLH1 or MSH2 genes is most common, but other important MMR genes include MSH6 and PMS2.	('MLH1', 'Gene', '4292', (12, 16))	('MLH1', 'Gene', (12, 16))	('MSH2', 'Gene', (20, 24))	('MSH6', 'Gene', '2956', (85, 89))	('Mutation', 'Var', (0, 8))	('PMS2', 'Gene', (94, 98))	('MSH2', 'Gene', '4436', (20, 24))	('MSH6', 'Gene', (85, 89))	('PMS2', 'Gene', '5395', (94, 98))
31541	24951283	In 15-20% of all sporadic endometrial carcinomas, MLH1 immunohistochemical loss and MSI results from MLH1 gene promoter methylation with subsequent transcriptional silencing.	('MLH1', 'Gene', '4292', (50, 54))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (26, 48))	('MLH1', 'Gene', (50, 54))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (26, 47))	('endometrial carcinomas', 'Disease', (26, 48))	('methylation', 'Var', (120, 131))	('transcriptional', 'MPA', (148, 163))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (26, 48))	('loss', 'NegReg', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('MLH1', 'Gene', '4292', (101, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('MLH1', 'Gene', (101, 105))
31544	24951283	Gene mutation of MMR genes or methylation of the MLH1 promoter typically results in loss of immunohistochemical expression of the corresponding protein.	('methylation', 'Var', (30, 41))	('loss', 'NegReg', (84, 88))	('MLH1', 'Gene', '4292', (49, 53))	('MLH1', 'Gene', (49, 53))	('immunohistochemical expression of the', 'MPA', (92, 129))	('MMR', 'Gene', (17, 20))	('mutation', 'Var', (5, 13))
31547	24951283	Loss of the MLH1 protein (due to mutation of the MLH1 gene or methylation of MLH1 gene promoter) typically results in loss of immunhistochemical expression of MLH1 and PMS2.	('MLH1', 'Gene', '4292', (12, 16))	('mutation', 'Var', (33, 41))	('MLH1', 'Gene', (12, 16))	('MLH1', 'Gene', '4292', (77, 81))	('MLH1', 'Gene', (77, 81))	('PMS2', 'Gene', (168, 172))	('methylation', 'Var', (62, 73))	('loss', 'NegReg', (118, 122))	('Loss', 'NegReg', (0, 4))	('PMS2', 'Gene', '5395', (168, 172))	('MLH1', 'Gene', '4292', (49, 53))	('immunhistochemical expression', 'MPA', (126, 155))	('MLH1', 'Gene', (49, 53))	('MLH1', 'Gene', '4292', (159, 163))	('MLH1', 'Gene', (159, 163))
31548	24951283	Mutation of MSH2 typically results in immunohistochemical loss of MSH2 and MSH6.	('MSH2', 'Gene', '4436', (12, 16))	('loss', 'NegReg', (58, 62))	('MSH6', 'Gene', '2956', (75, 79))	('Mutation', 'Var', (0, 8))	('MSH2', 'Gene', (66, 70))	('MSH6', 'Gene', (75, 79))	('MSH2', 'Gene', '4436', (66, 70))	('MSH2', 'Gene', (12, 16))
31549	24951283	On the other hand, mutation of MSH6 is associated with loss of MSH6 protein but retention of MSH2 by immunohistochemistry.	('MSH6', 'Gene', (63, 67))	('MSH6', 'Gene', (31, 35))	('loss', 'NegReg', (55, 59))	('mutation', 'Var', (19, 27))	('MSH6', 'Gene', '2956', (63, 67))	('MSH6', 'Gene', '2956', (31, 35))	('MSH2', 'Gene', (93, 97))	('MSH2', 'Gene', '4436', (93, 97))	('protein', 'Protein', (68, 75))
25950	24951283	Similarly, mutation of PMS2 is typically associated with loss of PMS2 protein but retained MLH1 immunohistochemical expression.	('PMS2', 'Gene', (23, 27))	('protein', 'Protein', (70, 77))	('PMS2', 'Gene', '5395', (23, 27))	('MLH1', 'Gene', '4292', (91, 95))	('PMS2', 'Gene', (65, 69))	('MLH1', 'Gene', (91, 95))	('PMS2', 'Gene', '5395', (65, 69))	('loss', 'NegReg', (57, 61))	('mutation', 'Var', (11, 19))
31551	24951283	Although MMR gene mutation carriers may show higher levels of concordance between complex atypical hyperplasia and endometrial carcinoma than patients with sporadic endometrial cancers, it is recommended that tissue testing always be carried out in foci of endometrial carcinoma rather than adjacent complex atypical hyperplasia (Figure 2).	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('concordance', 'MPA', (62, 73))	('endometrial carcinoma', 'Disease', (115, 136))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('sporadic endometrial cancers', 'Disease', 'MESH:D016889', (156, 184))	('hyperplasia', 'Disease', (317, 328))	('endometrial cancer', 'Phenotype', 'HP:0012114', (165, 183))	('endometrial carcinoma', 'Disease', (257, 278))	('mutation', 'Var', (18, 26))	('hyperplasia', 'Disease', 'MESH:D006965', (317, 328))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (115, 136))	('higher', 'PosReg', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (115, 136))	('hyperplasia', 'Disease', (99, 110))	('sporadic endometrial cancers', 'Disease', (156, 184))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (257, 278))	('hyperplasia', 'Disease', 'MESH:D006965', (99, 110))	('MMR', 'Gene', (9, 12))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (257, 278))	('patients', 'Species', '9606', (142, 150))
31554	24951283	A panel of 7 markers recommended by the NCI (BAT25, BAT26, BAT40, D2S123, D5S346, D173250, and TGF-betaR2) is used to detect changes in the number of microsatellite repeats in the tumor compared to normal tissue (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('D5S346', 'Var', (74, 80))	('D173250', 'Var', (82, 89))	('D2S123', 'Var', (66, 72))
31555	24951283	Tumors with allelic shift in 3 or more microsatellites in the panel are designated as MSI-high, while tumors with no allelic shift in all 7 microsatellites are considered microsatellite-stable (MSS).	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('allelic shift', 'Var', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
31559	24951283	MLH1 promoter methylation and gene silencing is the primary cause of MSI in sporadic endometrial cancers.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('MSI in sporadic endometrial cancers', 'Disease', (69, 104))	('cause', 'Reg', (60, 65))	('gene silencing', 'Var', (30, 44))	('MLH1', 'Gene', '4292', (0, 4))	('MLH1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('MSI in sporadic endometrial cancers', 'Disease', 'MESH:D016889', (69, 104))	('endometrial cancer', 'Phenotype', 'HP:0012114', (85, 103))
31575	24951283	Thus far, MLH1 methylation was observed in these cases, implying that these tumors are sporadic.	('methylation', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('MLH1', 'Gene', '4292', (10, 14))	('MLH1', 'Gene', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('observed', 'Reg', (31, 39))
31584	24951283	In some patients with known mutations in the MMR genes, the results of MSI analysis and/or MMR immunohistochemistry may not always be typical of Lynch Syndrome tumors.	('MMR', 'Gene', (45, 48))	('Lynch Syndrome tumors', 'Disease', 'MESH:D003123', (145, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('Lynch Syndrome tumors', 'Disease', (145, 166))	('mutations', 'Var', (28, 37))	('patients', 'Species', '9606', (8, 16))
31585	24951283	For example, missense mutations in MMR genes may generate full-length but non-functional MMR proteins, resulting in MSI-high tumors with intact expression of MMR proteins by immunohistochemistry.	('MSI-high tumors', 'Disease', 'MESH:D009369', (116, 131))	('proteins', 'Protein', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('resulting in', 'Reg', (103, 115))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('missense mutations', 'Var', (13, 31))	('MMR', 'Gene', (89, 92))	('MMR genes', 'Gene', (35, 44))	('MSI-high tumors', 'Disease', (116, 131))	('non-functional', 'NegReg', (74, 88))
31586	24951283	Tumors of other patients with known MMR gene mutations may have MMR loss by immunohistochemistry, but be MSI-low or MSS.	('MSI-low', 'Disease', 'MESH:D009800', (105, 112))	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (16, 24))	('MMR', 'MPA', (64, 67))	('MSI-low', 'Disease', (105, 112))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('loss', 'NegReg', (68, 72))	('MMR gene', 'Gene', (36, 44))
31592	24951283	Instances where MSI and MMR immunohistochemistry are both suggestive of Lynch Syndrome, but genetic analysis does not reveal a pathologic mutation in the MMR genes may occur due to mutations in less common genes which regulate the MMR genes, or in the setting of MMR gene variants of undetermined significance.	('Lynch Syndrome', 'Disease', 'MESH:D003123', (72, 86))	('MMR', 'Gene', (231, 234))	('MMR', 'Gene', (154, 157))	('Lynch Syndrome', 'Disease', (72, 86))	('mutations', 'Var', (181, 190))
31595	24951283	Therefore, it is suggested that such mutation negative and tissue testing positive patients should be included in heightened cancer prevention surveillance programs offered to patients with known deleterious mutations in MMR genes.	('patients', 'Species', '9606', (176, 184))	('MMR', 'Gene', (221, 224))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (208, 217))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
31597	24951283	A population-based study of 543 women with endometrial cancer identified 10 Lynch Syndrome mutation carriers.	('mutation', 'Var', (91, 99))	('women', 'Species', '9606', (32, 37))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('endometrial cancer', 'Disease', (43, 61))	('Lynch Syndrome', 'Disease', (76, 90))	('endometrial cancer', 'Disease', 'MESH:D016889', (43, 61))	('endometrial cancer', 'Phenotype', 'HP:0012114', (43, 61))
31601	24951283	10 of these patients were older than age 50 years and 7 were confirmed to have MMR gene mutations.	('patients', 'Species', '9606', (12, 20))	('MMR', 'Gene', (79, 82))	('mutations', 'Var', (88, 97))
31610	24951283	In particular, MSH6 mutation carriers are older, do not tend to have first degree relatives with Lynch Syndrome associated cancers and have endometrial tumors that are not typically MSI-high.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('endometrial tumors', 'Disease', 'MESH:D016889', (140, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (20, 28))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('MSH6', 'Gene', (15, 19))	('cancers', 'Disease', (123, 130))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (97, 111))	('Lynch Syndrome', 'Disease', (97, 111))	('endometrial tumors', 'Disease', (140, 158))	('MSH6', 'Gene', '2956', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
31611	24951283	Our limited preliminary evidence suggests that PMS2 mutation carriers may be phenotypically similar.	('PMS2', 'Gene', '5395', (47, 51))	('PMS2', 'Gene', (47, 51))	('mutation', 'Var', (52, 60))
31619	24951283	Sporadic endometrial carcinomas that are MSI-high due to MLH1 methylation are predominantly endometrioid, especially FIGO grades 2 and 3, and comprise as many as 96% of such tumors.	('Sporadic endometrial carcinomas', 'Disease', 'MESH:D016889', (0, 31))	('MLH1', 'Gene', '4292', (57, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('tumors', 'Disease', (174, 180))	('MLH1', 'Gene', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (9, 31))	('Sporadic endometrial carcinomas', 'Disease', (0, 31))	('methylation', 'Var', (62, 73))	('endometrioid', 'Disease', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('FIGO', 'Disease', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (9, 30))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
31622	24951283	These data suggest that there may be a genotype-phenotype relationship between MMR gene loss and endometrial tumor histotype, however, more studies of Lynch Syndrome associated endometrial tumors are required in order to substantiate this claim.	('endometrial tumor', 'Disease', (97, 114))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (151, 165))	('gene', 'Var', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('endometrial tumors', 'Disease', (177, 195))	('Lynch Syndrome', 'Disease', (151, 165))	('loss', 'NegReg', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('endometrial tumor', 'Disease', 'MESH:D016889', (97, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('endometrial tumors', 'Disease', 'MESH:D016889', (177, 195))	('MMR', 'Gene', (79, 82))	('endometrial tumor', 'Disease', 'MESH:D016889', (177, 194))
31625	24951283	Furthermore, most of these studies have not distinguished between sporadic MSI-high due to MLH1 methylation and MSI-high due to germline mutation of a DNA MMR gene.	('due', 'Reg', (84, 87))	('MLH1', 'Gene', '4292', (91, 95))	('MLH1', 'Gene', (91, 95))	('MSI-high', 'Disease', (75, 83))	('methylation', 'Var', (96, 107))	('germline mutation', 'Var', (128, 145))	('due', 'Reg', (121, 124))
31644	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))
31663	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))
31684	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))
31688	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))
31700	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))
31703	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))
31709	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))	('paclitaxel', 'Chemical', 'MESH:D017239', (232, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('ovarian clear cell carcinoma', 'Disease', (166, 194))
31711	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))
31723	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))
31733	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))
31743	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))
31745	23558962	As aberrant microRNA (miRNA) expression patterns represent putative diagnostic cancer markers, we aimed to identify miRNA expression profiles of the major uterine sarcoma subtypes and mixed epithelial-mesenchymal tumors of the uterus.	('miR', 'Gene', '220972', (22, 25))	('epithelial-mesenchymal tumors', 'Disease', (190, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('aberrant', 'Var', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('miR', 'Gene', '220972', (116, 119))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('miR', 'Gene', (116, 119))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (190, 219))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (163, 179))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (155, 170))	('cancer', 'Disease', (79, 85))	('miR', 'Gene', (22, 25))	('tumors of the uterus', 'Phenotype', 'HP:0010784', (213, 233))	('sarcoma subtypes', 'Disease', (163, 179))
31747	23558962	Tumor and control samples significantly (P < 0.05) differed in the expression of miR-23b, miR-1, let-7f, and let-7c in endometrial sarcomas, and miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214 in mixed epithelial-mesenchymal tumors.	('miR-222', 'Gene', '407007', (219, 226))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-143', 'Gene', '406935', (178, 185))	('miR-23b', 'Gene', (81, 88))	('let-7c', 'Gene', (109, 115))	('miR-143', 'Gene', (178, 185))	('miR-1', 'Gene', (160, 165))	('miR-1', 'Gene', '79187', (178, 183))	('endometrial sarcomas', 'Disease', 'MESH:D018203', (119, 139))	('let-7i', 'Gene', '406891', (228, 234))	('let-7c', 'Gene', '406885', (152, 158))	('miR-1', 'Gene', '79187', (145, 150))	('let-7b', 'Gene', '406884', (170, 176))	('miR-1', 'Gene', '79187', (90, 95))	('endometrial sarcomas', 'Disease', (119, 139))	('let-7f', 'Gene', (97, 103))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (257, 286))	('let-7a', 'Var', (187, 193))	('miR-214', 'Gene', '406996', (240, 247))	('epithelial-mesenchymal tumors', 'Disease', (257, 286))	('let-7d', 'Gene', '406886', (195, 201))	('miR-133b', 'Gene', (160, 168))	('let-7c', 'Gene', '406885', (109, 115))	('let-7i', 'Gene', (228, 234))	('let-7b', 'Gene', (170, 176))	('miR-1', 'Gene', '79187', (160, 165))	('let-7d', 'Gene', (195, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('miR-222', 'Gene', (219, 226))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('miR-23b', 'Gene', '407011', (81, 88))	('miR-214', 'Gene', (240, 247))	('miR-1', 'Gene', (178, 183))	('let-7e', 'Gene', (203, 209))	('miR-1', 'Gene', (145, 150))	('miR-1', 'Gene', (90, 95))	('let-7g', 'Gene', '406890', (211, 217))	('let-7c', 'Gene', (152, 158))	('miR-133b', 'Gene', '442890', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('differed', 'Reg', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('expression', 'MPA', (67, 77))	('let-7e', 'Gene', '406887', (203, 209))	('let-7g', 'Gene', (211, 217))
31787	23558962	The expression levels of 12 miRs, miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214, which were down-regulated in mixed epithelial-mesenchymal tumors are presented in Fig.	('let-7c', 'Gene', '406885', (41, 47))	('miR-143', 'Gene', (67, 74))	('miR-1', 'Gene', (49, 54))	('miR-1', 'Gene', '79187', (67, 72))	('let-7i', 'Gene', '406891', (117, 123))	('miR-1', 'Gene', '79187', (34, 39))	('miR-222', 'Gene', '407007', (108, 115))	('let-7b', 'Gene', '406884', (59, 65))	('miR', 'Gene', (108, 111))	('miR', 'Gene', '220972', (28, 31))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (173, 202))	('miR', 'Gene', (67, 70))	('miR-214', 'Gene', '406996', (129, 136))	('miR', 'Gene', '220972', (129, 132))	('let-7a', 'Var', (76, 82))	('let-7d', 'Gene', '406886', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('epithelial-mesenchymal tumors', 'Disease', (173, 202))	('miR-133b', 'Gene', (49, 57))	('miR-143', 'Gene', '406935', (67, 74))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', '220972', (49, 52))	('miR-1', 'Gene', '79187', (49, 54))	('let-7i', 'Gene', (117, 123))	('let-7b', 'Gene', (59, 65))	('miR', 'Gene', (28, 31))	('down-regulated', 'NegReg', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('miR', 'Gene', (129, 132))	('let-7d', 'Gene', (84, 90))	('miR-1', 'Gene', (67, 72))	('miR-214', 'Gene', (129, 136))	('miR', 'Gene', (34, 37))	('miR', 'Gene', (49, 52))	('let-7e', 'Gene', (92, 98))	('miR-1', 'Gene', (34, 39))	('miR-222', 'Gene', (108, 115))	('let-7g', 'Gene', '406890', (100, 106))	('let-7c', 'Gene', (41, 47))	('miR-133b', 'Gene', '442890', (49, 57))	('let-7e', 'Gene', '406887', (92, 98))	('let-7g', 'Gene', (100, 106))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', '220972', (67, 70))
31809	23558962	As we showed here, mixed epithelial-mesenchymal tumors compared to the normal uterine fragments, expressed decreased levels of 12 miRs (miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214).	('let-7e', 'Gene', '406887', (194, 200))	('let-7g', 'Gene', (202, 208))	('miR', 'Gene', '220972', (210, 213))	('miR', 'Gene', '220972', (169, 172))	('miR-143', 'Gene', '406935', (169, 176))	('miR-143', 'Gene', (169, 176))	('miR-1', 'Gene', '79187', (169, 174))	('levels', 'MPA', (117, 123))	('let-7c', 'Gene', '406885', (143, 149))	('miR-1', 'Gene', (151, 156))	('let-7i', 'Gene', '406891', (219, 225))	('let-7b', 'Gene', '406884', (161, 167))	('miR', 'Gene', '220972', (130, 133))	('miR-1', 'Gene', '79187', (136, 141))	('miR-222', 'Gene', '407007', (210, 217))	('miR', 'Gene', (210, 213))	('miR', 'Gene', (169, 172))	('let-7a', 'Var', (178, 184))	('let-7d', 'Gene', '406886', (186, 192))	('miR-214', 'Gene', '406996', (231, 238))	('miR', 'Gene', '220972', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (25, 54))	('miR-133b', 'Gene', (151, 159))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (130, 133))	('let-7b', 'Gene', (161, 167))	('miR-1', 'Gene', '79187', (151, 156))	('epithelial-mesenchymal tumors', 'Disease', (25, 54))	('let-7i', 'Gene', (219, 225))	('let-7d', 'Gene', (186, 192))	('miR', 'Gene', (231, 234))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('miR', 'Gene', (151, 154))	('miR-1', 'Gene', (169, 174))	('miR-214', 'Gene', (231, 238))	('miR', 'Gene', (136, 139))	('decreased', 'NegReg', (107, 116))	('miR-1', 'Gene', (136, 141))	('let-7e', 'Gene', (194, 200))	('miR-133b', 'Gene', '442890', (151, 159))	('miR-222', 'Gene', (210, 217))	('let-7g', 'Gene', '406890', (202, 208))	('let-7c', 'Gene', (143, 149))
31813	23558962	Studies in a mouse model of rhabdomyosarcoma have shown that reconstitution of miR-29b/c and miR-206 inhibits tumor growth and stimulates muscle differentiation, suggesting their role of a tumor suppressor.	('mouse', 'Species', '10090', (13, 18))	('tumor', 'Disease', (189, 194))	('miR-29b', 'Gene', '407024', (79, 86))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (28, 44))	('stimulates', 'PosReg', (127, 137))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('miR-29b', 'Gene', (79, 86))	('inhibits', 'NegReg', (101, 109))	('miR-206', 'Var', (93, 100))	('rhabdomyosarcoma', 'Disease', (28, 44))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('muscle differentiation', 'CPA', (138, 160))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (28, 44))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
31820	23558962	proved that phosphatase and tensin homolog (PTEN) is a target of miR-132, and that the induction of MCP-1 occurs via PTEN repression.	('PTEN', 'Gene', (117, 121))	('PTEN', 'Gene', '5728', (117, 121))	('MCP-1', 'Gene', (100, 105))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('miR-132', 'Var', (65, 72))	('MCP-1', 'Gene', '6347', (100, 105))
31821	23558962	Mutational inactivation of PTEN is not a common event in uterine sarcomas, though in carcinosarcomas it may play a tumorogenic role.	('play', 'Reg', (108, 112))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('sarcomas', 'Disease', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('carcinosarcomas', 'Disease', 'MESH:D002296', (85, 100))	('sarcomas', 'Disease', (65, 73))	('tumor', 'Disease', (115, 120))	('Mutational inactivation', 'Var', (0, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('carcinosarcomas', 'Disease', (85, 100))	('PTEN', 'Gene', (27, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('PTEN', 'Gene', '5728', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (57, 72))
31834	23558962	Yet our findings on a common decrease in the expression of the let-7 family members (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g and let-7i) in tumor samples support the notion of let-7 family members as tumor suppressors influencing survival [ and references therein].	('tumor', 'Disease', (155, 160))	('let-7i', 'Gene', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('decrease', 'NegReg', (29, 37))	('let-7b', 'Gene', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('let-7d', 'Gene', '406886', (109, 115))	('let-7c', 'Gene', (101, 107))	('let-7', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('let-7e', 'Gene', (117, 123))	('let-7f', 'Var', (125, 131))	('let-7d', 'Gene', (109, 115))	('let-7c', 'Gene', '406885', (101, 107))	('let-7g', 'Gene', '406890', (133, 139))	('tumor', 'Disease', (215, 220))	('let-7e', 'Gene', '406887', (117, 123))	('let-7i', 'Gene', '406891', (144, 150))	('let-7g', 'Gene', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('expression', 'MPA', (45, 55))	('let-7b', 'Gene', '406884', (93, 99))	('let-7a', 'Gene', (85, 91))
31868	22567163	Abnormal expression, regulation, or function of TNF receptors have been strongly implicated in autoimmune disease, osteoporosis, and cancer.	('autoimmune disease', 'Disease', (95, 113))	('osteoporosis', 'Phenotype', 'HP:0000939', (115, 127))	('TNF', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('implicated', 'Reg', (81, 91))	('osteoporosis', 'Disease', 'MESH:D010024', (115, 127))	('autoimmune disease', 'Disease', 'MESH:D001327', (95, 113))	('cancer', 'Disease', (133, 139))	('osteoporosis', 'Disease', (115, 127))	('autoimmune disease', 'Phenotype', 'HP:0002960', (95, 113))	('Abnormal', 'Var', (0, 8))	('function', 'MPA', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('regulation', 'MPA', (21, 31))
31965	22567163	Consistent with this, it was recently shown that soluble DR6 is the result of matrix metalloproteinase 14 (MMP-14) cleavage of membrane bound DR6.	('matrix metalloproteinase 14', 'Gene', (78, 105))	('DR6', 'Gene', (142, 145))	('matrix metalloproteinase 14', 'Gene', '4323', (78, 105))	('DR6', 'Gene', '27242', (57, 60))	('MMP-14', 'Gene', (107, 113))	('cleavage', 'Var', (115, 123))	('DR6', 'Gene', (57, 60))	('DR6', 'Gene', '27242', (142, 145))	('MMP-14', 'Gene', '4323', (107, 113))
31988	22355695	It is also noteworthy that mice with a targeted       disruption of LMP2, which is an interferon (IFN)-gamma-inducible proteasome subunit, exhibited       defects in tissue- and substrate-dependent proteasomal function, and that female       LMP2-deficient mice spontaneously developed uterine LMS with a disease prevalence of 37% by 12       months of age (see Supplementary Fig.	('interferon (IFN)-gamma', 'Gene', '15978', (86, 108))	('developed', 'Reg', (276, 285))	('uterine LMS', 'Disease', (286, 297))	('LMP2', 'Gene', (68, 72))	('mice', 'Species', '10090', (257, 261))	('mice', 'Species', '10090', (27, 31))	('disruption', 'Var', (54, 64))	('LMS', 'Phenotype', 'HP:0100243', (294, 297))	('interferon (IFN)-gamma', 'Gene', (86, 108))	('defects', 'NegReg', (155, 162))
31989	22355695	Defective LMP2 expression is therefore likely to be one of the risk factors in the development       of human uterine LMS as it is in LMP2-deficient mice.	('LMP2', 'Gene', (10, 14))	('expression', 'Species', '29278', (15, 25))	('human uterine LMS', 'Disease', (104, 121))	('human', 'Species', '9606', (104, 109))	('LMS', 'Phenotype', 'HP:0100243', (118, 121))	('mice', 'Species', '10090', (149, 153))	('Defective', 'Var', (0, 9))
31990	22355695	The importance of       the IFN-gamma pathway in the transcriptional regulation of the LMP2 promoter has been established       in another study, where defective LMP2 expression was attributable to a G871E mutation in the       ATP-binding region of JAK1 in a SKN cell line established from a patient with uterine LMS.	('G871E', 'Mutation', 'p.G871E', (200, 205))	('JAK1', 'Gene', (250, 254))	('patient', 'Species', '9606', (293, 300))	('a SKN', 'CellLine', 'CVCL:1700', (258, 263))	('LMS', 'Phenotype', 'HP:0100243', (314, 317))	('LMP2', 'Gene', (162, 166))	('ATP', 'Chemical', 'MESH:D000255', (228, 231))	('expression', 'Species', '29278', (167, 177))	('defective', 'NegReg', (152, 161))	('expression', 'MPA', (167, 177))	('G871E', 'Var', (200, 205))
31992	22355695	Biological and       histological findings showed that defective LMP2 expression contributed to abnormal cell       proliferation, which directly correlated to tumor progression.	('abnormal cell       proliferation', 'Phenotype', 'HP:0031377', (96, 129))	('correlated', 'Reg', (146, 156))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cell       proliferation', 'CPA', (105, 129))	('expression', 'Species', '29278', (70, 80))	('LMP2', 'Gene', (65, 69))	('defective', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))
31993	22355695	Disruption of LMP2 expression       stemmed from defects in the IFN-gamma signaling pathway, specifically from somatic mutations in       JAK1.	('IFN-gamma signaling pathway', 'Pathway', (64, 91))	('LMP2', 'Gene', (14, 18))	('JAK1', 'Gene', (138, 142))	('mutations', 'Var', (119, 128))	('defects', 'NegReg', (49, 56))	('expression', 'Species', '29278', (19, 29))	('Disruption', 'Var', (0, 10))
32001	22355695	All lymph nodes were negative for LMS metastases, and IHC analyses showed           positivity for MIB1(Ki-67) and negativity for LMP2.	('LMS', 'Phenotype', 'HP:0100243', (34, 37))	('MIB1', 'Gene', '57534', (99, 103))	('LMS metastases', 'Disease', (34, 48))	('LMP2', 'Gene', (130, 134))	('MIB1', 'Gene', (99, 103))	('LMS metastases', 'Disease', 'MESH:D009362', (34, 48))	('positivity', 'Var', (84, 94))
32004	22355695	Although our research group has previously demonstrated that the abnormal           expression of the ovarian steroid receptors TP53 and Ki-67 and mutations of TP53 were           frequently associated with uterine LMS, defective LMP2 expression appeared to be more           characteristic of uterine LMS (see Supplementary Table S1 online).	('uterine LMS', 'Disease', (207, 218))	('mutations', 'Var', (147, 156))	('abnormal', 'Var', (65, 73))	('defective', 'Var', (220, 229))	('uterine LMS', 'Disease', (294, 305))	('LMS', 'Phenotype', 'HP:0100243', (302, 305))	('LMP2', 'Gene', (230, 234))	('expression', 'Species', '29278', (84, 94))	('TP53', 'Gene', (160, 164))	('LMS', 'Phenotype', 'HP:0100243', (215, 218))	('associated', 'Reg', (191, 201))	('expression', 'Species', '29278', (235, 245))
32005	22355695	While it has been established that IFN-gamma markedly enhances LMP2 production through           JAK-STAT signaling, the NF-kappaB signaling pathway also reportedly induces LMP2 gene           expression in an independent manner; inhibition of NF-kappaB signaling resulted in a decrease           in LMP2 expression in human carcinoma cell lines and human lymphocytes (Fig.	('human', 'Species', '9606', (350, 355))	('expression', 'MPA', (305, 315))	('expression', 'Species', '29278', (193, 203))	('LMP2', 'Gene', (173, 177))	('enhances', 'PosReg', (54, 62))	('inhibition', 'Var', (230, 240))	('decrease', 'NegReg', (278, 286))	('carcinoma', 'Disease', 'MESH:D002277', (325, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('LMP2', 'Gene', (300, 304))	('expression', 'Species', '29278', (305, 315))	('carcinoma', 'Disease', (325, 334))	('human', 'Species', '9606', (319, 324))	('LMP2 production', 'MPA', (63, 78))
32016	22355695	Conversely, IRF-1 bound to the             Lmp2 regulatory region in TNF-alpha-deficient mice and wild-type mice, but a           deficiency in IFN-gamma resulted in undetectable IRF-1 occupancy in the Lmp2 regulatory           region (Fig.	('Lmp2', 'Gene', '16912', (43, 47))	('Lmp2', 'Gene', (202, 206))	('deficiency', 'Var', (130, 140))	('Lmp2', 'Gene', '16912', (202, 206))	('mice', 'Species', '10090', (89, 93))	('mice', 'Species', '10090', (108, 112))	('Lmp2', 'Gene', (43, 47))
32023	22355695	2), we next focused on whether the           defect in LMP2 expression in uterine LMS was attributable to mutations or deletions in           IFN-gamma signaling factors.	('expression', 'MPA', (60, 70))	('deletions', 'Var', (119, 128))	('LMP2', 'Gene', (55, 59))	('mutations', 'Var', (106, 115))	('expression', 'Species', '29278', (60, 70))	('LMS', 'Phenotype', 'HP:0100243', (82, 85))
32024	22355695	Following IFN-gamma binding to the type II IFN receptor,           Janus-activated kinase (JAK) 1 and JAK2 are activated and phosphorylate signal transducer           and activator of transcription (STAT) 1 on the tyrosine residue at position 701 (Tyr701)           and the serine residue at position 727 (Ser727) (see Supplementary Fig.	('JAK2', 'Gene', '3717', (102, 106))	('serine', 'Chemical', 'MESH:D012694', (274, 280))	('signal transducer           and activator of transcription (STAT) 1', 'Gene', '6772', (139, 206))	('binding', 'Interaction', (20, 27))	('Janus-activated kinase (JAK) 1', 'Gene', (67, 97))	('Janus-activated kinase (JAK) 1', 'Gene', '3716', (67, 97))	('Tyr701', 'Chemical', '-', (248, 254))	('JAK2', 'Gene', (102, 106))	('Tyr701', 'Var', (248, 254))	('tyrosine', 'Chemical', 'MESH:D014443', (214, 222))	('Ser727', 'Chemical', '-', (306, 312))
32027	22355695	Sequence analysis demonstrated that the loss of IFN-gamma responsiveness in a human uterine           LMS cell lines was attributable to inadequate JAK1 kinase activity due to a G781E mutation           in the ATP-binding region.	('G781E', 'Var', (178, 183))	('JAK1 kinase', 'Enzyme', (148, 159))	('G781E', 'Mutation', 'p.G781E', (178, 183))	('loss', 'NegReg', (40, 44))	('ATP', 'Chemical', 'MESH:D000255', (210, 213))	('inadequate', 'NegReg', (137, 147))	('human', 'Species', '9606', (78, 83))	('LMS', 'Phenotype', 'HP:0100243', (102, 105))
32028	22355695	Genetic alterations in tyrosine kinases have           previously been firmly implicated in tumorigenesis, but only a few serine/threonine           kinases are known to be mutated in human cancers.	('Genetic alterations', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('tyrosine kinases', 'Enzyme', (23, 39))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('implicated', 'Reg', (78, 88))	('tyrosine', 'Chemical', 'MESH:D014443', (23, 31))	('human', 'Species', '9606', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', (92, 97))	('serine', 'Chemical', 'MESH:D012694', (122, 128))
32029	22355695	The examination of 19 LMS tissue sections and patient-matched normal tissue controls was           performed to identify somatic (tumor-specific) mutations in the catalytic domains of the           IFN-gamma-signaling factors JAK1, JAK2, STAT1, and LMP2 enhancer/promoter region.	('patient', 'Species', '9606', (46, 53))	('mutations in', 'Var', (146, 158))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('JAK1', 'Gene', (226, 230))	('JAK2', 'Gene', (232, 236))	('LMS', 'Phenotype', 'HP:0100243', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('STAT1', 'Gene', (238, 243))	('STAT1', 'Gene', '6772', (238, 243))	('tumor', 'Disease', (130, 135))	('JAK2', 'Gene', '3717', (232, 236))
32031	22355695	Overall, nearly 36.8% (7/19) of uterine LMS tissues had somatic mutations in the           ATP-binding region or kinase active site of JAK1 (see Supplementary Fig.	('LMS', 'Phenotype', 'HP:0100243', (40, 43))	('ATP', 'Chemical', 'MESH:D000255', (91, 94))	('JAK1', 'Gene', (135, 139))	('mutations in', 'Var', (64, 76))
32032	22355695	No           somatic mutations at Tyr701 or Ser727, which are needed for STAT1 transcriptional           activation, were found in uterine LMS.	('uterine', 'Disease', (131, 138))	('Ser727', 'Chemical', '-', (44, 50))	('STAT1', 'Gene', (73, 78))	('LMS', 'Phenotype', 'HP:0100243', (139, 142))	('STAT1', 'Gene', '6772', (73, 78))	('Tyr701', 'Chemical', '-', (34, 40))	('Ser727', 'Var', (44, 50))
32033	22355695	Over a quarter (5/19) of uterine LMS tissues           unexpectedly had mutations in the STAT1 intermolecular region, an area not yet reported to           be of importance for transcriptional activation or other biological functions (see Supplementary Table S2-S3 online).	('mutations', 'Var', (72, 81))	('had', 'Reg', (68, 71))	('STAT1', 'Gene', '6772', (89, 94))	('LMS', 'Phenotype', 'HP:0100243', (33, 36))	('STAT1', 'Gene', (89, 94))
32035	22355695	There were 7 of 19 tumors without detectable mutations in the JAK1,           JAK2 or LMP2 promoter region in our tested samples, which implied that further           experiments might uncover additional somatic mutations in the catalytic subunit (p110) of           PI3K or PKC-delta.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('PKC-delta', 'Gene', (275, 284))	('PKC-delta', 'Gene', '5580', (275, 284))	('JAK2', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PI3K', 'Enzyme', (267, 271))	('mutations', 'Var', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('JAK2', 'Gene', '3717', (78, 82))
32036	22355695	MOTIF Search profiling and NCBI's Conserved Domain           Database and Search Service, v2.17 analysis, revealed that the somatic           mutations identified in the catalytic domains of these genes resulted in impaired           activation of tyrosine kinases or transcriptional factors.	('mutations', 'Var', (142, 151))	('transcriptional factors', 'Pathway', (268, 291))	('tyrosine kinases', 'MPA', (248, 264))	('impaired', 'NegReg', (215, 223))	('tyrosine', 'Chemical', 'MESH:D014443', (248, 256))	('activation', 'PosReg', (234, 244))
32038	22355695	Other reports showed that among the most intriguing changes in genes           were losses of JAK1 (1p31-p32) and LMP2 (6p21.3).	('JAK1', 'Gene', (94, 98))	('p32', 'Gene', (105, 108))	('losses', 'NegReg', (84, 90))	('6p21.3', 'Var', (120, 126))	('p32', 'Gene', '925', (105, 108))	('LMP2', 'Gene', (114, 118))
32040	22355695	Our           results showed that LMS having a clear functional loss at JAK1 (1p31-p32) and             LMP2 (6p21.3) also harbored one nonsense mutation and one deletion, suggesting a           possible homozygous loss of function (see Supplementary Fig.	('JAK1', 'Gene', (72, 76))	('LMS', 'Phenotype', 'HP:0100243', (34, 37))	('p32', 'Gene', '925', (83, 86))	('loss', 'NegReg', (215, 219))	('LMP2', 'Gene', (104, 108))	('loss', 'NegReg', (64, 68))	('6p21.3', 'Var', (110, 116))	('p32', 'Gene', (83, 86))
32042	22355695	It appeared likely that IFN-gamma-inducible LMP2 expression was impaired due to somatic           mutations in the catalytic domains, ATP-binding region, or kinase active site of JAK1 of           the IFN-gamma-pathway in uterine LMS.	('expression', 'Species', '29278', (49, 59))	('IFN-gamma-inducible', 'Gene', (24, 43))	('impaired', 'NegReg', (64, 72))	('ATP', 'Chemical', 'MESH:D000255', (134, 137))	('expression', 'MPA', (49, 59))	('mutations in', 'Var', (98, 110))	('uterine LMS', 'Disease', (222, 233))	('LMS', 'Phenotype', 'HP:0100243', (230, 233))
32043	22355695	To evaluate whether a mutation resulted in the loss of a           transcriptional response to IFN-gamma, wild-type JAK1 (JAK1wt) or JAK1 mutant expression           vectors were transiently introduced into JAK1-null cells.	('mutant', 'Var', (138, 144))	('JAK1', 'Gene', (133, 137))	('loss', 'NegReg', (47, 51))	('transcriptional response to IFN-gamma', 'MPA', (67, 104))	('expression           vectors', 'Species', '29278', (145, 173))
32044	22355695	Western blotting and RT-PCR           analyses showed that although exogenous JAK1wt restored the IFN-gamma inducibility of LMP2           expression, phospho-JAK1(p-JAK1) and phospho-STAT1(p-STAT1) could not be induced by any           exogenous JAK1 mutant except JAK1-G986P (Fig.	('G986P', 'Mutation', 'p.G986P', (271, 276))	('STAT1', 'Gene', '6772', (192, 197))	('JAK1-G986P', 'Var', (266, 276))	('STAT1', 'Gene', (184, 189))	('IFN-gamma inducibility', 'MPA', (98, 120))	('expression', 'Species', '29278', (139, 149))	('LMP2', 'Gene', (124, 128))	('STAT1', 'Gene', '6772', (184, 189))	('expression', 'MPA', (139, 149))	('phospho-JAK1', 'MPA', (151, 163))	('STAT1', 'Gene', (192, 197))
32045	22355695	Similarly,           electrophoresis mobility shift assays (EMSA) demonstrated that the DNA-binding activity of           STAT1 and IRF-1 to specific regions was absent in the presence of any exogenous JAK1           mutant except JAK1-G986P but was rescued by inclusion of JAK1wt (Fig.	('JAK1-G986P', 'Var', (231, 241))	('IRF-1', 'Gene', (132, 137))	('G986P', 'Mutation', 'p.G986P', (236, 241))	('JAK1', 'Gene', (202, 206))	('DNA-binding', 'Interaction', (88, 99))	('absent', 'NegReg', (162, 168))	('STAT1', 'Gene', (122, 127))	('STAT1', 'Gene', '6772', (122, 127))
32051	22355695	Therefore, the differential responsiveness to genetically modified stable LMP2 expression           of the SKN human uterine LMS cell line was investigated to determine whether reintroducing           LMP2 to a LMS cell line would affect its tumorigenic properties for development of uterine           LMS and if the observed effect was due to the immunoproteosomal function of the protein.	('expression', 'Species', '29278', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('LMS', 'Phenotype', 'HP:0100243', (302, 305))	('LMS', 'Phenotype', 'HP:0100243', (125, 128))	('human', 'Species', '9606', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('affect', 'Reg', (231, 237))	('LMS', 'Phenotype', 'HP:0100243', (211, 214))	('LMP2', 'Gene', (201, 205))	('tumor', 'Disease', (242, 247))	('reintroducing', 'Var', (177, 190))
32056	22355695	The growth rate, expressed as           doubling time, of typical SKN-LMP2wt (F type) colonies (8 clones) or SKN-LMP2K33A (F type)           colonies (4 clones) was generally lower than that of SKN-LMP2wt (P/F type) colonies (2           clones) and control SKN-CEM9 (T type) colonies (4 clones) (Fig.	('lower', 'NegReg', (175, 180))	('SKN-CEM9 (T type) colonies', 'Disease', 'MESH:D001260', (258, 284))	('K33A', 'Mutation', 'p.K33A', (117, 121))	('SKN-LMP2K33A', 'Var', (109, 121))	('growth rate', 'MPA', (4, 15))
32057	22355695	FACS analysis demonstrated that LMP2 expression might have induced G1 arrest in           the cell cycle of SKN-LMP2 (F type) colonies (see Supplementary Fig.	('expression', 'Var', (37, 47))	('arrest', 'Disease', 'MESH:D006323', (70, 76))	('arrest', 'Disease', (70, 76))	('expression', 'Species', '29278', (37, 47))	('induced', 'Reg', (59, 66))	('LMP2', 'Gene', (32, 36))
32059	22355695	Tumor growth was clearly observed in control mice inoculated with the SKN-CEM9 (T type)           clones; however, a reduction in tumor growth was observed in mice inoculated with the           SKN-LMP2wt (F type) clone or SKN-LMP2K33A (F type) clone (Fig.	('reduction', 'NegReg', (117, 126))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('SKN-LMP2K33A', 'Var', (223, 235))	('SKN-CEM9', 'CellLine', 'CVCL:1700', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', (130, 135))
32060	22355695	Since both wild type and mutant LMP2 blocked tumorigenesis, it became necessary           to rule out a toxic effect of LMP2 overexpression in a control cancer cell line.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('expression', 'Species', '29278', (129, 139))	('mutant', 'Var', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', (153, 159))	('tumor', 'Disease', (45, 50))	('blocked', 'NegReg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('LMP2', 'Gene', (32, 36))
32061	22355695	Additional experiments demonstrated no toxic effect of either wild type LMP2 or mutant           LMP2K33A overexpression in a HeLa control cancer cell line (see Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutant', 'Var', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'Species', '29278', (110, 120))	('overexpression', 'PosReg', (106, 120))	('HeLa', 'CellLine', 'CVCL:0030', (126, 130))	('LMP2K33A', 'Gene', (97, 105))	('cancer', 'Disease', (139, 145))
32065	22355695	The dysregulation of apoptotic mechanisms has also been associated with many human           malignancies.	('dysregulation', 'Var', (4, 17))	('apoptotic', 'CPA', (21, 30))	('associated', 'Reg', (56, 66))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('malignancies', 'Disease', (93, 105))	('human', 'Species', '9606', (77, 82))
32068	22355695	Tumors grew more slowly in mice inoculated with the SKN-p50p65 (T type)           clones, which had exogeous NF-kappaB function, compared with SKN-CEM9 (T type) clones (see             Supplementary Table S5 online).	('exogeous', 'MPA', (100, 108))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SKN-CEM9', 'CellLine', 'CVCL:1700', (143, 151))	('mice', 'Species', '10090', (27, 31))	('SKN-p50p65', 'Var', (52, 62))	('slowly', 'NegReg', (17, 23))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
32069	22355695	These findings suggested that NF-kappaB           activation was not involved in the tumorigenesis of human uterine LMS, and strengthened           the overall notion that the suppression of cell proliferation, tumorigenesis, and           morphological change of uterine LMS cells observed under stable LMP2 expression was           attributable to the biological function of single-molecule LMP2 only, without involvement           of its immunoproteasome function.	('tumor', 'Disease', (85, 90))	('LMP2', 'Gene', (304, 308))	('expression', 'Species', '29278', (309, 319))	('LMS', 'Phenotype', 'HP:0100243', (272, 275))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('suppression', 'NegReg', (176, 187))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cell proliferation', 'CPA', (191, 209))	('morphological change', 'CPA', (240, 260))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('single-molecule', 'Var', (377, 392))	('LMP2', 'Gene', (393, 397))	('LMS', 'Phenotype', 'HP:0100243', (116, 119))	('human', 'Species', '9606', (102, 107))
32080	22355695	The functionally inactivated K33A mutant of LMP2 has the same morphology in vitro as the wt         transfectant, suggesting that the action of LMP2 is not only through its role in         immunoproteasomes, but also as a single subunit.	('K33A', 'Mutation', 'p.K33A', (29, 33))	('LMP2', 'Gene', (44, 48))	('K33A', 'Var', (29, 33))	('LMP2', 'Gene', (144, 148))
32087	22355695	Genetic alterations in tyrosine kinases have been firmly implicated in tumorigenesis, but         only a few serine/threonine kinases are known to be mutated in human cancers.	('human', 'Species', '9606', (161, 166))	('Genetic alterations', 'Var', (0, 19))	('serine', 'Chemical', 'MESH:D012694', (109, 115))	('tyrosine kinases', 'Enzyme', (23, 39))	('implicated', 'Reg', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tyrosine', 'Chemical', 'MESH:D014443', (23, 31))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', (71, 76))
32088	22355695	For example, mice carrying a homozygous deletion of Pten alleles         developed widespread smooth muscle cell hyperplasias and abdominal sarcomas, and JUN         oncogene amplification and overexpression blocked adipocytic differentiation in highly         aggressive sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('mice', 'Species', '10090', (13, 17))	('sarcomas', 'Disease', (140, 148))	('abdominal sarcomas', 'Disease', 'MESH:D012509', (130, 148))	('hyperplasias', 'Disease', 'MESH:D006965', (113, 125))	('blocked', 'NegReg', (208, 215))	('deletion', 'Var', (40, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (272, 280))	('sarcomas', 'Disease', (272, 280))	('hyperplasias', 'Disease', (113, 125))	('abdominal sarcomas', 'Disease', (130, 148))	('adipocytic', 'MPA', (216, 226))	('expression', 'Species', '29278', (197, 207))	('Pten', 'Gene', (52, 56))	('sarcomas', 'Disease', 'MESH:D012509', (140, 148))	('sarcomas', 'Disease', 'MESH:D012509', (272, 280))	('Pten', 'Gene', '19211', (52, 56))
32092	22355695	Although heterozygosity for somatic         mutations was demonstrated to be significantly more frequent in uterine LMS, the evaluation         of a genotype-tumorigenesis correlation might not be statistically significant between         heterozygotes and homozygotes due to our small sample size.	('tumor', 'Disease', (158, 163))	('LMS', 'Phenotype', 'HP:0100243', (116, 119))	('frequent', 'Reg', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('uterine LMS', 'Disease', (108, 119))
32093	22355695	In addition, genetic alteration         in other malignant tumors reportedly occur in genes of the MAPK signaling, p53 signaling,         Wnt signaling, cell cycle, and mTOR pathways.	('occur', 'Reg', (77, 82))	('mTOR', 'Gene', '2475', (169, 173))	('genetic alteration', 'Var', (13, 31))	('mTOR', 'Gene', (169, 173))	('p53', 'Gene', (115, 118))	('Wnt signaling', 'Pathway', (138, 151))	('p53', 'Gene', '7157', (115, 118))	('malignant tumors', 'Disease', (49, 65))	('MAPK signaling', 'Pathway', (99, 113))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('malignant tumors', 'Disease', 'MESH:D018198', (49, 65))	('cell', 'Pathway', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
32095	22355695	From our data, we can infer a         heterogeneous genetic background of JAK somatic mutations, but we cannot definitively         conclude tumorigenesis by genotype.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))
32098	22355695	Furthermore, LMP2 expression appears to suppress cell         transformation, proliferation, and tumorigenesis in uterine LMS cells, which suggests that         LMP2 plays a key role as a tumor suppressor in uterine LMS.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('LMS', 'Phenotype', 'HP:0100243', (216, 219))	('LMP2', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cell         transformation', 'CPA', (49, 76))	('expression', 'Species', '29278', (18, 28))	('suppress', 'NegReg', (40, 48))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('expression', 'Var', (18, 28))	('LMS', 'Phenotype', 'HP:0100243', (122, 125))
32099	22355695	Defective LMP2 expression is likely to be one of the risk factors in the development of         human uterine LMS as it is in the LMP2-deficient mouse.	('human uterine LMS', 'Disease', (96, 113))	('mouse', 'Species', '10090', (145, 150))	('LMP2', 'Gene', (10, 14))	('expression', 'Species', '29278', (15, 25))	('human', 'Species', '9606', (96, 101))	('LMS', 'Phenotype', 'HP:0100243', (110, 113))	('Defective', 'Var', (0, 9))
32121	22355695	The supernatants           were incubated with primary antibody against the protein of interest between 4 h and           overnight at 4 C. Antisera were anti-RelA (Upstate, MA), anti-IRF-1 (Santa Cruz, CA, USA),           anti-SP1 (Santa Cruz) or normal rabbit IgG (Santa Cruz).	('anti-RelA', 'Var', (154, 163))	('anti-SP1', 'Var', (223, 231))	('anti-IRF-1', 'Var', (179, 189))	('rabbit', 'Species', '9986', (255, 261))
32131	33021035	MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways.	('Notch', 'Gene', (243, 248))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('UCS', 'Phenotype', 'HP:0002891', (9, 12))	('genetic alterations', 'Var', (33, 52))	('MBC', 'Disease', 'MESH:D001943', (0, 3))	('Notch', 'Gene', '4851;4853;4854;4855', (243, 248))	('PTEN', 'Gene', (81, 85))	('PIK3CA', 'Gene', (69, 75))	('PTEN', 'Gene', '5728', (81, 85))	('PIK3CA', 'Gene', '5290', (69, 75))	('alterations affecting', 'Reg', (158, 179))	('MBC', 'Disease', (0, 3))
32133	33021035	Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs.	('HRD', 'Disease', (70, 73))	('prevalent', 'Reg', (110, 119))	('HRD', 'Disease', 'None', (20, 23))	('MBC', 'Disease', 'MESH:D001943', (123, 126))	('HRD', 'Disease', 'None', (70, 73))	('MBC', 'Disease', (123, 126))	('biallelic alterations', 'Var', (28, 49))	('HRD', 'Disease', (20, 23))	('UCS', 'Phenotype', 'HP:0002891', (136, 139))
32135	33021035	Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.	('mutations', 'Var', (142, 151))	('MBC', 'Disease', 'MESH:D001943', (103, 106))	('UCS', 'Phenotype', 'HP:0002891', (86, 89))	('HER2', 'Gene', (153, 157))	('tumor', 'Disease', (275, 280))	('HRD', 'Disease', 'None', (185, 188))	('MBC', 'Disease', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('HER2', 'Gene', '2064', (153, 157))	('differ', 'Reg', (91, 97))	('FBXW7', 'Gene', '55294', (124, 129))	('amplification', 'Var', (158, 171))	('PPP2R1A', 'Gene', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('PPP2R1A', 'Gene', '5518', (134, 141))	('HRD', 'Disease', (185, 188))	('FBXW7', 'Gene', (124, 129))
32141	33021035	At the genetic level, MBCs are characterized by recurrent mutations affecting TP53 and genes related to the PI3K/AKT/mTOR, MAPK, Wnt, and Notch signaling pathways [2, 4, 8, 16, 17].	('mutations', 'Var', (58, 67))	('MBC', 'Disease', 'MESH:D001943', (22, 25))	('mTOR', 'Gene', (117, 121))	('mTOR', 'Gene', '2475', (117, 121))	('AKT', 'Gene', '207', (113, 116))	('Notch', 'Gene', (138, 143))	('MBC', 'Disease', (22, 25))	('TP53', 'Gene', (78, 82))	('Notch', 'Gene', '4851;4853;4854;4855', (138, 143))	('TP53', 'Gene', '7157', (78, 82))	('AKT', 'Gene', (113, 116))
32144	33021035	Akin to MBCs, UCSs have been found to harbor recurrent mutations affecting TP53 and the PI3K/AKT/mTOR signaling pathway [19] as well as mutations in chromatin remodeling and core histone genes [21, 22, 23].	('mTOR', 'Gene', '2475', (97, 101))	('UCS', 'Phenotype', 'HP:0002891', (14, 17))	('mutations', 'Var', (55, 64))	('AKT', 'Gene', '207', (93, 96))	('MBC', 'Disease', (8, 11))	('mTOR', 'Gene', (97, 101))	('AKT', 'Gene', (93, 96))	('mutations', 'Var', (136, 145))	('TP53', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (75, 79))	('MBC', 'Disease', 'MESH:D001943', (8, 11))	('chromatin remodeling', 'Gene', (149, 169))
32164	33021035	A somatic mutation was defined as pathogenic if it affected a mutational hotspot or was deleterious/loss-of-function (in the case of tumor suppressor genes).	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutation', 'Var', (10, 18))	('affected', 'Reg', (51, 59))	('tumor', 'Disease', (133, 138))	('deleterious/loss-of-function', 'NegReg', (88, 116))	('mutational hotspot', 'MPA', (62, 80))
32165	33021035	Allele-specific copy number alterations (CNAs), tumor purity, and ploidy were obtained from the WES data using facets [31].	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('copy number alterations', 'Var', (16, 39))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
32169	33021035	Homologous recombination DNA repair deficiency (HRD) was assessed by defining large-scale state transition (LST) scores, numerical telomeric allelic imbalance (NtAI) scores, mutational signature 3, microhomology-mediated deletions, and the length of small deletions.	('imbalance', 'Phenotype', 'HP:0002172', (149, 158))	('HRD', 'Disease', 'None', (48, 51))	('deficiency', 'Disease', (36, 46))	('deletions', 'Var', (221, 230))	('HRD', 'Disease', (48, 51))	('NtAI', 'Chemical', '-', (160, 164))	('deficiency', 'Disease', 'MESH:D007153', (36, 46))
32171	33021035	Mutational signatures were inferred from both synonymous and nonsynonymous somatic mutations in MBCs and UCSs with at least 20 single nucleotide variants (SNVs) using DeconstructSigs [39] with default parameters, based on the set of mutational signatures represented in version 2 as part of COSMIC release v89 (https://cancer.sanger.ac.uk/cosmic/signatures_v2), as previously described [35].	('MBC', 'Disease', (96, 99))	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('UCS', 'Phenotype', 'HP:0002891', (105, 108))	('MBC', 'Disease', 'MESH:D001943', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
32172	33021035	All but two MBCs (META55 and META61) had >= 20 SNVs for mutational signature analysis, and the dominant mutational signature of a given case is reported.	('META61', 'Var', (29, 35))	('MBC', 'Disease', (12, 15))	('MBC', 'Disease', 'MESH:D001943', (12, 15))
32173	33021035	Given that tumors with deficient HR have been shown to have an enrichment for small deletions >= 5bp and microhomology-mediated deletions [40, 41], the length of small deletions and the presence of deletions with microhomology were assessed in the samples analyzed, as described [35, 40, 41].	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('deficient HR', 'Disease', (23, 35))	('deficient HR', 'Disease', 'MESH:D001919', (23, 35))	('deletions', 'Var', (128, 137))
32177	33021035	Somatic mutations were excluded from the clonal decomposition analysis if they affected loci with (a) low total depth (< 20x) in the matched normal, (b) low total depth (< 50x) in any tumor component of a given case, (c) where the tumor variant allele fractions (VAFs) of both components of a given case were lower than five times the normal VAF, and (d) where the total tumor depth exceeds 1500x in any component of a given case.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('low', 'NegReg', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('VAFs', 'Disease', (263, 267))	('mutations', 'Var', (8, 17))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', (184, 189))	('affected', 'Reg', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('VAFs', 'Disease', 'None', (263, 267))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))
32182	33021035	Truncal mutations were defined as those displaying a modal clonal frequency/CCF in the clonally related mesenchymal and carcinoma components of a given case, whereas branch mutations were defined as all nontruncal mutations.	('carcinoma', 'Disease', (120, 129))	('CCF', 'Gene', (76, 79))	('carcinoma', 'Disease', 'MESH:D009369', (120, 129))	('CCF', 'Gene', '5307', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Truncal mutations', 'Var', (0, 17))
32190	33021035	Important differences were observed, however; MBCs more frequently displayed somatic mutations in FAT3 (26% vs 4%, P = 0.0028, Fisher's exact test), ABCA13 (14% vs 2%, P = 0.031, Fisher's exact test), FAT1, CHERP, and RYR1 (each, 11% vs 0%, P = 0.02; Fisher's exact test) than UCSs.	('MBC', 'Disease', 'MESH:D001943', (46, 49))	('ABCA13', 'Gene', '154664', (149, 155))	('FAT1', 'Gene', (201, 205))	('FAT3', 'Gene', (98, 102))	('RYR1', 'Gene', '6261', (218, 222))	('CHERP', 'Gene', (207, 212))	('RYR1', 'Gene', (218, 222))	('MBC', 'Disease', (46, 49))	('FAT3', 'Gene', '120114', (98, 102))	('CHERP', 'Gene', '10523', (207, 212))	('mutations', 'Var', (85, 94))	('ABCA13', 'Gene', (149, 155))	('UCS', 'Phenotype', 'HP:0002891', (277, 280))	('displayed', 'Reg', (67, 76))	('FAT1', 'Gene', '2195', (201, 205))
32192	33021035	In addition, although TP53 mutations were common in both tumor types, they were significantly more frequently found in UCSs than in MBCs (93% vs 69%; P = 0.004, Fisher's exact test).	('mutations', 'Var', (27, 36))	('MBC', 'Disease', 'MESH:D001943', (132, 135))	('found', 'Reg', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('MBC', 'Disease', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('TP53', 'Gene', '7157', (22, 26))	('UCSs', 'Disease', (119, 123))	('UCS', 'Phenotype', 'HP:0002891', (119, 122))	('tumor', 'Disease', (57, 62))	('TP53', 'Gene', (22, 26))
32198	33021035	A pathway analysis based on the somatic mutations and CNAs revealed an enrichment of genetic alterations targeting the canonical p53, PI3K/AKT/mTOR, Wnt, and Notch pathways, as defined by Sanchez-Vega et al.	('AKT', 'Gene', '207', (139, 142))	('targeting', 'Reg', (105, 114))	('alterations', 'Var', (93, 104))	('Notch', 'Gene', (158, 163))	('Wnt', 'Pathway', (149, 152))	('Notch', 'Gene', '4851;4853;4854;4855', (158, 163))	('AKT', 'Gene', (139, 142))	('p53', 'Gene', (129, 132))	('mTOR', 'Gene', '2475', (143, 147))	('p53', 'Gene', '7157', (129, 132))	('mTOR', 'Gene', (143, 147))
32203	33021035	Although PIK3CA (29% MBCs and 33% UCSs), PTEN (17% MBCs and 16% UCSs), and PIK3R1 (11% MBCs and 9% UCSs; all P > 0.05, Fisher's exact test) were PI3K signaling pathway components frequently affected by somatic mutations or CNAs in both MBCs and UCSs, other genes of the PI3K pathway such as PPP2R1A (27% UCSs vs 0% MBCs, P < 0.001; Fisher's exact test) and AKT2 (7% UCSs vs 0% MBCs, P = 0.154; Fisher's exact test) were affected exclusively in UCSs, whereas genetic alterations affecting AKT3 (9% MBCs vs 0% UCSs, P = 0.055; Fisher's exact test) and INPP4B (3% MBCs vs 0% UCSs, P = 0.389; Fisher's exact test) were uniquely found in MBCs (Fig.	('MBC', 'Disease', (377, 380))	('MBC', 'Disease', 'MESH:D001943', (561, 564))	('mutations', 'Var', (210, 219))	('MBC', 'Disease', (51, 54))	('MBC', 'Disease', 'MESH:D001943', (497, 500))	('INPP4B', 'Gene', '8821', (550, 556))	('UCS', 'Phenotype', 'HP:0002891', (245, 248))	('MBC', 'Disease', 'MESH:D001943', (377, 380))	('MBC', 'Disease', 'MESH:D001943', (51, 54))	('affected', 'Reg', (420, 428))	('affected', 'Reg', (190, 198))	('PIK3R1', 'Gene', (75, 81))	('AKT3', 'Gene', '10000', (488, 492))	('INPP4B', 'Gene', (550, 556))	('AKT2', 'Gene', '208', (357, 361))	('PIK3CA', 'Gene', (9, 15))	('PTEN', 'Gene', (41, 45))	('UCS', 'Phenotype', 'HP:0002891', (99, 102))	('AKT3', 'Gene', (488, 492))	('MBC', 'Disease', (87, 90))	('MBC', 'Disease', (633, 636))	('genetic alterations', 'Var', (458, 477))	('MBC', 'Disease', (236, 239))	('UCS', 'Phenotype', 'HP:0002891', (304, 307))	('AKT2', 'Gene', (357, 361))	('MBC', 'Disease', (315, 318))	('MBC', 'Disease', 'MESH:D001943', (87, 90))	('PTEN', 'Gene', '5728', (41, 45))	('PIK3R1', 'Gene', '5295', (75, 81))	('PPP2R1A', 'Gene', '5518', (291, 298))	('MBC', 'Disease', 'MESH:D001943', (633, 636))	('UCS', 'Phenotype', 'HP:0002891', (34, 37))	('MBC', 'Disease', (21, 24))	('MBC', 'Disease', 'MESH:D001943', (236, 239))	('MBC', 'Disease', 'MESH:D001943', (315, 318))	('MBC', 'Disease', (561, 564))	('MBC', 'Disease', 'MESH:D001943', (21, 24))	('MBC', 'Disease', (497, 500))	('PPP2R1A', 'Gene', (291, 298))	('UCS', 'Phenotype', 'HP:0002891', (64, 67))	('PIK3CA', 'Gene', '5290', (9, 15))
32205	33021035	Our analyses revealed that 43% (15/35) of MBCs and 53% (29/55) of UCSs harbored somatic genetic alterations affecting at least one gene of the canonical Wnt signaling pathway, of which 73% (11/15) of MBCs and 79% (23/29) of UCSs had at least one pathogenic mutation, amplification, or homozygous deletion (Fig.	('MBC', 'Disease', 'MESH:D001943', (200, 203))	('alterations', 'Var', (96, 107))	('MBC', 'Disease', (42, 45))	('UCS', 'Phenotype', 'HP:0002891', (224, 227))	('amplification', 'Var', (267, 280))	('mutation', 'Var', (257, 265))	('MBC', 'Disease', (200, 203))	('affecting', 'Reg', (108, 117))	('MBC', 'Disease', 'MESH:D001943', (42, 45))	('UCS', 'Phenotype', 'HP:0002891', (66, 69))
32206	33021035	The Wnt pathway genes most frequently affected by somatic mutations or CNAs among MBCs and UCSs were ARID1A (11% MBCs vs 9% UCSs, P = 0.731, Fisher's exact test) and MYC (26% MBCs vs 11% UCSs, P = 0.08; Fisher's exact test).	('MYC', 'Gene', '4609', (166, 169))	('ARID1A', 'Gene', (101, 107))	('UCS', 'Phenotype', 'HP:0002891', (124, 127))	('Wnt pathway genes', 'Gene', (4, 21))	('MBC', 'Disease', 'MESH:D001943', (113, 116))	('UCS', 'Phenotype', 'HP:0002891', (187, 190))	('MBC', 'Disease', 'MESH:D001943', (82, 85))	('affected', 'Reg', (38, 46))	('CNAs', 'Var', (71, 75))	('MBC', 'Disease', 'MESH:D001943', (175, 178))	('MYC', 'Gene', (166, 169))	('UCS', 'Phenotype', 'HP:0002891', (91, 94))	('MBC', 'Disease', (113, 116))	('ARID1A', 'Gene', '8289', (101, 107))	('MBC', 'Disease', (82, 85))	('MBC', 'Disease', (175, 178))
32207	33021035	Importantly, however, genetic alterations affecting FBXW7 were found exclusively in UCSs (38% UCSs vs 0% MBCs, P < 0.01; Fisher's exact test), whereas FAT1 (11% MBCs vs 0% UCSs, P = 0.02; Fisher's exact test) and APC (3% MBCs vs 0% UCSs, P = 0.389; Fisher's exact test) were altered in MBCs but not in UCSs (Fig.	('UCS', 'Phenotype', 'HP:0002891', (94, 97))	('APC', 'Disease', 'MESH:D011125', (213, 216))	('UCS', 'Phenotype', 'HP:0002891', (302, 305))	('APC', 'Disease', (213, 216))	('FBXW7', 'Gene', '55294', (52, 57))	('FAT1', 'Gene', '2195', (151, 155))	('MBC', 'Disease', (105, 108))	('MBC', 'Disease', (161, 164))	('UCS', 'Phenotype', 'HP:0002891', (172, 175))	('MBC', 'Disease', 'MESH:D001943', (105, 108))	('MBC', 'Disease', 'MESH:D001943', (161, 164))	('UCS', 'Phenotype', 'HP:0002891', (84, 87))	('MBC', 'Disease', (286, 289))	('MBC', 'Disease', (221, 224))	('UCS', 'Phenotype', 'HP:0002891', (232, 235))	('genetic alterations', 'Var', (22, 41))	('FAT1', 'Gene', (151, 155))	('FBXW7', 'Gene', (52, 57))	('MBC', 'Disease', 'MESH:D001943', (286, 289))	('MBC', 'Disease', 'MESH:D001943', (221, 224))
32208	33021035	Likewise, 43% (15/35) of MBCs and 56% (31/55) of UCSs harbored somatic genetic alterations affecting at least one gene of the canonical Notch signaling pathway, of which 73% (11/15) of MBCs and 81% (25/31) of UCSs were affected by at least one pathogenic mutation, amplification, or homozygous deletion (Fig.	('MBC', 'Disease', (185, 188))	('alterations', 'Var', (79, 90))	('Notch', 'Gene', (136, 141))	('UCS', 'Phenotype', 'HP:0002891', (49, 52))	('amplification', 'Var', (265, 278))	('affecting', 'Reg', (91, 100))	('Notch', 'Gene', '4851;4853;4854;4855', (136, 141))	('MBC', 'Disease', 'MESH:D001943', (25, 28))	('MBC', 'Disease', 'MESH:D001943', (185, 188))	('UCS', 'Phenotype', 'HP:0002891', (209, 212))	('affected by', 'Reg', (219, 230))	('MBC', 'Disease', (25, 28))
32209	33021035	The genes of the Notch signaling pathway most frequently affected by genetic alterations in MBCs and UCSs were HEY1 (9% MBCs vs 5% UCSs), NOTCH1 (3% MBCs vs 4% UCSs), and HES1 (3% MBCs vs 4% UCSs; all P > 0.05, Fisher's exact test).	('affected', 'Reg', (57, 65))	('MBC', 'Disease', 'MESH:D001943', (92, 95))	('HEY1', 'Gene', (111, 115))	('HEY1', 'Gene', '23462', (111, 115))	('UCS', 'Phenotype', 'HP:0002891', (101, 104))	('MBC', 'Disease', (120, 123))	('MBC', 'Disease', (149, 152))	('HES1', 'Gene', (171, 175))	('Notch', 'Gene', (17, 22))	('UCS', 'Phenotype', 'HP:0002891', (131, 134))	('MBC', 'Disease', 'MESH:D001943', (120, 123))	('MBC', 'Disease', 'MESH:D001943', (149, 152))	('NOTCH1', 'Gene', (138, 144))	('genetic alterations', 'Var', (69, 88))	('MBC', 'Disease', (180, 183))	('UCS', 'Phenotype', 'HP:0002891', (160, 163))	('Notch', 'Gene', '4851;4853;4854;4855', (17, 22))	('UCS', 'Phenotype', 'HP:0002891', (191, 194))	('MBC', 'Disease', (92, 95))	('NOTCH1', 'Gene', '4851', (138, 144))	('MBC', 'Disease', 'MESH:D001943', (180, 183))	('HES1', 'Gene', '3280', (171, 175))
32210	33021035	Mutations affecting NOTCH2 (6%), NOTCH3 (9%), DNER (3%), EP300 (3%), and CUL1 (3%) were found in MBCs, whereas NOTCH4 (2%) alterations were only detected in UCSs (Fig.	('NOTCH4', 'Gene', (111, 117))	('EP300', 'Gene', '2033', (57, 62))	('NOTCH4', 'Gene', '4855', (111, 117))	('NOTCH3', 'Gene', '4854', (33, 39))	('CUL1', 'Gene', (73, 77))	('MBC', 'Disease', (97, 100))	('DNER', 'Gene', '92737', (46, 50))	('NOTCH2', 'Gene', '4853', (20, 26))	('CUL1', 'Gene', '8454', (73, 77))	('DNER', 'Gene', (46, 50))	('Mutations', 'Var', (0, 9))	('UCS', 'Phenotype', 'HP:0002891', (157, 160))	('MBC', 'Disease', 'MESH:D001943', (97, 100))	('EP300', 'Gene', (57, 62))	('NOTCH3', 'Gene', (33, 39))	('NOTCH2', 'Gene', (20, 26))
32213	33021035	Our analyses revealed the presence of a dominant mutational signature 3 associated with HRD in 45% (15/33) of MBCs.	('mutational', 'Var', (49, 59))	('MBC', 'Disease', (110, 113))	('HRD', 'Disease', (88, 91))	('associated', 'Reg', (72, 82))	('MBC', 'Disease', 'MESH:D001943', (110, 113))	('HRD', 'Disease', 'None', (88, 91))
32215	33021035	Consistent with these findings, the median LST scores (24 vs 13, P < 0.002, Mann-Whitney U-test), NtAI scores (21 vs 16, P = 0.029, Mann-Whitney U-test), and deletion length of >= 5 bp (P = 0.008, Mann-Whitney U-test) in MBCs were statistically significantly higher than those in UCSs (Fig.	('deletion length', 'Var', (158, 173))	('NtAI scores', 'MPA', (98, 109))	('NtAI', 'Chemical', '-', (98, 102))	('LST', 'MPA', (43, 46))	('MBC', 'Disease', (221, 224))	('UCS', 'Phenotype', 'HP:0002891', (280, 283))	('higher', 'PosReg', (259, 265))	('MBC', 'Disease', 'MESH:D001943', (221, 224))
32216	33021035	All MBCs (15/33) with a dominant mutational signature 3 displayed other genomic features suggestive of HRD, such as high LST scores (> 15), NtAI scores > 16, average small deletion length >= 5 bp, and deletions with microhomology in 100% (15/15), 80% (12/15), and 73% (11/15) of cases, respectively (Fig.	('HRD', 'Disease', (103, 106))	('MBC', 'Disease', (4, 7))	('LST scores', 'MPA', (121, 131))	('mutational', 'Var', (33, 43))	('NtAI', 'Chemical', '-', (140, 144))	('HRD', 'Disease', 'None', (103, 106))	('MBC', 'Disease', 'MESH:D001943', (4, 7))	('deletions', 'Var', (201, 210))
32218	33021035	Our analyses revealed that of the 15 MBCs with genomic features suggestive of HRD, 9 demonstrated biallelic inactivation of HRD-related genes [38, 51].	('HRD', 'Disease', 'None', (78, 81))	('MBC', 'Disease', 'MESH:D001943', (37, 40))	('HRD', 'Disease', (78, 81))	('HRD', 'Disease', 'None', (124, 127))	('MBC', 'Disease', (37, 40))	('biallelic inactivation', 'Var', (98, 120))	('HRD', 'Disease', (124, 127))
32221	33021035	Of the four UCSs displaying genomic features of HRD, UCS11 and UCS12 were found to harbor homozygous deletions in USP11 and FANCA, respectively (Table S4).	('FANCA', 'Gene', (124, 129))	('UCS', 'Phenotype', 'HP:0002891', (63, 66))	('HRD', 'Disease', 'None', (48, 51))	('UCS', 'Phenotype', 'HP:0002891', (12, 15))	('UCS', 'Phenotype', 'HP:0002891', (53, 56))	('USP11', 'Gene', '8237', (114, 119))	('USP11', 'Gene', (114, 119))	('deletions', 'Var', (101, 110))	('HRD', 'Disease', (48, 51))	('FANCA', 'Gene', '2175', (124, 129))
32224	33021035	To define whether the histologically distinct components of MBCs and UCSs would be clonally related, we applied a previously validated approach to define clonal relatedness between tumor samples [43] (Data S1) based on the somatic mutations present in the histologically distinct microdissected components from 11 MBCs and 6 UCSs.	('MBC', 'Disease', 'MESH:D001943', (314, 317))	('tumor', 'Disease', (181, 186))	('UCS', 'Phenotype', 'HP:0002891', (69, 72))	('MBC', 'Disease', 'MESH:D001943', (60, 63))	('mutations', 'Var', (231, 240))	('MBC', 'Disease', (314, 317))	('UCS', 'Phenotype', 'HP:0002891', (325, 328))	('MBC', 'Disease', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
32230	33021035	In the remaining MBCs and UCSs, the chronology of the development of the different components could not be inferred based on the sequencing results, given that no clonal enrichment in the carcinomatous or sarcomatous component was observed on the basis of mutations affecting protein-coding genes and/or CNAs (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('MBC', 'Disease', 'MESH:D001943', (17, 20))	('mutations', 'Var', (256, 265))	('UCS', 'Phenotype', 'HP:0002891', (26, 29))	('carcinomatous or sarcomatous component', 'Disease', 'MESH:D018316', (188, 226))	('carcinomatous or sarcomatous component', 'Disease', (188, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('CNAs', 'Gene', (304, 308))	('MBC', 'Disease', (17, 20))	('protein-coding', 'Protein', (276, 290))
32233	33021035	These findings are supportive of the role of TP53 mutations as early drivers in the development of these cancers.	('TP53', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('mutations', 'Var', (50, 59))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', '7157', (45, 49))
32236	33021035	Here, we demonstrate that MBCs and UCSs harbor recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, consistent with prior studies [2, 5, 14, 17, 19], and that these tumors display overall similar patterns of gene CNAs.	('PIK3CA', 'Gene', '5290', (93, 99))	('TP53', 'Gene', '7157', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('MBC', 'Disease', 'MESH:D001943', (26, 29))	('UCS', 'Phenotype', 'HP:0002891', (35, 38))	('PTEN', 'Gene', (105, 109))	('TP53', 'Gene', (87, 91))	('genetic alterations', 'Var', (57, 76))	('PTEN', 'Gene', '5728', (105, 109))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('MBC', 'Disease', (26, 29))	('PIK3CA', 'Gene', (93, 99))
32237	33021035	Despite differences in the repertoire of somatic mutations observed between MBCs and UCSs, our analyses revealed an enrichment of genetic alterations affecting genes of the Wnt and Notch signaling pathways, which play pivotal roles in EMT [53, 54].	('Notch', 'Gene', (181, 186))	('affecting', 'Reg', (150, 159))	('MBC', 'Disease', (76, 79))	('genetic alterations', 'Var', (130, 149))	('Notch', 'Gene', '4851;4853;4854;4855', (181, 186))	('UCS', 'Phenotype', 'HP:0002891', (85, 88))	('MBC', 'Disease', 'MESH:D001943', (76, 79))
32238	33021035	In fact, several of the genetic alterations that were distinct between MBCs and UCSs affected the same pathway (e.g., such as FAT1 and FBXW7, which were restricted to MBCs and UCSs, respectively, but signal through the Wnt pathway).	('MBC', 'Disease', 'MESH:D001943', (71, 74))	('genetic alterations', 'Var', (24, 43))	('UCS', 'Phenotype', 'HP:0002891', (176, 179))	('Wnt pathway', 'Pathway', (219, 230))	('affected', 'Reg', (85, 93))	('alterations', 'Var', (32, 43))	('MBC', 'Disease', 'MESH:D001943', (167, 170))	('FBXW7', 'Gene', '55294', (135, 140))	('FAT1', 'Gene', '2195', (126, 130))	('MBC', 'Disease', (71, 74))	('UCS', 'Phenotype', 'HP:0002891', (80, 83))	('FAT1', 'Gene', (126, 130))	('MBC', 'Disease', (167, 170))	('FBXW7', 'Gene', (135, 140))	('signal', 'Reg', (200, 206))
32241	33021035	Despite the molecular similarities, in particular the high frequency of TP53 mutations and high levels of chromosomal instability found between MBCs and UCSs, important differences were observed.	('MBC', 'Disease', (144, 147))	('TP53', 'Gene', '7157', (72, 76))	('chromosomal instability', 'Phenotype', 'HP:0040012', (106, 129))	('TP53', 'Gene', (72, 76))	('UCS', 'Phenotype', 'HP:0002891', (153, 156))	('mutations', 'Var', (77, 86))	('MBC', 'Disease', 'MESH:D001943', (144, 147))	('chromosomal instability', 'MPA', (106, 129))
32245	33021035	We further demonstrate that, in agreement with previous observations by our group [38] and others [51], biallelic alterations affecting canonical homologous recombination DNA repair-related genes were the likely cause of HRD in the majority of MBCs and UCSs analyzed here.	('biallelic alterations', 'Var', (104, 125))	('MBC', 'Disease', (244, 247))	('HRD', 'Disease', (221, 224))	('cause', 'Reg', (212, 217))	('UCS', 'Phenotype', 'HP:0002891', (253, 256))	('MBC', 'Disease', 'MESH:D001943', (244, 247))	('HRD', 'Disease', 'None', (221, 224))
32251	33021035	While genomic features of HRD were rare in UCSs, we did identify a subset harboring HER2 amplification.	('HER2', 'Gene', (84, 88))	('HRD', 'Disease', (26, 29))	('HER2', 'Gene', '2064', (84, 88))	('UCS', 'Phenotype', 'HP:0002891', (43, 46))	('amplification', 'Var', (89, 102))	('HRD', 'Disease', 'None', (26, 29))
32254	33021035	Likewise, therapeutic strategies based on synthetic lethality to target tumors with FBXW7 mutations have emerged [66, 67]; given the relatively high frequency of FBXW7 mutations in UCSs (30%), further studies testing this potential treatment strategy might be entertained.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FBXW7', 'Gene', (84, 89))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('FBXW7', 'Gene', '55294', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('FBXW7', 'Gene', (162, 167))	('FBXW7', 'Gene', '55294', (84, 89))	('mutations', 'Var', (168, 177))	('UCS', 'Phenotype', 'HP:0002891', (181, 184))
32258	33021035	[69] reported on the presence of identical frameshift WISP3 somatic mutations in five out of 27 MBCs; however, none of the MBCs studied here had mutations affecting WISP3 even after inspection and manual curation of the sequencing results.	('MBC', 'Disease', (96, 99))	('WISP3', 'Gene', (165, 170))	('MBC', 'Disease', 'MESH:D001943', (123, 126))	('frameshift', 'Var', (43, 53))	('WISP3', 'Gene', '8838', (54, 59))	('MBC', 'Disease', 'MESH:D001943', (96, 99))	('WISP3', 'Gene', '8838', (165, 170))	('MBC', 'Disease', (123, 126))	('WISP3', 'Gene', (54, 59))
32261	33021035	Further studies are required to confirm the frequency of TERT promoter mutations in this rare type of breast cancer.	('breast cancer', 'Disease', (102, 115))	('TERT', 'Gene', (57, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('TERT', 'Gene', '7015', (57, 61))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
32265	33021035	It is possible that the different histologic components of these tumors evolved from a common histologic precursor and acquired either genetic alterations affecting genes other than protein-coding genes or epigenetic alterations that resulted in the acquisition of mesenchymal features.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('genetic alterations', 'Var', (135, 154))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('resulted in', 'Reg', (234, 245))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('epigenetic alterations', 'Var', (206, 228))	('mesenchymal features', 'CPA', (265, 285))	('acquisition', 'Reg', (250, 261))
32272	33021035	Genomic features of HRD were found to be significantly more prevalent in MBCs than in UCSs, whereas known therapeutic targets, such as HER2 gene amplification and FBXW7 mutations, were found to be significantly more frequent in UCSs than MBCs.	('HER2', 'Gene', (135, 139))	('mutations', 'Var', (169, 178))	('HRD', 'Disease', 'None', (20, 23))	('UCS', 'Phenotype', 'HP:0002891', (86, 89))	('HER2', 'Gene', '2064', (135, 139))	('UCS', 'Phenotype', 'HP:0002891', (228, 231))	('MBC', 'Disease', (73, 76))	('MBC', 'Disease', (238, 241))	('FBXW7', 'Gene', '55294', (163, 168))	('prevalent', 'Reg', (60, 69))	('MBC', 'Disease', 'MESH:D001943', (73, 76))	('MBC', 'Disease', 'MESH:D001943', (238, 241))	('HRD', 'Disease', (20, 23))	('FBXW7', 'Gene', (163, 168))
32273	33021035	Hence, despite the histologic similarities and similar pathways being affected by somatic genetic alterations, MBCs and UCSs are more than mere phenocopies of the same tumors in different anatomical sites.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('MBC', 'Disease', (111, 114))	('UCS', 'Phenotype', 'HP:0002891', (120, 123))	('alterations', 'Var', (98, 109))	('MBC', 'Disease', 'MESH:D001943', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
32340	33665168	Obviously, metastasis to PLN, PALN, or PLN plus PALN caused significantly decreased DFS, OS and cancer-specific OS in either the univariate or multivariate analysis (p values <0.05,  Tables 2  and  3 ).	('PALN', 'Var', (30, 34))	('DFS', 'Disease', (84, 87))	('PLN', 'Gene', '5350', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('metastasis', 'Var', (11, 21))	('PLN', 'Gene', (25, 28))	('PLN', 'Gene', '5350', (25, 28))	('decreased', 'NegReg', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('PLN', 'Gene', (39, 42))
32341	33665168	In the multivariate analysis, if lymphadenectomy was performed, metastasis to lymph nodes resulted in a similar recurrent risk compared with patients without metastasis to lymph nodes (p values <0.05), but resulted in a significantly higher risk of mortality (p values >0.05,  Table 3 ).	('mortality', 'Disease', (249, 258))	('mortality', 'Disease', 'MESH:D003643', (249, 258))	('metastasis', 'Var', (64, 74))	('patients', 'Species', '9606', (141, 149))
32351	33665168	A Cochrane review from 2017 found no evidence that lymphadenectomy for endometrial cancer decreased the risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease.	('death', 'Disease', 'MESH:D003643', (112, 117))	('lymphadenectomy', 'Var', (51, 66))	('death', 'Disease', (112, 117))	('stage I disease', 'Disease', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('disease recurrence', 'CPA', (121, 139))	('decreased', 'NegReg', (90, 99))	('endometrial cancer', 'Disease', (71, 89))	('stage I disease', 'Disease', 'MESH:D058625', (196, 211))	('endometrial cancer', 'Disease', 'MESH:D016889', (71, 89))	('endometrial cancer', 'Phenotype', 'HP:0012114', (71, 89))	('women', 'Species', '9606', (176, 181))
32352	33665168	Evidence regarding serious adverse events suggests that women who undergo lymphadenectomy are more likely to experience surgery-related systemic morbidity or lymphedema and/or lymphocyst formation.	('lymphocyst formation', 'CPA', (176, 196))	('surgery-related systemic', 'Disease', (120, 144))	('lymphedema', 'Phenotype', 'HP:0001004', (158, 168))	('lymphadenectomy', 'Var', (74, 89))	('lymphedema', 'Disease', (158, 168))	('women', 'Species', '9606', (56, 61))	('lymphedema', 'Disease', 'MESH:D008209', (158, 168))
32397	33665207	The results showed that ZIC2 also acted as a risk prognostic factor in bladder, breast and lung cancer Table 1.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('bladder', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('ZIC2', 'Var', (24, 28))	('breast and lung cancer', 'Disease', 'MESH:D001943', (80, 102))	('lung cancer', 'Disease', (91, 102))
32404	33665207	The results revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype in a variety of tumors including complement and coagulation cascades, P53 signaling pathway, basal cell carcinoma, PPAR signaling pathway, tight junction, etc (Figure 10).	('carcinoma', 'Disease', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tight junction', 'Disease', (279, 293))	('P53', 'Gene', (210, 213))	('PPAR', 'Gene', '5465', (255, 259))	('carcinoma', 'Disease', 'MESH:D009369', (244, 253))	('ZIC2', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('P53', 'Gene', '7157', (210, 213))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (233, 253))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (233, 253))	('basal cell carcinoma', 'Disease', (233, 253))	('high', 'Var', (107, 111))	('PPAR', 'Gene', (255, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('enriched', 'Reg', (90, 98))	('low', 'NegReg', (115, 118))
32483	30853364	Likewise, the risk for occult endometrial carcinoma was 0.18% (95% CI: 0.12-0.24%) in women undergoing laparoscopic supracervical hysterectomy versus 1.35% (95% CI: 1.25-1.45%) in women who underwent a total abdominal hysterectomy.	('women', 'Species', '9606', (180, 185))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (30, 51))	('laparoscopic', 'Var', (103, 115))	('occult endometrial carcinoma', 'Disease', 'MESH:D016889', (23, 51))	('occult endometrial carcinoma', 'Disease', (23, 51))	('women', 'Species', '9606', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
32504	30853364	Meta-analysis performed by the Agency for Healthcare Research and Quality (AHRQ) estimated that 0 021% (95% credible interval: 0-0.094%) of women in prospective studies and 0.085% (95% credible interval: 0.047-0.127%) in retrospective studies had unexpected leiomyosarcoma.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (258, 272))	('0.085', 'Var', (173, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('leiomyosarcoma', 'Disease', (258, 272))	('women', 'Species', '9606', (140, 145))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (258, 272))
32637	31764852	Besides, with the accumulation of cases, immunohistochemical indexes such as CD10, ER, PR, and Ki-67 may have reference significance in the prediction of prognosis and the selection of individualized treatment schemes.	('PR', 'Gene', '5241', (87, 89))	('CD10', 'Gene', (77, 81))	('Ki-67', 'Var', (95, 100))	('ER', 'Gene', '2099', (83, 85))
32644	31569439	Gynaecological cancers are variously interested by PTEN deregulation and many perspective in terms of additional prognostic information and new therapeutic approaches can be explored.	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('deregulation', 'Var', (56, 68))	('cancers', 'Disease', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
32656	31569439	In this review, we illustrate the incidence, the role in tumorigenesis and the clinical implications of PTEN deregulation in ovarian cancer (OC), endometrial cancer (EC), cervical cancer (CC), vulvar cancer (VC) and uterine cancer (UC), including mainly uterine carcinosarcoma/uterine malignant mixed mullerian tumour and leiomyosarcoma.	('ovarian cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (254, 276))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('deregulation', 'Var', (109, 121))	('vulvar cancer', 'Disease', (193, 206))	('cancer', 'Disease', (224, 230))	('uterine cancer', 'Phenotype', 'HP:0010784', (216, 230))	('leiomyosarcoma', 'Disease', (322, 336))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (158, 164))	('VC', 'Disease', 'MESH:D014846', (208, 210))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('PTEN', 'Gene', (104, 108))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (311, 317))	('tumour', 'Disease', 'MESH:D009369', (311, 317))	('vulvar cancer', 'Disease', 'MESH:D014846', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', (311, 317))	('EC', 'Disease', 'MESH:D016889', (166, 168))	('cancer', 'Disease', (133, 139))	('ovarian cancer', 'Disease', 'MESH:D010051', (125, 139))	('OC', 'Disease', 'MESH:D010051', (141, 143))	('vulvar cancer', 'Phenotype', 'HP:0030416', (193, 206))	('carcinosarcoma', 'Disease', (262, 276))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('endometrial cancer', 'Phenotype', 'HP:0012114', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinosarcoma', 'Disease', 'MESH:D002296', (262, 276))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (322, 336))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('endometrial cancer', 'Disease', (146, 164))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (322, 336))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('endometrial cancer', 'Disease', 'MESH:D016889', (146, 164))	('cancer', 'Disease', (200, 206))
32657	31569439	Considering the incidence of PTEN alterations (including all somatic chromosomal abnormalities and gene mutations) across human cancers, the highest percentages are found in endometrium, central nervous system (glioblastoma), skin, and prostate cancers according to the Catalogue of Somatic Mutations in Cancer (COSMIC) and The Cancer Genome Atlas Network (TGCA) datasets.	('human', 'Species', '9606', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('PTEN', 'Gene', (29, 33))	('prostate cancers', 'Phenotype', 'HP:0012125', (236, 252))	('prostate cancers', 'Disease', (236, 252))	('alterations', 'Var', (34, 45))	('glioblastoma', 'Disease', (211, 223))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (211, 223))	('cancers', 'Disease', (128, 135))	('central nervous system', 'Disease', (187, 209))	('Cancer', 'Phenotype', 'HP:0002664', (304, 310))	('Cancer', 'Phenotype', 'HP:0002664', (328, 334))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('endometrium', 'Disease', (174, 185))	('Cancer', 'Disease', (304, 310))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('Cancer', 'Disease', (328, 334))	('cancers', 'Disease', (245, 252))	('skin', 'Disease', (226, 230))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('prostate cancers', 'Disease', 'MESH:D011471', (236, 252))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('Cancer', 'Disease', 'MESH:D009369', (304, 310))	('somatic chromosomal abnormalities', 'Disease', 'MESH:D013001', (61, 94))	('Cancer', 'Disease', 'MESH:D009369', (328, 334))	('somatic chromosomal abnormalities', 'Disease', (61, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (211, 223))
32660	31569439	The incidence of somatic PTEN alteration in gynaecological cancers is illustrated in Figure 1 according to COSMIC and TGCA datasets, respectively.	('alteration', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Disease', (59, 66))
32663	31569439	PTEN alterations are much less present in the other gynaecological malignancies (OC, CC; VC and UC) but when they occur, seem to play a not negligible role in the development and progression of cancer.	('OC', 'Disease', 'MESH:D010051', (81, 83))	('cancer', 'Disease', (194, 200))	('malignancies', 'Disease', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('alterations', 'Var', (5, 16))	('malignancies', 'Disease', 'MESH:D009369', (67, 79))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('PTEN', 'Gene', (0, 4))	('VC', 'Disease', 'MESH:D014846', (89, 91))
32664	31569439	As previously mentioned, PTEN alterations in OC are around 6%, mostly due to gene deletion as illustrated in Figure 2.	('gene deletion', 'Var', (77, 90))	('OC', 'Disease', 'MESH:D010051', (45, 47))	('alterations', 'Reg', (30, 41))	('PTEN', 'Gene', (25, 29))	('due', 'Reg', (70, 73))
32665	31569439	Kurman and Shih's "dualistic" model of epithelial OC pathogenesis divides OC into two main categories, type I (low-grade, relatively indolent and genetically stable tumours that typically arise from recognizable precursor lesions, such as endometriosis (or so-called borderline) and type II (high-grade serous carcinomas, virtually all of which harbour mutant TP53 alleles).	('mutant', 'Var', (353, 359))	('endometriosis', 'Disease', 'MESH:D004715', (239, 252))	('TP53', 'Gene', (360, 364))	('OC', 'Disease', 'MESH:D010051', (74, 76))	('endometriosis', 'Phenotype', 'HP:0030127', (239, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('serous carcinomas', 'Disease', 'MESH:D018284', (303, 320))	('carcinomas', 'Phenotype', 'HP:0030731', (310, 320))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('serous carcinomas', 'Disease', (303, 320))	('tumour', 'Disease', (165, 171))	('OC', 'Disease', 'MESH:D010051', (50, 52))	('TP53', 'Gene', '7157', (360, 364))	('endometriosis', 'Disease', (239, 252))
32666	31569439	Type I OCs account for 30% of all epithelial OC, frequently harbour somatic mutations such as PTEN and include most endometrioid, clear cell, and mucinous carcinomas and low-grade serous carcinomas.	('carcinoma', 'Disease', 'MESH:D002277', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('mutations', 'Var', (76, 85))	('PTEN', 'Gene', (94, 98))	('clear cell', 'Disease', (130, 140))	('harbour', 'Reg', (60, 67))	('carcinoma', 'Disease', 'MESH:D002277', (187, 196))	('OC', 'Disease', 'MESH:D010051', (7, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('serous carcinomas', 'Disease', 'MESH:D018284', (180, 197))	('carcinoma', 'Disease', (155, 164))	('endometrioid', 'Disease', (116, 128))	('OC', 'Disease', 'MESH:D010051', (45, 47))	('serous carcinomas', 'Disease', (180, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('carcinoma', 'Disease', (187, 196))
32670	31569439	An analysis focused on 22 Japanese endometriosis-related ovarian carcinomas (13 endometrioid, and nine clear cell) revealed a 68.4% PTEN mutation rate.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('mutation', 'Var', (137, 145))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (57, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('endometriosis', 'Phenotype', 'HP:0030127', (35, 48))	('endometriosis', 'Disease', 'MESH:D004715', (35, 48))	('endometriosis', 'Disease', (35, 48))	('ovarian carcinomas', 'Disease', (57, 75))	('PTEN mutation', 'Var', (132, 145))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (57, 75))
32672	31569439	In contrast, type II OCs account for 70% of all epithelial OC and include mainly high-grade serous carcinomas, virtually all of which harbour mutant TP53 alleles.	('serous carcinomas', 'Disease', (92, 109))	('TP53', 'Gene', '7157', (149, 153))	('OC', 'Disease', 'MESH:D010051', (21, 23))	('mutant', 'Var', (142, 148))	('OC', 'Disease', 'MESH:D010051', (59, 61))	('TP53', 'Gene', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('serous carcinomas', 'Disease', 'MESH:D018284', (92, 109))
32676	31569439	It is well known that Type I tumours are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin.	('BRAF', 'Gene', '673', (142, 146))	('beta-catenin', 'Gene', (158, 170))	('PTEN', 'Gene', (148, 152))	('KRAS', 'Gene', '3845', (136, 140))	('beta-catenin', 'Gene', '1499', (158, 170))	('mutations', 'Var', (85, 94))	('KRAS', 'Gene', (136, 140))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))	('BRAF', 'Gene', (142, 146))	('Type I tumours', 'Disease', (22, 36))	('Type I tumours', 'Disease', 'MESH:D009369', (22, 36))
32678	31569439	PTEN mutations can co-exist and lead to PI3K/Akt/mTOR pathway aberrantly activation; the combination of PTEN mutations with KRAS ones in the ovary has been shown to induce invasive and widely metastatic endometrioid OC.	('mTOR', 'Gene', (49, 53))	('Akt', 'Gene', (45, 48))	('mTOR', 'Gene', '2475', (49, 53))	('KRAS', 'Gene', (124, 128))	('KRAS', 'Gene', '3845', (124, 128))	('induce', 'PosReg', (165, 171))	('OC', 'Disease', 'MESH:D010051', (216, 218))	('combination', 'Interaction', (89, 100))	('Akt', 'Gene', '207', (45, 48))	('mutations', 'Var', (109, 118))	('PTEN', 'Gene', (104, 108))
32679	31569439	Several published pre-clinical models suggest that the loss of PTEN in the fallopian tube is one of the multiple genetic modification that induce tumorigenesis.	('loss', 'Var', (55, 59))	('fallopian tube', 'Disease', (75, 89))	('fallopian tube', 'Disease', 'MESH:D005184', (75, 89))	('induce', 'PosReg', (139, 145))	('tumorigenesis', 'CPA', (146, 159))	('PTEN', 'Gene', (63, 67))
32680	31569439	It has been then demonstrated that the conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase is sufficient to drive endometrioid and serous borderline OC in mice models.	('drive', 'PosReg', (129, 134))	('endometrioid', 'Disease', (135, 147))	('PAX8', 'Gene', '18510', (91, 95))	('PAX8', 'Gene', (91, 95))	('PTEN', 'Gene', (74, 78))	('mice', 'Species', '10090', (176, 180))	('knockout', 'Var', (62, 70))	('OC', 'Disease', 'MESH:D010051', (170, 172))
32683	31569439	A key step in this process are mutations in the p53 gene leading to protein stabilization in the fallopian tube.	('p53', 'Gene', (48, 51))	('mutations', 'Var', (31, 40))	('protein stabilization', 'MPA', (68, 89))	('p53', 'Gene', '7157', (48, 51))	('fallopian tube', 'Disease', (97, 111))	('fallopian tube', 'Disease', 'MESH:D005184', (97, 111))
32686	31569439	According to the authors, this data suggested that alterations in the expression of PTEN, as well as PAX2, could be involved in the early stages of serous carcinogenesis, similar to endometrioid carcinomas of the uterus.	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('alterations', 'Var', (51, 62))	('endometrioid carcinomas', 'Disease', (182, 205))	('serous carcinogenesis', 'Disease', 'MESH:D063646', (148, 169))	('endometrioid carcinomas', 'Disease', 'MESH:D018269', (182, 205))	('involved', 'Reg', (116, 124))	('carcinomas of the uterus', 'Phenotype', 'HP:0010784', (195, 219))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (182, 205))	('PAX2', 'Gene', (101, 105))	('PTEN', 'Gene', (84, 88))	('expression', 'MPA', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('PAX2', 'Gene', '5076', (101, 105))	('serous carcinogenesis', 'Disease', (148, 169))
32688	31569439	Moreover, it was recently shown that the loss of PTEN allows the fallopian tube epithelia to form multicellular tumour spheroids, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary maybe contributing to seeding of the ovary in high grade serous OC patients.	('loss', 'Var', (41, 45))	('tumour spheroids', 'Disease', 'MESH:C535466', (112, 128))	('OC', 'Disease', 'MESH:D010051', (336, 338))	('contributing', 'Reg', (278, 290))	('PTEN', 'Gene', (49, 53))	('patients', 'Species', '9606', (339, 347))	('tumour spheroids', 'Disease', (112, 128))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('fallopian tube epithelia', 'Disease', 'MESH:D005184', (65, 89))	('fallopian tube epithelia', 'Disease', (65, 89))
32689	31569439	In fact, PTEN deletion has been associated with the acceleration of cell proliferation and cellular transformation in vitro and in vivo and the stimulation of MUC1 expression that is known to be involved in tumour cell migration and metastasis.	('tumour', 'Disease', (207, 213))	('MUC1', 'Gene', (159, 163))	('MUC1', 'Gene', '4582', (159, 163))	('stimulation', 'PosReg', (144, 155))	('acceleration', 'PosReg', (52, 64))	('expression', 'MPA', (164, 174))	('cellular transformation', 'CPA', (91, 114))	('cell proliferation', 'CPA', (68, 86))	('PTEN', 'Gene', (9, 13))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('deletion', 'Var', (14, 22))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
32690	31569439	Although pathogenic variants in PTEN do not appear to confer a significantly increased risk for OC, in patients affected by PTEN hamartoma tumour syndromes, it can be discussed the potential risks and benefits of risk reducing bilateral salpingo-oopherectomy in case of who a family history of OC.	('variants', 'Var', (20, 28))	('OC', 'Disease', 'MESH:D010051', (294, 296))	('PTEN', 'Gene', (32, 36))	('OC', 'Disease', 'MESH:D010051', (96, 98))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('hamartoma', 'Phenotype', 'HP:0010566', (129, 138))	('PTEN hamartoma tumour syndromes', 'Disease', (124, 155))	('patients', 'Species', '9606', (103, 111))	('PTEN hamartoma tumour syndromes', 'Disease', 'MESH:D006223', (124, 155))
32692	31569439	Its inactivation in high grade serous OC has been shown to contribute to acquired chemotherapy resistance.	('contribute', 'Reg', (59, 69))	('inactivation', 'Var', (4, 16))	('OC', 'Disease', 'MESH:D010051', (38, 40))	('acquired chemotherapy resistance', 'CPA', (73, 105))
32693	31569439	PTEN mutation is an inclusion criterion in nine clinical trials for OC (NCT01458067, NCT01226316 and NCT02660034 phase 1; NCT02583542 and NCT02797964 phase 1-2, NCT01283035, NCT03742895 and NCT03759600 phase 2; NCT02392676 phase 3), an inclusion criteria in a subprotocol of a clinical trial (NCT02465060, phase 2) and part of the rationale in another one (NCT01989546 phase 1-2).	('NCT01226316', 'Var', (85, 96))	('OC', 'Disease', 'MESH:D010051', (68, 70))	('NCT02465060', 'Var', (293, 304))	('NCT02660034', 'Var', (101, 112))	('NCT01458067', 'Var', (72, 83))	('NCT02583542', 'Var', (122, 133))	('PTEN', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('NCT01458067', 'Chemical', 'MESH:C079985', (72, 83))
32694	31569439	The reported prevalence of deleterious somatic PIK3CA and/or PTEN variants in germline mutation-negative OC individuals (13%), together with encouraging data from Phase 1 trials on gynaecological patients receiving PI3K/AKT/mTOR inhibitors, suggest that this pathway will be more investigated in the future.	('AKT', 'Gene', (220, 223))	('mTOR', 'Gene', (224, 228))	('PIK3CA', 'Gene', (47, 53))	('OC', 'Disease', 'MESH:D010051', (105, 107))	('PIK3CA', 'Gene', '5290', (47, 53))	('variants', 'Var', (66, 74))	('patients', 'Species', '9606', (196, 204))	('PTEN', 'Gene', (61, 65))	('AKT', 'Gene', '207', (220, 223))	('mTOR', 'Gene', '2475', (224, 228))
32695	31569439	As previously mentioned, PTEN alterations in EC are around 45%, mostly due to missense and nonsense substitutions as illustrated in Figure 3.	('due', 'Reg', (71, 74))	('EC', 'Disease', 'MESH:D016889', (45, 47))	('alterations', 'Reg', (30, 41))	('missense', 'Var', (78, 86))	('PTEN', 'Gene', (25, 29))	('nonsense substitutions', 'Var', (91, 113))
32697	31569439	Type I tumours are preferentially associated with genetic alterations in PTEN, KRAS, CTNNB1 and PIK3CA and MLH1 promoter hypermethylation, whereas type II, especially serous histotypes, prototypically harbour TP53 mutations.	('associated', 'Reg', (34, 44))	('PTEN', 'Gene', (73, 77))	('TP53', 'Gene', (209, 213))	('CTNNB1', 'Gene', (85, 91))	('Type I tumours', 'Disease', 'MESH:D009369', (0, 14))	('KRAS', 'Gene', '3845', (79, 83))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('genetic alterations', 'Var', (50, 69))	('CTNNB1', 'Gene', '1499', (85, 91))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('MLH1', 'Gene', '4292', (107, 111))	('MLH1', 'Gene', (107, 111))	('TP53', 'Gene', '7157', (209, 213))	('KRAS', 'Gene', (79, 83))	('Type I tumours', 'Disease', (0, 14))
32698	31569439	Among the four molecular categories of EC identified by the Cancer Genome Atlas Research Network ('ultramutated', 'hyper-mutated' and 'copy number low', which are predominantly endometrioid, and 'copy number high', most of which are serous), PTEN mutations were found in 94%, 88%, 77% and 15%, respectively.	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('PTEN', 'Gene', (242, 246))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('EC', 'Disease', 'MESH:D016889', (39, 41))	('mutations', 'Var', (247, 256))	('found', 'Reg', (262, 267))
32699	31569439	Several prior reports suggest that PTEN mutations occur early in the neoplastic process of Type I EC tumours.	('neoplastic process', 'Phenotype', 'HP:0002664', (69, 87))	('tumour', 'Disease', (101, 107))	('PTEN', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('EC', 'Disease', 'MESH:D016889', (98, 100))	('occur', 'Reg', (50, 55))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
32700	31569439	In animal models PTEN knockout mice develop endometrial cancer precursors and cancer and women with Cowden's disease, who carry germline PTEN mutations, are at elevated risk of EC.	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('endometrial cancer', 'Disease', 'MESH:D016889', (44, 62))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	("Cowden's disease", 'Disease', 'MESH:D006223', (100, 116))	('women', 'Species', '9606', (89, 94))	('mice', 'Species', '10090', (31, 35))	('EC', 'Disease', 'MESH:D016889', (177, 179))	('PTEN', 'Gene', (137, 141))	("Cowden's disease", 'Disease', (100, 116))	('endometrial cancer', 'Disease', (44, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('endometrial cancer', 'Phenotype', 'HP:0012114', (44, 62))
32708	31569439	PTEN is an inclusion criterion in 5 clinical trials for EC (NCT01226316 and NCT01458067 phase 1, NCT03675893 and NCT02549989 phase 2, NCT02189174 phase 2, closed) and an inclusion criteria in subprotocols in two clinical trials (NCT02583542 phase 1/2, NCT02465060 phase 2).	('NCT01226316', 'Var', (60, 71))	('EC', 'Disease', 'MESH:D016889', (56, 58))	('NCT02549989', 'Var', (113, 124))	('PTEN', 'Disease', (0, 4))	('NCT01458067', 'Chemical', 'MESH:C079985', (76, 87))	('NCT01458067', 'Var', (76, 87))
32709	31569439	Moreover, in five other clinical trials (NCT03016338, NCT02990728, NCT02228681 and NCT03660826 phase 2, NCT02684318 phase1/2,) a PTEN analysis is planned as part of secondary objectives.	('NCT02228681', 'Var', (67, 78))	('NCT03660826', 'Var', (83, 94))	('NCT03016338', 'Var', (41, 52))	('NCT02990728', 'Var', (54, 65))	('NCT03016338', 'Chemical', 'MESH:C079985', (41, 52))
32713	31569439	In 285 Chinese CC patients (179 squamous CC, 62 with adeno CC, 34 with adenosquamous CC, and 10 with other rare histopathological types) PTEN mutation rate analysed by Sanger sequencing was 2.8%.	('mutation', 'Var', (142, 150))	('PTEN', 'Gene', (137, 141))	('patients', 'Species', '9606', (18, 26))
32714	31569439	Adenocarcinoma and endocervical samples seems to show a higher rate of PTEN mutations compared to squamous histotype in both datasets.	('Adenocarcinoma', 'Disease', (0, 14))	('mutations', 'Var', (76, 85))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('PTEN', 'Gene', (71, 75))
32723	31569439	In a genomic characterization of 299 cases of CC, the authors found that together with TP53, ARID5B, ARID1A, and CTNNB1, PTEN was significantly differentially mutated between HPV+ and HPV- tumors (<15% vs. 33.33%, respectively).	('PTEN', 'Gene', (121, 125))	('mutated', 'Var', (159, 166))	('CTNNB1', 'Gene', (113, 119))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('HPV', 'Species', '10566', (184, 187))	('CTNNB1', 'Gene', '1499', (113, 119))	('HPV', 'Species', '10566', (175, 178))	('HPV+', 'Disease', (175, 179))
32724	31569439	This may be related to the fact that HPV+ patients can slowly develop CC by accumulating somatic mutations in cancer driver genes while HPV- patients tend to accumulate higher levels of those mutations, more quickly.	('mutations', 'Var', (97, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HPV', 'Species', '10566', (37, 40))	('patients', 'Species', '9606', (42, 50))	('HPV', 'Species', '10566', (136, 139))	('patients', 'Species', '9606', (141, 149))
32726	31569439	PTEN is an inclusion criterion in a phase 1 clinical trials including CC patients (NCT01226316, active not recruiting) and in a substudy of a phase 2 clinical trial (NCT02465060).	('PTEN', 'Gene', (0, 4))	('patients', 'Species', '9606', (73, 81))	('NCT01226316', 'Var', (83, 94))
32728	31569439	Therefore, further evaluation of a therapy regimen targeting downstream effectors such as PI3K or mTOR is warranted considering also it has already provided meaningful clinical benefits.	('mTOR', 'Gene', (98, 102))	('PI3K', 'Var', (90, 94))	('mTOR', 'Gene', '2475', (98, 102))
32729	31569439	Recent data suggest that CC cell signalling through the PI3K/AKT pathway is distinct in obese (BMI >= 30) versus non-obese patients; in particular obese (BMI >= 30) CC patients with a PIK3CA and PTEN mutation fail to express high levels of phosphorylated AKT as expected.	('obese', 'Disease', 'MESH:D009765', (88, 93))	('AKT', 'Gene', (255, 258))	('PIK3CA', 'Gene', '5290', (184, 190))	('phosphorylated', 'MPA', (240, 254))	('AKT', 'Gene', '207', (61, 64))	('obese', 'Disease', (88, 93))	('obese', 'Disease', 'MESH:D009765', (147, 152))	('obese', 'Disease', 'MESH:D009765', (117, 122))	('patients', 'Species', '9606', (123, 131))	('AKT', 'Gene', '207', (255, 258))	('patients', 'Species', '9606', (168, 176))	('PIK3CA', 'Gene', (184, 190))	('AKT', 'Gene', (61, 64))	('PTEN', 'Gene', (195, 199))	('obese', 'Disease', (117, 122))	('obese', 'Disease', (147, 152))	('mutation', 'Var', (200, 208))
32730	31569439	As previously mentioned, PTEN alterations in VC are around 7%, mostly due to missense substitution as illustrated in Figure 5.	('missense substitution', 'Var', (77, 98))	('VC', 'Disease', 'MESH:D014846', (45, 47))	('due', 'Reg', (70, 73))
32732	31569439	Recently, two groups published on molecular characteristics of VC according to HPV status, revealing a 9% (2/22) and 2% (1/52) rate, respectively, of PTEN mutations in HPV related tumours and 0% in HPV-tumours.	('HPV', 'Species', '10566', (168, 171))	('mutations', 'Var', (155, 164))	('HPV', 'Species', '10566', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('HPV', 'Disease', (168, 171))	('VC', 'Disease', 'MESH:D014846', (63, 65))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('HPV', 'Species', '10566', (198, 201))	('tumour', 'Disease', (202, 208))	('PTEN', 'Gene', (150, 154))	('tumour', 'Disease', (180, 186))
32740	31569439	It remains unclear, however, whether this pathway significantly contributes to VC pathogenesis but it seems that PIK3CA mutations require a secondary defect in a co-regulator of PI3K activity, such as PTEN, to promote transformation.	('PIK3CA', 'Gene', (113, 119))	('PIK3CA', 'Gene', '5290', (113, 119))	('VC', 'Disease', 'MESH:D014846', (79, 81))	('promote', 'PosReg', (210, 217))	('mutations', 'Var', (120, 129))	('defect', 'NegReg', (150, 156))
32741	31569439	No studies are currently on going regarding PTEN mutations in VC.	('VC', 'Disease', 'MESH:D014846', (62, 64))	('PTEN', 'Gene', (44, 48))	('mutations', 'Var', (49, 58))
32744	31569439	Finally, an integrated genome analysis was performed on 84 uterine leiomyosarcoma samples (60 new samples and 24 from TGCA) by the same group, revealing a significantly higher rate of PTEN alterations (75% of samples), mainly due to gene deletions (71%) resulting in downregulation in 58% of cases.	('alterations', 'Reg', (189, 200))	('higher', 'PosReg', (169, 175))	('downregulation', 'NegReg', (267, 281))	('leiomyosarcoma', 'Disease', (67, 81))	('PTEN', 'Gene', (184, 188))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (67, 81))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (67, 81))	('84 uterine leiomyosarcoma', 'Phenotype', 'HP:0000131', (56, 81))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('gene deletions', 'Var', (233, 247))
32747	31569439	A previous study suggested that the PTEN mutation might be a useful biomarker of cell proliferation in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('PTEN', 'Gene', (36, 40))	('sarcomas', 'Disease', (103, 111))	('mutation', 'Var', (41, 49))
32748	31569439	PTEN is an inclusion criterion in two phase 2 clinical trials regarding leiomyosarcoma (NCT02987959, NCT03718091).	('leiomyosarcoma', 'Disease', 'MESH:D007890', (72, 86))	('NCT03718091', 'Var', (101, 112))	('leiomyosarcoma', 'Disease', (72, 86))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (72, 86))	('NCT03718091', 'Chemical', 'MESH:C079985', (101, 112))
32754	31569439	It has been suggested that PTEN can increase Treg stability and that the loss of PTEN can lead to spontaneous inflammatory disorder.	('Treg stability', 'CPA', (45, 59))	('inflammatory disorder', 'Disease', (110, 131))	('loss', 'Var', (73, 77))	('increase', 'PosReg', (36, 44))	('inflammatory disorder', 'Disease', 'MESH:D009220', (110, 131))	('PTEN', 'Gene', (81, 85))	('lead to', 'Reg', (90, 97))
32756	31569439	More recently, somatic PTEN mutations have been associated with resistance to immune checkpoint inhibitors by altering immunosuppressive environments in patients with uterine leiomyosarcoma, melanoma and glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (204, 217))	('patients', 'Species', '9606', (153, 161))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('associated', 'Reg', (48, 58))	('melanoma', 'Disease', (191, 199))	('leiomyosarcoma', 'Disease', (175, 189))	('altering', 'Reg', (110, 118))	('glioblastomas', 'Disease', (204, 217))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (167, 189))	('PTEN', 'Gene', (23, 27))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (175, 189))	('immunosuppressive environments', 'MPA', (119, 149))	('glioblastomas', 'Phenotype', 'HP:0012174', (204, 217))	('mutations', 'Var', (28, 37))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (175, 189))
32757	31569439	Two clinical trials in solid malignancies, including gynaecological cancers, are currently combining immunotherapy and PI3K/Akt inhibitors (NCT03772561, phase 1 on going, NCT03842228 phase 1 on going).	('malignancies', 'Disease', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Akt', 'Gene', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('malignancies', 'Disease', 'MESH:D009369', (29, 41))	('Akt', 'Gene', '207', (124, 127))	('NCT03772561', 'Var', (140, 151))
32759	31569439	Recent evidence suggests that, like BRCA mutant cells, PTEN mutant cells are also characterized by an increase in DNA double-strand breaks and defects in homologous recombination.	('BRCA', 'Gene', (36, 40))	('PTEN', 'Gene', (55, 59))	('BRCA', 'Gene', '672', (36, 40))	('defects', 'NegReg', (143, 150))	('increase', 'PosReg', (102, 110))	('homologous recombination', 'CPA', (154, 178))	('mutant', 'Var', (60, 66))	('DNA double-strand breaks', 'MPA', (114, 138))
32762	31569439	Further studies to clinically characterize patients with PTEN alterations are warranted in order to offer potential approaches for development of personalized therapies.	('PTEN', 'Gene', (57, 61))	('patients', 'Species', '9606', (43, 51))	('alterations', 'Var', (62, 73))
32781	31138229	In the KEYNOTE-158 trial, administration of Pembrolizumab in 98 pretreated, advanced cervical cancer patients resulted in an ORR of 13.3% (95% CI, 7.3-21.6%) and 16.0% (95% CI, 8.8-25.9%) in the whole and PD-L1-positive cohort (n = 81) respectively.	('Pembrolizumab', 'Var', (44, 57))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (44, 57))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
32787	31138229	However, POLE-mutated and MSI EC constitute only a minority of patients with recurrent EC.	('EC', 'Phenotype', 'HP:0012114', (30, 32))	('MSI', 'Disease', (26, 29))	('EC', 'Phenotype', 'HP:0012114', (87, 89))	('MSI', 'Disease', 'None', (26, 29))	('patients', 'Species', '9606', (63, 71))	('POLE-mutated', 'Var', (9, 21))
32939	30131556	For example, one study reported that even after adjusting for smoking status and sex, race was still significantly associated with EGFR mutations.	('associated', 'Reg', (115, 125))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (131, 135))	('mutations', 'Var', (136, 145))
32940	30131556	EGFR mutations were highly prevalent in Asians at 30% vs. 7% in Whites.	('prevalent', 'Reg', (27, 36))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
32945	30131556	Studies have also reported notable genetic variation in cancers by stage.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('genetic variation', 'Var', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
33040	30089500	The gene somatic mutation data include: mutation rates in cancers; variants classification in cancers; comparisons of mutation rates between different cancer phenotypes such as stage and grade; comparisons of gene expression between gene-mutated and gene-wildtype cancers; associations of gene mutations with survival prognosis in cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('associations', 'Interaction', (273, 285))	('cancer', 'Disease', (264, 270))	('cancers', 'Disease', (264, 271))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancers', 'Disease', 'MESH:D009369', (331, 338))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('mutations', 'Var', (294, 303))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))	('cancer', 'Disease', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancers', 'Disease', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('cancers', 'Phenotype', 'HP:0002664', (331, 338))	('cancers', 'Disease', (331, 338))	('cancer', 'Disease', (331, 337))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
33044	30089500	There are ten cancer types that have a TP53 mutation rate greater than 50% in total (Fig.	('cancer', 'Disease', (14, 20))	('mutation', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('TP53', 'Gene', (39, 43))
33045	30089500	Moreover, we can find a summary of the variant classification of TP53 mutations in cancers, e.g., in pancreatic adenocarcinoma (PAAD), 64 and 12% of TP53 mutations being missense and frame-shift insertion, respectively (Fig.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 126))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', '7157', (149, 153))	('missense', 'Var', (170, 178))	('pancreatic adenocarcinoma', 'Disease', (101, 126))	('TP53', 'Gene', (149, 153))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (101, 126))	('mutations', 'Var', (154, 163))	('PAAD', 'Phenotype', 'HP:0006725', (128, 132))	('frame-shift insertion', 'Var', (183, 204))	('cancers', 'Disease', (83, 90))
33046	30089500	Importantly, we can find the associations of TP53 mutations with survival prognosis in cancers.	('cancers', 'Disease', (87, 94))	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('associations', 'Interaction', (29, 41))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('survival prognosis', 'CPA', (65, 83))	('TP53', 'Gene', '7157', (45, 49))
33047	30089500	For example, TP53 mutations are associated with worse survival (overall and disease free survival) prognosis in PAAD (Fig.	('TP53', 'Gene', (13, 17))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('PAAD', 'Disease', (112, 116))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (18, 27))
33049	30089500	In fact, previous studies have shown that PLK1 interacted with TP53, and that p53 dysfunction caused enhanced expression of PLK1 in cancers.	('PLK1', 'Gene', (124, 128))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('PLK1', 'Gene', '5347', (42, 46))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('PLK1', 'Gene', '5347', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('p53', 'Gene', (78, 81))	('enhanced', 'PosReg', (101, 109))	('expression', 'MPA', (110, 120))	('p53', 'Gene', '7157', (78, 81))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('PLK1', 'Gene', (42, 46))	('dysfunction', 'Var', (82, 93))
33074	30089500	In addition, TCOA shows that mir-1269, mir-10b, mir-224, and mir-183 are overexpressed in LIHC with more than 4-fold expression increase compared to normal tissue, while mir-1258, mir-675, mir-490, mir-424, mir-483, mir-1247, mir-199b, mir-199a-2, mir-139, mir-199a-1, mir-3607, and mir-451 are underexpressed in LIHC with more than 4-fold expression decrease compared to normal tissue (Fig.	('mir-183', 'Gene', '406959', (61, 68))	('mir-10b', 'Gene', '406903', (39, 46))	('mir-483', 'Gene', '619552', (207, 214))	('mir-675', 'Gene', '100033819', (180, 187))	('mir-199b', 'Gene', (226, 234))	('mir-451', 'Gene', '574411', (283, 290))	('TCOA', 'Chemical', '-', (13, 17))	('mir-139', 'Gene', '406931', (248, 255))	('mir-139', 'Gene', (248, 255))	('mir-199a-2', 'Gene', (236, 246))	('mir-10b', 'Gene', (39, 46))	('mir-451', 'Gene', (283, 290))	('mir-199a-2', 'Gene', '406977', (236, 246))	('mir-1269', 'Var', (29, 37))	('expression', 'MPA', (117, 127))	('mir-224', 'Gene', '407009', (48, 55))	('mir-483', 'Gene', (207, 214))	('mir-199b', 'Gene', '406978', (226, 234))	('mir-424', 'Gene', '494336', (198, 205))	('mir-424', 'Gene', (198, 205))	('decrease', 'NegReg', (351, 359))	('mir-183', 'Gene', (61, 68))	('mir-199a-1', 'Gene', (257, 267))	('increase', 'PosReg', (128, 136))	('mir-490', 'Gene', '574443', (189, 196))	('expression', 'MPA', (340, 350))	('mir-675', 'Gene', (180, 187))	('mir-490', 'Gene', (189, 196))	('mir-199a-1', 'Gene', '406976', (257, 267))	('mir-224', 'Gene', (48, 55))
33095	30089500	Kaplan-Meier survival curves were used to show the survival (OS or DFS) differences between gene-mutated cancer patients and gene-wildtype cancer patients, and between gene, miRNA or protein higher-expression-level patients and lower-expression-level patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (215, 223))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('protein', 'Protein', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (112, 120))	('gene-mutated', 'Var', (92, 104))	('higher-expression-level', 'PosReg', (191, 214))	('OS', 'Chemical', '-', (61, 63))	('miRNA', 'Protein', (174, 179))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (139, 145))
33201	29967705	identified breakages at three loci, i.e., YWHAE (17p13), FAM22A (10q23), and FAM22B (10q22) in the case of uterine angiosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('FAM22A', 'Gene', '728118', (57, 63))	('angiosarcoma', 'Disease', 'MESH:D006394', (115, 127))	('angiosarcoma', 'Disease', (115, 127))	('p13', 'Gene', (51, 54))	('YWHAE', 'Gene', (42, 47))	('uterine angiosarcoma', 'Phenotype', 'HP:0000131', (107, 127))	('angiosarcoma', 'Phenotype', 'HP:0200058', (115, 127))	('FAM22B', 'Gene', (77, 83))	('p13', 'Gene', '440926', (51, 54))	('FAM22A', 'Gene', (57, 63))	('YWHAE', 'Gene', '7531', (42, 47))	('FAM22B', 'Gene', '729262', (77, 83))	('breakages', 'Var', (11, 20))
33202	29967705	These findings suggest that an abnormality in the loci of YWHAE, FAM22A, and FAM22B may contribute to the development of uterine angiosarcoma.	('contribute', 'Reg', (88, 98))	('angiosarcoma', 'Disease', 'MESH:D006394', (129, 141))	('abnormality', 'Var', (31, 42))	('YWHAE', 'Gene', (58, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('FAM22A', 'Gene', (65, 71))	('uterine angiosarcoma', 'Phenotype', 'HP:0000131', (121, 141))	('FAM22B', 'Gene', (77, 83))	('angiosarcoma', 'Disease', (129, 141))	('FAM22B', 'Gene', '729262', (77, 83))	('FAM22A', 'Gene', '728118', (65, 71))	('YWHAE', 'Gene', '7531', (58, 63))	('angiosarcoma', 'Phenotype', 'HP:0200058', (129, 141))
33221	27016222	On a genomic level, mutations in potential oncogenic driver genes such as KRAS are much more commonly observed in type I compared with type II EOCs.	('type I', 'Disease', (114, 120))	('observed', 'Reg', (102, 110))	('KRAS', 'Gene', (74, 78))	('KRAS', 'Gene', '3845', (74, 78))	('mutations', 'Var', (20, 29))
33222	27016222	In addition, genomic alterations in other regulators of the mitogen-activated protein kinase (MAPK) pathway (eg, BRAF), receptor tyrosine kinases (eg, ERBB2), and loss of function mutations in PTEN also occur at a higher frequency in type I tumors.	('BRAF', 'Gene', '673', (113, 117))	('type I tumors', 'Disease', (234, 247))	('mutations', 'Var', (180, 189))	('BRAF', 'Gene', (113, 117))	('PTEN', 'Gene', (193, 197))	('PTEN', 'Gene', '5728', (193, 197))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('loss of function', 'NegReg', (163, 179))	('ERBB2', 'Gene', (151, 156))	('ERBB2', 'Gene', '2064', (151, 156))	('type I tumors', 'Disease', 'MESH:D005776', (234, 247))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
33223	27016222	Regarding type II EOCs, high-grade serous ovarian cancer is characterized by nearly ubiquitous presence of mutations in TP53, a relatively high rate of defects in BRCA1/2, and a higher burden of genomic alterations, which are rarely seen in type I tumors.	('serous ovarian cancer', 'Disease', (35, 56))	('mutations', 'Var', (107, 116))	('BRCA1/2', 'Gene', (163, 170))	('type I tumors', 'Disease', (241, 254))	('ovarian cancer', 'Phenotype', 'HP:0100615', (42, 56))	('defects', 'Var', (152, 159))	('BRCA1/2', 'Gene', '672;675', (163, 170))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (35, 56))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('type I tumors', 'Disease', 'MESH:D005776', (241, 254))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
33232	27016222	In this precision medicine approach, identified and potentially "actionable" genomic alterations can inform treatment decisions for individual patients in the setting of routine clinical care, particularly in cases where conventional cancer assessments and treatments are suboptimal.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('inform', 'Reg', (101, 107))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('genomic alterations', 'Var', (77, 96))	('cancer', 'Disease', (234, 240))
33249	27016222	Targeted therapies included FDA-approved, on- or off-label targeted therapies, cytotoxic agents, or radiation therapy for patients with tumors characterized by DNA repair pathway defects.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('DNA repair pathway', 'Pathway', (160, 178))	('patients', 'Species', '9606', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('defects', 'Var', (179, 186))
33296	27016222	Examples of implemented MTB-based therapies included the use of an mTOR inhibitor with or without an aromatase inhibitor, or a MEK inhibitor, in patients with endometrial carcinoma characterized by a PIK3CA or PI3K pathway mutation or a KRAS mutation, respectively.	('patients', 'Species', '9606', (145, 153))	('KRAS', 'Gene', (237, 241))	('MEK', 'Gene', (127, 130))	('KRAS', 'Gene', '3845', (237, 241))	('MEK', 'Gene', '5609', (127, 130))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (159, 180))	('PIK3CA', 'Gene', '5290', (200, 206))	('mTOR', 'Gene', (67, 71))	('mutation', 'Var', (223, 231))	('mTOR', 'Gene', '2475', (67, 71))	('PIK3CA', 'Gene', (200, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('endometrial carcinoma', 'Disease', (159, 180))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (159, 180))	('mutation', 'Var', (242, 250))
33297	27016222	In addition, platinum-based chemotherapy or radiation therapy was recommended in patients with genomic evidence of defective DNA damage repair, such as mutations in BRCA2 or ATM, respectively.	('BRCA2', 'Gene', '675', (165, 170))	('mutations', 'Var', (152, 161))	('patients', 'Species', '9606', (81, 89))	('ATM', 'Gene', (174, 177))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('BRCA2', 'Gene', (165, 170))	('ATM', 'Gene', '472', (174, 177))
33305	27016222	The duration of PFS was longer on the MTB-based therapy compared with the prior therapy for three patients in the subgroup with ongoing PFS.	('MTB-based', 'Var', (38, 47))	('patients', 'Species', '9606', (98, 106))	('PFS', 'Disease', (16, 19))
33329	27016222	Of significance were the findings of multiple independent reversions of germline BRCA1 and BRCA2 mutations, loss of BRCA1 promoter methylation, and recurrent promoter fusion that resulted in P-gp (ABCB1) overexpression.	('BRCA2', 'Gene', '675', (91, 96))	('BRCA1', 'Gene', (116, 121))	('ABCB1', 'Gene', (197, 202))	('mutations', 'Var', (97, 106))	('BRCA1', 'Gene', (81, 86))	('promoter fusion', 'Var', (158, 173))	('loss', 'NegReg', (108, 112))	('ABCB1', 'Gene', '5243', (197, 202))	('BRCA2', 'Gene', (91, 96))	('resulted in', 'Reg', (179, 190))	('P-gp', 'Gene', '283871', (191, 195))	('promoter methylation', 'MPA', (122, 142))	('BRCA1', 'Gene', '672', (116, 121))	('BRCA1', 'Gene', '672', (81, 86))	('P-gp', 'Gene', (191, 195))	('overexpression', 'PosReg', (204, 218))
33342	28927463	We discovered twenty (20) mutated genes and three (3) potential pathways causing promoter changes in different gynaecological cancer types.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutated', 'Var', (26, 33))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
33345	28927463	The proposed BIOOPENER platform enriches mutations by filling in missing links from TCGA, COSMIC, REACTOME, KEGG and GO datasets and provides an interlinking mechanism to understand cancer progression from normal to diseased tissues with pathway components, which in turn helped to map mutations, associated phenotypes, pathways, and mechanism.	('links', 'Interaction', (73, 78))	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('TCGA', 'Gene', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
33349	28927463	In our initial work we presented an approach to link and query three large repositories - TCGA2, COSMIC3, and Illumina Human Body Map 2.04 - to analyse the expression of specific genes in different tissues and its variants by:    Ovarian Serous Cystadenocarcinoma (OV), Uterine Corpus Endometrial Carcinoma (UCEC), Uterine Carcinosarcoma (UCS), Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) datasets.	('Carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma', 'Disease', 'MESH:D002294', (345, 409))	('Human', 'Species', '9606', (119, 124))	('Ovarian Serous Cystadenocarcinoma', 'Phenotype', 'HP:0012887', (230, 263))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (278, 306))	('Ovarian Serous Cystadenocarcinoma', 'Disease', 'MESH:D018284', (230, 263))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (354, 377))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (285, 306))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (323, 337))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (315, 337))	('Carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('variants', 'Var', (214, 222))	('Map 2', 'Gene', '4133', (130, 135))	('Ovarian Serous Cystadenocarcinoma', 'Disease', (230, 263))	('Corpus Endometrial Carcinoma', 'Disease', (278, 306))	('Carcinosarcoma', 'Disease', (323, 337))	('Map 2', 'Gene', (130, 135))
33367	28927463	In our initial work, we have identified MYH7 as one of the potential biomarker based on copy number variation (CNV) frequencies.	('copy number variation', 'Var', (88, 109))	('MYH7', 'Gene', (40, 44))	('MYH7', 'Gene', '4625', (40, 44))
33375	28927463	Linking COSMIC and TCGA with REACTOME, KEGG, & GO: We link COSMIC and TCGA with Gene Ontology (GO) datasets to understand the biological processed involved with each mutation or CNVs and the underlying impact of these mutations on cancer and healthy cells.	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('each', 'Var', (161, 165))
33380	28927463	In our initial work we queried mutations and CNV data to identify the novel mutations and their somatic behavior from healthy to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
33386	28927463	For instance, we have queried MYH7 (gene) for promotor region cg05744229 at the chromosome 14 (region of methylation) and extracted two promotor regions from TCGA and COSMIC with the start value of DNA promotor range such as 23904678 (TCGA) and 23435469 (COSMIC).	('23435469', 'Var', (245, 253))	('MYH7', 'Gene', (30, 34))	('cg05744229', 'Chemical', '-', (62, 72))	('MYH7', 'Gene', '4625', (30, 34))	('cg05744229', 'Var', (62, 72))	('23904678', 'Var', (225, 233))
33390	28927463	8) clearly indicate a mutation frequency elevated distribution of these genes in UCS, CESC, UCEC and OV cancers.	('CESC', 'Disease', (86, 90))	('OV cancers', 'Disease', 'MESH:D009369', (101, 111))	('UCS', 'Disease', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('OV cancers', 'Disease', (101, 111))	('UCEC', 'Disease', (92, 96))	('mutation frequency', 'Var', (22, 40))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))
33392	28927463	This study targets genes based on their contribution in mutations15, the listing 8 shows the highly relevant driver genes transforming healthy human tissues into diseased ones for respective cancer types.	('human', 'Species', '9606', (143, 148))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('mutations15', 'Var', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
33397	28927463	For instance, MYH7 primarily carried the LOSS type of a mutation for chr14 which is a dominant mutation with all its regulation of over, under and normally expressed.	('mutation', 'Var', (56, 64))	('MYH7', 'Gene', '4625', (14, 18))	('MYH7', 'Gene', (14, 18))	('chr14', 'Gene', (69, 74))
33401	28927463	As reported in our initial work major changes are occurring nearby -0.773 beta-value and their corresponding composite element reference ids are cg01429391, cg05744229, cg26670875, cg18205205, cg21242212, cg08240074, cg13785779, cg05744229.	('cg13785779', 'Var', (217, 227))	('cg05744229', 'Chemical', '-', (229, 239))	('ids', 'Gene', (137, 140))	('cg08240074', 'Var', (205, 215))	('cg21242212', 'Var', (193, 203))	('cg18205205', 'Chemical', '-', (181, 191))	('cg05744229', 'Var', (229, 239))	('cg01429391', 'Chemical', '-', (145, 155))	('cg26670875', 'Var', (169, 179))	('cg26670875', 'Chemical', '-', (169, 179))	('cg18205205', 'Var', (181, 191))	('cg13785779', 'Chemical', '-', (217, 227))	('cg01429391', 'Var', (145, 155))	('cg05744229', 'Var', (157, 167))	('ids', 'Gene', '3423', (137, 140))	('cg05744229', 'Chemical', '-', (157, 167))	('cg08240074', 'Chemical', '-', (205, 215))	('cg21242212', 'Chemical', '-', (193, 203))
33408	28927463	The dysregulation of s-nitrosylation in severe pathological events including cancer onset, progression, and treatment resistance leads to controlled epigenetic and treatment response.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('dysregulation', 'Var', (4, 17))
33419	28927463	Multiple pathways are involved to translate a particular gene A single disease can be treated by eliminating effect of the combination of multiple drugs Selection of these drugs is majorally based on the inhibitors (i.e., combination of gene-pathways) Effect of one pathway alteration can change the modification of single gene and yields into multiple genes In cancer genomics field massive amount of data exist with complex associations.	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('single gene', 'MPA', (316, 327))	('cancer', 'Disease', (362, 368))	('alteration', 'Var', (274, 284))	('modification', 'MPA', (300, 312))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('change', 'Reg', (289, 295))
33423	28927463	In this paper, we have presented a data-interlinked platform called BIOOPENER which enables querying different types of mutations and genomic alterations to contribute to molecular and clinical insights of cancer by defining most relevant variants and their prioritization.	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('variants', 'Var', (239, 247))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))
33426	28927463	In future, we plan to extend by covering the breast cancer type including additional genomic signatures, e.g., fusion gene, structural variations.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('fusion gene', 'Var', (111, 122))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('structural variations', 'Var', (124, 145))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))
33433	28170390	However, most approaches for identifying cancer mutations focus on either the entire-gene or single amino-acid level.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (41, 47))
33438	28170390	Identifying driver mutations in cancer has been a major challenge in cancer research, with the ultimate goal of understanding the detailed molecular origins of cancer and providing genetically personalized treatments.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
33439	28170390	For decades, the cancer research community has known that mutations in certain genes:such as tumor suppressors like P53:can drive cancer.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('P53', 'Gene', (116, 119))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('P53', 'Gene', '7157', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('drive', 'Reg', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
33440	28170390	In some cases it is also clear that mutations within cancer genes are localized in a single amino:such as the V600E mutation in BRAF.	('V600E', 'Mutation', 'rs113488022', (110, 115))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('V600E', 'Var', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRAF', 'Gene', '673', (128, 132))	('BRAF', 'Gene', (128, 132))
33443	28170390	This is a PLOS Computational Biology Methods paper Somatic mutations are amongst the most frequent genomic aberrations associated with cancer.	('Somatic mutations', 'Var', (51, 68))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
33445	28170390	To date, millions of distinct somatic mutations have been observed in human cancers through genome wide characterization projects such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC).	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('Cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Disease', (142, 148))	('mutations', 'Var', (38, 47))	('Cancer Genome Atlas', 'Disease', (142, 161))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))	('Cancer', 'Disease', (187, 193))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (142, 161))
33446	28170390	Computational methods are particularly well suited for the assessment of somatic mutations at this scale in order to identify those with cancer-associated functional consequences.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutations', 'Var', (81, 90))
33448	28170390	In addition, methods including PolyPhen, SIFT, and CADD utilize prior knowledge such as conservation and machine learning based on disease associated variants to predict functional mutation impact.	('SIFT', 'Disease', 'None', (41, 45))	('SIFT', 'Disease', (41, 45))	('variants', 'Var', (150, 158))
33449	28170390	Yet other methods including OncodriveCLUST and CLUMPS, iPAC, and graphPAC take a parameterized, data-driven approach to predict cancer-associated mutations based on spatial clustering of linear sequence, three-dimensional protein structure, and graphical representations thereof.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (146, 155))	('cancer', 'Disease', (128, 134))
33450	28170390	Importantly, functional mutations that occur within the coding sequence and are known to be associated with cancer do not occur at random positions.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (24, 33))	('associated', 'Reg', (92, 102))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
33451	28170390	On the contrary, hotspots or clusters are frequently observed as recurrent missense mutations across a significant fraction of cancer samples.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('missense mutations', 'Var', (75, 93))	('cancer', 'Disease', (127, 133))
33452	28170390	These sets of mutations are typically attributed to alterations in function at specific sites of the protein that give rise to a variety of cancer phenotypes.	('alterations', 'Reg', (52, 63))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('give rise to', 'Reg', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (14, 23))	('function', 'MPA', (67, 75))
33453	28170390	Oftentimes, these mutation clusters can be readily interpreted in the context of their protein structure and function; for example, mutations in the GTP binding pocket of KRAS that modulates intrinsic GTPase activity, lead to constitutive activation of KRAS and persistent stimulation of downstream signaling pathways.	('stimulation', 'PosReg', (273, 284))	('downstream signaling pathways', 'Pathway', (288, 317))	('mutations', 'Var', (132, 141))	('GTP', 'Chemical', 'MESH:D006160', (149, 152))	('GTP', 'Chemical', 'MESH:D006160', (201, 204))	('activation', 'PosReg', (239, 249))	('KRAS', 'Gene', (253, 257))	('KRAS', 'Gene', (171, 175))	('KRAS', 'Gene', '3845', (253, 257))	('KRAS', 'Gene', '3845', (171, 175))
33454	28170390	Such mutation clusters need not be located within structural protein domains; for example, N-terminal mutations of beta-catenin (CTNNB1) affect protein phosphorylation sites and thereby abrogate ubiquitin-mediated proteasomal degradation.	('protein phosphorylation sites', 'MPA', (144, 173))	('abrogate', 'NegReg', (186, 194))	('CTNNB1', 'Gene', (129, 135))	('beta-catenin', 'Gene', (115, 127))	('ubiquitin-mediated proteasomal degradation', 'MPA', (195, 237))	('mutations', 'Var', (102, 111))	('CTNNB1', 'Gene', '1499', (129, 135))	('beta-catenin', 'Gene', '1499', (115, 127))	('affect', 'Reg', (137, 143))
33455	28170390	These mutations then result in beta-catenin accumulating in the nucleus and continuously driving transcription of its target genes.	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('transcription', 'MPA', (97, 110))	('accumulating', 'PosReg', (44, 56))	('driving', 'Reg', (89, 96))	('result in', 'Reg', (21, 30))	('mutations', 'Var', (6, 15))
33456	28170390	While these examples highlight readily identifiable and interpretable focal mutation clusters that lead to cancer-associated effects on protein function, such mutation consequences need not be restricted to dense clusters at just a few amino acid positions in the protein sequence.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('protein function', 'MPA', (136, 152))	('effects', 'MPA', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('mutation', 'Var', (76, 84))	('cancer', 'Disease', (107, 113))
33457	28170390	For example, tumor protein p53 (TP53) contains a combination of mutations that are recurrently located at specific amino acids that bind directly to DNA (e.g., R248Q, R273C) as well as more broadly distributed sets of mutations throughout the core DNA binding domain of TP53 that disrupt the folding and stability of the protein.	('tumor', 'Disease', (13, 18))	('R273C', 'Mutation', 'rs121913343', (167, 172))	('p53', 'Gene', '7157', (27, 30))	('R248Q', 'Mutation', 'rs11540652', (160, 165))	('folding', 'MPA', (292, 299))	('disrupt', 'NegReg', (280, 287))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', '7157', (270, 274))	('R273C', 'Var', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('TP53', 'Gene', (32, 36))	('stability of the', 'MPA', (304, 320))	('TP53', 'Gene', (270, 274))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('R248Q', 'Var', (160, 165))	('p53', 'Gene', (27, 30))
33458	28170390	Additionally, sets of mutations do not only affect individual regions or domains of proteins; rather, functional mutations are observed in distinct clusters within different regions or domains of individual proteins (e.g., PIK3CA), indicating the possibility for differential functional consequences of such mutation clusters.	('PIK3CA', 'Gene', (223, 229))	('mutations', 'Var', (113, 122))	('PIK3CA', 'Gene', '5290', (223, 229))	('mutations', 'Var', (22, 31))
33465	28170390	A cluster is assigned as positive (1) to a tumor sample if that sample contains at least one non-synonymous mutation within the cluster and negative (0) otherwise.	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('non-synonymous mutation', 'Var', (93, 116))
33470	28170390	We assigned clusters to specific tumor samples if there was at least one non-synonymous mutation in a sample at an amino acid position within a cluster.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('non-synonymous mutation', 'Var', (73, 96))	('tumor', 'Disease', (33, 38))
33474	28170390	On the high end, lung squamous cell carcinoma and uterine carcinosarcoma have over 80% of their non-synonymous mutations in clusters.	('carcinosarcoma', 'Disease', 'MESH:D002296', (58, 72))	('non-synonymous mutations', 'Var', (96, 120))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 45))	('lung squamous cell carcinoma', 'Disease', (17, 45))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (50, 72))	('carcinosarcoma', 'Disease', (58, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (17, 45))
33475	28170390	On the low end, acute myeloid leukemia and thyroid carcinoma have 23% and 34% of their non-synonymous mutations in clusters, respectively.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (22, 38))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('acute myeloid leukemia', 'Disease', (16, 38))	('non-synonymous mutations', 'Var', (87, 111))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (43, 60))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (16, 38))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (43, 60))	('thyroid carcinoma', 'Disease', (43, 60))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (16, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
33480	28170390	We found 426 mutational clusters enriched for a specific tumor type at a false discovery rate of 1% and 996 at a false discovery rate of 10%.	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutational', 'Var', (13, 23))
33482	28170390	The statistical associations were carried out on binary vectors that indicate whether a sample in a specific tumor type had a mutation in a specific cluster (1) or not (0).	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutation', 'Var', (126, 134))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
33483	28170390	This methodology was chosen because, in general, gene expression from a particular pathway is not universally upregulated or downregulated due to cancer mutations.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('mutations', 'Var', (153, 162))	('upregulated', 'PosReg', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('downregulated', 'NegReg', (125, 138))
33491	28170390	Note that associations were not computed if fewer than 5 samples in a given gene and tumor type had non-synonymous mutations outside of all clusters.	('non-synonymous mutations', 'Var', (100, 124))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
33493	28170390	Significant results for PFAM domains can be found in and T6C in S1 Tables (global) and T7C in S1 Tables (pathway).	('T6C', 'Var', (57, 60))	('PFAM', 'Protein', (24, 28))	('T7C', 'Var', (87, 90))	('T6C', 'Mutation', 'rs754763517', (57, 60))	('T7C', 'Mutation', 'rs768725324', (87, 90))
33497	28170390	Here, we highlight several well-known and novel clusters in the cancer literature recovered by M2C: Two of PIK3CA's eleven mutation clusters are associated with global changes of gene expression in breast invasive carcinoma: amino acid positions 539-547 and 1043-1049.	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('amino acid positions 539-547', 'Var', (225, 253))	('associated', 'Reg', (145, 155))	('gene expression', 'MPA', (179, 194))	('1043-1049', 'Var', (258, 267))	('changes', 'Reg', (168, 175))	('PIK3CA', 'Gene', (107, 113))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (198, 223))	('breast invasive carcinoma', 'Disease', (198, 223))	('PIK3CA', 'Gene', '5290', (107, 113))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (198, 223))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
33498	28170390	We note that the first clusters are significantly enriched for mutations in the following tumor types: breast invasive carcinoma, head and neck squamous cell carcinoma, uterine corpus endometrial carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma (FDR < 1%).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (139, 167))	('breast invasive carcinoma', 'Disease', (103, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('mutations', 'Var', (63, 72))	('tumor', 'Disease', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (103, 128))	('squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (216, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (184, 205))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (103, 128))	('corpus endometrial carcinoma', 'Disease', (177, 205))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (177, 205))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('neck squamous cell carcinoma', 'Disease', (139, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))
33499	28170390	The second cluster is significantly enriched for mutations in breast invasive carcinoma and uterine corpus endometrial carcinoma (FDR < 1%).	('corpus endometrial carcinoma', 'Disease', (100, 128))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (100, 128))	('mutations', 'Var', (49, 58))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (62, 87))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (62, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('breast invasive carcinoma', 'Disease', (62, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (107, 128))
33504	28170390	The cluster is also enriched for mutations in lung adenocarcinoma (FDR < 5%), as well as in uterine corpus endometrial carcinoma (FDR < 1%).	('corpus endometrial carcinoma', 'Disease', (100, 128))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (100, 128))	('lung adenocarcinoma', 'Disease', (46, 65))	('mutations', 'Var', (33, 42))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (107, 128))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
33509	28170390	Different GATA3 mutations have been associated with Luminal A and B subtypes of breast cancer and changes in survival prognoses.	('GATA3', 'Gene', '2625', (10, 15))	('changes', 'Reg', (98, 105))	('associated', 'Reg', (36, 46))	('GATA3', 'Gene', (10, 15))	('mutations', 'Var', (16, 25))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('survival prognoses', 'CPA', (109, 127))	('Luminal A', 'Disease', (52, 61))
33510	28170390	We note that all three of these clusters are enriched for mutations in breast invasive carcinoma (FDR<1%).	('mutations', 'Var', (58, 67))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (71, 96))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (71, 96))	('breast invasive carcinoma', 'Disease', (71, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
33517	28170390	Previously single nucleotide mutations in ZBTB20 have been associated with gastric cancer.	('gastric cancer', 'Disease', (75, 89))	('ZBTB20', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('associated', 'Reg', (59, 69))	('single nucleotide mutations', 'Var', (11, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('ZBTB20', 'Gene', '26137', (42, 48))
33519	28170390	We note that this cluster is enriched in gastric cancer along with two other clusters in ZBTB20, 190-248 and 345-504 (FDR < 1%).	('ZBTB20', 'Gene', (89, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('345-504', 'Var', (109, 116))	('ZBTB20', 'Gene', '26137', (89, 95))	('190-248', 'Var', (97, 104))	('gastric cancer', 'Disease', (41, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
33520	28170390	The 190-248 cluster is also enriched for mutations in low grade glioma (FDR < 10%).	('mutations', 'Var', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
33524	28170390	This cluster is enriched for mutations in uterine corpus endometrial carcinoma and uterine carcinosarcoma (FDR < 1%).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (57, 78))	('carcinosarcoma', 'Disease', (91, 105))	('mutations', 'Var', (29, 38))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (50, 78))	('corpus endometrial carcinoma', 'Disease', (50, 78))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (83, 105))	('carcinosarcoma', 'Disease', 'MESH:D002296', (91, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
33525	28170390	Additionally, the 237-275 in PPP2R1A is enriched for mutations in lung squamous cell carcinoma and gastric cancer (FDR<10%).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 94))	('lung squamous cell carcinoma', 'Disease', (66, 94))	('gastric cancer', 'Disease', (99, 113))	('mutations', 'Var', (53, 62))	('237-275', 'Var', (18, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('PPP2R1A', 'Gene', '5518', (29, 36))	('PPP2R1A', 'Gene', (29, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))
33526	28170390	The 391-490 cluster is enriched for mutations in uterine corpus endometrial carcinoma (FDR <1%).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (64, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('mutations', 'Var', (36, 45))	('corpus endometrial carcinoma', 'Disease', (57, 85))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (57, 85))
33534	28170390	Similarly, in thyroid carcinoma the 600-601 mutation cluster has 235 non-synonymous mutations and is more significantly associated to global changes in gene expression (P<10-82) than any-non-synonymous mutation which has 237 total non-synonymous mutations (P<10-80).	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (14, 31))	('associated', 'Reg', (120, 130))	('thyroid carcinoma', 'Disease', (14, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('600-601 mutation', 'Var', (36, 52))	('changes', 'Reg', (141, 148))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (14, 31))	('non-synonymous mutations', 'MPA', (69, 93))	('gene expression', 'MPA', (152, 167))
33542	28170390	Mutations in this cluster are likely to affect this binding and thereby the regulation of Beta-catenin.	('regulation', 'MPA', (76, 86))	('Beta-catenin', 'Gene', '1499', (90, 102))	('binding', 'Interaction', (52, 59))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (40, 46))	('Beta-catenin', 'Gene', (90, 102))
33545	28170390	One example is the 248-254 cluster in FGFR3 in bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('FGFR3', 'Gene', '2261', (38, 43))	('248-254 cluster', 'Var', (19, 34))	('FGFR3', 'Gene', (38, 43))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (47, 75))	('bladder urothelial carcinoma', 'Disease', (47, 75))
33546	28170390	Point mutations in this region have been previously implicated in low grade glioma tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('glioma tumors', 'Disease', (76, 89))	('glioma tumors', 'Disease', 'MESH:D005910', (76, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('Point mutations', 'Var', (0, 15))	('implicated', 'Reg', (52, 62))
33549	28170390	This cluster is also enriched for mutations in both bladder cancer (FDR < 1%) and lung squamous cell carcinoma (FDR < 10%).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 110))	('lung squamous cell carcinoma', 'Disease', (82, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (82, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('mutations', 'Var', (34, 43))
33551	28170390	We note that this cluster is enriched for mutations in gastric cancer (FDR < 1%) and the 456-522 cluster is enriched in lung adenocarcinoma (FDR < 5%).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('gastric cancer', 'Disease', (55, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('mutations', 'Var', (42, 51))	('lung adenocarcinoma', 'Disease', (120, 139))
33556	28170390	FUBP1 has two clusters each with predominantly nonsense mutations with differential pathway association in lower grade glioma.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('FUBP1', 'Gene', (0, 5))	('glioma', 'Disease', (119, 125))	('nonsense mutations', 'Var', (47, 65))	('FUBP1', 'Gene', '8880', (0, 5))
33561	28170390	Specifically, there are 10 drug associations with the BRAF mutation cluster 600-601, 6 with NRAS mutation cluster at amino acid 61 and 4 with KRAS mutation cluster 12-13.	('KRAS', 'Gene', (142, 146))	('BRAF', 'Gene', (54, 58))	('NRAS', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (54, 58))	('KRAS', 'Gene', '3845', (142, 146))	('NRAS', 'Gene', '4893', (92, 96))	('mutation cluster 600-601', 'Var', (59, 83))
33564	28170390	First, we observed that cell lines with mutations in the cluster 116-146 in PTEN strongly responded to mTOR inhibitor Temsirolimus, whereas mutations across the entire gene showed only a small indication of drug sensitivity (Fig 6A).	('mTOR', 'Gene', (103, 107))	('drug sensitivity', 'Phenotype', 'HP:0020174', (207, 223))	('PTEN', 'Gene', (76, 80))	('mutations in', 'Var', (40, 52))	('PTEN', 'Gene', '5728', (76, 80))	('mTOR', 'Gene', '2475', (103, 107))
33565	28170390	Second, we observed that cell lines with mutations in the cluster 1043-1049 in PIK3CA showed a stronger response to a PI3K beta inhibitor than other mutation clusters or the any non-synonymous mutation feature (Fig 6B).	('stronger', 'PosReg', (95, 103))	('PI3K beta', 'Gene', (118, 127))	('PI3K beta', 'Gene', '5291', (118, 127))	('PIK3CA', 'Gene', (79, 85))	('mutations in', 'Var', (41, 53))	('PIK3CA', 'Gene', '5290', (79, 85))
33566	28170390	This corresponds with our observation that in breast cancer this same mutation cluster is very strongly associated with global changes in gene expression compared to other clusters in PIK3CA.	('PIK3CA', 'Gene', '5290', (184, 190))	('changes', 'Reg', (127, 134))	('associated', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('PIK3CA', 'Gene', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('mutation', 'Var', (70, 78))	('gene expression', 'MPA', (138, 153))	('breast cancer', 'Disease', (46, 59))
33567	28170390	These results provide additional support for the idea that it is important to consider mutations in a specific region of a cancer gene, and not merely a single amino acid alteration or a mutation anywhere in the entire gene.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (123, 129))	('mutations', 'Var', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
33570	28170390	We show that many of the clusters found by M2C are representative of functional regions of proteins where mutations have a larger effect in terms of influencing the hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('M2C', 'Gene', (43, 46))	('influencing', 'Reg', (149, 160))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('mutations', 'Var', (106, 115))
33573	28170390	Furthermore, we have shown that certain genes contain multiple clusters that may have different functional consequences, suggesting that different mutations in these genes may play different roles in cancer onset and progression based upon the location of the mutation.	('mutations', 'Var', (147, 156))	('play', 'Reg', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
33574	28170390	Finally, we investigated whether mutation clusters are associated with drug response data in cancer cell lines and found many mutation clusters which are associated with differential drug sensitivity.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('drug sensitivity', 'Phenotype', 'HP:0020174', (183, 199))	('mutation', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (154, 164))
33575	28170390	These genes were further filtered to ensure that there are in total at least 15 mutations in each gene across all 23 cancer types considered.	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (80, 89))
33578	28170390	First, M2C converts TCGA mutation calls in amino acid space from all 23 cancers into multiple continuous probability density functions (Fig 7A and section C step 1 in S1 Text).	('M2C', 'Var', (7, 10))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TCGA', 'Gene', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
33579	28170390	The score, Sc, of cluster c, is given by the log of the ratio of the emission probability of the mutations in the cluster with the emission probability of the same mutations based upon the null hypothesis of a uniform mutation distribution across the cluster,  M is the set of all N pan-cancer mutations in cluster c. G(x; muc, sigmac) is the normalized Gaussian distribution with mean muc and standard deviation sigmac representing the unweighted component of the mixture model corresponding to cluster c. Finally U = L-1 is the emission probability of single mutation by a uniform distribution over the gene containing the clusters of length L (in amino acids).	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('L-1', 'Gene', '3897', (519, 522))	('L-1', 'Gene', (519, 522))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('mutations', 'Var', (294, 303))
33580	28170390	To determine whether specific cancer types are enriched for specific mutation clusters, we used Fisher's exact test to calculate an enrichment P-value.	('mutation', 'Var', (69, 77))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
33583	28170390	A binary feature matrix represents which tumor samples contain mutations in which clusters.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (41, 46))
33584	28170390	A tumor sample is said to be positive (1) for a given cluster if it contains a non-synonymous or nonsense mutation within the cluster (see boxes B and C of Fig 7 for an illustration).	('aid', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('aid', 'Gene', '57379', (19, 22))	('tumor', 'Disease', (2, 7))	('nonsense mutation', 'Var', (97, 114))
33612	26348313	Patients receiving CT + RT had significantly improved PFS compared to those receiving CT alone (aHR = 0.43, p = 0.04), but no difference in OS.	('improved', 'PosReg', (45, 53))	('Patients', 'Species', '9606', (0, 8))	('CT + RT', 'Var', (19, 26))	('PFS', 'MPA', (54, 57))
33632	26348313	A 2008 European Organization for Research and Treatment of Cancer [EORTC protocol 55,874] trial of sarcoma patients included 91 women with early stage CS and showed that pelvic radiation decreased local recurrence but did not improve OS.	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('women', 'Species', '9606', (128, 133))	('pelvic', 'Var', (170, 176))	('local', 'CPA', (197, 202))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('Cancer', 'Disease', (59, 65))	('Cancer', 'Disease', 'MESH:D009369', (59, 65))	('sarcoma', 'Disease', (99, 106))	('decreased', 'NegReg', (187, 196))	('patients', 'Species', '9606', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
33667	26348313	There was significantly higher PFS in patients with early stage disease in the CT + RT group compared to the CT group.	('PFS', 'MPA', (31, 34))	('CT + RT', 'Var', (79, 86))	('higher', 'PosReg', (24, 30))	('patients', 'Species', '9606', (38, 46))
33764	26097728	Unbalanced karyotypic defects are the only shared features observed across different leiomyosarcoma subtypes.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (85, 99))	('leiomyosarcoma subtypes', 'Disease', (85, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('leiomyosarcoma subtypes', 'Disease', 'MESH:D007890', (85, 108))	('Unbalanced karyotypic defects', 'Var', (0, 29))
33784	26097728	The familial syndrome hereditary leiomyomatosis with renal cell carcinoma (HLRCC), in which there are germline mutations in fumarate hydratase, has also been associated with an increased risk of uterine leiomyosarcomas.	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (195, 218))	('mutations', 'Var', (111, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (210, 218))	('associated', 'Reg', (158, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('familial syndrome hereditary leiomyomatosis', 'Disease', (4, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('renal cell carcinoma', 'Disease', (53, 73))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (203, 218))	('familial syndrome hereditary leiomyomatosis', 'Disease', 'MESH:C535516', (4, 47))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (203, 218))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (195, 217))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (203, 217))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (53, 73))	('fumarate hydratase', 'Gene', '2271', (124, 142))	('fumarate hydratase', 'Gene', (124, 142))	('leiomyosarcomas', 'Disease', (203, 218))
33793	26097728	Karyotypes of soft tissue leiomyosarcomas are usually highly complex with genomic instability, and often associated with defects in TP53 or sometimes FANCA and ATM.	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (26, 41))	('soft tissue leiomyosarcomas', 'Phenotype', 'HP:0030448', (14, 41))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (26, 41))	('ATM', 'Gene', (160, 163))	('defects', 'Var', (121, 128))	('TP53', 'Gene', '7157', (132, 136))	('leiomyosarcomas', 'Disease', (26, 41))	('TP53', 'Gene', (132, 136))	('FANCA', 'Gene', '2175', (150, 155))	('ATM', 'Gene', '472', (160, 163))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (26, 40))	('FANCA', 'Gene', (150, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('associated', 'Reg', (105, 115))
33797	26097728	There is frequent involvement of the retinoblastoma-cyclin D pathway with genomic loss at 13q14 centred on the RB1 gene.	('retinoblastoma', 'Phenotype', 'HP:0009919', (37, 51))	('RB1', 'Gene', (111, 114))	('genomic loss at', 'Var', (74, 89))	('RB1', 'Gene', '5925', (111, 114))	('retinoblastoma', 'Gene', '5925', (37, 51))	('involvement', 'Reg', (18, 29))	('retinoblastoma', 'Gene', (37, 51))
33924	23019529	Endometrial cancer risk has been previously associated with several host factors, including high body mass index, nulliparity or low parity, early age at first birth, history of type 2 diabetes mellitus (non-insulin dependent), and family history of cancer, particularly endometrial cancer.	('endometrial cancer', 'Disease', (271, 289))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('endometrial cancer', 'Disease', 'MESH:D016889', (271, 289))	('Endometrial cancer', 'Disease', 'MESH:D016889', (0, 18))	('type 2 diabetes mellitus', 'Disease', (178, 202))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (178, 202))	('insulin', 'Gene', '3630', (208, 215))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (185, 202))	('cancer', 'Disease', (283, 289))	('Endometrial cancer', 'Disease', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('nulliparity', 'Var', (114, 125))	('associated', 'Reg', (44, 54))	('insulin', 'Gene', (208, 215))	('endometrial cancer', 'Phenotype', 'HP:0012114', (271, 289))	('cancer', 'Disease', (12, 18))	('Endometrial cancer', 'Phenotype', 'HP:0012114', (0, 18))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
33946	23019529	Besides these risk factors, having a family history of the disease increases risk, as does being a carrier of mutations in BRCA1/BRCA2 genes, or being affected by hereditary non-polyposis colorectal cancer syndrome.	('BRCA1', 'Gene', '672', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (110, 119))	('BRCA2', 'Gene', (129, 134))	('BRCA1', 'Gene', (123, 128))	('affected', 'Reg', (151, 159))	('BRCA2', 'Gene', '675', (129, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('hereditary non-polyposis colorectal cancer syndrome', 'Disease', 'MESH:D015179', (163, 214))
33972	23019529	The available human evidence considered by the IARC Working Group to classify tetrachloroethylene as probably carcinogenic to the cervix uteri comes from 3 cohort studies.	('tetrachloroethylene', 'Chemical', 'MESH:D013750', (78, 97))	('human', 'Species', '9606', (14, 19))	('tetrachloroethylene', 'Var', (78, 97))	('cervix uteri', 'Phenotype', 'HP:0000139', (130, 142))	('carcinogenic', 'Disease', 'MESH:D063646', (110, 122))	('carcinogenic', 'Disease', (110, 122))
33974	23019529	Since the publication of the IARC Monograph, updates of the 2 cohorts of dry cleaners confirmed the increased risk of cervical cancer with exposure to tetrachloroethylene, with excess risks of 60% (standardized mortality ratio [SMR] 1.6, 95% confidence interval [CI] 1.0-2.3, based on 27 deaths) and 95% (SMR 1.95, 95% CI 1.00-3.40).	('cervical cancer', 'Disease', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('death', 'Disease', 'MESH:D003643', (288, 293))	('death', 'Disease', (288, 293))	('tetrachloroethylene', 'Chemical', 'MESH:D013750', (151, 170))	('tetrachloroethylene', 'Var', (151, 170))	('cervical cancer', 'Disease', 'MESH:D002583', (118, 133))
33983	23019529	A Finnish record-linkage study reported excess risks of cervical cancer of about 20 to 40% with exposures to aliphatic and alicyclic, aromatic, and chlorinated hydrocarbon solvents.	('aliphatic', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('hydrocarbon', 'Chemical', 'MESH:D006838', (160, 171))	('cervical cancer', 'Disease', (56, 71))	('cervical cancer', 'Disease', 'MESH:D002583', (56, 71))
34025	23019529	In summary, if occupational exposures to X-radiation or gamma-radiation do confer an increased risk of ovarian cancer, their overall impact is likely to be limited compared to other risk factors.	('X-radiation', 'Disease', 'MESH:D004194', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gamma-radiation', 'Var', (56, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('X-radiation', 'Disease', (41, 52))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('ovarian cancer', 'Disease', (103, 117))
34084	22767667	Inhibition of non-VEGF pathways is a strategy that may improve antitumor activity and address resistance to anti-VEGF therapies.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('VEGF', 'Gene', (113, 117))	('VEGF', 'Gene', '7422', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('improve', 'PosReg', (55, 62))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (67, 72))	('VEGF', 'Gene', '7422', (113, 117))	('VEGF', 'Gene', (18, 22))
34088	22767667	CD105 is essential for normal vascular development, and heterozygous expression of CD105 is associated with hereditary hemorrhagic telangiectasia type 1 (HHT-1, Rendu-Osler-Webber syndrome), a human disease characterized by ectatic blood vessel formation.	('telangiectasia', 'Phenotype', 'HP:0001009', (131, 145))	('hereditary hemorrhagic telangiectasia type', 'Disease', 'MESH:D013683', (108, 150))	('CD105', 'Gene', (0, 5))	('CD105', 'Gene', '13805', (0, 5))	('HHT-1, Rendu-Osler-Webber syndrome', 'Disease', 'MESH:D013683', (154, 188))	('CD105', 'Gene', (83, 88))	('ectatic blood vessel', 'Phenotype', 'HP:0004948', (224, 244))	('hereditary hemorrhagic telangiectasia type', 'Disease', (108, 150))	('CD105', 'Gene', '13805', (83, 88))	('heterozygous expression', 'Var', (56, 79))	('associated', 'Reg', (92, 102))	('human', 'Species', '9606', (193, 198))
34091	22767667	In preclinical experiments, SN6j, the murine parental monoclonal antibody of TRC105, inhibited tumor growth and tumor angiogenesis.	('tumor', 'Disease', (112, 117))	('inhibited', 'NegReg', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SN6j', 'Var', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('murine', 'Species', '10090', (38, 44))	('TRC105', 'Chemical', 'MESH:C579557', (77, 83))	('tumor', 'Disease', (95, 100))
34092	22767667	The growth of human and syngeneic breast and colorectal cancer cell line xenografts was inhibited by monotherapy, while the antibody potentiated chemotherapy and was well tolerated, without dose limiting toxicity, in animal models.	('inhibited', 'NegReg', (88, 97))	('growth', 'CPA', (4, 10))	('antibody', 'Var', (124, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('human', 'Species', '9606', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('potentiated', 'PosReg', (133, 144))	('toxicity', 'Disease', 'MESH:D064420', (204, 212))	('toxicity', 'Disease', (204, 212))	('syngeneic breast and colorectal cancer', 'Disease', 'MESH:D015179', (24, 62))
34109	22767667	The first 21 patients (cohorts 1 to 5A) were administered material produced in mouse myeloma NS0 cells at doses of 0.01, 0.03, 0.1, 0.3, and 1 mg/kg every 2 weeks infused over 1 hour without premedication.	('mouse', 'Species', '10090', (79, 84))	('myeloma', 'Disease', (85, 92))	('patients', 'Species', '9606', (13, 21))	('0.1', 'Var', (127, 130))	('myeloma', 'Disease', 'MESH:D009101', (85, 92))	('0.03', 'Var', (121, 125))
34146	22767667	One additional patient who received CHO-produced TRC105 at 1 mg/kg developed a grade 3 infusion reaction with the third dose given over 2 hours.	('patient', 'Species', '9606', (15, 22))	('TRC105', 'Chemical', 'MESH:C579557', (49, 55))	('grade 3 infusion reaction', 'MPA', (79, 104))	('TRC105', 'Var', (49, 55))	('CHO', 'CellLine', 'CVCL:0213', (36, 39))
34156	22767667	Fatigue was one of the more common adverse event attributable to TRC105 and was more prevalent at doses above 3 mg/kg (Table 2).	('TRC105', 'Var', (65, 71))	('Fatigue', 'Disease', (0, 7))	('TRC105', 'Chemical', 'MESH:C579557', (65, 71))	('Fatigue', 'Phenotype', 'HP:0012378', (0, 7))
34168	22767667	In patients administered NS0-produced TRC105 (0.01 to 1 mg/kg), HAMA and HACA were detected in 9.5% and 35% of patients, respectively.	('TRC105', 'Chemical', 'MESH:C579557', (38, 44))	('HAMA', 'Disease', (64, 68))	('patients', 'Species', '9606', (3, 11))	('TRC105', 'Var', (38, 44))	('patients', 'Species', '9606', (111, 119))
34189	22767667	Telangiectasias are a notable clinical feature of patients with HHT-1, a genetically inherited disease characterized by mutation of one copy of the CD105 gene.	('inherited disease', 'Disease', (85, 102))	('Telangiectasias', 'Disease', 'MESH:D013684', (0, 15))	('patients', 'Species', '9606', (50, 58))	('mutation', 'Var', (120, 128))	('inherited disease', 'Disease', 'MESH:D030342', (85, 102))	('CD105', 'Gene', (148, 153))	('CD105', 'Gene', '13805', (148, 153))	('Telangiectasias', 'Disease', (0, 15))	('HHT-1', 'Disease', (64, 69))
34198	22767667	Infusion reactions were more prominent with CHO-produced TRC105 which has a higher degree of afucosylated glycans and therefore more potent ADCC activity than TRC105 from NS0 cells.	('CHO', 'CellLine', 'CVCL:0213', (44, 47))	('more potent', 'PosReg', (128, 139))	('TRC105', 'Var', (57, 63))	('TRC105', 'Chemical', 'MESH:C579557', (159, 165))	('activity', 'MPA', (145, 153))	('TRC105', 'Chemical', 'MESH:C579557', (57, 63))	('glycans', 'Chemical', 'MESH:D011134', (106, 113))	('higher', 'PosReg', (76, 82))	('afucosylated glycans', 'Protein', (93, 113))	('ADCC', 'Enzyme', (140, 144))
34201	22767667	Host anti-TRC105 antibodies were detected in patients administered NS0-produced TRC105 but not in patients treated with CHO-produced TRC105 that is being used in phase 1b and phase 2 trials.	('NS0-produced TRC105', 'Var', (67, 86))	('TRC105', 'Chemical', 'MESH:C579557', (10, 16))	('TRC105', 'Chemical', 'MESH:C579557', (80, 86))	('CHO', 'CellLine', 'CVCL:0213', (120, 123))	('patients', 'Species', '9606', (98, 106))	('detected', 'Reg', (33, 41))	('patients', 'Species', '9606', (45, 53))	('TRC105', 'Chemical', 'MESH:C579557', (133, 139))	('TRC105', 'Var', (80, 86))	('anti-TRC105', 'Gene', (5, 16))
34202	22767667	The immunogenicity of NS0-produced TRC105 was not surprising since the glycosylation of antibodies produced in NS0 cells results in the attachment of immunogenic oligosaccharides (e.g., galactose-alpha-1,3-galactose) that are not present in antibodies manufactured from CHO cells.	('NS0', 'Var', (111, 114))	('attachment', 'MPA', (136, 146))	('oligosaccharides', 'Chemical', 'MESH:D009844', (162, 178))	('man', 'Species', '9606', (252, 255))	('TRC105', 'Chemical', 'MESH:C579557', (35, 41))	('galactose-alpha-1,3-galactose', 'Chemical', 'MESH:C055075', (186, 215))	('oligosaccharides', 'Protein', (162, 178))	('results in', 'Reg', (121, 131))	('CHO', 'CellLine', 'CVCL:0213', (270, 273))
34215	22767667	hypertension, proteinuria and thrombosis) were not associated with TRC105, suggesting that TRC105 may be combined safely with VEGF-targeted agents to enhance clinical benefit.	('proteinuria', 'Disease', (14, 25))	('hypertension', 'Disease', 'MESH:D006973', (0, 12))	('thrombosis', 'Disease', 'MESH:D013927', (30, 40))	('TRC105', 'Var', (91, 97))	('proteinuria', 'Phenotype', 'HP:0000093', (14, 25))	('VEGF', 'Gene', '7422', (126, 130))	('hypertension', 'Disease', (0, 12))	('proteinuria', 'Disease', 'MESH:D011507', (14, 25))	('TRC105', 'Chemical', 'MESH:C579557', (67, 73))	('TRC105', 'Chemical', 'MESH:C579557', (91, 97))	('hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('combined', 'Interaction', (105, 113))	('VEGF', 'Gene', (126, 130))	('thrombosis', 'Disease', (30, 40))	('enhance', 'PosReg', (150, 157))
34220	22767667	By binding CD105, TRC105 inhibits angiogenesis and appears to have a safety profile distinct from VEGF inhibitors.	('TRC105', 'Var', (18, 24))	('VEGF', 'Gene', '7422', (98, 102))	('inhibits', 'NegReg', (25, 33))	('binding', 'Interaction', (3, 10))	('TRC105', 'Chemical', 'MESH:C579557', (18, 24))	('CD105', 'Gene', '13805', (11, 16))	('CD105', 'Gene', (11, 16))	('angiogenesis', 'CPA', (34, 46))	('VEGF', 'Gene', (98, 102))
34221	22767667	This phase 1 first-in-human study presents safety, pharmacokinetics, and antitumor activity data in patients with advanced solid tumors that supports ongoing phase 1b and phase 2 studies of TRC105 in combination with chemotherapy, with VEGF inhibitors, and as a single agent in patients with advanced prostate, ovarian, breast, bladder, and hepatocellular cancer.	('VEGF', 'Gene', '7422', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('patients', 'Species', '9606', (100, 108))	('VEGF', 'Gene', (236, 240))	('tumor', 'Disease', (129, 134))	('hepatocellular cancer', 'Disease', (341, 362))	('solid tumors', 'Disease', (123, 135))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (341, 362))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('TRC105', 'Chemical', 'MESH:C579557', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (341, 362))	('ovarian', 'Disease', (311, 318))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('breast', 'Disease', (320, 326))	('bladder', 'Disease', (328, 335))	('solid tumors', 'Disease', 'MESH:D009369', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('advanced prostate', 'Disease', 'MESH:D011472', (292, 309))	('human', 'Species', '9606', (22, 27))	('advanced prostate', 'Disease', (292, 309))	('TRC105', 'Var', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('patients', 'Species', '9606', (278, 286))	('tumor', 'Disease', (77, 82))
34266	21326237	Mid-secretory endometrium also has prominent peaks in the lipid region (1735 cm-1), Amide I (1666, 1627, 1597 cm-1), Amide II (1516 cm-1), other protein regions (1481, 1435 cm-1), nuasPO2- (1215 cm-1), and symmetric phosphate stretching vibrations (nusPO2- (1095 cm-1)) regions.	('Amide', 'Chemical', 'MESH:D000577', (117, 122))	('1666', 'Var', (93, 97))	('1481', 'Var', (162, 166))	('Amide II', 'MPA', (117, 125))	('lipid', 'Chemical', 'MESH:D008055', (58, 63))	('symmetric phosphate stretching vibrations', 'MPA', (206, 247))	('nuasPO2', 'Chemical', '-', (180, 187))	('lipid region', 'MPA', (58, 70))	('Amide', 'Chemical', 'MESH:D000577', (84, 89))	('Amide I', 'MPA', (84, 91))	('phosphate', 'Chemical', 'MESH:D010710', (216, 225))
34274	21326237	Between 1800 and 1500 cm-1, the vectors differ in magnitude of absorbance, with larger lipid (1735 cm-1), Amide I (1624 cm-1) and Amide II (1570, 1516 cm-1) peaks together with a separate peak at 1681 cm-1 (Amide I) for endometrioid cancers (see Table 2 for a full list of distinguishing wavenumbers).	('endometrioid cancers', 'Disease', 'MESH:D016889', (220, 240))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lipid', 'Chemical', 'MESH:D008055', (87, 92))	('lipid', 'MPA', (87, 92))	('endometrioid cancers', 'Disease', (220, 240))	('1735', 'Var', (94, 98))	('Amide', 'MPA', (106, 111))	('Amide', 'Chemical', 'MESH:D000577', (207, 212))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('Amide', 'Chemical', 'MESH:D000577', (106, 111))	('Amide', 'Chemical', 'MESH:D000577', (130, 135))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (220, 239))
34286	21326237	The most important wavenumbers in distinguishing between proliferative endometrium and endometrioid cancer are 1732 cm-1 (lipid), 1681/1620 cm-1 (both Amide I), 1581/1516 cm-1 (both Amide II), 1234 cm-1 (nuasPO2-), 1149 cm-1 (carbohydrate), 1020 cm-1 (glycogen), and 968 cm-1 (protein phosphorylation).	('1581/1516 cm-1', 'Var', (161, 175))	('carbohydrate', 'Chemical', 'MESH:D002241', (226, 238))	('lipid', 'Chemical', 'MESH:D008055', (122, 127))	('Amide', 'Chemical', 'MESH:D000577', (151, 156))	('Amide', 'Chemical', 'MESH:D000577', (182, 187))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (87, 106))	('proliferative endometrium', 'Phenotype', 'HP:0040298', (57, 82))	('1681/1620 cm-1', 'Var', (130, 144))	('endometrioid cancer', 'Disease', (87, 106))	('nuasPO2', 'Chemical', '-', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('proliferative endometrium', 'Disease', (57, 82))	('1234 cm-1', 'Var', (193, 202))	('1732 cm-1', 'Var', (111, 120))	('glycogen', 'Chemical', 'MESH:D006003', (252, 260))	('endometrioid cancer', 'Disease', 'MESH:D016889', (87, 106))
34452	33173419	Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('overexpression', 'PosReg', (37, 51))	('AKT', 'Gene', (24, 27))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('mTOR', 'Gene', '2475', (19, 23))	('sarcoma', 'Disease', (111, 118))	('Hyperactivation', 'Var', (0, 15))	('carcinosarcoma', 'Disease', (123, 137))	('mTOR', 'Gene', (19, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', (130, 137))	('PI3', 'Gene', '5266', (28, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('AKT', 'Gene', '207', (24, 27))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (103, 118))	('PI3', 'Gene', (28, 31))	('carcinosarcoma', 'Disease', 'MESH:D002296', (123, 137))
34510	33173419	GEM+MLN combination showed additivity also in ESS-1, in this cell line addition was also deteted in combinations: GEM+RAP and MLN+RAP.	('GEM', 'Chemical', 'MESH:C056507', (114, 117))	('RAP', 'Chemical', '-', (118, 121))	('ESS-1', 'Gene', '7046', (46, 51))	('ESS-1', 'Gene', (46, 51))	('MLN', 'Gene', (4, 7))	('MLN', 'Gene', (126, 129))	('GEM+RAP', 'Var', (114, 121))	('RAP', 'Chemical', '-', (130, 133))	('MLN', 'Gene', '4295', (126, 129))	('MLN', 'Gene', '4295', (4, 7))	('GEM', 'Chemical', 'MESH:C056507', (0, 3))
34511	33173419	Additivity was observed for MLN+RAP and GAM+RAP.	('MLN', 'Gene', '4295', (28, 31))	('RAP', 'Chemical', '-', (32, 35))	('RAP', 'Chemical', '-', (44, 47))	('MLN', 'Gene', (28, 31))	('GAM+RAP', 'Var', (40, 47))
34578	32942614	NAA40 (NatD) emerged as a NAT with particularly interesting cancer biology and therapeutic potential, especially in liver cancer where a novel oncogenic role was supported by its increased expression in multiple studies and its association with patient survival.	('liver cancer', 'Disease', 'MESH:D006528', (116, 128))	('liver cancer', 'Disease', (116, 128))	('association', 'Interaction', (228, 239))	('NAT', 'Gene', '80155', (26, 29))	('NAA40', 'Var', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('NatD', 'Gene', '8260', (7, 11))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('NAT', 'Gene', (26, 29))	('NatD', 'Gene', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('patient', 'Species', '9606', (245, 252))	('liver cancer', 'Phenotype', 'HP:0002896', (116, 128))
34590	32942614	In contrast to this more widespread NATs, NAA40 (NatD) and NAA80 (NatH) are much more selective, with NAA40 acting on histones H2A and H4, while NAA80 acts on Actin.	('histones H2A', 'Protein', (118, 130))	('NAT', 'Gene', '80155', (36, 39))	('acting', 'Reg', (108, 114))	('NAA40', 'Var', (102, 107))	('NatH', 'Gene', (66, 70))	('NatD', 'Gene', '8260', (49, 53))	('NAA80', 'Gene', (59, 64))	('NAA80', 'Gene', '24142', (59, 64))	('NAT', 'Gene', (36, 39))	('NAA80', 'Gene', '24142', (145, 150))	('NatD', 'Gene', (49, 53))	('NatH', 'Gene', '80155', (66, 70))	('NAA80', 'Gene', (145, 150))
34593	32942614	NAA40 modifies histone proteins which contain the unique "SGRG" sequence, while NAA80 acts post-translationally on actin N-termini.	('NAA80', 'Gene', '24142', (80, 85))	('NAA40', 'Var', (0, 5))	('histone proteins', 'Protein', (15, 31))	('modifies', 'Reg', (6, 14))	('NAA80', 'Gene', (80, 85))
34597	32942614	Moreover, NAA40 uniquely for a NAT member can also modulate the establishment and cross-talk of histone modifications which impact chromatin structure and gene expression.	('impact', 'Reg', (124, 130))	('NAT', 'Gene', (31, 34))	('NAA40', 'Var', (10, 15))	('gene expression', 'MPA', (155, 170))	('chromatin structure', 'MPA', (131, 150))	('histone', 'Protein', (96, 103))	('NAT', 'Gene', '80155', (31, 34))	('modulate', 'Reg', (51, 59))
34599	32942614	Different NATs have been reported to be involved in cancer e.g., NAA30 with glioblastoma, NAA20 in hepatocellular carcinoma, NAA40 in colon and lung and NAA10 with various types.	('NAT', 'Gene', (10, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('NAA10', 'Gene', (153, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('NAA30', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('involved', 'Reg', (40, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Disease', (76, 88))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))	('NAA10', 'Gene', '8260', (153, 158))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('NAA30', 'Gene', '122830', (65, 70))	('NAT', 'Gene', '80155', (10, 13))	('cancer', 'Disease', (52, 58))	('hepatocellular carcinoma', 'Disease', (99, 123))	('colon', 'Disease', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('NAA20', 'Gene', (90, 95))	('NAA40', 'Var', (125, 130))	('colon', 'Disease', 'MESH:D003110', (134, 139))	('NAA20', 'Gene', '51126', (90, 95))
34612	32942614	Moreover, for NAA40 in UCS, NAA50 in LUSC (lung squamous carcinoma), and NAA16 in prostate adenocarcinoma (PRAD), for which a sufficient number of samples displayed gene amplifications, CNVs were associated with increased transcript levels (Figure 1B, right panel), thus supporting gene amplification being a mechanism for their transcriptional deregulation.	('prostate adenocarcinoma', 'Disease', (82, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('NAA16', 'Gene', '79612', (73, 78))	('CS', 'Chemical', 'MESH:D002586', (24, 26))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (82, 105))	('NAA50', 'Gene', (28, 33))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (43, 66))	('CNVs', 'Var', (186, 190))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (43, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('NAA40', 'Var', (14, 19))	('transcript levels', 'MPA', (222, 239))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (48, 66))	('increased', 'PosReg', (212, 221))	('lung squamous carcinoma', 'Disease', (43, 66))	('NAA16', 'Gene', (73, 78))	('NAA50', 'Gene', '80218', (28, 33))
34615	32942614	The increased rate of mutations for these auxiliary subunits in comparison to other NATs was evident across all tumour types (Figure 1A).	('NAT', 'Gene', '80155', (84, 87))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('mutations', 'Var', (22, 31))	('NAT', 'Gene', (84, 87))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))
34617	32942614	Interestingly, normalisation for ORF length revealed a clear predominance of truncating:nonsense, frameshift, and splicing mutations:but not of missense mutations for the auxiliary NAT subunits, except for HYPK (Figure 1D).	('HYPK', 'Gene', '25764', (206, 210))	('NAT', 'Gene', (181, 184))	('nonsense', 'Var', (88, 96))	('truncating', 'MPA', (77, 87))	('frameshift', 'Var', (98, 108))	('NAT', 'Gene', '80155', (181, 184))	('HYPK', 'Gene', (206, 210))
34619	32942614	Furthermore, it is of much interest that certain truncating NAT mutations are recurring across the TCGA pan-cancer study, especially in uterine corpus endometrial carcinoma (UCEC) (Figure 1F).	('endometrial carcinoma', 'Disease', (151, 172))	('NAT', 'Gene', '80155', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (151, 172))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('truncating', 'Var', (49, 59))	('NAT', 'Gene', (60, 63))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (151, 172))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
34620	32942614	Thus, truncating mutations of specific auxiliary NATs could be selectively occurring in tumours.	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('NAT', 'Gene', (49, 52))	('tumours', 'Disease', (88, 95))	('NAT', 'Gene', '80155', (49, 52))	('truncating mutations', 'Var', (6, 26))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))
34621	32942614	In conclusion, our analyses of genomic alterations of NATs in cancers found these to be relatively low frequency events, with some notable exceptions, such as NAA40 amplification in UCS, and NAA15 truncating mutations in UCEC.	('NAT', 'Gene', '80155', (54, 57))	('NAA15', 'Gene', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('UCS', 'Disease', (182, 185))	('amplification', 'Var', (165, 178))	('NAA40 amplification', 'Var', (159, 178))	('UCEC', 'Gene', (221, 225))	('NAA15', 'Gene', '80155', (191, 196))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('NAT', 'Gene', (54, 57))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('CS', 'Chemical', 'MESH:D002586', (183, 185))
34622	32942614	Besides the mutation of NAT genes themselves, it is possible that mutations of residues within their protein substrates can also disrupt NAT-associated regulation in cancers.	('mutations', 'Var', (66, 75))	('cancers', 'Disease', (166, 173))	('NAT', 'Gene', (137, 140))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('NAT', 'Gene', (24, 27))	('NAT', 'Gene', '80155', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('NAT', 'Gene', '80155', (24, 27))	('disrupt', 'NegReg', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
34623	32942614	For example, a loss of Nt-Ac could potentially destabilise tumour suppressor proteins or favour more oncogenic functions.	('Nt-Ac', 'Chemical', '-', (23, 28))	('destabilise', 'NegReg', (47, 58))	('oncogenic functions', 'CPA', (101, 120))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('loss', 'Var', (15, 19))	('favour', 'PosReg', (89, 95))	('Nt-Ac', 'Gene', (23, 28))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))
34624	32942614	We, therefore, examined the degree to which mutations of protein residues targeted by NATs are important tumour events.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('NAT', 'Gene', (86, 89))	('tumour', 'Disease', (105, 111))	('mutations', 'Var', (44, 53))	('NAT', 'Gene', '80155', (86, 89))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('protein', 'Protein', (57, 64))
34626	32942614	Examination of the missense mutational count for the first five amino acid residues (P1-P5) across the TCGA pan-cancer study found similar levels for each amino acid position, thus mutations of the first two amino acids that would be associated with NAT regulation are not globally enriched in cancers (Figure 2B).	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('NAT', 'Gene', '80155', (250, 253))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('cancer', 'Disease', (294, 300))	('mutations', 'Var', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NAT', 'Gene', (250, 253))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
34627	32942614	Notably, mutations of P2 in TCGA are widely but thinly distributed, with the vast majority of genes being mutated at this position in only one or two tumour patient samples (Figure 2C).	('patient', 'Species', '9606', (157, 164))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (9, 18))	('tumour', 'Disease', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('TCGA', 'Gene', (28, 32))
34628	32942614	Furthermore, almost a third of all identified mutations of P2 (706/2183) are likely not significant in terms of their effect on Nt-Ac, as they involve exchanges that preserve amino acid targets of NatA (e.g., serine to alanine) or NatB (e.g., aspartate to glutamate).	('Nt-Ac', 'Chemical', '-', (128, 133))	('NatB', 'Chemical', '-', (231, 235))	('aspartate', 'Chemical', 'MESH:D001224', (243, 252))	('mutations', 'Var', (46, 55))	('amino acid targets', 'MPA', (175, 193))	('serine', 'Chemical', 'MESH:D012694', (209, 215))	('involve', 'Reg', (143, 150))	('alanine', 'Chemical', 'MESH:D000409', (219, 226))	('glutamate', 'Chemical', 'MESH:D018698', (256, 265))
34629	32942614	Given that mutation data were collected from more than 9000 tumour samples, it is evident therefore that mutations of P2 are not mutational hotspots in cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', (60, 66))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
34631	32942614	Examining the presence of missense mutations within the "SRGR" motif across the TCGA pan-cancer study, we found that mutations within this motif of individual H2A/H4 genes was low.	('missense mutations', 'Var', (26, 44))	('mutations', 'Var', (117, 126))	('H2A/H4', 'Gene', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
34632	32942614	Second, specific H2A and H4 mutations were recurring, e.g., serine 1 to cysteine and arginine 3 to glutamine for H2A (Figure 2F) (Tables S1 and S2).	('arginine 3 to glutamine', 'Mutation', 'rs781118026', (85, 108))	('H2A', 'Gene', (17, 20))	('serine 1 to cysteine', 'Mutation', 'p.S1C', (60, 80))	('serine 1 to cysteine and arginine', 'SUBSTITUTION', 'None', (60, 93))	('mutations', 'Var', (28, 37))
34633	32942614	It is interesting to note that H2A/H4 missense mutations make up a significant proportion of all detected mutations of serine at P2 of proteins across the TCGA pan-cancer study (7%), and an even greater proportion of serine to cysteine mutations at this position (23%).	('serine', 'Chemical', 'MESH:D012694', (119, 125))	('serine', 'Chemical', 'MESH:D012694', (217, 223))	('cysteine', 'Chemical', 'MESH:D003545', (227, 235))	('missense mutations', 'Var', (38, 56))	('serine', 'MPA', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('mutations', 'Var', (106, 115))	('H2A/H4', 'Gene', (31, 37))
34636	32942614	Across the TCGA pan-cancer study, only three cases of missense mutations of the N-terminal amino acid of the actin isoforms were found, suggesting that this is not a significant carcinogenic mechanism.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('carcinogenic', 'Disease', 'MESH:D063646', (178, 190))	('missense mutations', 'Var', (54, 72))	('carcinogenic', 'Disease', (178, 190))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))
34637	32942614	In conclusion, mutations of protein substrates of NATs do not appear to be significant genetic alterations in cancers, with the exception of recurrent mutations of H2A/H4.	('NAT', 'Gene', '80155', (50, 53))	('cancers', 'Disease', (110, 117))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (151, 160))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('NAT', 'Gene', (50, 53))	('H2A/H4', 'Gene', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
34648	32942614	For certain NATs, it was found that multiple independent datasets corroborate the altered transcript levels observed in the TCGA pan-cancer comparison of tumour vs. normal samples, e.g., NAA10 and NAA20 in colorectal cancer and NAA40 in liver cancer.	('NAA40', 'Var', (228, 233))	('colorectal cancer', 'Phenotype', 'HP:0003003', (206, 223))	('liver cancer', 'Phenotype', 'HP:0002896', (237, 249))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('liver cancer', 'Disease', (237, 249))	('NAA10', 'Gene', '8260', (187, 192))	('NAT', 'Gene', '80155', (12, 15))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('tumour', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('NAA20', 'Gene', (197, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (206, 223))	('NAA20', 'Gene', '51126', (197, 202))	('transcript levels', 'MPA', (90, 107))	('cancer', 'Disease', (133, 139))	('colorectal cancer', 'Disease', (206, 223))	('NAT', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('liver cancer', 'Disease', 'MESH:D006528', (237, 249))	('NAA10', 'Gene', (187, 192))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('altered', 'Reg', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
34651	32942614	Altered DNA methylation was the first epigenetic dysregulation identified in cancer and is highly prevalent.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Altered', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('methylation', 'Var', (12, 23))
34652	32942614	Therefore, we sought to find whether altered methylation of DNA could drive the altered expression of NATs between normal and tumour tissue.	('NAT', 'Gene', (102, 105))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('NAT', 'Gene', '80155', (102, 105))	('tumour', 'Disease', (126, 132))	('altered', 'Var', (37, 44))	('expression', 'MPA', (88, 98))
34654	32942614	Our filtering criteria were set as follows: (i) DNA probes were examined in tissues where NAT transcript levels were at least 1.5 fold different between tumour and normal tissue, (ii) DNA probes with beta values below 0.2 were not considered further, (iii) significant associations were deemed those with median Deltabeta < 0.1, correlation between transcript levels and probe methylation was <-0.2, and p < 0.01.	('tumour', 'Disease', (153, 159))	('associations', 'Interaction', (269, 281))	('NAT', 'Gene', (90, 93))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('NAT', 'Gene', '80155', (90, 93))	('Deltabeta', 'Var', (312, 321))	('tumour', 'Disease', 'MESH:D009369', (153, 159))
34657	32942614	The cg10759293 probe located within the first intron of NAA20 displayed both the most prominent decreases in its methylation (Figure 3B, right panel) and strongest anti-correlation with gene expression in two tumour types, lung squamous carcinoma (LUSC, r = -0.61) and esophageal carcinoma (ESCA, r = -0.56) (Figure 3C).	('cg10759293', 'Chemical', '-', (4, 14))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (228, 246))	('NAA20', 'Gene', (56, 61))	('esophageal carcinoma', 'Disease', (269, 289))	('cg10759293', 'Var', (4, 14))	('NAA20', 'Gene', '51126', (56, 61))	('lung squamous carcinoma', 'Disease', (223, 246))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('tumour', 'Disease', 'MESH:D009369', (209, 215))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (223, 246))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (269, 289))	('tumour', 'Disease', (209, 215))	('methylation', 'MPA', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('gene expression', 'MPA', (186, 201))	('decreases', 'NegReg', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (223, 246))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (269, 289))
34658	32942614	Of the other DNA methylation probes which display a more moderate relationship (r = -0.23 to -0.34), three (cg22971920, cg02602300, cg25758314) are located in the promoter of NAA10 and one (cg00356723) in the promoter of NAA40.	('cg02602300', 'Var', (120, 130))	('cg25758314', 'Var', (132, 142))	('cg22971920', 'Var', (108, 118))	('NAA10', 'Gene', '8260', (175, 180))	('cg00356723', 'Var', (190, 200))	('NAA10', 'Gene', (175, 180))
34664	32942614	Collectively, the analyses conducted here support that the gene deregulation of NATs is a common tumour event and can be correlated with disease survival.	('tumour', 'Disease', (97, 103))	('NAT', 'Gene', '80155', (80, 83))	('gene deregulation', 'Var', (59, 76))	('NAT', 'Gene', (80, 83))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (97, 103))
34665	32942614	Altered DNA methylation may drive the deregulation of NATs in some tumours.	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('NAT', 'Gene', '80155', (54, 57))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('DNA', 'Protein', (8, 11))	('Altered', 'Var', (0, 7))	('NAT', 'Gene', (54, 57))	('deregulation', 'MPA', (38, 50))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
34679	32942614	This analysis found that, compared to NATs, cancer cells can in general tolerate to a greater degree the genomic deletion of KATs compared to NATs, with a small fraction of highly essential enzymes (e.g., TAF1 and ELP3) (Figure S4).	('TAF1', 'Gene', '6872', (205, 209))	('KATs', 'Gene', (125, 129))	('ELP3', 'Gene', (214, 218))	('TAF1', 'Gene', (205, 209))	('genomic', 'Var', (105, 112))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('NAT', 'Gene', (38, 41))	('NAT', 'Gene', (142, 145))	('ELP3', 'Gene', '55140', (214, 218))	('NAT', 'Gene', '80155', (38, 41))	('NAT', 'Gene', '80155', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
34689	32942614	For the link between sensitivity to NAT targeting and transcript levels of other NATs, two significant correlations were found: High levels of NAA11 were associated with reduced sensitivity to NAA10 deletion (r = 0.74; top ranked such correlation) and of NAA16 with targeting of NAA15 (r = 0.18, ranked 16th strongest) (Figure S5).	('NAA10', 'Gene', '8260', (193, 198))	('NAT', 'Gene', '80155', (36, 39))	('NAT', 'Gene', '80155', (81, 84))	('NAA15', 'Gene', '80155', (279, 284))	('NAA11', 'Gene', '84779', (143, 148))	('sensitivity', 'MPA', (178, 189))	('NAA10', 'Gene', (193, 198))	('reduced', 'NegReg', (170, 177))	('NAA16', 'Gene', '79612', (255, 260))	('NAT', 'Gene', (36, 39))	('deletion', 'Var', (199, 207))	('NAT', 'Gene', (81, 84))	('NAA11', 'Gene', (143, 148))	('NAA16', 'Gene', (255, 260))	('NAA15', 'Gene', (279, 284))
34699	32942614	In 10 out of the 20 studies, NAA40 mRNA levels were greater than 1.5-fold in this specific cancer tissue, while it was not downregulated in any of them (Figure 5A, right panel).	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('greater', 'PosReg', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NAA40', 'Var', (29, 34))
34701	32942614	Hence, the upregulation NAA40 is a common event in liver cancer and is associated with worse patient survival.	('liver cancer', 'Phenotype', 'HP:0002896', (51, 63))	('liver cancer', 'Disease', 'MESH:D006528', (51, 63))	('NAA40', 'Var', (24, 29))	('liver cancer', 'Disease', (51, 63))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('upregulation', 'PosReg', (11, 23))
34704	32942614	Likewise, with tumours, levels of NAA40 were relatively low in the normal liver tissue, being the second lowest amongst 54 human tissues, and 10-fold lower than pituitary and cerebellum (Figure 5C, right).	('lower', 'NegReg', (150, 155))	('human', 'Species', '9606', (123, 128))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumours', 'Disease', (15, 22))	('NAA40', 'Var', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
34706	32942614	In both the developing liver in vivo and in the differentiating ES models, the levels of NAA40 were gradually decreasing, indicating that NAA40 is developmentally repressed in the liver lineage, but reactivated in tumour tissue.	('levels', 'MPA', (79, 85))	('tumour', 'Disease', (214, 220))	('NAA40', 'Var', (138, 143))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('decreasing', 'NegReg', (110, 120))
34713	32942614	Nevertheless, three interesting cases of genomic alterations revealed by this study were (1) NAA40 amplification in UCS, (2) NAA15 truncating mutations in Uterine CS, and (3) recurrent H2A/H4 mutations.	('H2A/H4', 'Gene', (185, 191))	('mutations', 'Var', (192, 201))	('CS', 'Chemical', 'MESH:D002586', (163, 165))	('NAA15', 'Gene', '80155', (125, 130))	('UCS', 'Disease', (116, 119))	('CS', 'Chemical', 'MESH:D002586', (117, 119))	('NAA40 amplification', 'Var', (93, 112))	('NAA15', 'Gene', (125, 130))
34717	32942614	Regarding the recurring truncating NAA15 mutations, these have been associated previously with intellectual disability and congenital disorders, although not cancer.	('mutations', 'Var', (41, 50))	('associated', 'Reg', (68, 78))	('intellectual disability', 'Disease', (95, 118))	('NAA15', 'Gene', '80155', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('NAA15', 'Gene', (35, 40))	('congenital disorders', 'Disease', 'MESH:D009358', (123, 143))	('intellectual disability', 'Phenotype', 'HP:0001249', (95, 118))	('congenital disorders', 'Disease', (123, 143))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
34718	32942614	The high prevalence of truncating NAA15 mutations was somewhat surprising, given that it is also highly essential to cancer cells (Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('NAA15', 'Gene', (34, 39))	('truncating', 'MPA', (23, 33))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('NAA15', 'Gene', '80155', (34, 39))
34719	32942614	It is interesting to note that both S1C and R3C mutations are expected to impact not only NAA40 substrate recognition and Nt-Ac, but also crosstalk with other internal histone modifications (S1 phosphorylation and R3 methylation).	('R3C', 'Gene', (44, 47))	('Nt-Ac', 'MPA', (122, 127))	('impact', 'Reg', (74, 80))	('Nt-Ac', 'Chemical', '-', (122, 127))	('NAA40', 'Protein', (90, 95))	('crosstalk', 'Reg', (138, 147))	('S1C', 'Gene', (36, 39))	('mutations', 'Var', (48, 57))
34723	32942614	A second observation was that some NATs were deregulated in multiple tumour types (e.g., NAA10, NAA20, and NAA40), while others in few or none (e.g., NAA30, NAA60, NAA35).	('tumour', 'Disease', (69, 75))	('NAA35', 'Gene', (164, 169))	('deregulated', 'Reg', (45, 56))	('NAA20', 'Gene', (96, 101))	('NAA30', 'Gene', '122830', (150, 155))	('NAA10', 'Gene', '8260', (89, 94))	('NAT', 'Gene', (35, 38))	('NAA20', 'Gene', '51126', (96, 101))	('NAA30', 'Gene', (150, 155))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('NAA40', 'Var', (107, 112))	('NAT', 'Gene', '80155', (35, 38))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('NAA35', 'Gene', '60560', (164, 169))	('NAA60', 'Gene', '79903', (157, 162))	('NAA10', 'Gene', (89, 94))	('NAA60', 'Gene', (157, 162))
34725	32942614	We have also shown potential mechanistic links between altered DNA methylation and the deregulation of NATs in some tumours.	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('DNA', 'Protein', (63, 66))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('altered', 'Var', (55, 62))	('NAT', 'Gene', (103, 106))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumours', 'Disease', (116, 123))	('NAT', 'Gene', '80155', (103, 106))	('deregulation', 'MPA', (87, 99))
34740	32942614	Finally, NAA30 and NAA40 were essential to some, but not all, cancer cells, indicating that their targeting could be particularly effective in specific genetic or transcriptomic contexts.	('NAA40', 'Var', (19, 24))	('NAA30', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('NAA30', 'Gene', '122830', (9, 14))
34753	32942614	Given the low levels of expression of NAA40 in normal liver, the potentially druggable nature of NAA40, the increasing incidence of liver cancers in the developed world, and the lack of efficacious cures for liver cancer, further investigations into the cancer role of this NAT in liver cancer are warranted.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('liver cancer', 'Phenotype', 'HP:0002896', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('liver cancers', 'Phenotype', 'HP:0002896', (132, 145))	('cancer', 'Disease', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('liver cancer', 'Disease', 'MESH:D006528', (281, 293))	('cancer', 'Disease', (214, 220))	('NAT', 'Gene', '80155', (274, 277))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('liver cancer', 'Disease', 'MESH:D006528', (208, 220))	('NAA40', 'Var', (97, 102))	('liver cancers', 'Disease', (132, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('liver cancer', 'Phenotype', 'HP:0002896', (281, 293))	('liver cancer', 'Disease', (281, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('NAT', 'Gene', (274, 277))	('NAA40', 'Gene', (38, 43))	('liver cancer', 'Phenotype', 'HP:0002896', (208, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('liver cancer', 'Disease', (208, 220))	('liver cancer', 'Disease', 'MESH:D006528', (132, 144))	('liver cancers', 'Disease', 'MESH:D006528', (132, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))
34766	32942614	For liver analyses, the following studies were examined: Liver regeneration data after hepatectomy (GSE63742); developing mouse liver (GSE13149); differentiating ES (GSE19044).	('Liver regeneration data', 'CPA', (57, 80))	('mouse', 'Species', '10090', (122, 127))	('GSE19044', 'Var', (166, 174))
34769	32942614	Using a multi-omics approach, we have uncovered, in this study, several novel interesting NAT-tumour connections, such as: tumour specific amplifications of NAA40 and NAA15 truncating mutations; recurring mutations of H2A/H4 NAA40 motif; strong anti-correlations between NAA20 first intron methylation and its expression in LUSC and ESCA tumours; ability of NAA11 to compensate for targeting of its homolog NAA10; and an oncogenic role for NAA40 in liver cancer.	('tumour', 'Disease', (94, 100))	('NAA20', 'Gene', (271, 276))	('NAA40', 'Gene', (225, 230))	('NAA10', 'Gene', (407, 412))	('tumour', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (455, 461))	('liver cancer', 'Phenotype', 'HP:0002896', (449, 461))	('tumour', 'Disease', 'MESH:D009369', (338, 344))	('tumour', 'Disease', (338, 344))	('NAA20', 'Gene', '51126', (271, 276))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('liver cancer', 'Disease', (449, 461))	('NAA11', 'Gene', (358, 363))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('NAT-tumour', 'Disease', 'MESH:D009369', (90, 100))	('tumour', 'Disease', (123, 129))	('expression', 'MPA', (310, 320))	('NAA11', 'Gene', '84779', (358, 363))	('H2A/H4 NAA40', 'Gene', (218, 230))	('ESCA tumours', 'Disease', 'MESH:D009369', (333, 345))	('NAA10', 'Gene', '8260', (407, 412))	('NAA15', 'Gene', (167, 172))	('mutations', 'Var', (205, 214))	('NAA40', 'Gene', (157, 162))	('NAA15', 'Gene', '80155', (167, 172))	('NAT-tumour', 'Disease', (90, 100))	('anti-correlations', 'NegReg', (245, 262))	('ESCA tumours', 'Disease', (333, 345))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (338, 345))	('liver cancer', 'Disease', 'MESH:D006528', (449, 461))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
34773	32942614	Studies with significant NAT gene deregulation in Oncomine Database, Figure S4.	('Oncomine', 'Chemical', '-', (50, 58))	('NAT', 'Gene', (25, 28))	('deregulation', 'Var', (34, 46))	('NAT', 'Gene', '80155', (25, 28))
34776	32942614	Histone H2A missense mutations of "SRGR" motif in TCGA pan-cancer, Table S2.	('missense mutations', 'Var', (12, 30))	('Histone H2A', 'Protein', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
34777	32942614	Histone H4 missense mutations of "SRGR" motif in TCGA pan-cancer, Table S3.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Histone H4', 'Gene', (0, 10))	('Histone H4', 'Gene', '8361', (0, 10))	('missense mutations', 'Var', (11, 29))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
34801	32270788	The inclusion criteria were: (1) identified as leiomyosarcoma with ICD-O-3/WHO 2008 histology codes (8890, 8891, 8896); (2) tumor anatomic site codes (C54.0-C54.3, C54.8-54.9, C55.9); and (3) diagnosed between 2004 and 2015.	('leiomyosarcoma', 'Disease', (47, 61))	('C55.9', 'Var', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (47, 61))	('tumor', 'Disease', (124, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (47, 61))	('C54.0-C54.3', 'Var', (151, 162))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
34863	32140533	The significance of HER2/neu (i.e., the human epidermal growth factor receptor 2 encoded by the c-erbB2 gene) overexpression and/or gene amplification has been well established in the pathogenesis and targeted treatment of breast, gastric, and gastroesophageal junction carcinomas.	('HER2/neu', 'Gene', (20, 28))	('c-erbB2', 'Gene', '2064', (96, 103))	('breast', 'Disease', (223, 229))	('c-erbB2', 'Gene', (96, 103))	('gastroesophageal junction carcinomas', 'Disease', (244, 280))	('epidermal growth factor receptor 2', 'Gene', (46, 80))	('gastroesophageal junction carcinomas', 'Disease', 'MESH:D008309', (244, 280))	('epidermal growth factor receptor 2', 'Gene', '2064', (46, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('gene amplification', 'Var', (132, 150))	('HER2/neu', 'Gene', '2064', (20, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (270, 280))	('gastric', 'Disease', (231, 238))	('human', 'Species', '9606', (40, 45))	('overexpression', 'PosReg', (110, 124))
34865	32140533	Importantly, HER2/neu overexpression and/or gene amplification have been previously correlated to worse overall survival in many human tumors, including USC patients.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('overexpression', 'PosReg', (22, 36))	('USC', 'Disease', (153, 156))	('HER2/neu', 'Gene', '2064', (13, 21))	('patients', 'Species', '9606', (157, 165))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('HER2/neu', 'Gene', (13, 21))	('human', 'Species', '9606', (129, 134))	('gene amplification', 'Var', (44, 62))
34907	32140533	Indeed, in gastric cancer, the frequency of intra-tumoral HER2/neu heterogeneity by IHC has been reported in up to 45-79% of the tumors.	('HER2/neu', 'Gene', (58, 66))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('intra-tumoral HER2', 'Disease', 'MESH:D009369', (44, 62))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (11, 25))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('heterogeneity', 'Var', (67, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (11, 25))	('HER2/neu', 'Gene', '2064', (58, 66))	('intra-tumoral HER2', 'Disease', (44, 62))	('gastric cancer', 'Disease', (11, 25))
34909	32140533	Accordingly, study authors suggested that intra-tumoral HER2/neu heterogeneity was the pivotal predictor of clinical response and a poor prognosticator for trastuzumab-based chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('intra-tumoral HER2', 'Disease', 'MESH:D009369', (42, 60))	('intra-tumoral HER2', 'Disease', (42, 60))	('HER2/neu', 'Gene', (56, 64))	('heterogeneity', 'Var', (65, 78))	('trastuzumab', 'Chemical', 'MESH:D000068878', (156, 167))	('HER2/neu', 'Gene', '2064', (56, 64))
34911	32140533	In a study comparing ASCO/CAP and FDA scoring criteria to assess HER2/neu in 108 endometrial carcinoma cases (85 pure serous carcinomas and 23 mixed carcinomas with a serous component), thirty-eight cases (35%) showed HER2/neu overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by IHC.	('carcinomas', 'Disease', (149, 159))	('HER2/neu', 'Gene', '2064', (218, 226))	('carcinomas', 'Disease', (125, 135))	('HER2/neu', 'Gene', '2064', (65, 73))	('overexpression', 'PosReg', (227, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('endometrial carcinoma', 'Disease', (81, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Disease', 'MESH:D002277', (125, 135))	('pure serous carcinomas', 'Disease', (113, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('carcinomas', 'Disease', 'MESH:D002277', (149, 159))	('pure serous carcinomas', 'Disease', 'MESH:C536289', (113, 135))	('gene amplification', 'Var', (249, 267))	('HER2/neu', 'Gene', (218, 226))	('HER2/neu', 'Gene', (65, 73))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (81, 102))
35046	29850320	In the absence of infection, C. perfringens has no clinical significance and causes clinical illness in only about 5% of isolates.	('absence of infection', 'Disease', (7, 27))	('clinical illness', 'Disease', (84, 100))	('C. perfringens', 'Var', (29, 43))	('causes', 'Reg', (77, 83))	('absence of infection', 'Disease', 'MESH:D004832', (7, 27))
35076	28541635	The following inclusion criteria were applied: 1) patient age <=50 years; 2) diagnosis of a primary tumor with malignant behavior located at the uterus (International Classification of Diseases for Oncology, 3rd Edition [ICD-O-3]/World Health Organization [WHO] 2008 site-specific codes C540-549, 559); 3) active follow-up (diagnosis not obtained from autopsy or death certificate); and 4) histologically confirmed sarcoma limited to the uterus (FIGO stage I disease).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('sarcoma', 'Disease', (415, 422))	('death', 'Disease', 'MESH:D003643', (363, 368))	('C540-549', 'Var', (287, 295))	('death', 'Disease', (363, 368))	('Oncology', 'Phenotype', 'HP:0002664', (198, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (415, 422))	('primary tumor', 'Disease', (92, 105))	('sarcoma', 'Disease', 'MESH:D012509', (415, 422))	('C540-549', 'CellLine', 'CVCL:0023', (287, 295))	('primary tumor', 'Disease', 'MESH:D009369', (92, 105))	('patient', 'Species', '9606', (50, 57))	('sarcoma limited to the uterus', 'Phenotype', 'HP:0010784', (415, 444))
35101	28541635	According to the histopathology report, LND was performed in 29.4% of the patients; higher rates of LND were noted for women with AS (50.6%) and LG-ESS (29.0%) compared to LMS (25.3%) (p<0.001).	('patients', 'Species', '9606', (74, 82))	('women', 'Species', '9606', (119, 124))	('LG-ESS', 'Var', (145, 151))	('higher', 'PosReg', (84, 90))
35380	22953093	Unfavorable prognostic factors for mullerian adenosarcoma are cytological atypia, high-mitotic rate, SO, presence of heterologous elements, dep myometrium invasion, necrosis and extra-uterine spread.	('necrosis', 'Disease', (165, 173))	('dep myometrium invasion', 'CPA', (140, 163))	('extra-uterine spread', 'CPA', (178, 198))	('necrosis', 'Disease', 'MESH:D009336', (165, 173))	('presence', 'Var', (105, 113))	('adenosarcoma', 'Disease', (45, 57))	('adenosarcoma', 'Disease', 'MESH:D018195', (45, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('high-mitotic rate', 'CPA', (82, 99))
35401	34036097	Loss of function (LOF) mutation of PTEN is an early event occurring in normal glandular cells, but it is insufficient to initiate tumorigenesis of endometrioid EC.	('mutation', 'Var', (23, 31))	('PTEN', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Loss of function', 'NegReg', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('endometrioid EC', 'Disease', (147, 162))	('tumor', 'Disease', (130, 135))	('EC', 'Phenotype', 'HP:0012114', (160, 162))
35402	34036097	Numerous studies have reported that the cooccurrence of mutations in PTEN and other genes, such as the activating mutation of PIK3CA (catalytic subunit alpha of PI3K), PIK3R1, PIK3R2, MLH1 inactivation, LOF mutation of ARID1A, and mutation of CTNNB1, contributed to endometrial carcinogenesis.	('PIK3R1', 'Gene', '5295', (168, 174))	('PIK3R2', 'Gene', '5296', (176, 182))	('activating', 'PosReg', (103, 113))	('inactivation', 'Var', (189, 201))	('mutation', 'Var', (114, 122))	('LOF', 'NegReg', (203, 206))	('mutations', 'Var', (56, 65))	('CTNNB1', 'Gene', (243, 249))	('mutation', 'Var', (207, 215))	('mutation', 'Var', (231, 239))	('PIK3R1', 'Gene', (168, 174))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (266, 292))	('endometrial carcinogenesis', 'Disease', (266, 292))	('MLH1', 'Gene', (184, 188))	('PIK3CA', 'Gene', (126, 132))	('PIK3R2', 'Gene', (176, 182))	('ARID1A', 'Gene', (219, 225))	('MLH1', 'Gene', '4292', (184, 188))	('PTEN', 'Gene', (69, 73))
35403	34036097	The role of PIK3CA mutation on the existing PTEN mutation in complex atypical hyperplasia of endometrial epithelium has been studied.	('mutation', 'Var', (49, 57))	('hyperplasia of endometrial epithelium', 'Phenotype', 'HP:0040298', (78, 115))	('PTEN', 'Gene', (44, 48))	('hyperplasia', 'Disease', (78, 89))	('hyperplasia', 'Disease', 'MESH:D006965', (78, 89))	('PIK3CA', 'Gene', (12, 18))
35404	34036097	Knockdown of PTEN expression in a cell line with a PIK3CA mutation resulted in the enhancement of phosphorylation of Akt, suggesting that an aberration of PIK3CA exerts an additive effect on PI3K activation, leading to endometrioid carcinogenesis.	('enhancement', 'PosReg', (83, 94))	('phosphorylation', 'MPA', (98, 113))	('leading to', 'Reg', (208, 218))	('endometrioid carcinogenesis', 'Disease', (219, 246))	('Akt', 'Gene', (117, 120))	('mutation', 'Var', (58, 66))	('PIK3CA', 'Gene', (51, 57))	('endometrioid carcinogenesis', 'Disease', 'MESH:D063646', (219, 246))	('aberration', 'Var', (141, 151))	('PIK3CA', 'Gene', (155, 161))	('Akt', 'Gene', '207', (117, 120))	('PTEN', 'Gene', (13, 17))
35405	34036097	The cooperative role of PIK3CA mutation with PTEN inactivation in endometrioid carcinogenesis was also investigated with genetically engineered mouse models.	('mouse', 'Species', '10090', (144, 149))	('PIK3CA', 'Gene', (24, 30))	('mutation', 'Var', (31, 39))	('endometrioid carcinogenesis', 'Disease', (66, 93))	('endometrioid carcinogenesis', 'Disease', 'MESH:D063646', (66, 93))
35406	34036097	The endometrial epithelium of mouse models harboring PIK3CAE545K developed into hyperplasia or cancer, while mice models with an activated mutation of PIK3CA on the underlying PTEN loss caused endometrial carcinoma, suggesting the distinct but integrative role of PTEN inactivation and activated PIK3CA.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (193, 214))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PIK3CA', 'Gene', (151, 157))	('developed', 'Reg', (65, 74))	('cancer', 'Disease', (95, 101))	('caused', 'Reg', (186, 192))	('PTEN loss', 'Disease', (176, 185))	('hyperplasia', 'Disease', 'MESH:D006965', (80, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('mice', 'Species', '10090', (109, 113))	('PIK3CAE545K', 'Var', (53, 64))	('endometrial carcinoma', 'Disease', (193, 214))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (193, 214))	('mouse', 'Species', '10090', (30, 35))	('PTEN loss', 'Disease', 'MESH:D006223', (176, 185))	('hyperplasia', 'Disease', (80, 91))
35407	34036097	The importance of additional genetic aberration on the background PTEN mutation has also been demonstrated using heterozygous PTEN and biallelic MLH1-deficient (PTEN+/-MLH-/-) mice, by showing an acceleration of endometrial tumorigenesis.	('endometrial tumorigenesis', 'Disease', 'MESH:D016889', (212, 237))	('acceleration', 'PosReg', (196, 208))	('PTEN', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('mutation', 'Var', (71, 79))	('endometrial tumorigenesis', 'Disease', (212, 237))	('mice', 'Species', '10090', (176, 180))	('MLH1-deficient', 'Disease', (145, 159))	('MLH1-deficient', 'Disease', 'MESH:D007153', (145, 159))
35408	34036097	The role of concurrent mutations of multiple driver genes in endometrioid carcinogenesis was also shown in an in vivo castrated female mouse model harboring a CTNNB1 exon 3 mutation, a LOF mutation of PTEN, and a PIK3CA activating mutation in the endometrial epithelium.	('PIK3CA', 'Gene', (213, 219))	('PTEN', 'Gene', (201, 205))	('mouse', 'Species', '10090', (135, 140))	('endometrioid carcinogenesis', 'Disease', 'MESH:D063646', (61, 88))	('mutation', 'Var', (189, 197))	('CTNNB1', 'Gene', (159, 165))	('endometrioid carcinogenesis', 'Disease', (61, 88))	('LOF', 'NegReg', (185, 188))	('mutation', 'Var', (173, 181))
35409	34036097	A CTNNB1 mutation was revealed to be critical in the growth of ovarian steroids retaining preneoplastic epithelial cells with PTEN and PIK3CA mutations and myometrial invasion of endometrioid carcinoma in castrated mice harboring PTEN LOF and PIK3CA activating mutations.	('CTNNB1', 'Gene', (2, 8))	('mutations', 'Var', (142, 151))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (179, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('ovarian', 'Disease', 'MESH:D010049', (63, 70))	('ovarian', 'Disease', (63, 70))	('endometrioid carcinoma', 'Disease', (179, 201))	('PIK3CA', 'Gene', (135, 141))	('mice', 'Species', '10090', (215, 219))	('myometrial invasion', 'CPA', (156, 175))	('PTEN', 'Gene', (126, 130))	('steroids', 'Chemical', 'MESH:D013256', (71, 79))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (179, 201))
35410	34036097	The ARID1A tumor suppressor gene, a commonly found mutation across cancers, has also showed its potential in endometrial carcinogenesis by integrating with PTEN inactivation.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('inactivation', 'Var', (161, 173))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('tumor', 'Disease', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (109, 135))	('endometrial carcinogenesis', 'Disease', (109, 135))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
35413	34036097	An in vitro cell culture assay also showed a greater proliferative activity in human endometrial epithelial cells with concurrent ARID1A and PTEN inactivation than cells with either PTEN or ARID1A inactivated, suggesting the potential of ARID1A as a gatekeeper in the preneoplastic endometrial epithelium to carcinoma transition.	('ARID1A', 'Gene', (130, 136))	('PTEN', 'Gene', (141, 145))	('human', 'Species', '9606', (79, 84))	('carcinoma', 'Disease', 'MESH:D009369', (308, 317))	('proliferative activity', 'CPA', (53, 75))	('gatekeeper', 'Species', '111938', (250, 260))	('greater', 'PosReg', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('inactivation', 'Var', (146, 158))	('carcinoma', 'Disease', (308, 317))
35415	34036097	Additionally, ARID1A deficiency was revealed to contribute to sensitization of cancer cells to Poly (ADP-Ribose) Polymerase (PARP) inhibitors.	('PARP', 'Gene', '142', (125, 129))	('sensitization', 'MPA', (62, 75))	('Poly (ADP-Ribose) Polymerase', 'Gene', (95, 123))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Poly (ADP-Ribose) Polymerase', 'Gene', '142', (95, 123))	('deficiency', 'Var', (21, 31))	('ARID1A', 'Gene', (14, 20))	('PARP', 'Gene', (125, 129))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
35417	34036097	Molecular alteration of the TP53 tumor suppressor gene is the most frequently occurring genetic event in serous carcinoma.	('occurring', 'Reg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('serous carcinoma', 'Disease', 'MESH:D018297', (105, 121))	('serous carcinoma', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('tumor', 'Disease', (33, 38))	('Molecular alteration', 'Var', (0, 20))
35418	34036097	p53 stabilization was demonstrated in SEIC, and now, TP53 mutations and/or p53 stabilization is regarded as a crucial early event in serous carcinoma tumorigenesis.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', (53, 57))	('serous carcinoma tumorigenesis', 'Disease', 'MESH:D063646', (133, 163))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SEIC', 'Phenotype', 'HP:0012887', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('serous carcinoma tumorigenesis', 'Disease', (133, 163))
35419	34036097	Significance of TP53 mutations and/or p53 stabilization in carcinogenesis from precursor lesions to type II ECs has also been demonstrated in an in vivo mouse model with endometrium-specific deletion of Trp53.	('deletion', 'Var', (191, 199))	('Trp53', 'Gene', (203, 208))	('mouse', 'Species', '10090', (153, 158))	('EC', 'Phenotype', 'HP:0012114', (108, 110))	('Trp53', 'Gene', '22059', (203, 208))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
35420	34036097	Dysregulation of the HER2/neu (ERBB2) receptor tyrosine kinase is another noteworthy molecular aberration in serous EC considering that HER2 is a proven druggable molecular target in other cancers, such as breast or gastric cancer.	('receptor tyrosine kinase', 'Gene', (38, 62))	('Dysregulation', 'Var', (0, 13))	('neu', 'Gene', '2064', (26, 29))	('HER2', 'Gene', '2064', (136, 140))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('EC', 'Phenotype', 'HP:0012114', (116, 118))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('HER2', 'Gene', '2064', (21, 25))	('ERBB2', 'Gene', (31, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('neu', 'Gene', (26, 29))	('HER2', 'Gene', (136, 140))	('ERBB2', 'Gene', '2064', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancers', 'Disease', (189, 196))	('breast or gastric cancer', 'Disease', (206, 230))	('serous EC', 'Disease', (109, 118))	('breast or gastric cancer', 'Disease', 'MESH:D001943', (206, 230))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('receptor tyrosine kinase', 'Gene', '5979', (38, 62))	('HER2', 'Gene', (21, 25))
35424	34036097	Other studied genetic aberrations that are implicated in serous carcinogenesis are somatic mutations in several genes, FBXW7, PPP2R1A, STOP, CHD4, TAF1, PIK3CA, and PTEN, although functional effects of these molecular events remain to be elucidated.	('FBXW7', 'Gene', '55294', (119, 124))	('PPP2R1A', 'Gene', '5518', (126, 133))	('PIK3CA', 'Gene', (153, 159))	('CHD4', 'Gene', (141, 145))	('serous carcinogenesis', 'Disease', (57, 78))	('FBXW7', 'Gene', (119, 124))	('STOP', 'Gene', (135, 139))	('mutations', 'Var', (91, 100))	('CHD4', 'Gene', '1108', (141, 145))	('TAF1', 'Gene', (147, 151))	('serous carcinogenesis', 'Disease', 'MESH:D063646', (57, 78))	('PTEN', 'Gene', (165, 169))	('PPP2R1A', 'Gene', (126, 133))
35425	34036097	Molecular aberrations in PIK3CA, PTEN, PPP2R1A, STOP, ARID1A, TAF1, and TP53 have been frequently reported genetic events in nonendometrioid ECs, including clear cell ECs.	('clear cell ECs', 'Disease', (156, 170))	('nonendometrioid ECs', 'Disease', (125, 144))	('PTEN', 'Gene', (33, 37))	('Molecular aberrations', 'Var', (0, 21))	('EC', 'Phenotype', 'HP:0012114', (141, 143))	('PIK3CA', 'Gene', (25, 31))	('TP53', 'Gene', (72, 76))	('PPP2R1A', 'Gene', (39, 46))	('PPP2R1A', 'Gene', '5518', (39, 46))	('EC', 'Phenotype', 'HP:0012114', (167, 169))
35426	34036097	Mutations in PIK3CA, KRAS, and PIK3R1 genes were found in reclassified clear cell ECs.	('KRAS', 'Gene', '3845', (21, 25))	('EC', 'Phenotype', 'HP:0012114', (82, 84))	('PIK3CA', 'Gene', (13, 19))	('PIK3R1', 'Gene', '5295', (31, 37))	('PIK3R1', 'Gene', (31, 37))	('reclassified clear cell ECs', 'Disease', (58, 85))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (21, 25))	('found', 'Reg', (49, 54))
35430	34036097	However, cooccurrence of mutations in TP53 and PTEN genes in tumors from carcinosarcoma, otherwise those two genes were mutually exclusive and showed a tendency to be found exclusively in one of two (endometrioid or serous) histologic subtypes in previous studies, suggested that carcinosarcoma originated from a common origin for carcinomatous and sarcomatous components.	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (331, 360))	('mutations', 'Var', (25, 34))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('carcinosarcoma', 'Disease', (280, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('TP53', 'Gene', (38, 42))	('carcinosarcoma', 'Disease', 'MESH:D002296', (73, 87))	('PTEN', 'Gene', (47, 51))	('carcinosarcoma', 'Disease', 'MESH:D002296', (280, 294))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('carcinosarcoma', 'Disease', (73, 87))
35433	34036097	Other potentially druggable molecular aberrations include a POLE gene mutation, a molecular event reported to have a favorable prognosis in patients with endometrioid ECs, and mutations in AKT2, STK11, CCND1, CDKN2B, ERBB2, ERBB3, BRCA2, ATM, FGFR2, and SMARCA4.	('mutations', 'Var', (176, 185))	('STK11', 'Gene', (195, 200))	('BRCA2', 'Gene', (231, 236))	('CCND1', 'Gene', '595', (202, 207))	('ERBB2', 'Gene', '2064', (217, 222))	('ATM', 'Gene', (238, 241))	('FGFR2', 'Gene', (243, 248))	('CCND1', 'Gene', (202, 207))	('SMARCA4', 'Gene', (254, 261))	('ERBB3', 'Gene', (224, 229))	('BRCA2', 'Gene', '675', (231, 236))	('STK11', 'Gene', '6794', (195, 200))	('patients', 'Species', '9606', (140, 148))	('FGFR2', 'Gene', '2263', (243, 248))	('CDKN2B', 'Gene', (209, 215))	('EC', 'Phenotype', 'HP:0012114', (167, 169))	('endometrioid ECs', 'Disease', (154, 170))	('AKT2', 'Gene', '208', (189, 193))	('ATM', 'Gene', '472', (238, 241))	('SMARCA4', 'Gene', '6597', (254, 261))	('ERBB3', 'Gene', '2065', (224, 229))	('ERBB2', 'Gene', (217, 222))	('AKT2', 'Gene', (189, 193))	('POLE', 'Gene', (60, 64))	('CDKN2B', 'Gene', '1030', (209, 215))	('mutation', 'Var', (70, 78))
35434	34036097	Defective DNA mismatch repair (MMR) has also been reported to be an early molecular event, giving rise to expectation for application of immune checkpoint inhibitors in the treatment of uterine carcinosarcomas with microsatellite instability (MSI).	('carcinosarcomas', 'Disease', 'MESH:D002296', (194, 209))	('sarcomas', 'Phenotype', 'HP:0100242', (201, 209))	('carcinosarcomas', 'Disease', (194, 209))	('Defective', 'Var', (0, 9))	('microsatellite instability', 'Var', (215, 241))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (186, 208))
35435	34036097	Potential of an immune checkpoint inhibitor as a promising targeted agent was also shown in a uterine carcinosarcoma patient harboring POLE mutation, reported to occur in about 2-4% of uterine carcinosarcomas.	('carcinosarcomas', 'Disease', 'MESH:D002296', (193, 208))	('carcinosarcoma', 'Disease', (193, 207))	('carcinosarcoma', 'Disease', (102, 116))	('carcinosarcomas', 'Disease', (193, 208))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (185, 207))	('mutation', 'Var', (140, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('carcinosarcoma', 'Disease', 'MESH:D002296', (193, 207))	('patient', 'Species', '9606', (117, 124))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (94, 116))	('carcinosarcoma', 'Disease', 'MESH:D002296', (102, 116))
35436	34036097	Individuals with hereditary predisposition to Lynch syndrome (hereditary nonpolyposis colorectal cancer) harbor germline mutations in one of the following DNA MMR genes: MLH1, MSH2, MSH6, PMS2, or EPCAM.	('mutations', 'Var', (121, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('Lynch syndrome', 'Disease', (46, 60))	('MSH2', 'Gene', '4436', (176, 180))	('MSH6', 'Gene', (182, 186))	('EPCAM', 'Gene', (197, 202))	('hereditary nonpolyposis colorectal cancer', 'Disease', (62, 103))	('MSH6', 'Gene', '2956', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Lynch syndrome', 'Disease', 'MESH:D003123', (46, 60))	('MLH1', 'Gene', (170, 174))	('PMS2', 'Gene', '5395', (188, 192))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (62, 103))	('MLH1', 'Gene', '4292', (170, 174))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (62, 103))	('DNA MMR', 'Gene', (155, 162))	('EPCAM', 'Gene', '4072', (197, 202))	('MSH2', 'Gene', (176, 180))	('PMS2', 'Gene', (188, 192))
35438	34036097	On the other hand, sporadic ECs with MMR defects are mainly attributed to methylation of the MLH1 promoter, leading to epigenetic silencing.	('methylation', 'Var', (74, 85))	('MMR defects', 'Gene', (37, 48))	('attributed', 'Reg', (60, 70))	('EC', 'Phenotype', 'HP:0012114', (28, 30))	('epigenetic silencing', 'MPA', (119, 139))	('MLH1', 'Gene', '4292', (93, 97))	('ECs', 'Disease', (28, 31))	('MLH1', 'Gene', (93, 97))
35439	34036097	Microsatellite instability (MSI) is the phenotype of tumors with MMR defects resulting from hereditary or sporadic mutations of MMR genes.	('MMR genes', 'Gene', (128, 137))	('mutations', 'Var', (115, 124))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Microsatellite instability', 'Disease', (0, 26))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('MMR defects', 'Gene', (65, 76))	('resulting from', 'Reg', (77, 91))	('tumors', 'Disease', (53, 59))
35440	34036097	Defective MMR has been reported to occur less frequently in uterine carcinosarcomas than in endometrioid ECs, with a rate range of 3.5 to 21% and reported to be uncommon in serous ECs.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (60, 82))	('carcinosarcomas', 'Disease', 'MESH:D002296', (68, 83))	('EC', 'Phenotype', 'HP:0012114', (180, 182))	('Defective', 'Var', (0, 9))	('carcinosarcomas', 'Disease', (68, 83))	('MMR', 'Gene', (10, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('EC', 'Phenotype', 'HP:0012114', (105, 107))
35441	34036097	In contrast to a favorable prognosis of colorectal cancer patients with MMR defects, adverse clinicopathologic features such as higher-grade cancers and more frequent lymphovascular invasion were reported to be associated with MMR defects in endometrioid ECs.	('patients', 'Species', '9606', (58, 66))	('endometrioid ECs', 'Disease', (242, 258))	('colorectal cancer', 'Disease', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('EC', 'Phenotype', 'HP:0012114', (255, 257))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('lymphovascular invasion', 'CPA', (167, 190))	('MMR', 'Var', (227, 230))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
35442	34036097	Furthermore, progression-free survival (PFS) of patients with tumors harboring epigenetic MMR defects was worse comparing with patients with proficient MMR endometrioid ECs.	('MMR', 'Gene', (90, 93))	('worse', 'NegReg', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('defects', 'Var', (94, 101))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('patients', 'Species', '9606', (127, 135))	('EC', 'Phenotype', 'HP:0012114', (169, 171))	('epigenetic', 'Var', (79, 89))	('patients', 'Species', '9606', (48, 56))	('progression-free survival', 'CPA', (13, 38))
35443	34036097	The POLE-mutated (ultramutated) group regarded tumors characterized by an increased frequency of C A transversions, recurrent mutations at POLEP286R and POLEV411L.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('mutations at POLEP286R', 'Var', (126, 148))	('C A transversions', 'Phenotype', 'HP:0011540', (97, 114))	('POLEV411L', 'Var', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
35446	34036097	The hypermutated subgroup included tumors with MSI, most with MLH1 promoter hypermethylation, and with few somatic copy number alterations.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('MSI', 'Disease', (47, 50))	('promoter hypermethylation', 'Var', (67, 92))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('MLH1', 'Gene', '4292', (62, 66))	('MLH1', 'Gene', (62, 66))
35447	34036097	The third group, tumors with low copy-number, most with MSS, was shown to have frequent mutations in CTNNB1, the only mutated gene occurring more frequently than in the MSI subgroup.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (88, 97))	('low copy-number', 'Var', (29, 44))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CTNNB1', 'Gene', (101, 107))	('MSS', 'Disease', (56, 59))
35449	34036097	Tumors in this group had frequent TP53 mutations, few DNA methylation changes, and low estrogen receptor (ER)/PR levels.	('ER', 'Gene', '2099', (106, 108))	('PR', 'Gene', '5241', (110, 112))	('TP53', 'Gene', (34, 38))	('estrogen receptor', 'Gene', (87, 104))	('estrogen receptor', 'Gene', '2099', (87, 104))	('mutations', 'Var', (39, 48))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('low', 'NegReg', (83, 86))
35463	34036097	Immunotherapies with checkpoint inhibitors have shown efficacy in solid tumors with MSI-high/defective MMR or with a high concentration of tumor-infiltrating lymphocytes (TIL).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (72, 77))	('MSI-high/defective', 'Var', (84, 102))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
35473	34036097	Several studies have suggested hypermutation or high TILs combined with positive immune checkpoint-related protein expression, as a result of MMR deficiency or POLE mutation, as possible biomarkers for response in treatment with immune checkpoint inhibitors.	('MMR deficiency', 'Disease', (142, 156))	('immune checkpoint-related protein', 'Gene', (81, 114))	('positive', 'PosReg', (72, 80))	('hypermutation', 'Var', (31, 44))	('MMR deficiency', 'Disease', 'MESH:C536928', (142, 156))	('high TILs', 'MPA', (48, 57))
35481	34036097	Although amplification/overexpression of HER2 has been reported to be frequently found in ECs, particularly in serous ECs, the benefits of anti-HER2 therapy have yet to be demonstrated.	('amplification/overexpression', 'Var', (9, 37))	('HER2', 'Gene', '2064', (144, 148))	('amplification/overexpression', 'PosReg', (9, 37))	('found', 'Reg', (81, 86))	('EC', 'Phenotype', 'HP:0012114', (90, 92))	('serous ECs', 'Disease', (111, 121))	('HER2', 'Gene', (144, 148))	('HER2', 'Gene', (41, 45))	('EC', 'Phenotype', 'HP:0012114', (118, 120))	('HER2', 'Gene', '2064', (41, 45))	('ECs', 'Disease', (90, 93))
35483	34036097	In addition, no association was shown between HER2 amplification or overexpression and treatment outcomes.	('HER2', 'Gene', '2064', (46, 50))	('HER2', 'Gene', (46, 50))	('amplification', 'Var', (51, 64))
35486	34036097	An earlier study with two cases of EC harboring amplification of HER2 also showed clinical responses when treated in combination with chemotherapy, giving rise to the significance of patients' selection, according to histological/molecular classification.	('HER2', 'Gene', '2064', (65, 69))	('EC', 'Phenotype', 'HP:0012114', (35, 37))	('HER2', 'Gene', (65, 69))	('patients', 'Species', '9606', (183, 191))	('amplification', 'Var', (48, 61))
35489	34036097	ARID1A deficiency, resulting in impairment of HR DNA repair, has provided a potential for clinical utility of PARP inhibitors in ARID1A-deficient EC.	('impairment of HR', 'Disease', 'MESH:D001919', (32, 48))	('impairment of HR', 'Disease', (32, 48))	('ARID1A-deficient EC', 'Disease', (129, 148))	('deficiency', 'Var', (7, 17))	('ARID1A-deficient EC', 'Disease', 'MESH:D005955', (129, 148))	('ARID1A', 'Gene', (0, 6))	('PARP', 'Gene', (110, 114))	('EC', 'Phenotype', 'HP:0012114', (146, 148))	('PARP', 'Gene', '142', (110, 114))
35490	34036097	Frequent mutations of ARID1A in EC led to the design of a randomized phase II clinical trial comparing the efficacy of olaparib (a PARP inhibitor), cediranib (a small molecule inhibitor targeting VEGFR, PDGFR, and FGFR), or the combination of both agents in patients with metastatic/recurrent ECs (ClinicalTrials.gov NCT 03660826), and its results are awaited.	('cediranib', 'Chemical', 'MESH:C500926', (148, 157))	('EC', 'Phenotype', 'HP:0012114', (32, 34))	('PDGFR', 'Gene', '5159', (203, 208))	('PARP', 'Gene', '142', (131, 135))	('mutations', 'Var', (9, 18))	('VEGFR', 'Gene', '3791', (196, 201))	('metastatic/recurrent ECs', 'Disease', (272, 296))	('EC', 'Phenotype', 'HP:0012114', (293, 295))	('patients', 'Species', '9606', (258, 266))	('PDGFR', 'Gene', (203, 208))	('VEGFR', 'Gene', (196, 201))	('PARP', 'Gene', (131, 135))	('ARID1A', 'Gene', (22, 28))	('olaparib', 'Chemical', 'MESH:C531550', (119, 127))
35575	32899298	Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('as', 'Gene', '112935892', (76, 78))	('cancers', 'Disease', (111, 118))	('as', 'Gene', '112935892', (12, 14))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('activity', 'MPA', (80, 88))	('aberrant', 'Var', (60, 68))	('as', 'Gene', '112935892', (7, 9))
35597	32899298	The unlimited proliferative capacity of cancer cells can, in part, be attributed to aberrant telomerase activity, which is repressed in most somatic cells but present in up to 90% of cancers.	('cancer', 'Disease', (183, 189))	('cancers', 'Disease', (183, 190))	('activity', 'MPA', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('as', 'Gene', '112935892', (100, 102))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('aberrant', 'Var', (84, 92))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
35660	32899298	There were 105 endometrioid-specific DEGs that were identified, and the highest upregulated genes included CEACAM5, S100P and PCSK9, and the highest downregulated genes were IQSEC3, H19 and ELOVL4.	('ELOVL4', 'Gene', '6785', (190, 196))	('ELOVL4', 'Gene', (190, 196))	('PCSK9', 'Gene', (126, 131))	('S100P', 'SUBSTITUTION', 'None', (116, 121))	('IQSEC3', 'Gene', (174, 180))	('S100P', 'Var', (116, 121))	('upregulated', 'PosReg', (80, 91))	('downregulated', 'NegReg', (149, 162))	('CEACAM5', 'Gene', (107, 114))	('H19', 'Gene', '283120', (182, 185))	('H19', 'Gene', (182, 185))	('IQSEC3', 'Gene', '440073', (174, 180))
35697	32899298	As genes dysregulated in higher grade or later stage disease may indicate that a tumour is more aggressive, the list of DEGs from the comparison of stage I and IV EC, and grade 1 and 3 endometrioid, were intersected with the list of prognostic genes (Figure 10, Table S35).	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('aggressive', 'CPA', (96, 106))	('more', 'PosReg', (91, 95))	('As', 'Gene', '112935892', (0, 2))	('dysregulated', 'Var', (9, 21))	('tumour', 'Disease', (81, 87))	('stage disease', 'Disease', (47, 60))	('stage disease', 'Disease', 'MESH:D058625', (47, 60))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
35703	32899298	The dysregulation of many telomere maintenance genes and proteins have been linked to telomere shortening and telomerase activity in cancer.	('as', 'Gene', '112935892', (117, 119))	('linked', 'Reg', (76, 82))	('activity', 'MPA', (121, 129))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('telomere maintenance genes', 'Gene', (26, 52))	('telomere shortening', 'Phenotype', 'HP:0031413', (86, 105))	('telomere shortening', 'CPA', (86, 105))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
35729	32899298	Overexpression of BLM, AURKA and PITX1 has previously been linked with poor survival in breast, lung, bladder and pancreatic cancer.	('BLM,', 'Gene', '641', (18, 22))	('lung', 'Disease', (96, 100))	('AURKA', 'Gene', '6790', (23, 28))	('bladder', 'Disease', 'MESH:D001745', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', (114, 131))	('as', 'Gene', '112935892', (40, 42))	('PITX1', 'Gene', (33, 38))	('bladder', 'Disease', (102, 109))	('AURKA', 'Gene', (23, 28))	('Overexpression', 'Var', (0, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('as', 'Gene', '112935892', (91, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))
35732	32899298	S100P was only found to be overexpressed in endometrioid tumours.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('S100P', 'SUBSTITUTION', 'None', (0, 5))	('endometrioid tumours', 'Disease', (44, 64))	('endometrioid tumours', 'Disease', 'MESH:D016889', (44, 64))	('S100P', 'Var', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('as', 'Gene', '112935892', (7, 9))
35734	32899298	Previous studies have also linked S100P expression with the squamous and adenosquamous subtypes of EC, but its association with endometrioid tumours has not been investigated.	('expression', 'MPA', (40, 50))	('endometrioid tumours', 'Disease', 'MESH:D016889', (128, 148))	('linked', 'Reg', (27, 33))	('S100P', 'Var', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('as', 'Gene', '112935892', (111, 113))	('S100P', 'SUBSTITUTION', 'None', (34, 39))	('as', 'Gene', '112935892', (150, 152))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('squamous', 'Disease', (60, 68))	('adenosquamous', 'Disease', (73, 86))	('endometrioid tumours', 'Disease', (128, 148))
35753	32899298	In accordance with this, previous studies have shown that inhibition of KIF4A contributes to decreased EC cell proliferation in vitro.	('inhibition', 'Var', (58, 68))	('as', 'Gene', '112935892', (98, 100))	('KIF4A', 'Gene', (72, 77))
35762	32899298	Inhibition of EZH2, CDK1, PLK1 and AURKA have been shown to suppress EC cell proliferation and invasion, and increase cellular apoptosis in vitro.	('AURKA', 'Gene', '6790', (35, 40))	('as', 'Gene', '112935892', (114, 116))	('increase cellular apoptosis', 'Phenotype', 'HP:0030887', (109, 136))	('AURKA', 'Gene', (35, 40))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('suppress', 'NegReg', (60, 68))	('CDK1', 'Gene', (20, 24))	('PLK1', 'Gene', (26, 30))	('CDK1', 'Gene', '983', (20, 24))	('Inhibition', 'Var', (0, 10))	('as', 'Gene', '112935892', (98, 100))	('PLK1', 'Gene', '5347', (26, 30))	('cellular apoptosis', 'CPA', (118, 136))
35767	32899298	Polymorphisms within the RAD51 gene have been associated with EC progression and recurrence.	('as', 'Gene', '112935892', (46, 48))	('RAD51', 'Gene', (25, 30))	('Polymorphisms', 'Var', (0, 13))	('RAD51', 'Gene', '5888', (25, 30))
35777	32899298	Three enriched TFs were identified from the analysis of DEGs in EC and all were associated with telomere maintenance.	('DEGs', 'Var', (56, 60))	('TF', 'Gene', '2152', (15, 17))	('telomere maintenance', 'CPA', (96, 116))	('as', 'Gene', '112935892', (80, 82))
35785	32899298	Aberrant expression of MZF1 has been implicated in various cancer types, and can increase cancer cell proliferation, invasion and metastasis.	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('implicated', 'Reg', (37, 47))	('MZF1', 'Gene', '7593', (23, 27))	('as', 'Gene', '112935892', (86, 88))	('as', 'Gene', '112935892', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('as', 'Gene', '112935892', (136, 138))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('as', 'Gene', '112935892', (120, 122))	('as', 'Gene', '112935892', (133, 135))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('MZF1', 'Gene', (23, 27))
35798	32899298	Knockdown of TPX2 has been demonstrated to result in diminished telomerase activity and its overexpression has been linked with increased invasion and metastasis.	('diminished', 'NegReg', (53, 63))	('Knockdown', 'Var', (0, 9))	('as', 'Gene', '112935892', (141, 143))	('overexpression', 'PosReg', (92, 106))	('as', 'Gene', '112935892', (108, 110))	('TPX2', 'Gene', (13, 17))	('as', 'Gene', '112935892', (71, 73))	('as', 'Gene', '112935892', (19, 21))	('as', 'Gene', '112935892', (154, 156))	('activity', 'MPA', (75, 83))	('as', 'Gene', '112935892', (133, 135))	('as', 'Gene', '112935892', (157, 159))
35816	32899298	Alterations in telomere biology function of these TTAGPs are not likely to be their only causative involvement in endometrial carcinogenesis, but they are likely to be influencing the carcinogenic aberrations in various other important cellular functions such as cell cycle progression, transcription or DNA replication.	('TTAGPs', 'Chemical', '-', (50, 56))	('influencing', 'Reg', (168, 179))	('carcinogenic aberrations', 'Disease', (184, 208))	('Alterations', 'Var', (0, 11))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (114, 140))	('endometrial carcinogenesis', 'Disease', (114, 140))	('transcription', 'CPA', (287, 300))	('carcinogenic aberrations', 'Disease', 'MESH:D002869', (184, 208))	('cell cycle progression', 'CPA', (263, 285))	('as', 'Gene', '112935892', (260, 262))	('DNA replication', 'CPA', (304, 319))
35823	32899298	); the Wellbeing of Women (grant number RG2137, C.J.H., and D.K.H.).	('Women', 'Species', '9606', (20, 25))	('C.J.H.', 'Var', (48, 54))	('D.K.H.', 'Var', (60, 66))	('Wellbeing', 'CPA', (7, 16))
35857	32854748	This DNA purification step has been demonstrated to remove contaminating traces of high-molecular weight genomic DNA (~ 10,380 bp) from tumor-derived DNA (~ 150-200 bp).	('cat', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cat', 'Gene', '847', (15, 18))	('tumor', 'Disease', (136, 141))	('~ 10,380 bp', 'Var', (118, 129))
35888	32854748	Cox-proportional hazard modelling showed that the LMW cfDNA concentration is strongly associated with overall survival (p < 0.01), with hazard ratio at 1.53 as the concentration doubles.	('LMW', 'Var', (50, 53))	('LMW', 'Chemical', '-', (50, 53))	('overall survival', 'MPA', (102, 118))	('associated with', 'Reg', (86, 101))
35913	32854748	While our study is too small to perform multivariate survival analysis, these findings suggest that LMW cfDNA concentration is associated with tumor aggressiveness beyond the risk conferred by stage of disease or specific histology.	('tumor aggressiveness', 'Disease', (143, 163))	('aggressiveness', 'Phenotype', 'HP:0000718', (149, 163))	('associated', 'Reg', (127, 137))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (143, 163))	('LMW', 'Var', (100, 103))	('LMW', 'Chemical', '-', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
35920	32854748	In summary, quantitative analysis of LMW cfDNA may hold promise, in combination with other traditional assays, as a clinically important adjunctive test in risk stratification of women with uterine cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cat', 'Gene', (169, 172))	('cancer', 'Disease', (198, 204))	('LMW', 'Var', (37, 40))	('LMW', 'Chemical', '-', (37, 40))	('uterine cancer', 'Phenotype', 'HP:0010784', (190, 204))	('cat', 'Gene', '847', (169, 172))	('women', 'Species', '9606', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
35926	32630498	Low-Volume Nodal Metastasis in Endometrial Cancer: Risk Factors and Prognostic Significance Objective: To evaluate the oncological outcomes of patients with low-volume metastasis compared to those with macrometastasis and negative nodes in endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (240, 258))	('endometrial cancer', 'Phenotype', 'HP:0012114', (240, 258))	('low-volume metastasis', 'Var', (157, 178))	('Endometrial Cancer', 'Phenotype', 'HP:0012114', (31, 49))	('patients', 'Species', '9606', (143, 151))	('Nodal', 'Gene', (11, 16))	('Nodal', 'Gene', '4838', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Endometrial Cancer', 'Disease', 'MESH:D016889', (31, 49))	('Endometrial Cancer', 'Disease', (31, 49))	('endometrial cancer', 'Disease', (240, 258))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
35931	32630498	After a median (range) follow-up of 60 (0-146) months, patients with macrometastasis showed a significantly worse PFS compared to LVM and node-negative patients (61.1% vs. 71.4% vs. 83.2%, respectively; p = 0.018), and similar results were obtained for 5-year OS (50% vs. 78.6% vs. 81.5%, respectively; p < 0.001).	('macrometastasis', 'Var', (69, 84))	('LVM', 'Chemical', '-', (130, 133))	('worse', 'NegReg', (108, 113))	('PFS', 'MPA', (114, 117))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (152, 160))
35933	32630498	Moreover, LVM had a moderate nonsignificant decrease in 5-year PFS compared to node-negative patients.	('decrease', 'NegReg', (44, 52))	('LVM', 'Var', (10, 13))	('PFS', 'MPA', (63, 66))	('LVM', 'Chemical', '-', (10, 13))	('patients', 'Species', '9606', (93, 101))
35935	32630498	Low-volume metastasis did not show worse oncological outcomes than node-negative patients, although there was a slight decrease in progression-free survival.	('Low-volume', 'Var', (0, 10))	('progression-free survival', 'CPA', (131, 156))	('decrease', 'NegReg', (119, 127))	('patients', 'Species', '9606', (81, 89))
35947	32630498	The main aim of our study is to evaluate the oncological outcomes of patients with low-volume metastasis compared to those with macrometastasis and negative nodes in endometrial cancer.	('endometrial cancer', 'Disease', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('endometrial cancer', 'Phenotype', 'HP:0012114', (166, 184))	('low-volume', 'Var', (83, 93))	('endometrial cancer', 'Disease', 'MESH:D016889', (166, 184))	('patients', 'Species', '9606', (69, 77))
35978	32630498	Adjuvant therapy was significantly higher in the group of MAC and LVM compared to patients with negative nodes (p < 0.001).	('MAC', 'Var', (58, 61))	('LVM', 'Chemical', '-', (66, 69))	('patients', 'Species', '9606', (82, 90))	('Adjuvant therapy', 'CPA', (0, 16))	('higher', 'PosReg', (35, 41))
35990	32630498	included 780 patients with endometrial cancer, where the group of sentinel node mapping had twice as many lymph node metastases as the nonmapped group (30.3% vs. 14.7%, p < 0.001), the majority due to the identification of micrometastases and ITCs.	('sentinel', 'Var', (66, 74))	('endometrial cancer', 'Disease', (27, 45))	('metastases', 'Disease', (228, 238))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('patients', 'Species', '9606', (13, 21))	('endometrial cancer', 'Phenotype', 'HP:0012114', (27, 45))	('endometrial cancer', 'Disease', 'MESH:D016889', (27, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('metastases', 'Disease', 'MESH:D009362', (228, 238))	('metastases', 'Disease', (117, 127))
36039	32412047	Lots of CpGs were hyper-methylated in breast cancer samples compared with adjacent normal tissues, which tend to be negatively correlated with gene expressions.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('hyper-methylated', 'Var', (18, 34))
36049	32412047	For example, BRCA1/2 germline mutations, which are widely considered to cause DNA damage repair (DDR) defection, have been extensively applied in BRCA diagnosis and early screening, as well as the subsequent treatment decision making worldwide.	('BRCA1/2', 'Gene', '672;675', (13, 20))	('BRCA', 'Phenotype', 'HP:0003002', (146, 150))	('BRCA', 'Gene', '672', (146, 150))	('BRCA', 'Gene', (146, 150))	('germline mutations', 'Var', (21, 39))	('BRCA', 'Phenotype', 'HP:0003002', (13, 17))	('BRCA', 'Gene', '672', (13, 17))	('BRCA1/2', 'Gene', (13, 20))	('BRCA', 'Gene', (13, 17))
36053	32412047	Specifically, hyper-methylation particularly those located at cis-regulation element (CRE), including enhancer and promoter, could hinder the binding of transcription factor and hence cause gene transcription silencing, which is considered as the basic mechanism of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (266, 280))	('transcription', 'Protein', (153, 166))	('carcinogenesis', 'Disease', (266, 280))	('hinder', 'NegReg', (131, 137))	('gene transcription', 'MPA', (190, 208))	('binding', 'Interaction', (142, 149))	('hyper-methylation', 'Var', (14, 31))	('cause', 'Reg', (184, 189))
36054	32412047	What's more, DNA methylation as the most common epigenetics modification could contribute lots of other biological processes, such as cell division and stem cell differentiation, which could consequently influence physical activities, such as aging, tumorigenesis, metabolism, and so on.	('modification', 'Var', (60, 72))	('metabolism', 'CPA', (265, 275))	('methylation', 'Var', (17, 28))	('aging', 'CPA', (243, 248))	('contribute', 'Reg', (79, 89))	('cell division', 'CPA', (134, 147))	('physical activities', 'CPA', (214, 233))	('influence', 'Reg', (204, 213))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (250, 255))	('stem cell differentiation', 'CPA', (152, 177))
36073	32412047	Aberrant methylation of promoter CpGs may induce the altered expression of the corresponding gene through cleaving transcription factor from oligonucleotides, and this process is called as cis-regulation between CpG and gene.	('methylation', 'Var', (9, 20))	('induce', 'Reg', (42, 48))	('Aberrant methylation', 'Var', (0, 20))	('cleaving', 'MPA', (106, 114))	('oligonucleotides', 'Chemical', 'MESH:D009841', (141, 157))	('altered expression', 'MPA', (53, 71))
36080	32412047	Raw sequencing data were obtained from GEO with the following accession numbers: GSM2714245 (ATAC-seq, MCF-7), GSM2067520 (H3K27ac ChIP-seq, MCF-7), GSM1855976/GSM1855977/GSM1855978 (ATAC-seq rep1/rep2/rep3, MDA-MB-231), GSM1855991/GSM1855992 (H3K27ac ChIP-seq rep1/rep2, MDA-MB-231).	('rep2', 'Gene', (266, 270))	('rep1', 'Gene', '1121', (192, 196))	('GSM1855991/GSM1855992', 'Var', (221, 242))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (272, 282))	('rep1', 'Gene', (261, 265))	('rep2', 'Gene', (197, 201))	('GSM2714245', 'Var', (81, 91))	('rep1', 'Gene', '1121', (261, 265))	('MCF-7', 'CellLine', 'CVCL:0031', (103, 108))	('MCF-7', 'CellLine', 'CVCL:0031', (141, 146))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (208, 218))	('rep2', 'Gene', '1122', (266, 270))	('GSM1855976/GSM1855977/GSM1855978', 'Var', (149, 181))	('rep2', 'Gene', '1122', (197, 201))	('rep1', 'Gene', (192, 196))
36084	32412047	Preprocessing of raw TCGA-BRCA methylation datasets retained a total of 343,451 CpGs that located at autosomes and with low detection P value (<0.01) across more than half of samples.	('TCGA-BRCA', 'Gene', (21, 30))	('BRCA', 'Phenotype', 'HP:0003002', (26, 30))	('CpGs', 'Var', (80, 84))	('TCGA-BRCA', 'Gene', '672', (21, 30))
36094	32412047	all BRCA tumor samples versus adjacent normal samples, which including 15,415 hyper-methylation CpGs (hyper-CpGs) and 11,003 hypo-methylation CpGs (hypo-CpGs).	('BRCA', 'Phenotype', 'HP:0003002', (4, 8))	('BRCA tumor', 'Disease', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('hyper-methylation', 'Var', (78, 95))	('hyper-CpGs', 'Disease', 'MESH:D053306', (102, 112))	('hyper-CpGs', 'Disease', (102, 112))	('hypo-methylation', 'Var', (125, 141))	('BRCA tumor', 'Disease', 'MESH:D009369', (4, 14))
36098	32412047	Besides, genes were more frequently hyper-methylated at the upstream of the TSS, including TSS200, TSS1500, and FstExon, which were more likely CREs, and hypo-methylated at the downstream of the TSS in our study as shown in Figure 2D.	('CREs', 'Gene', (144, 148))	('TSS1500', 'Gene', (99, 106))	('hyper-methylated', 'Var', (36, 52))	('CREs', 'Gene', '10047', (144, 148))
36101	32412047	In trans-regulations, we mainly focused on those correlations between DMCs and DEGs, which including 3486 up- and 2437 down-regulated ones in BRCA tumor samples, and similar results were obtained as cis-regulation analysis.	('down-regulated', 'NegReg', (119, 133))	('DMCs', 'Chemical', '-', (70, 74))	('BRCA', 'Phenotype', 'HP:0003002', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('up-', 'PosReg', (106, 109))	('BRCA tumor', 'Disease', (142, 152))	('DMCs', 'Var', (70, 74))	('BRCA tumor', 'Disease', 'MESH:D009369', (142, 152))
36108	32412047	Eight CpGs, including cg02156680, cg05227549, cg06100368, cg16171526, cg18565473, cg22548054, cg25097074, and cg25199322, were finally retained out of the 13,575 CpGs and used as BRCA-specific diagnostic markers for their significantly higher methylations in BRCA tumor samples than any of the other 10 cancers' tumor as well as adjacent normal samples.	('BRCA', 'Gene', '672', (259, 263))	("cancers' tumor", 'Disease', (303, 317))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('BRCA', 'Gene', '672', (179, 183))	('higher', 'PosReg', (236, 242))	('cg25097074', 'Var', (94, 104))	('cg22548054', 'Var', (82, 92))	('cg22548054', 'Chemical', '-', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cg16171526', 'Var', (58, 68))	('BRCA', 'Gene', (259, 263))	('BRCA tumor', 'Disease', 'MESH:D009369', (259, 269))	('cg18565473', 'Var', (70, 80))	('cg02156680', 'Var', (22, 32))	('BRCA', 'Gene', (179, 183))	('BRCA tumor', 'Disease', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('methylations', 'MPA', (243, 255))	('cg05227549', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('cg16171526', 'Chemical', '-', (58, 68))	('cg06100368', 'Var', (46, 56))	('cg25199322', 'Var', (110, 120))	('BRCA', 'Phenotype', 'HP:0003002', (259, 263))	('BRCA', 'Phenotype', 'HP:0003002', (179, 183))	("cancers' tumor", 'Disease', 'MESH:D009369', (303, 317))
36114	32412047	The eight BRCA-specific CpGs were annotated to four genes: cg02156680 (ENPP2), cg18565473 (ETS1), cg25097074 (ESPN), cg06100368, and cg25199322 (RIIAD1).	('ETS1', 'Gene', '2113', (91, 95))	('ETS1', 'Gene', (91, 95))	('BRCA', 'Gene', '672', (10, 14))	('ENPP2', 'Gene', '5168', (71, 76))	('BRCA', 'Phenotype', 'HP:0003002', (10, 14))	('ENPP2', 'Gene', (71, 76))	('BRCA', 'Gene', (10, 14))	('RIIAD1', 'Gene', '284485', (145, 151))	('cg18565473', 'Var', (79, 89))	('ESPN', 'Gene', '83715', (110, 114))	('cg25097074', 'Var', (98, 108))	('RIIAD1', 'Gene', (145, 151))	('cg02156680', 'Var', (59, 69))	('cg25199322', 'Var', (133, 143))	('ESPN', 'Gene', (110, 114))	('cg06100368', 'Var', (117, 127))
36115	32412047	Cg05227549, cg16171526, and cg22548054 were not annotated by any gene.	('Cg05227549', 'Var', (0, 10))	('cg16171526', 'Var', (12, 22))	('Cg05227549', 'Chemical', '-', (0, 10))	('cg22548054', 'Var', (28, 38))	('cg22548054', 'Chemical', '-', (28, 38))	('cg16171526', 'Chemical', '-', (12, 22))
36118	32412047	As a result, consistent with their expression changes in tumor samples compared with adjacent samples, ENPP2 and ETS1 showed decreased expression levels in MDA-MB-231, a highly aggressive cell line, compared with MCF-7, a weakly aggressive cell line.	('MCF-7', 'CellLine', 'CVCL:0031', (213, 218))	('ETS1', 'Gene', '2113', (113, 117))	('decreased', 'NegReg', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('MDA-MB-231', 'Var', (156, 166))	('expression levels', 'MPA', (135, 152))	('ENPP2', 'Gene', '5168', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (156, 166))	('ENPP2', 'Gene', (103, 108))	('tumor', 'Disease', (57, 62))	('ETS1', 'Gene', (113, 117))
36119	32412047	And ESPN and RIIAD1 illustrated increased expression levels in MDA-MB-231 compared with MCF-7 cell line (Supplementary Figure S3).	('RIIAD1', 'Gene', '284485', (13, 19))	('expression levels', 'MPA', (42, 59))	('MDA-MB-231', 'Var', (63, 73))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (63, 73))	('RIIAD1', 'Gene', (13, 19))	('ESPN', 'Gene', (4, 8))	('ESPN', 'Gene', '83715', (4, 8))	('increased', 'PosReg', (32, 41))	('MCF-7', 'CellLine', 'CVCL:0031', (88, 93))
36126	32412047	Mechanistic exploration implies potential manipulation of CpGs in chromatin accessibility, by which aberrant methylation may modulate expression of cancer-related genes.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('expression', 'MPA', (134, 144))	('modulate', 'Reg', (125, 133))	('aberrant', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methylation', 'MPA', (109, 120))
36129	32412047	Cancer screening is included in most of health checkup by detecting serum tumor biomarkers, including CA72-4, CA19-9, and so on, but the sensitivity and specificity are both unsatisfactory for its broad spectrum, as well as personal difference in biomarkers' response.	('CA72-4', 'Var', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', (74, 79))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('detecting', 'Reg', (58, 67))	('CA19-9', 'Var', (110, 116))
36133	32412047	In the present study, BRCA samples with CIMP showed significantly inferior OS compared with those without CIMP, which was consistent with observations in lots of other cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CIMP', 'Chemical', '-', (40, 44))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('CIMP', 'Chemical', '-', (106, 110))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('BRCA', 'Phenotype', 'HP:0003002', (22, 26))	('inferior', 'NegReg', (66, 74))	('BRCA', 'Gene', '672', (22, 26))	('CIMP', 'Var', (40, 44))	('BRCA', 'Gene', (22, 26))
36135	32412047	consensus clustering analysis based on the most variable CpGs, and defined those patients that with coincident cancer-specific hypermethylation at some CpGs as having CIMP.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (81, 89))	('CIMP', 'Chemical', '-', (167, 171))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('hypermethylation', 'Var', (127, 143))
36136	32412047	patients with CIMP tend to have superior overall survival and low metastasis risk compared with those without CIMP, which might be caused by differences in feature selection for CIMP definition.	('superior', 'PosReg', (32, 40))	('CIMP', 'Chemical', '-', (178, 182))	('CIMP', 'Var', (14, 18))	('patients', 'Species', '9606', (0, 8))	('CIMP', 'Chemical', '-', (14, 18))	('CIMP', 'Chemical', '-', (110, 114))	('overall survival', 'CPA', (41, 57))	('metastasis', 'CPA', (66, 76))
36154	32412047	Besides, survival analysis through kmplotter online tool (http://kmplot.com/analysis/) indicated the favorable role of high ETS1 mRNA level for BRCA relapse-free survival (Supplementary Figure S7).	('BRCA', 'Gene', (144, 148))	('high', 'Var', (119, 123))	('ETS1', 'Gene', '2113', (124, 128))	('ETS1', 'Gene', (124, 128))	('BRCA', 'Phenotype', 'HP:0003002', (144, 148))	('BRCA', 'Gene', '672', (144, 148))
36160	32412047	Besides, association between high ENPP2 mRNA level and superior BRCA relapse-free survival was also confirmed using kmplotter (data not shown).	('high', 'Var', (29, 33))	('ENPP2', 'Gene', '5168', (34, 39))	('BRCA', 'Gene', '672', (64, 68))	('BRCA', 'Phenotype', 'HP:0003002', (64, 68))	('ENPP2', 'Gene', (34, 39))	('BRCA', 'Gene', (64, 68))
36172	32160708	Pan-Cancer Analysis Reveals the Diverse Landscape of Novel Sense and Antisense Fusion Transcripts Gene fusions that contribute to oncogenicity can be explored for identifying cancer biomarkers and potential drug targets.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Antisense Fusion Transcripts', 'Var', (69, 97))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Sense', 'Var', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
36175	32160708	The majority of the recurrent non-canonical fusions found in our study are novel, unexplored, and exhibited highly variable profiles across cancers, with breast cancer and glioblastoma having the highest and lowest rates, respectively.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('glioblastoma', 'Disease', (172, 184))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('non-canonical', 'Var', (30, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
36177	32160708	Genomic instability, a hallmark of cancer, leads to the accumulation of dynamic changes in the genome manifested as structural variants (SVs) that include quantitative (copy number variations [CNVs]), positional (translocations), or orientational (inversions) rearrangements.	('hallmark of cancer', 'Disease', (23, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('translocations', 'Var', (213, 227))	('hallmark of cancer', 'Disease', 'MESH:D009369', (23, 41))
36179	32160708	Fusion transcripts that originate from fusion genes are likely unique to a cancer type, which can be exploited to understand the underlying mechanisms of malignancy and can serve as effective diagnostic or prognostic markers.	('cancer type', 'Disease', 'MESH:D009369', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('fusion genes', 'Var', (39, 51))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('cancer type', 'Disease', (75, 86))	('malignancy', 'Disease', (154, 164))
36180	32160708	These chimeras could contribute to oncogenicity by altering the expression of tumor suppressor or proto-oncogenes, or by modifying the original function of a protein resulting in an abnormal chimeric protein that stimulates tumorigenesis.	('modifying', 'Reg', (121, 130))	('expression', 'MPA', (64, 74))	('abnormal', 'Var', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor suppressor', 'Gene', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('altering', 'Reg', (51, 59))	('stimulates', 'PosReg', (213, 223))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor suppressor', 'Gene', '7248', (78, 94))	('contribute', 'Reg', (21, 31))	('tumor', 'Disease', (78, 83))	('chimeric protein', 'MPA', (191, 207))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
36181	32160708	Examples of established cancer-specific biomarkers include the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion transcript for the identification of NPM-ALK-positive anaplastic large cell lymphoma (ALCL), and BCR-ABL1 fusion in chronic myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (254, 270))	('cancer', 'Disease', (24, 30))	('NPM', 'Gene', (114, 117))	('NPM', 'Gene', '4869', (114, 117))	('ALK', 'Gene', '238', (171, 174))	('BCR-ABL1', 'Gene', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('ALK', 'Gene', (171, 174))	('cell lymphoma', 'Phenotype', 'HP:0012191', (201, 214))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (184, 214))	('anaplastic large cell lymphoma', 'Disease', (184, 214))	('chronic myeloid leukemia', 'Disease', (246, 270))	('NPM', 'Gene', (167, 170))	('NPM', 'Gene', '4869', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (77, 96))	('ALCL', 'Phenotype', 'HP:0012193', (216, 220))	('ALK', 'Gene', '238', (118, 121))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (246, 270))	('ALK', 'Gene', (118, 121))	('fusion', 'Var', (236, 242))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (246, 270))
36186	32160708	Although fusions were initially found to be more prevalent in liquid cancers, later they were discovered to be prominent in solid tumors.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('prevalent', 'Reg', (49, 58))	('fusions', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
36187	32160708	Furthermore, fusion transcripts were initially assumed to be exclusive to cancer cells, but several reports identified a large number of fusion transcripts in non-cancerous cells, suggesting that they are prevalent in normal cells as well.	('fusion', 'Var', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
36192	32160708	ChimeRScope employs short k-mer-based unique transcript fingerprints to serve as a reference to match with k-mers from cancer transcriptome reads and identify fusion transcripts in cancer cells that harbor frequent chromosomal abnormalities and mutations.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (245, 254))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('chromosomal abnormalities', 'Disease', (215, 240))	('mers', 'Species', '1335626', (109, 113))	('cancer', 'Disease', (181, 187))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (215, 240))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
36196	32160708	We also screened for fusions that are recurrent in the common cancer cell lines (CCLE) as a means to corroborate fusions that are co-occurring in corresponding primary tumors.	('CCLE', 'Chemical', '-', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('primary tumors', 'Disease', 'MESH:D001932', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (113, 120))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('primary tumors', 'Disease', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
36197	32160708	Fusions in CCLE that are also detected in TCGA patients serve as a valuable resource to carry out mechanistic studies aimed at exploring the functional significance of these events.	('Fusions', 'Var', (0, 7))	('CCLE', 'Gene', (11, 15))	('patients', 'Species', '9606', (47, 55))	('CCLE', 'Chemical', '-', (11, 15))
36199	32160708	In addition to fusion detection from 33 cancer types, we also experimentally validated some of the predicted fusions by Sanger sequencing of fusion transcripts identified from CCLE cell lines.	('cancer type', 'Disease', 'MESH:D009369', (40, 51))	('fusions', 'Var', (109, 116))	('CCLE', 'Chemical', '-', (176, 180))	('cancer type', 'Disease', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
36219	32160708	In general, a very high percentage of CCLE samples contained recurrent fusions across all cancers compared to those of TCGA (Figure 1B).	('cancers', 'Disease', (90, 97))	('CCLE', 'Disease', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('fusions', 'Var', (71, 78))	('CCLE', 'Chemical', '-', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
36221	32160708	MESO (mesothelioma) and PAAD (pancreatic adenocarcinoma) had more non-canonical fusions in CCLE than did corresponding primary tumors in TCGA.	('non-canonical fusions', 'Var', (66, 87))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (30, 55))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mesothelioma', 'Disease', (6, 18))	('CCLE', 'Chemical', '-', (91, 95))	('pancreatic adenocarcinoma', 'Disease', (30, 55))	('primary tumors', 'Disease', 'MESH:D001932', (119, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (30, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (6, 18))	('primary tumors', 'Disease', (119, 133))	('CCLE', 'Disease', (91, 95))
36230	32160708	FGFR3-TACC3 (fibroblast growth factor receptor 3 and transforming acidic coiled-coil containing protein 3) fusion associated with multiple cancers was also found to be recurrent in BLCA, ESCA (esophageal carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), HNSC, LIHC (liver hepatocellular carcinoma), and LUSC.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (307, 331))	('HNSC', 'Disease', (289, 293))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('fusion', 'Var', (107, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('BLCA', 'Disease', (181, 185))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (301, 331))	('LUSC', 'Disease', (338, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('endocervical adenocarcinoma', 'Disease', (259, 286))	('multiple cancers', 'Disease', (130, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (193, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('esophageal carcinoma', 'Disease', (193, 213))	('liver hepatocellular carcinoma', 'Disease', (301, 331))	('cervical squamous cell carcinoma', 'Disease', (222, 254))	('TACC3', 'Gene', '10460', (6, 11))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (259, 286))	('TACC3', 'Gene', (6, 11))	('FGFR3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (114, 124))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 254))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (193, 213))	('multiple cancers', 'Disease', 'MESH:D009369', (130, 146))	('FGFR3', 'Gene', '2261', (0, 5))
36231	32160708	The occurrence of FGFR3-TACC3 fusion in CESC, ESCA, and LIHC has not been reported previously, signifying that this common fusion is prevalent in more tissue types than previously discovered.	('FGFR3', 'Gene', '2261', (18, 23))	('fusion', 'Var', (30, 36))	('TACC3', 'Gene', '10460', (24, 29))	('CESC', 'Disease', (40, 44))	('TACC3', 'Gene', (24, 29))	('FGFR3', 'Gene', (18, 23))	('ESCA', 'Disease', (46, 50))
36232	32160708	Other FGFR fusions partnering with BicC family RNA binding protein 1 (BICC1), shootin 1 (SHTN1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and arginyltransferase 1 (ATE1) have also been detected in multiple cancers from our analysis.	('ATE1', 'Gene', (173, 177))	('GAPDH', 'Gene', (139, 144))	('FGF', 'Gene', '2247', (6, 9))	('shootin 1', 'Gene', (78, 87))	('SHTN1', 'Gene', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (206, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('detected', 'Reg', (194, 202))	('SHTN1', 'Gene', '57698', (89, 94))	('FGF', 'Gene', (6, 9))	('fusions', 'Var', (11, 18))	('arginyltransferase 1', 'Gene', (151, 171))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ATE1', 'Gene', '11101', (173, 177))	('shootin 1', 'Gene', '57698', (78, 87))	('multiple cancers', 'Disease', (206, 222))	('BICC1', 'Gene', '80114', (70, 75))	('GAPDH', 'Gene', '2597', (139, 144))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (97, 137))	('BICC1', 'Gene', (70, 75))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (97, 137))	('arginyltransferase 1', 'Gene', '11101', (151, 171))
36233	32160708	Several of these FGFR fusions have been identified as activating fusions that have been linked to activation of downstream genes.	('FGF', 'Gene', (17, 20))	('FGF', 'Gene', '2247', (17, 20))	('fusions', 'Var', (22, 29))
36234	32160708	Following the same trend, ETV6-NTRK3 (ETS variant 6 and neurotrophic tyrosine kinase, receptor, type 3) fusions were also identified in multiple cancers including breast, colon, skin, and thyroid cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('multiple cancers', 'Disease', 'MESH:D009369', (136, 152))	('colon', 'Disease', (171, 176))	('ETV6', 'Gene', '2120', (26, 30))	('fusions', 'Var', (104, 111))	('thyroid cancers', 'Disease', 'MESH:D013964', (188, 203))	('breast', 'Disease', (163, 169))	('NTRK3', 'Gene', '4916', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('NTRK3', 'Gene', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('thyroid cancer', 'Phenotype', 'HP:0002890', (188, 202))	('identified', 'Reg', (122, 132))	('multiple cancers', 'Disease', (136, 152))	('ETV6', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('skin', 'Disease', (178, 182))	('thyroid cancers', 'Disease', (188, 203))
36235	32160708	This ETV6 fusion with NTRK3 has also been identified as oncogenic by the activation of the Ras-MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT pathways.	('phosphatidylinositol 3-kinase', 'Gene', (104, 133))	('activation', 'PosReg', (73, 83))	('MAPK', 'Gene', (95, 99))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (104, 133))	('NTRK3', 'Gene', '4916', (22, 27))	('AKT', 'Gene', (141, 144))	('fusion', 'Var', (10, 16))	('ETV6', 'Gene', (5, 9))	('AKT', 'Gene', '207', (141, 144))	('NTRK3', 'Gene', (22, 27))	('MAPK', 'Gene', '5594', (95, 99))	('ETV6', 'Gene', '2120', (5, 9))
36236	32160708	In contrast, most of the ESR1 (estrogen receptor 1) fusions except for ESR1-CCDC170 (coiled-coil domain containing 170) were found to be exclusively present in breast cancer.	('ESR1', 'Gene', (25, 29))	('coiled-coil domain containing 170', 'Gene', '80129', (85, 118))	('ESR1', 'Gene', '2099', (71, 75))	('estrogen receptor 1', 'Gene', '2099', (31, 50))	('CCDC170', 'Gene', '80129', (76, 83))	('present', 'Reg', (149, 156))	('estrogen receptor 1', 'Gene', (31, 50))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('ESR1', 'Gene', '2099', (25, 29))	('coiled-coil domain containing 170', 'Gene', (85, 118))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ESR1', 'Gene', (71, 75))	('CCDC170', 'Gene', (76, 83))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('fusions', 'Var', (52, 59))
36248	32160708	IL34 expression has been associated with the progression of tumor growth, metastasis, and poor prognosis in several cancers.	('associated', 'Reg', (25, 35))	('IL34', 'Gene', (0, 4))	('expression', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('metastasis', 'CPA', (74, 84))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('tumor', 'Disease', (60, 65))	('IL34', 'Gene', '146433', (0, 4))
36256	32160708	An earlier report also identified a high percentage of recurrent kinase fusions in thyroid cancer, indicating that kinase fusions could be explored as biomarkers or therapeutic targets in this cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))	('kinase fusions', 'Var', (65, 79))
36261	32160708	EML4 (echinoderm microtubule-associated protein-like 4) fusions with ALK (ALK receptor tyrosine kinase) that were previously associated with non-small-cell lung cancer (NSCLC) were identified in LUAD along with KIRP and THCA at low frequency.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('fusions', 'Var', (56, 63))	('ALK', 'Gene', '238', (69, 72))	('echinoderm microtubule-associated protein-like 4', 'Gene', (6, 54))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('ALK', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('associated', 'Reg', (125, 135))	('ALK', 'Gene', '238', (74, 77))	('ALK', 'Gene', (74, 77))	('non-small-cell lung cancer', 'Disease', (141, 167))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('KIRP', 'Chemical', '-', (211, 215))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (6, 54))	('EML4', 'Gene', (0, 4))	('NSCLC', 'Disease', (169, 174))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('EML4', 'Gene', '27436', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
36266	32160708	Since alteration of oncogene or tumor suppressor functions can be key to the initiation and progression of cancer, we also screened for these fusions in our dataset.	('tumor suppressor', 'Gene', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor suppressor', 'Gene', '7248', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('oncogene', 'Protein', (20, 28))	('alteration', 'Var', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
36269	32160708	CCDC6-RET fusions in thyroid and CBFB-MYH11 (core-binding factor, beta subunit and myosin heavy chain 11) fusions in LAML (acute myeloid leukemia) were recurrent.	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('RET', 'Gene', '5979', (6, 9))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (129, 145))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (123, 145))	('CBFB', 'Gene', '865', (33, 37))	('MYH11', 'Gene', (38, 43))	('acute myeloid leukemia', 'Disease', (123, 145))	('RET', 'Gene', (6, 9))	('CCDC6', 'Gene', '8030', (0, 5))	('CBFB', 'Gene', (33, 37))	('CCDC6', 'Gene', (0, 5))	('fusions', 'Var', (106, 113))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (123, 145))	('MYH11', 'Gene', '4629', (38, 43))	('fusions', 'Var', (10, 17))
36274	32160708	PRKAR1A fusions were recurrent across and within several cancer types.	('cancer type', 'Disease', 'MESH:D009369', (57, 68))	('fusions', 'Var', (8, 15))	('PRKAR1A', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer type', 'Disease', (57, 68))	('PRKAR1A', 'Gene', '5573', (0, 7))
36276	32160708	The percentage of TSG/oncogene fusions among the recurrent non-canonical fusions predicted was similar to those in the canonical fusions, although the majority of these fusions were identified from BRCA (Table S11).	('S11', 'Gene', (210, 213))	('TSG', 'Gene', (18, 21))	('TSG', 'Gene', '57045', (18, 21))	('BRCA', 'Gene', '672', (198, 202))	('S11', 'Gene', '6267', (210, 213))	('fusions', 'Var', (31, 38))	('BRCA', 'Gene', (198, 202))
36279	32160708	Another interesting observation of breast cancer was the occurrence of ErbB2 fusions.	('ErbB2', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('fusions', 'Var', (77, 84))	('ErbB2', 'Gene', '2064', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
36280	32160708	BRCA samples that are HER2 positive or the HER2-E PAM50 subtype had statistically higher ErbB2 fusions (Fisher's exact test p = 0.004 and 0.002, respectively).	('BRCA', 'Gene', (0, 4))	('HER2', 'Gene', (43, 47))	('ErbB2', 'Gene', (89, 94))	('PAM50', 'Var', (50, 55))	('higher', 'PosReg', (82, 88))	('HER2', 'Gene', (22, 26))	('HER2', 'Gene', '2064', (43, 47))	('HER2', 'Gene', '2064', (22, 26))	('ErbB2', 'Gene', '2064', (89, 94))	('BRCA', 'Gene', '672', (0, 4))
36282	32160708	Overexpression of ErbB2, a receptor tyrosine kinase with intrinsic tyrosine kinase activity, is associated with breast cancer metastasis and lower survival rates.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer metastasis', 'Disease', (112, 136))	('associated', 'Reg', (96, 106))	('ErbB2', 'Gene', (18, 23))	('lower', 'NegReg', (141, 146))	('Overexpression', 'Var', (0, 14))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (112, 136))	('ErbB2', 'Gene', '2064', (18, 23))	('survival rates', 'CPA', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
36283	32160708	These observations indicate the need to investigate ErbB2 fusions in breast cancer and their association with gene expression and patient survival.	('patient', 'Species', '9606', (130, 137))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ErbB2', 'Gene', (52, 57))	('breast cancer', 'Disease', (69, 82))	('fusions', 'Var', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('ErbB2', 'Gene', '2064', (52, 57))
36284	32160708	To investigate oncogenic pathways that are affected by fusions in each TCGA cancer type, we cataloged recurrent fusions identified across 10 important oncogenic pathways (selection based on a previous report).	('cancer type', 'Disease', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('fusions', 'Var', (112, 119))	('oncogenic pathways', 'Pathway', (151, 169))	('cancer type', 'Disease', 'MESH:D009369', (76, 87))
36285	32160708	RTKRAS, NOTCH, PI3K, and HIPPO signaling pathways were found to be the most affected oncogenic pathways by recurrent canonical fusions (Figure 3A; Table S12).	('NOTCH', 'Pathway', (8, 13))	('HIPPO signaling pathways', 'Pathway', (25, 49))	('PI3K', 'Pathway', (15, 19))	('oncogenic pathways', 'Pathway', (85, 103))	('S12', 'Gene', '6268', (153, 156))	('affected', 'Reg', (76, 84))	('canonical fusions', 'Var', (117, 134))	('S12', 'Gene', (153, 156))
36286	32160708	Thyroid cancer had more than 50% of the recurrent canonical fusions in the RTK (receptor tyrosine kinase)-RAS pathway, with a high frequency of CCDC-RET fusion.	('RET', 'Gene', '5979', (149, 152))	('Thyroid cancer', 'Disease', 'MESH:D013964', (0, 14))	('fusions', 'Var', (60, 67))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Thyroid cancer', 'Disease', (0, 14))	('RET', 'Gene', (149, 152))
36289	32160708	OV, ESCA, and LAML mainly contributed to the pool of read-through fusions (>40%) while some cancers have none (Table S1).	('ESCA', 'Disease', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('read-through fusions', 'Var', (53, 73))	('fusions', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
36291	32160708	For example, ZCCHC8-RSRC2 fusion was detected in five cancers (BLCA, BRCA, CESC, HNSC, and PAAD) at very low frequency (Table S13).	('fusion', 'Var', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('BRCA', 'Gene', '672', (69, 73))	('HNSC', 'Disease', (81, 85))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('BRCA', 'Gene', (69, 73))	('RSRC2', 'Gene', (20, 25))	('RSRC2', 'Gene', '65117', (20, 25))	('detected', 'Reg', (37, 45))	('CESC', 'Disease', (75, 79))	('ZCCHC8', 'Gene', '55596', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ZCCHC8', 'Gene', (13, 19))
36303	32160708	LUSC and THYM shared 39 recurrent fusions, including RAB3IP (interactor of the Ras-like GTPase Rab3A) and CHRM3 as recurrent 5' fusion partners with other genes in both cancers.	('Rab3A', 'Gene', '5864', (95, 100))	('cancers', 'Disease', (169, 176))	('Ras-like GTPase', 'Gene', '282808', (79, 94))	('CHRM3', 'Gene', (106, 111))	('Rab3A', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('RAB3IP', 'Gene', (53, 59))	('RAB3IP', 'Gene', '117177', (53, 59))	('CHRM3', 'Gene', '1131', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('Ras-like GTPase', 'Gene', (79, 94))	('fusions', 'Var', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
36305	32160708	We also identified RAB3IP fusions in gastrointestinal (GI) cancers, including STAD, COAD, CHOL, and LIHC.	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D005770', (37, 66))	('RAB3IP', 'Gene', '117177', (19, 25))	('fusions', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('RAB3IP', 'Gene', (19, 25))	('CHOL', 'CellLine', 'None', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('COAD', 'Disease', (84, 88))	('CHOL', 'Disease', (90, 94))	('STAD', 'Disease', (78, 82))	('LIHC', 'Disease', (100, 104))
36315	32160708	Fusions involving CHRM3 were expressed in several GI tract cancers studied.	('Fusions', 'Var', (0, 7))	('GI tract cancers', 'Disease', 'MESH:D005770', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('expressed', 'Reg', (29, 38))	('GI tract cancers', 'Disease', (50, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('CHRM3', 'Gene', (18, 23))	('CHRM3', 'Gene', '1131', (18, 23))
36319	32160708	RXR is a master regulator and plays a central role in nuclear signaling, and a truncated RXR has been associated with oncogenicity.	('associated', 'Reg', (102, 112))	('oncogenicity', 'CPA', (118, 130))	('truncated', 'Var', (79, 88))	('RXR', 'Gene', '6256', (89, 92))	('RXR', 'Gene', '6256', (0, 3))	('RXR', 'Gene', (89, 92))	('RXR', 'Gene', (0, 3))
36330	32160708	Among the recurrent non-canonical fusions, ErBB2 and ESR1 fusions were druggable and were only identified in breast cancer samples.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('ErBB2', 'Gene', '2064', (43, 48))	('ESR1', 'Gene', '2099', (53, 57))	('fusions', 'Var', (58, 65))	('ErBB2', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ESR1', 'Gene', (53, 57))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
36339	32160708	We identified 2,524 unique recurrent fusions from these cell lines with approximately equal distribution of canonical and non-canonical fusions (Figure 1; Tables S16 and S17).	('S17', 'Gene', '6218', (170, 173))	('S16', 'Gene', (162, 165))	('S16', 'Gene', '6217', (162, 165))	('fusions', 'Var', (37, 44))	('S17', 'Gene', (170, 173))
36342	32160708	A large number of recurrent canonical fusions (91 fusions) were identified in more than 35% of the cancer cell lines analyzed across cancers, indicating that fusions present in cell lines are more pervasive across cancers than the ones identified in primary tumors.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('primary tumors', 'Disease', 'MESH:D001932', (250, 264))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', (99, 105))	('fusions', 'Var', (158, 165))	('primary tumors', 'Disease', (250, 264))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
36348	32160708	We also identified a high frequency of chromosome Y genes in non-canonical fusions in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('chromosome Y genes', 'Gene', (39, 57))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('lung squamous cell carcinoma', 'Disease', (86, 114))	('non-canonical fusions', 'Var', (61, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
36351	32160708	Hierarchical clustering analysis of recurrent canonical or non-canonical fusions in CCLE revealed different patterns, except for some cancers of squamous origin (ESCA and HNSC), which clustered together in both groups (Figures S10A, S10B, S11A, and S11B).	('S10A', 'SUBSTITUTION', 'None', (227, 231))	('S10B', 'SUBSTITUTION', 'None', (233, 237))	('S11A', 'SUBSTITUTION', 'None', (239, 243))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('S10A', 'Var', (227, 231))	('S10B', 'Var', (233, 237))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('S11A', 'Var', (239, 243))	('S11B', 'SUBSTITUTION', 'None', (249, 253))	('S11B', 'Var', (249, 253))	('CCLE', 'Chemical', '-', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
36353	32160708	The pool of recurrent fusions identified from CCLE samples was vastly different from those identified in TCGA tumors, with minimal overlap (Figures S12A and S12B).	('S12B', 'SUBSTITUTION', 'None', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('CCLE', 'Disease', (46, 50))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('CCLE', 'Chemical', '-', (46, 50))	('S12A', 'Var', (148, 152))	('S12B', 'Var', (157, 161))	('S12A', 'SUBSTITUTION', 'None', (148, 152))
36354	32160708	Of the common fusions identified between the two groups, canonical fusions were found to be more common (9%) than non-canonical fusions (2%) (Table S18).	('canonical', 'Var', (57, 66))	('S18', 'Gene', '6222', (148, 151))	('S18', 'Gene', (148, 151))
36355	32160708	Hierarchical clustering analysis of recurrent fusions identified in CCLE and TCGA also revealed separate clusters for primary tumor and cell lines for both canonical and non-canonical fusions, indicating that fusions in cell lines are vastly different from the primary tumors (Figures 5A-5D).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('primary tumors', 'Disease', (261, 275))	('fusions', 'Var', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('tumor', 'Disease', (269, 274))	('TCGA', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('CCLE', 'Gene', (68, 72))	('primary tumors', 'Disease', 'MESH:D001932', (261, 275))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CCLE', 'Chemical', '-', (68, 72))	('tumor', 'Disease', (126, 131))
36359	32160708	In contrast to other cancers, breast cancer also had a high frequency of recurrent non-canonical fusions that were common between CCLE and TCGA samples.	('non-canonical fusions', 'Var', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancers', 'Disease', (21, 28))	('CCLE', 'Chemical', '-', (130, 134))
36361	32160708	Most of the reported fusions in TCGA that are also common between cell lines and TCGA primary tumors were non-recurrent canonical fusions.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('primary tumors', 'Disease', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('primary tumors', 'Disease', 'MESH:D001932', (86, 100))	('fusions', 'Var', (21, 28))	('TCGA', 'Disease', (32, 36))
36366	32160708	Among the samples screened for structural variations using BreakDancer, inter-chromosomal translocations (CTXs) and insertions (INSs) were relatively rare compared to other structural variations within a cancer (Table S20).	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('insertions', 'Var', (116, 126))	('S20', 'Gene', (218, 221))	('S20', 'Gene', '6224', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))
36367	32160708	Breast cancer displayed the highest percentage of both intra-chromosomal translocations (ITXs) and inversions (INVs), accounting for the majority of non-canonical fusions identified in these samples.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('intra-chromosomal', 'Var', (55, 72))	('inversions', 'Var', (99, 109))	('Breast cancer', 'Disease', (0, 13))
36373	32160708	We were also able to validate the existence of non-canonical fusions (at least one partner in antisense orientation: GBA-MTX1, DNHD1-RRP8, PRDM4-PWP1, RPL39L-ST6GAL1, BOP1-MROH1, SPDYE3-UPK3B) in CCLE cell lines, indicating that ChimeRScope can accurately predict fusions containing antisense genes along with canonical fusions (Figure S15).	('RRP8', 'Gene', '23378', (133, 137))	('BOP1', 'Gene', (167, 171))	('RRP8', 'Gene', (133, 137))	('RPL39L', 'Gene', '116832', (151, 157))	('ST6GAL1', 'Gene', '6480', (158, 165))	('MTX1', 'Gene', (121, 125))	('ST6GAL1', 'Gene', (158, 165))	('S15', 'Gene', '2202', (336, 339))	('UPK3B', 'Gene', (186, 191))	('UPK3B', 'Gene', '80761', (186, 191))	('PRDM4', 'Gene', '11108', (139, 144))	('BOP1', 'Gene', '23246', (167, 171))	('GBA', 'Gene', (117, 120))	('MROH1', 'Gene', '727957', (172, 177))	('PRDM4', 'Gene', (139, 144))	('MTX1', 'Gene', '4580', (121, 125))	('S15', 'Gene', (336, 339))	('CCLE', 'Chemical', '-', (196, 200))	('DNHD1', 'Gene', '144132', (127, 132))	('MROH1', 'Gene', (172, 177))	('GBA', 'Gene', '2629', (117, 120))	('SPDYE3', 'Gene', (179, 185))	('RPL39L', 'Gene', (151, 157))	('fusions', 'Var', (264, 271))	('SPDYE3', 'Gene', '441272', (179, 185))	('PWP1', 'Gene', (145, 149))	('PWP1', 'Gene', '11137', (145, 149))	('antisense genes', 'Var', (283, 298))	('DNHD1', 'Gene', (127, 132))
36375	32160708	Within these recurrent fusions, non-canonical fusions were more prevalent than canonical fusions in this cancer (Table S1).	('cancer', 'Disease', (105, 111))	('non-canonical fusions', 'Var', (32, 53))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('prevalent', 'Reg', (64, 73))
36380	32160708	Mutual exclusivity of mutations and fusions was recently identified as an important driver of genes in cancer.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (22, 31))
36382	32160708	TP53 mutations were found to be significantly lower in the samples with high fusion category (23%) when compared to low fusion samples (51%, adjusted p = 0.01) (Figure 7).	('TP53', 'Gene', '7157', (0, 4))	('lower', 'NegReg', (46, 51))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
36384	32160708	We limited our analysis only to fusion transcripts that were recurrent (n >= 2) either within or across cancers and generated a catalog of frequent high-confidence fusions across pan-cancer primary tumor and cell line samples.	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('fusions', 'Var', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (104, 110))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
36386	32160708	ChimeRScope also detected fusions in several of the normal samples, which is consistent with a recent report that fusions are also common in non-tumor cells.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('fusions', 'Var', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('detected', 'Reg', (17, 25))
36391	32160708	This observation is consistent with earlier reports that suggest breast cancer harbors a large number of structural variations compared to other cancers, specifically intrachromosomal translocations and inversions being the most common types.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', (65, 78))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('intrachromosomal', 'Var', (167, 183))	('inversions', 'Var', (203, 213))
36392	32160708	We also detected a high incidence of inversions and intrachromosomal variations in the BRCA-WGS data, which supports a large number of non-canonical fusions identified in breast cancer compared to other cancers (Table S20).	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('BRCA', 'Gene', '672', (87, 91))	('S20', 'Gene', (218, 221))	('inversions', 'Var', (37, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('S20', 'Gene', '6224', (218, 221))	('BRCA', 'Gene', (87, 91))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('intrachromosomal variations', 'Var', (52, 79))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
36393	32160708	A recent report on the transcriptional costs of structural variation in breast cancer identified the presence of genes in opposite transcriptional orientation resulting in stable antisense transcription.	('antisense transcription', 'MPA', (179, 202))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('structural variation', 'Var', (48, 68))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
36396	32160708	The pervasive expression of antisense transcripts has been reported in many cancers, which accounts for about 38% of the annotated transcripts.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('reported', 'Reg', (59, 67))	('antisense transcripts', 'Var', (28, 49))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
36400	32160708	Nevertheless, BreakDancer was selected as a structural variation detection tool for validation because this tool was able to detect more translocations, deletions, and inversions compared to other popular tools, such as SVDetect, DELLY, and Meerkat.	('translocations', 'Var', (137, 151))	('inversions', 'Var', (168, 178))	('Meerkat', 'Species', '37032', (241, 248))	('deletions', 'Var', (153, 162))
36405	32160708	We also identified several transcriptional read-through fusions that are recurrent in various cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('fusions', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
36411	32160708	Our data reconfirm the previous observation that thyroid cancer is one of the cancers that have the highest percentage of recurrent kinase fusions.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('thyroid cancer', 'Disease', (49, 63))	('kinase fusions', 'Var', (132, 146))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('fusions', 'Var', (139, 146))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
36415	32160708	Understanding the possible involvement of SMG1 fusions in the accumulation of non-canonical fusions containing antisense transcripts requires further investigation.	('SMG1', 'Gene', '23049', (42, 46))	('fusions', 'Var', (47, 54))	('SMG1', 'Gene', (42, 46))
36418	32160708	It is also interesting that most of the recurrent fusions (78%) were recurrent only within breast cancer and are not found in other TCGA cancer samples (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('fusions', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
36420	32160708	In addition, TP53 mutations were almost doubled in patients with low fusions, indicating that mutations on major oncogenes might be mutually exclusive with fusions.	('TP53', 'Gene', (13, 17))	('low fusions', 'Var', (65, 76))	('patients', 'Species', '9606', (51, 59))	('TP53', 'Gene', '7157', (13, 17))	('doubled', 'PosReg', (40, 47))	('mutations', 'Var', (18, 27))
36421	32160708	A recent study also found that fusions and mutations in driver genes are mutually exclusive across cancer types in TGCA.	('TGCA', 'Disease', (115, 119))	('cancer type', 'Disease', 'MESH:D009369', (99, 110))	('cancer type', 'Disease', (99, 110))	('fusions', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
36422	32160708	Analysis of fusions in 802 tumor-derived cell lines from CCLE using ChimeRScope revealed a high frequency of recurrent fusions across several cell lines irrespective of the tissue of origin.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('fusions', 'Var', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CCLE', 'Chemical', '-', (57, 61))
36423	32160708	Several reports, including a recent study on recurrent fusions across multiple cancer types, also identified fusions that were frequent across cell lines, but the mechanism behind this phenomenon is unexplored.	('cancer type', 'Disease', 'MESH:D009369', (79, 90))	('cancer type', 'Disease', (79, 90))	('fusions', 'Var', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
36425	32160708	We were able to identify only 150 (including both canonical and non-canonical) recurrent fusions that were common between TCGA and CCLE.	('CCLE', 'Disease', (131, 135))	('TCGA', 'Disease', (122, 126))	('fusions', 'Var', (89, 96))	('CCLE', 'Chemical', '-', (131, 135))
36428	32160708	Most of these studies have compared gene expression profiles, copy number variations, and mutation profiles but have not investigated the differences in fusion profiles among the primary tumor and tumor-derived cell lines.	('gene expression', 'MPA', (36, 51))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('copy number variations', 'Var', (62, 84))
36431	32160708	Our analysis using ChimeRScope identified several recurrent fusion transcripts that are common across cancers, reemphasizing the need for identifying therapy focused on actionable targets.	('fusion', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
36470	32160708	Gene set enrichment analysis (GSEA) was used to identify enriched upregulated and downregulated pathways among the high and low fusion groups.	('high', 'Var', (115, 119))	('downregulated', 'NegReg', (82, 95))	('upregulated', 'PosReg', (66, 77))	('low', 'NegReg', (124, 127))	('GSEA', 'Chemical', '-', (30, 34))
36474	31672974	We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes.	('endometrial carcinoma', 'Disease', (68, 89))	('POLE-mutated', 'Var', (91, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('copy number high', 'Var', (133, 149))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('microsatellite instability', 'MPA', (105, 131))	('copy number low', 'Var', (155, 170))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (68, 89))
36475	31672974	These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes.	('DNA', 'Disease', (41, 44))	('linked', 'Reg', (29, 35))	('deficiencies', 'Var', (52, 64))	('patient', 'Species', '9606', (153, 160))
36491	31672974	Microsatellite instability, caused by defective mismatch repair, is observed in 20-40% of endometrial endometrioid carcinoma and is associated with higher histological grade and more lymphovascular space invasion but better prognosis.	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (90, 124))	('mismatch repair', 'Protein', (48, 63))	('defective', 'Var', (38, 47))	('observed', 'Reg', (68, 76))	('Microsatellite instability', 'Disease', (0, 26))	('lymphovascular space invasion', 'CPA', (183, 212))	('endometrial endometrioid carcinoma', 'Disease', (90, 124))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (102, 124))
36492	31672974	The ultramutated phenotype, resulting from mutations in the exonuclease domain of DNA polymerase epsilon (POLE), is present in several cancer types, including endometrial cancer, and linked with diseases at an earlier stage and with a more favorable prognosis.	('linked with', 'Reg', (183, 194))	('cancer', 'Disease', (135, 141))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations in', 'Var', (43, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('POLE', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('present', 'Reg', (116, 123))
36493	31672974	Copy number aberration is a dominant characteristic of the genome in endometrial and ovarian serous carcinoma, and is associated with a more advanced disease and poor patient outcomes.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('patient', 'Species', '9606', (167, 174))	('Copy number aberration', 'Var', (0, 22))	('endometrial and ovarian serous carcinoma', 'Disease', 'MESH:D010051', (69, 109))	('advanced disease', 'Disease', (141, 157))	('associated', 'Reg', (118, 128))	('advanced disease', 'Disease', 'MESH:D020178', (141, 157))
36500	31672974	We used a modified version of the molecular subtyping method based on genomic aberration profiling (described in the Methods) on 109 uterine and ovarian CS samples, and then used a decision tree to classify samples into four molecular subtypes: POLE-mutated (POLE), microsatellite instability (MSI), copy number high (CNH), and copy number low (CNL) subtypes.	('ovarian CS', 'Disease', (145, 155))	('copy number', 'Var', (328, 339))	('ovarian CS', 'Disease', 'MESH:D010049', (145, 155))	('microsatellite', 'MPA', (266, 280))	('copy', 'Var', (300, 304))
36502	31672974	MSI tumors exhibited numerous indels (range: 10-63, median: 27) and a moderately increased number of SNVs (range: 8-207, median: 55) but fewer CNVs (range: 0-7, median: 2).	('MSI tumors', 'Disease', (0, 10))	('indels', 'Var', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SNVs', 'MPA', (101, 105))	('CNVs', 'MPA', (143, 147))	('MSI tumors', 'Disease', 'MESH:D009369', (0, 10))
36503	31672974	The remaining tumors were assigned as CNL subtype, with few SNVs, indels, or CNVs (Fig.	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('CNVs', 'Var', (77, 81))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('indels', 'Var', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
36511	31672974	The ovarian CS and endometrial carcinoma share a subset of SNVs/indels, including the POLE p.P286R mutation.	('ovarian CS', 'Disease', (4, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('p.P286R', 'Var', (91, 98))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (19, 40))	('endometrial carcinoma', 'Disease', (19, 40))	('ovarian CS', 'Disease', 'MESH:D010049', (4, 14))	('p.P286R', 'Mutation', 'p.P286R', (91, 98))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (19, 40))
36515	31672974	Moreover, the multivariate Cox regression analysis with FIGO stage, tumor size, and primary tumor anatomical site confirmed that each of these genomic aberration subtypes was independent (POLE: p = 0.9985 and 0.9987, HR = 0.0000 and 0.0000; MSI: p = 0.0068 and 0.0205, HR = 0.1937 and 0.0937; CNH: p = 0.0007 and 0.0296, HR = 3.9048 and 2.6047; CNL: p = 0.1782 and 0.0025, HR = 1.9214 and 4.1512).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('0.0937', 'Var', (285, 291))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
36518	31672974	We curated gene sets for mismatch repair (MMR) and homologous recombination (HR) pathways that were relevant for hereditary breast, endometrial, and ovarian cancer, and subsequently assessed whether a tumor retained a germline and/or somatic mutation or CpG-site hypermethylation in the selected genes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ovarian cancer', 'Disease', (149, 163))	('endometrial', 'Disease', (132, 143))	('hereditary breast', 'Disease', (113, 130))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('endometrial', 'Disease', 'MESH:D016889', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('tumor', 'Disease', (201, 206))	('hereditary breast', 'Disease', 'MESH:D061325', (113, 130))	('CpG-site hypermethylation', 'Var', (254, 279))
36521	31672974	Defective MMR was observed in the MSI subtype, including MLH1 promoter hypermethylation and germline/somatic mutations in MLH1, MSH2, MSH6, or PMS2 loci.	('MLH1', 'Gene', '4292', (57, 61))	('PMS2', 'Gene', '5395', (143, 147))	('MLH1', 'Gene', (57, 61))	('MSH6', 'Gene', '2956', (134, 138))	('MLH1', 'Gene', (122, 126))	('MLH1', 'Gene', '4292', (122, 126))	('MSH2', 'Gene', (128, 132))	('MSH2', 'Gene', '4436', (128, 132))	('hypermethylation', 'Var', (71, 87))	('MSH6', 'Gene', (134, 138))	('PMS2', 'Gene', (143, 147))
36522	31672974	HR deficiency was a distinctive feature of the CNH subtype, as exemplified by (1) BRCA1 and RAD51C promoter hypermethylation; (2) germline inactivation plus loss of heterozygosity (LOH) in the loci of BRCA1/2, ATM, RAD50, and BLM; and (3) somatic mutation of the PTEN gene.	('BRCA1', 'Gene', (82, 87))	('ATM', 'Gene', '472', (210, 213))	('HR deficiency', 'Disease', (0, 13))	('BRCA1/2', 'Gene', (201, 208))	('loss of', 'NegReg', (157, 164))	('PTEN', 'Gene', (263, 267))	('RAD51C', 'Gene', (92, 98))	('BRCA1/2', 'Gene', '672;675', (201, 208))	('RAD51C', 'Gene', '5889', (92, 98))	('ATM', 'Gene', (210, 213))	('BRCA1', 'Gene', '672', (201, 206))	('BRCA1', 'Gene', '672', (82, 87))	('PTEN', 'Gene', '5728', (263, 267))	('HR deficiency', 'Disease', 'MESH:D001919', (0, 13))	('inactivation', 'Var', (139, 151))	('RAD50', 'Gene', (215, 220))	('RAD50', 'Gene', '10111', (215, 220))	('BRCA1', 'Gene', (201, 206))
36524	31672974	CCNE1 amplification and homozygous deletions of RB1 and NF1 loci were previously reported to be involved in chromosomal instability through a distinct mechanism not involving HR deficiency (non-HRD).	('chromosomal instability', 'MPA', (108, 131))	('RB1', 'Gene', (48, 51))	('HRD', 'Disease', 'MESH:C537157', (194, 197))	('NF1', 'Gene', '4763', (56, 59))	('CCNE1', 'Gene', '898', (0, 5))	('HR deficiency', 'Disease', (175, 188))	('HRD', 'Disease', (194, 197))	('involved', 'Reg', (96, 104))	('CCNE1', 'Gene', (0, 5))	('RB1', 'Gene', '5925', (48, 51))	('HR deficiency', 'Disease', 'MESH:D001919', (175, 188))	('chromosomal instability', 'Phenotype', 'HP:0040012', (108, 131))	('amplification', 'Var', (6, 19))	('NF1', 'Gene', (56, 59))	('homozygous deletions', 'Var', (24, 44))
36525	31672974	Within the CNH subtype, 17 (26.6%) of 64 CNH tumors (15 CCNE1 amplification and 2 RB1 deletion) exhibited this non-HRD-type chromosomal instability.	('RB1', 'Gene', '5925', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('exhibited', 'Reg', (96, 105))	('HRD', 'Disease', (115, 118))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('CNH tumors', 'Disease', 'MESH:D009369', (41, 51))	('chromosomal instability', 'Phenotype', 'HP:0040012', (124, 147))	('CCNE1', 'Gene', '898', (56, 61))	('CCNE1', 'Gene', (56, 61))	('RB1', 'Gene', (82, 85))	('amplification', 'Var', (62, 75))	('HRD', 'Disease', 'MESH:C537157', (115, 118))	('CNH tumors', 'Disease', (41, 51))	('deletion', 'Var', (86, 94))
36526	31672974	The CNH subtype with non-HRD chromosomal instability showed worse prognosis than CNH tumors with HRD in terms of overall survival (p = 0.0427 by Gehan-Breslow-Wilcoxon test; Fig.	('CNH tumors', 'Disease', 'MESH:D009369', (81, 91))	('CNH tumors', 'Disease', (81, 91))	('HRD', 'Disease', (97, 100))	('chromosomal instability', 'Var', (29, 52))	('HRD', 'Disease', 'MESH:C537157', (25, 28))	('chromosomal instability', 'Phenotype', 'HP:0040012', (29, 52))	('HRD', 'Disease', 'MESH:C537157', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HRD', 'Disease', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('worse', 'NegReg', (60, 65))
36530	31672974	Also, by GISTIC analysis of SNP6 data, copy number amplification was highly significant for MECOM, MYC, and CCNE1.	('MECOM', 'Gene', (92, 97))	('CCNE1', 'Gene', (108, 113))	('MECOM', 'Gene', '2122', (92, 97))	('MYC', 'Disease', (99, 102))	('CCNE1', 'Gene', '898', (108, 113))	('copy number amplification', 'Var', (39, 64))
36548	31672974	The phylogenetic trees of the CNL and CNH subtype tumors had a high proportion of trunks: the carcinoma and sarcoma components shared most of the SNVs/indels of the 596 genes (Fig.	('CNH subtype tumors', 'Disease', 'MESH:C535673', (38, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('CNH subtype tumors', 'Disease', (38, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('SNVs/indels', 'Var', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (94, 115))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
36550	31672974	Whereas none of the 26 (0%) and only 2 of the 12 (16.7%) drivers on the carcinoma- or sarcoma-branches were clonal among the POLE and MSI subtypes, 21 of 43 (48.8%) and 9 of 12 (75.0%) driver mutations on the trunk were clonal, respectively (Fig.	('carcinoma- or sarcoma-branches', 'Disease', (72, 102))	('carcinoma- or sarcoma-branches', 'Disease', 'MESH:D012509', (72, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('mutations', 'Var', (192, 201))
36552	31672974	CS tumors of the CNH subtype frequently had longer trunks with shorter branches for both carcinoma and sarcoma components, and this branching pattern was also confirmed with tree analyses with SNVs/indels from the exome data (when available) and with CNVs of the target panel or exome data (Supplementary Fig.	('CS tumors', 'Disease', 'MESH:D006223', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('longer', 'PosReg', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (89, 110))	('CS tumors', 'Disease', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('shorter', 'NegReg', (63, 70))	('SNVs/indels', 'Var', (193, 204))	('CNH', 'Disease', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
36558	31672974	However, in the CNH subtype (GY030 tumor), similarities between T2 (carcinoma-dominant) and T3 (sarcoma-dominant), and between T4 (carcinoma-dominant) and T6 (sarcoma-dominant) suggest parallel evolution of the bimodal T2/T3 and T4/T6 regions.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('carcinoma-dominant', 'Disease', 'MESH:D002277', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinoma-dominant', 'Disease', (68, 86))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('sarcoma-dominant', 'Disease', (96, 112))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (159, 175))	('CNH', 'Disease', (16, 19))	('sarcoma-dominant', 'Disease', (159, 175))	('tumor', 'Disease', (35, 40))	('carcinoma-dominant', 'Disease', 'MESH:D002277', (131, 149))	('carcinoma-dominant', 'Disease', (131, 149))	('GY030', 'Var', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (96, 112))
36562	31672974	No recurrent genetic mutations in SNVs/indels or CNVs were differentially detected between carcinoma- and sarcoma-dominant regions with multi-regional sequenced data of 3 cases (EN676, GY030, and EN558; the data from EN482 were not used for this purpose since sarcoma-dominant region sequenced data was not available for the case; also described in Supplementary Note 3).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('sarcoma-dominant', 'Disease', (106, 122))	('EN558', 'Var', (196, 201))	('sarcoma-dominant', 'Disease', (260, 276))	('carcinoma- and sarcoma-dominant regions', 'Disease', 'MESH:D012509', (91, 130))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (106, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('EN676', 'Var', (178, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('GY030', 'Var', (185, 190))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (260, 276))
36590	31672974	ARID1A mutation was correlated with better patient outcomes when all cases were included in the analysis, because it was more frequently mutated in POLE and MSI subtypes, which show an intrinsically more favorable prognosis.	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('patient', 'Species', '9606', (43, 50))
36591	31672974	On the contrary, in the CNH subgroup, patients with ARID1A mutant tumors showed substantially poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutant', 'Var', (59, 65))	('tumors', 'Disease', (66, 72))	('ARID1A', 'Gene', '8289', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('ARID1A', 'Gene', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (38, 46))	('poor', 'NegReg', (94, 98))
36592	31672974	Since ARID1A has been reported to be involved in DNA double-strand break repair, there is a possible interaction between DNA copy number aberration and ARID1A protein loss in CS aggressiveness.	('protein loss', 'Disease', 'MESH:D058495', (159, 171))	('ARID1A', 'Gene', '8289', (152, 158))	('aggressiveness', 'Disease', (178, 192))	('DNA', 'Gene', (121, 124))	('ARID1A', 'Gene', '8289', (6, 12))	('ARID1A', 'Gene', (6, 12))	('copy number aberration', 'Var', (125, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (178, 192))	('protein loss', 'Disease', (159, 171))	('ARID1A', 'Gene', (152, 158))	('aggressiveness', 'Disease', 'MESH:D001523', (178, 192))
36598	31672974	Whereas CTNNB1-activating mutations have long been recognized as a driving mechanism of EMT in multiple cancer types, including uterine endometrioid carcinoma, in the current CS cohort and contrary to our expectations, the mutational status was independent of the EMT score but, instead, associated with hypomethylation of the miR-200a/200b/429 and miR-141/200c promotors.	('hypomethylation', 'MPA', (304, 319))	('mutational', 'Var', (223, 233))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('endometrioid carcinoma', 'Disease', (136, 158))	('miR-141', 'Gene', (349, 356))	('CTNNB1', 'Gene', '1499', (8, 14))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('miR-200a', 'Gene', '406983', (327, 335))	('miR-200a', 'Gene', (327, 335))	('miR-141', 'Gene', '406933', (349, 356))	('endometrioid carcinoma', 'Disease', 'MESH:D018269', (136, 158))	('CTNNB1', 'Gene', (8, 14))	('cancer', 'Disease', (104, 110))	('associated with', 'Reg', (288, 303))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (136, 158))
36604	31672974	In the current cohort, 2 cases (OV594 and OV343) had synchronous endometrial and ovarian carcinomas (SEOC) and were associated with endometriosis in the ovary.	('associated with', 'Reg', (116, 131))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('endometriosis', 'Phenotype', 'HP:0030127', (132, 145))	('OV594', 'Var', (32, 37))	('OV343', 'Var', (42, 47))	('synchronous endometrial', 'Disease', 'MESH:D016889', (53, 76))	('endometriosis', 'Disease', (132, 145))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (81, 99))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (81, 98))	('endometriosis', 'Disease', 'MESH:D004715', (132, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('ovarian carcinomas', 'Disease', (81, 99))	('synchronous endometrial', 'Disease', (53, 76))
36638	31672974	Loss of heterozygosity (LOH) in copy number was determined by the number of variant sequence reads compared with the wildtype in the tumor DNA.	('variant', 'Var', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', (133, 138))
36644	31672974	The timing of a driver event is inferred from the cancer cell fraction calculated from the mutant allele frequency of a SNV/indel and the copy number state where the SNV/indel resides.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutant', 'Var', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('SNV/indel', 'Gene', (120, 129))
36648	31672974	Samples were first categorized by POLE hotspot mutations in the exonuclease domain (POLE mutated; POLE) and then by MSI-high status (microsatellite instability; MSI), which was determined by deviations from paired normal control in electropherograms of 2 or more among 6 DNA markers (BAT25, BAT26, D2S123, D5S346, D17S250, and BAT40), as previously described.	('D17S250', 'Var', (314, 321))	('D2S123', 'Chemical', 'MESH:C492712', (298, 304))	('BAT25', 'Var', (284, 289))	('BAT40', 'Var', (327, 332))	('D2S123', 'Var', (298, 304))	('D5S346', 'Var', (306, 312))	('BAT26', 'Var', (291, 296))
36650	31672974	We used another molecular subtyping method based on major driver mutations observed in carcinomas with endometrioid or serous histology.	('endometrioid', 'Disease', (103, 115))	('carcinomas', 'Disease', 'MESH:D002277', (87, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('carcinomas', 'Disease', (87, 97))	('serous', 'Disease', (119, 125))	('mutations', 'Var', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
36651	31672974	For this analysis, samples with PTEN or ARID1A mutations were assigned as endometrioid-like, samples with TP53 or PPP2R1A mutations were classified as serous-like, and the remaining samples lacking any mutation in these four genes were assigned to the unclassified group.	('ARID1A', 'Gene', (40, 46))	('ARID1A', 'Gene', '8289', (40, 46))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('mutations', 'Var', (47, 56))	('PPP2R1A', 'Gene', (114, 121))	('PPP2R1A', 'Gene', '5518', (114, 121))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('endometrioid-like', 'Disease', (74, 91))
36657	31151482	Mismatch repair pathways play a vital role in identifying and repairing mismatched bases during DNA replication and genetic recombination in normal and cancer cells.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mismatched bases', 'Var', (72, 88))
36658	31151482	Defects in DNA mismatch repair proteins and subsequent microsatellite instability-high lead to the accumulation of mutation loads in cancer-related genes and the generation of neoantigens, which stimulate the anti-tumor immune response of the host.	('Defects', 'NegReg', (0, 7))	('neoantigens', 'MPA', (176, 187))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('DNA mismatch repair proteins', 'Protein', (11, 39))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('stimulate', 'PosReg', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('microsatellite', 'MPA', (55, 69))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', (214, 219))	('lead', 'Reg', (87, 91))	('mutation', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
36659	31151482	Mismatch repair deficiency/microsatellite instability-high represents a good prognosis in early colorectal cancer settings without adjuvant treatment and a poor prognosis in patients with metastasis.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('patients', 'Species', '9606', (174, 182))	('deficiency', 'Disease', (16, 26))	('colorectal cancer', 'Disease', (96, 113))	('deficiency', 'Disease', 'MESH:D007153', (16, 26))	('Mismatch', 'Var', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
36660	31151482	Several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors.	('mismatch repair', 'Protein', (47, 62))	('associated', 'Reg', (126, 136))	('colorectal and noncolorectal malignancies', 'Disease', 'MESH:D009369', (208, 249))	('deficiency', 'Disease', (63, 73))	('deficiency', 'Disease', 'MESH:D007153', (63, 73))	('microsatellite instability-high', 'Var', (77, 108))
36661	31151482	To date, the anti-programmed cell death-1 inhibitor pembrolizumab has been approved for mismatch repair deficiency/microsatellite instability-high refractory or metastatic solid tumors, and nivolumab has been approved for colorectal cancer patients with mismatch repair deficiency/microsatellite instability-high.	('solid tumors', 'Disease', 'MESH:D009369', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('colorectal cancer', 'Disease', (222, 239))	('pembrolizumab', 'Chemical', 'MESH:C582435', (52, 65))	('deficiency', 'Disease', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('refractory', 'Disease', (147, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('deficiency', 'Disease', 'MESH:D007153', (104, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))	('solid tumors', 'Disease', (172, 184))	('patients', 'Species', '9606', (240, 248))	('deficiency', 'Disease', (270, 280))	('nivolumab', 'Chemical', 'MESH:D000077594', (190, 199))	('mismatch', 'Var', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('deficiency', 'Disease', 'MESH:D007153', (270, 280))
36663	31151482	This review summarizes the features of mismatch repair deficiency/microsatellite instability-high, its relationship with programmed death-ligand 1/programmed cell death-1, and the recent advances in predicting immunotherapy efficacy.	('deficiency', 'Disease', 'MESH:D007153', (55, 65))	('deficiency', 'Disease', (55, 65))	('mismatch', 'Var', (39, 47))
36677	31151482	MSH2/MSH6 heterodimers are responsible for binding to the initial DNA mismatched base errors (including single-base mismatch and incorrect insertion or deletion loop mismatch) by conformational changes, and MLH1/PMS2 heterodimers are in charge of the excision and synthesis of corrected DNA chains in the mismatch site (see Fig.	('binding', 'Interaction', (43, 50))	('deletion', 'Var', (152, 160))	('MSH2', 'Gene', (0, 4))	('PMS2', 'Gene', '5395', (212, 216))	('MSH6', 'Gene', (5, 9))	('mismatched', 'Var', (70, 80))	('MSH2', 'Gene', '4436', (0, 4))	('mismatch', 'Var', (166, 174))	('incorrect insertion', 'Var', (129, 148))	('MLH1', 'Gene', '4292', (207, 211))	('PMS2', 'Gene', (212, 216))	('MSH6', 'Gene', '2956', (5, 9))	('MLH1', 'Gene', (207, 211))
36680	31151482	The dysfunction of MLH1 or MSH2 leads to the inactivation of MLH1/PMS2 or MSH2/MSH6 and the degradation of PMS2 or MSH6 (see Fig.	('MSH2', 'Gene', '4436', (74, 78))	('MSH6', 'Gene', '2956', (79, 83))	('PMS2', 'Gene', '5395', (66, 70))	('MLH1', 'Gene', (61, 65))	('PMS2', 'Gene', (107, 111))	('dysfunction', 'Var', (4, 15))	('degradation', 'MPA', (92, 103))	('MLH1', 'Gene', (19, 23))	('MLH1', 'Gene', '4292', (61, 65))	('MSH6', 'Gene', (115, 119))	('MSH2', 'Gene', (27, 31))	('PMS2', 'Gene', (66, 70))	('MSH6', 'Gene', '2956', (115, 119))	('MLH1', 'Gene', '4292', (19, 23))	('MSH2', 'Gene', (74, 78))	('inactivation', 'NegReg', (45, 57))	('MSH2', 'Gene', '4436', (27, 31))	('PMS2', 'Gene', '5395', (107, 111))	('MSH6', 'Gene', (79, 83))
36681	31151482	Lynch syndrome is a common hereditary disease that is characterized by germline mutations in MMR genes.	('MMR', 'Gene', (93, 96))	('hereditary disease', 'Disease', (27, 45))	('germline mutations', 'Var', (71, 89))	('hereditary disease', 'Disease', 'MESH:D030342', (27, 45))	('Lynch syndrome', 'Disease', (0, 14))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
36683	31151482	A lack of MSH2, substantial mutations in the MLH1 or MSH2 genes, MLH1-methylation inactivation, and transcriptional silencing lead to Lynch syndrome.	('MSH2', 'Gene', (53, 57))	('MSH2', 'Gene', '4436', (53, 57))	('Lynch syndrome', 'Disease', 'MESH:D003123', (134, 148))	('MSH2', 'Gene', (10, 14))	('silencing', 'NegReg', (116, 125))	('MLH1', 'Gene', '4292', (45, 49))	('MSH2', 'Gene', '4436', (10, 14))	('MLH1', 'Gene', '4292', (65, 69))	('MLH1', 'Gene', (45, 49))	('MLH1', 'Gene', (65, 69))	('lead to', 'Reg', (126, 133))	('Lynch syndrome', 'Disease', (134, 148))	('lack', 'NegReg', (2, 6))	('mutations', 'Var', (28, 37))
36684	31151482	Deletion mutations in MLH1 and MSH2 account for 42-50% and 33-39%; however, MSH6 and PMS2 mutations account for only 7-18% and less than 7%, respectively.	('PMS2', 'Gene', (85, 89))	('PMS2', 'Gene', '5395', (85, 89))	('MLH1', 'Gene', '4292', (22, 26))	('MLH1', 'Gene', (22, 26))	('MSH6', 'Gene', (76, 80))	('MSH6', 'Gene', '2956', (76, 80))	('MSH2', 'Gene', (31, 35))	('MSH2', 'Gene', '4436', (31, 35))	('Deletion mutations', 'Var', (0, 18))
36685	31151482	A hypothesis that heterozygous germline deletions in the epithelial cell adhesion molecule (EPCAM) gene as one factor that leads to MSH2 defects has been confirmed, and the addition of EPCAM to the diagnostic panel for Lynch syndrome in MSH2-defective tumors has been advised.	('epithelial cell adhesion molecule', 'Gene', '4072', (57, 90))	('EPCAM', 'Gene', (92, 97))	('Lynch syndrome', 'Disease', 'MESH:D003123', (219, 233))	('Lynch syndrome', 'Disease', (219, 233))	('MSH2-defective tumors', 'Disease', (237, 258))	('MSH2', 'Gene', (237, 241))	('EPCAM', 'Gene', '4072', (92, 97))	('EPCAM', 'Gene', (185, 190))	('MSH2', 'Gene', (132, 136))	('MSH2-defective tumors', 'Disease', 'MESH:D009369', (237, 258))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('defects', 'Var', (137, 144))	('EPCAM', 'Gene', '4072', (185, 190))	('MSH2', 'Gene', '4436', (237, 241))	('MSH2', 'Gene', '4436', (132, 136))	('leads to', 'Reg', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('epithelial cell adhesion molecule', 'Gene', (57, 90))
36686	31151482	The inactivation of MMR genes and MMR protein dysfunction may be the results of germline mutations or spontaneous hypermutation alterations, which may induce microsatellite instability (MSI).	('protein dysfunction', 'Disease', 'MESH:D011488', (38, 57))	('inactivation', 'Var', (4, 16))	('induce', 'Reg', (151, 157))	('protein dysfunction', 'Disease', (38, 57))	('MMR genes', 'Gene', (20, 29))	('MMR', 'Gene', (34, 37))	('microsatellite instability', 'MPA', (158, 184))
36687	31151482	Two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D5S346, D2S123, and D17S250) are the standard sites in panels for MSI testing, as recommended by the National Cancer Institute in 1998.	('Cancer', 'Disease', 'MESH:D009369', (187, 193))	('BAT26', 'Var', (38, 43))	('Cancer', 'Disease', (187, 193))	('dinucleotide', 'Chemical', 'MESH:D015226', (55, 67))	('D5S346', 'Var', (77, 83))	('mononucleotide', 'Chemical', '-', (4, 18))	('D2S123', 'Var', (85, 91))	('BAT25', 'Var', (28, 33))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))	('D17S250', 'Var', (97, 104))
36708	31151482	In general, dMMR is correlated with an improved median overall survival (mOS) in most tumors other than head and neck cancer and pancreatic cancer.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('overall survival', 'MPA', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('head and neck cancer', 'Phenotype', 'HP:0012288', (104, 124))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('mOS', 'Gene', (73, 76))	('tumors', 'Disease', (86, 92))	('neck cancer', 'Disease', 'MESH:D006258', (113, 124))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mOS', 'Gene', '17451', (73, 76))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('dMMR', 'Var', (12, 16))	('neck cancer', 'Disease', (113, 124))	('pancreatic cancer', 'Disease', (129, 146))	('improved', 'PosReg', (39, 47))	('dMMR', 'Chemical', '-', (12, 16))
36718	31151482	They pooled the data and showed that MSS patients treated with 5-fluorouracil had a better prognosis but that the benefit was not obvious for MSI-H CRC patients (OR 0.52, 95% CI 0.4-0.6, P < 0.0001 versus OR 0.69, 95% CI 0.3-1.5, P = 0.10).	('5-fluorouracil', 'Var', (63, 77))	('patients', 'Species', '9606', (41, 49))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('MSI-H', 'Disease', (142, 147))	('better', 'PosReg', (84, 90))	('patients', 'Species', '9606', (152, 160))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (63, 77))	('MSI-H', 'Disease', 'MESH:D000848', (142, 147))
36719	31151482	also concluded that patients with stages II-III CRC with pMMR exhibited improved DFS (hazard ratio [HR] 0.67, 95% CI 0.48-0.93, P = 0.02) resulting from adjuvant therapy compared with those who underwent surgery alone.	('DFS', 'MPA', (81, 84))	('pMMR', 'Var', (57, 61))	('pMMR', 'Chemical', '-', (57, 61))	('improved', 'PosReg', (72, 80))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('patients', 'Species', '9606', (20, 28))
36723	31151482	A meta-analysis confirmed that mCRC patients with dMMR had poorer survival compared with pMMR patients, which might be due to a BRAF V600E mutation.	('survival', 'MPA', (66, 74))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (36, 44))	('poorer', 'NegReg', (59, 65))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('pMMR', 'Chemical', '-', (89, 93))	('V600E', 'Var', (133, 138))	('BRAF', 'Gene', '673', (128, 132))	('dMMR', 'Chemical', '-', (50, 54))	('BRAF', 'Gene', (128, 132))
36788	31151482	A higher number of mutations in DNA coding sequences in MSI-H tumors have more potential to stimulate the host to generate neoantigens and trigger immune activation.	('immune activation', 'MPA', (147, 164))	('stimulate', 'PosReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('MSI-H tumors', 'Disease', 'MESH:D009369', (56, 68))	('generate neoantigens', 'MPA', (114, 134))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('MSI-H tumors', 'Disease', (56, 68))	('mutations', 'Var', (19, 28))	('DNA', 'Gene', (32, 35))
36794	31151482	In the CheckMate 568 trial, the ORR was 4%, 10%, 44%, and 39% when the TMB cutoffs were < 5, < 10, >= 10, and >= 15 mut/Mb in NSCLC patients treated with nivolumab plus ipilimumab as a first-line therapy.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('< 10', 'Var', (93, 97))	('mut/Mb', 'Gene', (116, 122))	('>= 15', 'Var', (110, 115))	('ipilimumab', 'Chemical', 'MESH:D000074324', (169, 179))	('< 5', 'Var', (88, 91))	('>= 10', 'Var', (99, 104))	('nivolumab', 'Chemical', 'MESH:D000077594', (154, 163))	('CheckMate', 'Chemical', 'MESH:C049437', (7, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('TMB', 'Chemical', '-', (71, 74))	('SCLC', 'Phenotype', 'HP:0030357', (127, 131))	('patients', 'Species', '9606', (132, 140))	('NSCLC', 'Disease', (126, 131))
36796	31151482	The prospective phase III trial confirmed that nivolumab plus ipilimumab resulted in a significantly longer PFS and higher ORR only in high TMB patients with stage IV or recurrent NSCLC compared with chemotherapy (mPFS 7.2 months vs 5.5 months; ORR 45.3% vs 26.9%).	('ORR', 'MPA', (123, 126))	('longer', 'PosReg', (101, 107))	('SCLC', 'Phenotype', 'HP:0030357', (181, 185))	('TMB', 'Chemical', '-', (140, 143))	('ipilimumab', 'Chemical', 'MESH:D000074324', (62, 72))	('nivolumab', 'Chemical', 'MESH:D000077594', (47, 56))	('NSCLC', 'Disease', (180, 185))	('PFS', 'MPA', (108, 111))	('high TMB', 'Var', (135, 143))	('patients', 'Species', '9606', (144, 152))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('ipilimumab', 'Gene', (62, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))
36798	31151482	The CheckMate 032 trial demonstrated better clinical benefit in high TMB (TMB >= 248 mutations) patients with SCLC.	('high', 'Var', (64, 68))	('SCLC', 'Phenotype', 'HP:0030357', (110, 114))	('CheckMate', 'Chemical', 'MESH:C049437', (4, 13))	('TMB', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (96, 104))	('TMB', 'Chemical', '-', (74, 77))	('SCLC', 'Disease', (110, 114))	('SCLC', 'Disease', 'MESH:D018288', (110, 114))
36804	31151482	In clinical validation, 50 patients with NSCLC with high bTMB (>= 6 mut/Mb) was associated with prolonged mPFS and higher ORR than patients with low bTMB (< 6 mut/Mb) (mPFS not reach vs 2.9 m; ORR 39.3% vs 9.1%) when treated with anti-PD-1/PD-L1 therapies (see Table 5).	('patients', 'Species', '9606', (131, 139))	('PD-1', 'Gene', '5133', (235, 239))	('NSCLC', 'Disease', (41, 46))	('SCLC', 'Phenotype', 'HP:0030357', (42, 46))	('ORR', 'MPA', (122, 125))	('mPFS', 'CPA', (106, 110))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('patients', 'Species', '9606', (27, 35))	('high', 'Var', (52, 56))	('PD-L1', 'Gene', (240, 245))	('bTMB', 'Chemical', '-', (149, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('PD-L1', 'Gene', '29126', (240, 245))	('PD-1', 'Gene', (235, 239))	('bTMB', 'Chemical', '-', (57, 61))
36809	31151482	Patients with high-TMB and positive PD-L1 expression had the highest rate of durable clinical benefit than that with only one or neither variable presence (50% vs. 18.2-35.5%).	('PD-L1', 'Gene', (36, 41))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', '29126', (36, 41))	('expression', 'Var', (42, 52))	('TMB', 'Chemical', '-', (19, 22))	('high-TMB', 'Var', (14, 22))
36855	29992073	Serum AFP did not show response and was further elevated to 41826 ug/l after cycle two [Figure 2], accompanied by the development of ureteric obstruction, ascites, and radiological evidence of liver and peritoneal metastases [Figure 6].	('ureteric obstruction', 'Disease', 'MESH:D014517', (133, 153))	('41826 ug/l', 'Var', (60, 70))	('ureteric obstruction', 'Disease', (133, 153))	('ureteric obstruction', 'Phenotype', 'HP:0006000', (133, 153))	('metastases', 'Disease', (214, 224))	('ascites', 'Disease', (155, 162))	('AFP', 'Gene', (6, 9))	('ascites', 'Phenotype', 'HP:0001541', (155, 162))	('metastases', 'Disease', 'MESH:D009362', (214, 224))	('ascites', 'Disease', 'MESH:D001201', (155, 162))	('AFP', 'Gene', '174', (6, 9))	('elevated', 'PosReg', (48, 56))
36985	27921159	In comparison to ALM, LMS were associated with higher intensity image-based and Gabor edge image-based contrast, lower energy, and lower homogeneity (p<0.001 for each feature); furthermore, LMS had higher SD and lower kurtosis (p<0.001 for both features), indicative of less peaked and more variable distribution of intensities.	('lower kurtosis', 'Disease', 'MESH:D016472', (212, 226))	('lower kurtosis', 'Disease', (212, 226))	('homogeneity', 'MPA', (137, 148))	('higher', 'PosReg', (47, 53))	('energy', 'MPA', (119, 125))	('SD', 'Disease', 'MESH:D029461', (205, 207))	('LMS', 'Var', (190, 193))	('higher', 'PosReg', (198, 204))	('Gabor', 'Chemical', '-', (80, 85))	('intensity image-based', 'MPA', (54, 75))
37219	27894165	A phase II study of the Southwest Oncology Group (SWOG) reported a response rate of 40% (95% CI, 26%-56%), a median OS of 14 months (95% CI, 12-17 months), and tolerable toxicity with a regimen of paclitaxel (175 mg/m2) and carboplatin (AUC 6).	('carboplatin', 'Chemical', 'MESH:D016190', (224, 235))	('paclitaxel', 'Chemical', 'MESH:D017239', (197, 207))	('Oncology', 'Phenotype', 'HP:0002664', (34, 42))	('175 mg/m2', 'Var', (209, 218))	('OS', 'Chemical', '-', (116, 118))	('toxicity', 'Disease', 'MESH:D064420', (170, 178))	('toxicity', 'Disease', (170, 178))	('AUC 6', 'Chemical', '-', (237, 242))
37274	27894165	In a phase III trial, the Pazopanib for metastatic soft-tissue sarcoma (PALETTE) study, which reported interim results in 2012, in patients with metastatic and recurrent uterine LMS, PFS was improved using pazopanib compared with the placebo group (36.5% vs. 12.0% at the cutoff date of October 24, 2011).	('patients', 'Species', '9606', (131, 139))	('sarcoma', 'Disease', (63, 70))	('Pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('improved', 'PosReg', (191, 199))	('pazopanib', 'Chemical', 'MESH:C516667', (206, 215))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (55, 70))	('PFS', 'MPA', (183, 186))	('pazopanib', 'Var', (206, 215))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
37536	24804134	Immunohistochemical staining was performed using the avidin-biotin complex method with antibodies direct against the following antigens: synaptophysin (1 : 100, Dako, Glostrup, Denmark), chromogranin A (1 : 700, Dako), neuron-specific enolase (1 : 200, Dako), carcinoembryonic antigens (CEA) (1 : 100, Dako), vimentin (1 : 700, Dako), and E-cadherin (1 : 60, Dako).	('EA', 'Phenotype', 'HP:0012114', (288, 290))	('vimentin', 'Gene', (309, 317))	('carcinoembryonic', 'Disease', (260, 276))	('chromogranin A', 'Gene', '1113', (187, 201))	('synaptophysin', 'Gene', (137, 150))	('1 : 700', 'Var', (203, 210))	('carcinoembryonic', 'Disease', 'None', (260, 276))	('chromogranin A', 'Gene', (187, 201))	('synaptophysin', 'Gene', '6855', (137, 150))	('E-cadherin', 'Gene', (339, 349))	('CEA', 'Gene', '5670', (287, 290))	('E-cadherin', 'Gene', '999', (339, 349))	('CEA', 'Gene', (287, 290))	('avidin-biotin', 'Chemical', '-', (53, 66))	('vimentin', 'Gene', '7431', (309, 317))	('1 : 700', 'Var', (319, 326))
37590	24804134	Preliminary data suggest that strong diffuse expression of p16ink4, which occurs in close to 100% of cervical squamous carcinomas and adenocarcinomas, is either absent or only patchy in endometrioid carcinomas.	('squamous carcinomas', 'Disease', (110, 129))	('adenocarcinomas', 'Disease', (134, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('squamous carcinomas', 'Disease', 'MESH:D002294', (110, 129))	('endometrioid carcinomas', 'Disease', (186, 209))	('p16ink4', 'Var', (59, 66))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (186, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (186, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (186, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('adenocarcinomas', 'Disease', 'MESH:D000230', (134, 149))
37591	24804134	p16ink4 is expressed strongly in lesions associated with intermediate- and high-risk HPV types, in contrast to low-risk HPV infection.	('HPV', 'Disease', (85, 88))	('p16ink4', 'Var', (0, 7))	('HPV infection', 'Disease', (120, 133))	('HPV', 'Species', '10566', (85, 88))	('HPV infection', 'Disease', 'MESH:D030361', (120, 133))	('HPV', 'Species', '10566', (120, 123))
37592	24804134	In selected head and neck squamous cell carcinomas, mainly from the oropharynx and sinonasal cavity, p16ink4 positivity correlates well with high-risk HPV infection.	('positivity', 'Var', (109, 119))	('HPV infection', 'Disease', 'MESH:D030361', (151, 164))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (26, 50))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (21, 50))	('p16ink4 positivity', 'Var', (101, 119))	('HPV infection', 'Disease', (151, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('neck squamous cell carcinomas', 'Disease', (21, 50))
37613	23705661	Specifically, advanced age (>55 years), high tumor grade, larger tumor size (>5 cm), high mitotic index (>= 15 per high power field), and omission of bilateral oophrectomies have been correlated with worse outcomes.	('high', 'Var', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (45, 50))	('high mitotic index', 'CPA', (85, 103))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
37639	23705661	On univariate analysis, there were fewer LRs in patients who received pelvic RT compared to those treated with surgery alone (3y-LR 19% vs. 39%, Gray's p = 0.019) as illustrated in Figure 1 and Table 2.	('pelvic RT', 'Var', (70, 79))	('fewer', 'NegReg', (35, 40))	('patients', 'Species', '9606', (48, 56))	('LRs', 'Disease', (41, 44))
37640	23705661	Patients with large tumor size, more advanced stage disease, positive surgical margin or who received postoperative chemotherapy also were more likely to experience LR.	('positive', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
37649	23705661	On univariate analysis, DFS was significantly worse in the setting of large tumor size, advanced stage, positive margins or the use of postoperative chemotherapy (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('positive', 'Var', (104, 112))	('worse', 'NegReg', (46, 51))	('DFS', 'MPA', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
37668	23705661	Using a competing risk multivariate model (Table 3), pelvic RT was found to be associated with a significant reduction in the risk of DM early after diagnosis and treatment but this benefit diminished with time and was lost by 10 months (Figure 2).	('DM', 'Disease', 'MESH:D009223', (134, 136))	('diminished', 'NegReg', (190, 200))	('pelvic', 'Var', (53, 59))	('reduction', 'NegReg', (109, 118))
37670	23705661	An important beneficial effect of pelvic RT on overall patient outcome is supported by the fact that pelvic RT was associated with a 2.3-fold improvement in survival independent of other important prognostic factors (Figure 3b and Table 3).	('patient', 'Species', '9606', (55, 62))	('improvement', 'PosReg', (142, 153))	('pelvic RT', 'Var', (101, 110))	('survival', 'MPA', (157, 165))
37696	22091277	Specific rearrangement of 12p15 and 6p21 resulting in HMGI-C and HMGI(Y) dysregulation have been reported in stromal cells of endometrial polyps.	('HMGI(Y)', 'Gene', '3159', (65, 72))	('endometrial polyps', 'Disease', 'MESH:D011127', (126, 144))	('endometrial polyps', 'Disease', (126, 144))	('HMGI-C', 'Gene', (54, 60))	('HMGI(Y', 'Gene', (65, 71))	('rearrangement', 'Var', (9, 22))	('HMGI-C', 'Gene', '8091', (54, 60))	('6p21', 'Protein', (36, 40))
37716	22091277	Figure 2D shows p53 positivity in clear cell carcinoma obtained by endometrial biopsy.	('positivity', 'Var', (20, 30))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (34, 54))	('p53', 'Gene', (16, 19))	('clear cell carcinoma', 'Disease', (34, 54))	('p53', 'Gene', '7157', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
37737	22091277	Although the presence of multifocal or multi-centric serous neoplaia is possible, identical p53 mutation in multiple sites indicates metastatic origin.	('metastatic origin', 'CPA', (133, 150))	('mutation', 'Var', (96, 104))	('p53', 'Gene', (92, 95))	('multi-centric serous neoplaia', 'Disease', 'MESH:C537372', (39, 68))	('p53', 'Gene', '7157', (92, 95))	('multi-centric serous neoplaia', 'Disease', (39, 68))
37829	30931136	Risk factors for endometrial cancer include oestrogen replacement, obesity, polycystic ovarian syndrome, null parity, tamoxifen and diabetes mellitus.	('obesity', 'Disease', 'MESH:D009765', (67, 74))	('tamoxifen', 'Chemical', 'MESH:D013629', (118, 127))	('diabetes mellitus', 'Disease', (132, 149))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (132, 149))	('tamoxifen', 'Disease', (118, 127))	('obesity', 'Disease', (67, 74))	('polycystic ovarian syndrome', 'Disease', 'MESH:D011085', (76, 103))	('polycystic ovarian syndrome', 'Phenotype', 'HP:0000147', (76, 103))	('obesity', 'Phenotype', 'HP:0001513', (67, 74))	('endometrial cancer', 'Phenotype', 'HP:0012114', (17, 35))	('endometrial cancer', 'Disease', 'MESH:D016889', (17, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('diabetes mellitus', 'Disease', 'MESH:D003920', (132, 149))	('polycystic ovarian syndrome', 'Disease', (76, 103))	('endometrial cancer', 'Disease', (17, 35))	('null parity', 'Var', (105, 116))
37866	30612635	Cancer susceptibility gene mutations in type I and II endometrial cancer To determine the incidence of germline cancer predisposition gene mutations in patients with endometrial cancer (EC) subtypes.	('mutations', 'Var', (27, 36))	('endometrial cancer', 'Disease', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('endometrial cancer', 'Disease', 'MESH:D016889', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (54, 72))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('endometrial cancer', 'Disease', (54, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('endometrial cancer', 'Disease', 'MESH:D016889', (54, 72))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (152, 160))	('mutations', 'Var', (139, 148))	('EC', 'Disease', 'MESH:D016889', (186, 188))	('endometrial cancer', 'Phenotype', 'HP:0012114', (166, 184))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', (66, 72))
37870	30612635	BRCA1 mutations were enriched in Type II EC compared to Type I EC (0.93% vs. 0.12%, p=0.07).	('BRCA1', 'Gene', (0, 5))	('EC', 'Disease', 'MESH:D016889', (41, 43))	('EC', 'Disease', 'MESH:D016889', (63, 65))	('BRCA1', 'Gene', '672', (0, 5))	('mutations', 'Var', (6, 15))
37871	30612635	Lynch Syndrome (LS) mutations were identified in 1.4% of type I and 1.6% of type II EC (p=0.79), including 1.5% for USC.	('type II EC', 'Disease', (76, 86))	('type II EC', 'Disease', 'MESH:D016889', (76, 86))	('Lynch Syndrome', 'Disease', (0, 14))	('LS', 'Disease', 'MESH:D003123', (16, 18))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (0, 14))	('mutations', 'Var', (20, 29))
37872	30612635	In total, predisposition gene mutations were present in 4.2% of type I and 5.3% of type II EC, as well as 6.7% of patients with USC).	('patients', 'Species', '9606', (114, 122))	('type II EC', 'Disease', (83, 93))	('mutations', 'Var', (30, 39))	('type II EC', 'Disease', 'MESH:D016889', (83, 93))
37879	30612635	Several small, retrospective studies have suggested a link between BRCA1 mutations and uterine serous cancer, while others have found no such risk.	('link', 'Interaction', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('BRCA1', 'Gene', '672', (67, 72))	('mutations', 'Var', (73, 82))	('BRCA1', 'Gene', (67, 72))
37882	30612635	In this investigation, 4 out of 627 women with BRCA1 mutations developed serous/serous-like EC after 3781.0 woman-years of follow-up.	('BRCA1', 'Gene', (47, 52))	('BRCA1', 'Gene', '672', (47, 52))	('developed', 'Reg', (63, 72))	('women', 'Species', '9606', (36, 41))	('mutations', 'Var', (53, 62))	('EC', 'Disease', 'MESH:D016889', (92, 94))	('woman', 'Species', '9606', (108, 113))
37890	30612635	Another study including 134 patients with USC identified an MMR mutation in a single case with primarily endometrioid histology and only 1% serous component.	('MMR', 'Gene', (60, 63))	('patients', 'Species', '9606', (28, 36))	('endometrioid', 'Disease', (105, 117))	('mutation', 'Var', (64, 72))
37901	30612635	Analyses were focused on pathogenic variants in mismatch repair genes associated with LS (MSH2, MSH6, PMS2, and MLH1) as well as other hereditary breast and/or ovarian cancer cancer predisposition genes (ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, NF1, PALB2, RAD51C, RAD51D, and TP53) defined as "increased risk" of either breast or ovarian cancer with recommendations for clinical management in NCCN Clinical Practice Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian in both EC cases and gnomAD non-Finnish European (NFE) public reference controls.	('PMS2', 'Gene', (102, 106))	('Ovarian', 'Disease', (479, 486))	('BRIP1', 'Gene', '83990', (223, 228))	('hereditary breast and/or ovarian cancer', 'Disease', (135, 174))	('MLH1', 'Gene', '4292', (112, 116))	('EC', 'Disease', 'MESH:D016889', (495, 497))	('RAD51D', 'Gene', (262, 268))	('PALB2', 'Gene', '79728', (247, 252))	('Breast', 'Disease', (468, 474))	('RAD51C', 'Gene', (254, 260))	('TP53', 'Gene', (274, 278))	('MSH2', 'Gene', '4436', (90, 94))	('BRCA2', 'Gene', '675', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BRCA1', 'Gene', '672', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('NBN', 'Gene', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('RAD51C', 'Gene', '5889', (254, 260))	('NF1', 'Gene', '4763', (242, 245))	('BRCA1', 'Gene', (209, 214))	('ATM', 'Gene', '472', (204, 207))	('ovarian cancer', 'Phenotype', 'HP:0100615', (328, 342))	('breast or ovarian cancer', 'Disease', (318, 342))	('BRIP1', 'Gene', (223, 228))	('NF1', 'Gene', (242, 245))	('CHEK2', 'Gene', (230, 235))	('PMS2', 'Gene', '5395', (102, 106))	('breast and/or ovarian cancer cancer', 'Disease', (146, 181))	('TP53', 'Gene', '7157', (274, 278))	('RAD51D', 'Gene', '5892', (262, 268))	('breast and/or ovarian cancer cancer', 'Disease', 'MESH:D001943', (146, 181))	('breast or ovarian cancer', 'Disease', 'MESH:D061325', (318, 342))	('CHEK2', 'Gene', '11200', (230, 235))	('MSH6', 'Gene', (96, 100))	('LS', 'Disease', 'MESH:D003123', (86, 88))	('hereditary breast and/or ovarian cancer', 'Disease', 'MESH:D061325', (135, 174))	('ATM', 'Gene', (204, 207))	('MLH1', 'Gene', (112, 116))	('MSH6', 'Gene', '2956', (96, 100))	('BRCA2', 'Gene', (216, 221))	('PALB2', 'Gene', (247, 252))	('variants', 'Var', (36, 44))	('MSH2', 'Gene', (90, 94))	('NBN', 'Gene', '4683', (237, 240))	('ovarian cancer', 'Phenotype', 'HP:0100615', (160, 174))
37905	30612635	Stop-gain, frameshift, and essential splice site (+/- 1-2 consensus region) variants were considered pathogenic unless functional evidence or ClinVar assertions from clinical groups (SCRP, Invitae, Ambry Genetics, GeneDx, Emory, InSiGHT) suggested otherwise.	('GeneDx', 'Chemical', 'MESH:C040626', (214, 220))	('variants', 'Var', (76, 84))	('InSiGHT', 'Chemical', 'MESH:D012825', (229, 236))	('frameshift', 'Var', (11, 21))
37906	30612635	In addition, nonsense mediated mRNA decay effects were considered for BRIP1, with variants in the last exon or last 55 nucleotides of the penultimate exon excluded.	('nonsense', 'Var', (13, 21))	('BRIP1', 'Gene', (70, 75))	('BRIP1', 'Gene', '83990', (70, 75))
37907	30612635	Variants in exons 9 and 11-15 of PMS2 were not included in analyses due to homology with the PMS2L pseudogene in these regions.	('Variants', 'Var', (0, 8))	('PMS2', 'Gene', (93, 97))	('PMS2', 'Gene', (33, 37))	('PMS2', 'Gene', '5395', (93, 97))	('PMS2', 'Gene', '5395', (33, 37))
37916	30612635	Among these 1170 patients, 53 mutations were identified in 12 cancer predisposition genes (MSH2, MSH6, PMS2, ATM, BRCA1, BRCA1, BRIP1, CHEK2, NBN, RAD51C, P53, NF1).	('NF1', 'Gene', (160, 163))	('MSH2', 'Gene', '4436', (91, 95))	('BRIP1', 'Gene', '83990', (128, 133))	('ATM', 'Gene', '472', (109, 112))	('NBN', 'Gene', (142, 145))	('BRCA1', 'Gene', '672', (121, 126))	('BRCA1', 'Gene', '672', (114, 119))	('PMS2', 'Gene', '5395', (103, 107))	('BRCA1', 'Gene', (121, 126))	('cancer', 'Disease', (62, 68))	('BRCA1', 'Gene', (114, 119))	('P53', 'Gene', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('ATM', 'Gene', (109, 112))	('BRIP1', 'Gene', (128, 133))	('CHEK2', 'Gene', (135, 140))	('mutations', 'Var', (30, 39))	('patients', 'Species', '9606', (17, 25))	('P53', 'Gene', '7157', (155, 158))	('RAD51C', 'Gene', '5889', (147, 153))	('MSH2', 'Gene', (91, 95))	('MSH6', 'Gene', (97, 101))	('PMS2', 'Gene', (103, 107))	('CHEK2', 'Gene', '11200', (135, 140))	('NF1', 'Gene', '4763', (160, 163))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('MSH6', 'Gene', '2956', (97, 101))	('RAD51C', 'Gene', (147, 153))	('NBN', 'Gene', '4683', (142, 145))
37917	30612635	Overall, cancer predisposition gene mutations were identified in 4.2% (36/849) of type I EC, 5.3% (17/321) of type II EC, and 6.7% (9/135) of USC.	('cancer', 'Disease', (9, 15))	('type II EC', 'Disease', (110, 120))	('type II EC', 'Disease', 'MESH:D016889', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (36, 45))	('EC', 'Disease', 'MESH:D016889', (118, 120))	('EC', 'Disease', 'MESH:D016889', (89, 91))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
37918	30612635	When further stratified by histology, cancer predisposition gene mutations were identified in 5.6% (2/36) with clear cell histology, 4.6% (2/43) with carcinosarcoma, and 3.7% (4/107) with grade 3 endometrioid cancer.	('endometrioid cancer', 'Phenotype', 'HP:0012114', (196, 215))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('endometrioid cancer', 'Disease', (196, 215))	('carcinosarcoma', 'Disease', (150, 164))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (209, 215))	('clear cell', 'Disease', (111, 121))	('cancer', 'Disease', (38, 44))	('endometrioid cancer', 'Disease', 'MESH:D009369', (196, 215))	('carcinosarcoma', 'Disease', 'MESH:D002296', (150, 164))	('mutations', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
37919	30612635	Non-LS cancer predisposition gene mutations occurred in 2.8% (24/849) patients with type I EC compared to 3.7% (12/321) patients with type II EC, including 5.2% (7/135) patients with USC (Figure 1).	('patients', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('patients', 'Species', '9606', (169, 177))	('EC', 'Disease', 'MESH:D016889', (142, 144))	('EC', 'Disease', 'MESH:D016889', (91, 93))	('type II EC', 'Disease', (134, 144))	('patients', 'Species', '9606', (120, 128))	('type II EC', 'Disease', 'MESH:D016889', (134, 144))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('LS', 'Disease', 'MESH:D003123', (4, 6))	('mutations', 'Var', (34, 43))
37920	30612635	Demographic and clinical characteristics were compared between cancer predisposition gene mutation carriers and non-carriers in Table 2.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutation', 'Var', (90, 98))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
37921	30612635	Mean age at surgery was significantly lower among patients with cancer predisposition gene mutations (mean (SD), 60.1 (9.7) vs. 63.8 (10.2); p=0.01).	('patients', 'Species', '9606', (50, 58))	('lower', 'NegReg', (38, 43))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
37922	30612635	However, this difference is likely explained by the younger age at diagnosis among patients with MMR/Lynch syndrome gene mutations (mean (SD), 56.6 (7.2) years).	('Lynch syndrome', 'Disease', (101, 115))	('patients', 'Species', '9606', (83, 91))	('mutations', 'Var', (121, 130))	('Lynch syndrome', 'Disease', 'MESH:D003123', (101, 115))
37923	30612635	There was no statistically significant age difference between cancer predisposition gene mutation carriers and wildtype patients when the 17 patients with LS gene mutations were excluded (61.8 (10.3) vs. 63.8 (10.2), p=0.24).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutation', 'Var', (89, 97))	('LS', 'Disease', 'MESH:D003123', (155, 157))	('cancer', 'Disease', (62, 68))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('patients', 'Species', '9606', (141, 149))
37924	30612635	Overall, 9% (9/100) of pre- or peri-menopausal women had a cancer predisposition gene mutation compared with 4.1% (43/1058) of post-menopausal women (p=0.038).	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('women', 'Species', '9606', (47, 52))	('mutation', 'Var', (86, 94))	('women', 'Species', '9606', (143, 148))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('peri-menopausal women', 'Phenotype', 'HP:0008209', (31, 52))
37925	30612635	For type I EC, mean BMI was significantly lower in cancer predisposition gene mutation carriers compared to non-carriers (mean (SD), 31.3 (7.7) vs. 36.4 (9.5); p=0.002).	('mutation', 'Var', (78, 86))	('EC', 'Disease', 'MESH:D016889', (11, 13))	('lower', 'NegReg', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('BMI', 'MPA', (20, 23))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
37926	30612635	Stage at diagnosis was not significantly different between patients with and without cancer predisposition gene mutations.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', (85, 91))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
37927	30612635	The incidence of germline BRCA1/2 mutations was low in type I EC, type II EC, and USC with rates of 0.47% (95% CI, 0.13-1.20%), 0.93% (95% CI, 0.19-2.71%), and 0.74% (95% CI, 0.02-4.06%), respectively.	('EC', 'Disease', 'MESH:D016889', (62, 64))	('type II EC', 'Disease', (66, 76))	('USC', 'Disease', (82, 85))	('BRCA1/2', 'Gene', (26, 33))	('EC', 'Disease', 'MESH:D016889', (74, 76))	('BRCA1/2', 'Gene', '672;675', (26, 33))	('mutations', 'Var', (34, 43))	('type II EC', 'Disease', 'MESH:D016889', (66, 76))
37928	30612635	The rate of BRCA1 mutations was higher among patients with type II compared to type I EC, though the difference was not statistically significant.	('mutations', 'Var', (18, 27))	('EC', 'Disease', 'MESH:D016889', (86, 88))	('higher', 'Reg', (32, 38))	('patients', 'Species', '9606', (45, 53))	('BRCA1', 'Gene', '672', (12, 17))	('BRCA1', 'Gene', (12, 17))
37929	30612635	BRCA1 mutations were found in only 0.12% (1/852) of type I EC (95% CI 0-0.65%) compared to 0.93% (3/321) of type II EC (95% CI 0.19-2.71%) (p=0.07) (Figure 1 and Table 2).	('BRCA1', 'Gene', (0, 5))	('type II EC', 'Disease', (108, 118))	('type II EC', 'Disease', 'MESH:D016889', (108, 118))	('EC', 'Disease', 'MESH:D016889', (59, 61))	('EC', 'Disease', 'MESH:D016889', (116, 118))	('BRCA1', 'Gene', '672', (0, 5))	('mutations', 'Var', (6, 15))
37931	30612635	Family history of breast cancer was present in all four BRCA1 mutation carriers, but there was no family history of EC or ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('BRCA1', 'Gene', '672', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('ovarian cancer', 'Disease', (122, 136))	('breast cancer', 'Disease', (18, 31))	('BRCA1', 'Gene', (56, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('mutation', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('EC', 'Disease', 'MESH:D016889', (116, 118))	('present', 'Reg', (36, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))
37932	30612635	One BRCA1 mutation carrier also had a personal history of breast cancer.	('BRCA1', 'Gene', (4, 9))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutation', 'Var', (10, 18))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BRCA1', 'Gene', '672', (4, 9))
37933	30612635	All BRCA1 mutation carriers were post-menopausal at EC diagnosis.	('EC', 'Disease', 'MESH:D016889', (52, 54))	('BRCA1', 'Gene', (4, 9))	('mutation', 'Var', (10, 18))	('carriers', 'Reg', (19, 27))	('menopausal at EC', 'Phenotype', 'HP:0008209', (38, 54))	('BRCA1', 'Gene', '672', (4, 9))
37934	30612635	BRCA2 mutations were identified in three patients with type I EC (0.35%), including two diagnosed with grade 2 endometrioid and one diagnosed with grade 1 endometrioid.	('BRCA2', 'Gene', '675', (0, 5))	('EC', 'Disease', 'MESH:D016889', (62, 64))	('identified', 'Reg', (21, 31))	('patients', 'Species', '9606', (41, 49))	('BRCA2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
37935	30612635	No type II EC cases had BRCA2 mutations.	('type II EC', 'Disease', (3, 13))	('BRCA2', 'Gene', '675', (24, 29))	('mutations', 'Var', (30, 39))	('BRCA2', 'Gene', (24, 29))	('type II EC', 'Disease', 'MESH:D016889', (3, 13))
37936	30612635	None of the BRCA2 mutation carriers had a personal history of breast cancer or a family history of breast, ovarian, or endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (119, 137))	('BRCA2', 'Gene', (12, 17))	('endometrial cancer', 'Disease', 'MESH:D016889', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ovarian', 'Disease', (107, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('mutation', 'Var', (18, 26))	('BRCA2', 'Gene', '675', (12, 17))	('endometrial cancer', 'Disease', (119, 137))	('breast', 'Disease', (99, 105))
37937	30612635	In addition, none of the patients with USC and a history of breast cancer and/or tamoxifen exposure were found to have BRCA1/2 mutations.	('breast cancer', 'Disease', (60, 73))	('tamoxifen', 'Chemical', 'MESH:D013629', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1/2', 'Gene', (119, 126))	('patients', 'Species', '9606', (25, 33))	('BRCA1/2', 'Gene', '672;675', (119, 126))	('mutations', 'Var', (127, 136))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
37938	30612635	LS gene mutations were identified in 1.4% (12/849) of type I and 1.6% (5/321) of type II EC (p=0.79), including 1.5% (2/135) in USC.	('LS', 'Disease', 'MESH:D003123', (0, 2))	('type II EC', 'Disease', (81, 91))	('type II EC', 'Disease', 'MESH:D016889', (81, 91))	('mutations', 'Var', (8, 17))
37939	30612635	MSH6 (n=9) and PMS2 (n=2) were the most common LS gene mutations among patients with type I EC.	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (71, 79))	('MSH6', 'Gene', '2956', (0, 4))	('LS', 'Disease', 'MESH:D003123', (47, 49))	('PMS2', 'Gene', (15, 19))	('MSH6', 'Gene', (0, 4))	('EC', 'Disease', 'MESH:D016889', (92, 94))	('PMS2', 'Gene', '5395', (15, 19))
37940	30612635	In patients with type II EC, there were three mutations in MSH6, one in MSH2, and one in PMS2.	('type II EC', 'Disease', (17, 27))	('PMS2', 'Gene', (89, 93))	('mutations', 'Var', (46, 55))	('MSH6', 'Gene', '2956', (59, 63))	('PMS2', 'Gene', '5395', (89, 93))	('patients', 'Species', '9606', (3, 11))	('MSH2', 'Gene', (72, 76))	('MSH2', 'Gene', '4436', (72, 76))	('type II EC', 'Disease', 'MESH:D016889', (17, 27))	('MSH6', 'Gene', (59, 63))
37941	30612635	Two patients with clear cell histology, and one patient with serous histology had an MSH6 mutation.	('MSH6', 'Gene', '2956', (85, 89))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (48, 55))	('patients', 'Species', '9606', (4, 12))	('MSH6', 'Gene', (85, 89))	('mutation', 'Var', (90, 98))
37942	30612635	The PMS2 mutation occurred in a patient with serous histology, and the MSH2 mutation occurred with a grade 3 endometrioid tumor.	('mutation', 'Var', (9, 17))	('patient', 'Species', '9606', (32, 39))	('PMS2', 'Gene', (4, 8))	('MSH2', 'Gene', '4436', (71, 75))	('PMS2', 'Gene', '5395', (4, 8))	('endometrioid tumor', 'Disease', 'MESH:D018269', (109, 127))	('endometrioid tumor', 'Disease', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('occurred', 'Reg', (85, 93))	('mutation', 'Var', (76, 84))	('occurred', 'Reg', (18, 26))	('MSH2', 'Gene', (71, 75))
37945	30612635	Several recurrent pathogenic variants were observed in this study including: ATM c.1564_1565delGA (n=2), BRIP1 c.R798X (n=2), MSH6 p.R298X (n=2), MSH6 c.3439-2A>G (n=2), and CHEK2 c.1100delC (n=6).	('c.1564_1565delGA', 'Mutation', 'rs587779817', (81, 97))	('ATM', 'Gene', '472', (77, 80))	('MSH6', 'Gene', (126, 130))	('MSH6', 'Gene', '2956', (126, 130))	('BRIP1', 'Gene', (105, 110))	('c.3439-2A>G', 'Mutation', 'rs267608098', (151, 162))	('c.1100delC', 'Mutation', 'rs555607708', (180, 190))	('MSH6', 'Gene', (146, 150))	('c.R798X', 'Mutation', 'rs137852986', (111, 118))	('ATM', 'Gene', (77, 80))	('c.1564_1565delGA', 'Var', (81, 97))	('BRIP1', 'Gene', '83990', (105, 110))	('c.3439-2A>G', 'Var', (151, 162))	('p.R298X', 'Var', (131, 138))	('MSH6', 'Gene', '2956', (146, 150))	('CHEK2', 'Gene', (174, 179))	('c.R798X', 'Var', (111, 118))	('pathogenic', 'CPA', (18, 28))	('CHEK2', 'Gene', '11200', (174, 179))	('p.R298X', 'Mutation', 'rs146816935', (131, 138))
37946	30612635	Frequencies of pathogenic variants amongst EC cases and gnomAD non-Finnish European reference controls were compared to determine the association of specific genes with EC overall and type I EC; there were insufficient cases to determine specific gene associations with type II EC.	('association', 'Interaction', (134, 145))	('EC', 'Disease', 'MESH:D016889', (278, 280))	('EC', 'Disease', 'MESH:D016889', (169, 171))	('EC', 'Disease', 'MESH:D016889', (191, 193))	('type II EC', 'Disease', (270, 280))	('type II EC', 'Disease', 'MESH:D016889', (270, 280))	('EC', 'Disease', 'MESH:D016889', (43, 45))	('variants', 'Var', (26, 34))
37949	30612635	Despite high frequencies of ATM and CHEK2 mutations in the study, no significant associations with EC were observed (ATM OR 1.86, p=0.07; CHEK2 OR 1.04, p=0.85).	('CHEK2', 'Gene', (36, 41))	('CHEK2', 'Gene', '11200', (138, 143))	('ATM', 'Gene', '472', (117, 120))	('ATM', 'Gene', '472', (28, 31))	('CHEK2', 'Gene', (138, 143))	('EC', 'Disease', 'MESH:D016889', (99, 101))	('ATM', 'Gene', (28, 31))	('CHEK2', 'Gene', '11200', (36, 41))	('mutations', 'Var', (42, 51))	('ATM', 'Gene', (117, 120))
37950	30612635	Germline mutations in BRCA and LS genes were relatively rare in this cohort of unselected patients with EC.	('EC', 'Disease', 'MESH:D016889', (104, 106))	('Germline', 'Var', (0, 8))	('BRCA', 'Gene', '672', (22, 26))	('LS', 'Disease', 'MESH:D003123', (31, 33))	('patients', 'Species', '9606', (90, 98))	('BRCA', 'Gene', (22, 26))
37951	30612635	While the overall rate of BRCA1 mutations was similar to that in the general population, the rate of BRCA1 mutations eight times higher among patients with type II compared to type I EC.	('mutations', 'Var', (107, 116))	('BRCA1', 'Gene', (26, 31))	('BRCA1', 'Gene', '672', (101, 106))	('EC', 'Disease', 'MESH:D016889', (183, 185))	('higher', 'PosReg', (129, 135))	('BRCA1', 'Gene', (101, 106))	('BRCA1', 'Gene', '672', (26, 31))	('patients', 'Species', '9606', (142, 150))
37952	30612635	While our data suggest a potential association between type II EC and BRCA1 mutations, a larger cohort will be needed to confirm this finding.	('mutations', 'Var', (76, 85))	('type II EC', 'Disease', (55, 65))	('type II EC', 'Disease', 'MESH:D016889', (55, 65))	('BRCA1', 'Gene', '672', (70, 75))	('BRCA1', 'Gene', (70, 75))
37953	30612635	It is difficult to recommend changes in clinical management of patients with BRCA1 mutations based on these data.	('BRCA1', 'Gene', (77, 82))	('BRCA1', 'Gene', '672', (77, 82))	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (63, 71))
37954	30612635	There was no difference in the incidence of BRCA2 mutations between the two groups, and no BRCA2 mutations were detected among patients with type II EC.	('type II EC', 'Disease', (141, 151))	('type II EC', 'Disease', 'MESH:D016889', (141, 151))	('mutations', 'Var', (50, 59))	('BRCA2', 'Gene', (91, 96))	('patients', 'Species', '9606', (127, 135))	('BRCA2', 'Gene', (44, 49))	('BRCA2', 'Gene', '675', (91, 96))	('BRCA2', 'Gene', '675', (44, 49))
37955	30612635	MSH6 mutations were significantly associated with EC overall and with both EC subtypes.	('associated with', 'Reg', (34, 49))	('MSH6', 'Gene', '2956', (0, 4))	('mutations', 'Var', (5, 14))	('EC', 'Disease', 'MESH:D016889', (50, 52))	('EC', 'Disease', 'MESH:D016889', (75, 77))	('MSH6', 'Gene', (0, 4))
37957	30612635	We reliably ruled out CHEK2 and ATM as EC predisposition mutations, as these variants were not associated with EC despite a sufficient number of mutations in our cohort.	('variants', 'Var', (77, 85))	('ATM', 'Gene', (32, 35))	('EC', 'Disease', 'MESH:D016889', (39, 41))	('ATM', 'Gene', '472', (32, 35))	('EC', 'Disease', 'MESH:D016889', (111, 113))	('CHEK2', 'Gene', '11200', (22, 27))	('CHEK2', 'Gene', (22, 27))
37959	30612635	Interestingly, about 4-5% of all patients with endometrial cancer were found to have a mutation when panel testing for all cancer predisposition genes was performed.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('endometrial cancer', 'Disease', (47, 65))	('cancer', 'Disease', (123, 129))	('mutation', 'Var', (87, 95))	('endometrial cancer', 'Phenotype', 'HP:0012114', (47, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('endometrial cancer', 'Disease', 'MESH:D016889', (47, 65))
37961	30612635	Other studies have reported similar rates of BRCA mutations in patients with USC.	('BRCA', 'Gene', '672', (45, 49))	('BRCA', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('USC', 'Disease', (77, 80))	('patients', 'Species', '9606', (63, 71))
37962	30612635	performed germline panel testing on 151 unselected patients with USC and found a 2% rate of BRCA1/2 mutations.	('mutations', 'Var', (100, 109))	('patients', 'Species', '9606', (51, 59))	('BRCA1/2', 'Gene', (92, 99))	('BRCA1/2', 'Gene', '672;675', (92, 99))
37964	30612635	Another study of 56 patients with USC found no germline BRCA mutations.	('patients', 'Species', '9606', (20, 28))	('BRCA', 'Gene', (56, 60))	('BRCA', 'Gene', '672', (56, 60))	('mutations', 'Var', (61, 70))
37966	30612635	In contrast, some studies have found a higher proportion of BRCA mutations among patients with USC.	('patients', 'Species', '9606', (81, 89))	('BRCA', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))	('BRCA', 'Gene', '672', (60, 64))
37967	30612635	One study found a 27% rate of BRCA mutations in a cohort of 22 Jewish patients with USC.	('patients', 'Species', '9606', (70, 78))	('BRCA', 'Gene', (30, 34))	('BRCA', 'Gene', '672', (30, 34))	('mutations', 'Var', (35, 44))
37968	30612635	This rate is likely to be confounded by the increased frequency of BRCA mutations in Ashkenazi Jewish populations and has not been replicated in studies of unselected patients.	('BRCA', 'Gene', (67, 71))	('patients', 'Species', '9606', (167, 175))	('BRCA', 'Gene', '672', (67, 71))	('mutations', 'Var', (72, 81))
37975	30612635	For this reason, we examined the association of BRCA1/2 and other cancer predisposition gene mutations with both type II EC and USC separately.	('BRCA1/2', 'Gene', (48, 55))	('mutations', 'Var', (93, 102))	('type II EC', 'Disease', 'MESH:D016889', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('examined', 'Reg', (20, 28))	('BRCA1/2', 'Gene', '672;675', (48, 55))	('association', 'Interaction', (33, 44))	('type II EC', 'Disease', (113, 123))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('USC', 'Disease', (128, 131))	('cancer', 'Disease', (66, 72))
37982	30612635	A similar model of universal or age-related tumor testing, with validation of germline mutation status, could identify patients with cancer predisposition gene mutations, allowing for more rigorous breast and/or ovarian cancer screening after an EC diagnosis as well as early identification and prophylactic treatment in affected relatives.	('mutations', 'Var', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('ovarian cancer', 'Disease', (212, 226))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (212, 226))	('breast', 'Disease', (198, 204))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('EC', 'Disease', 'MESH:D016889', (246, 248))	('cancer', 'Disease', (220, 226))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
37983	30612635	performed somatic testing in 3 patients with germline BRCA mutations who developed uterine serous or serous-like cancer after prophylactic oophorectomy.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('developed', 'Reg', (73, 82))	('cancer', 'Disease', (113, 119))	('patients', 'Species', '9606', (31, 39))	('BRCA', 'Gene', '672', (54, 58))	('mutations', 'Var', (59, 68))	('BRCA', 'Gene', (54, 58))
37986	30612635	This suggests that IHC protocols used for LS testing could be modified to detect cancer predisposition gene mutations in patients with EC, though larger IHC studies are needed to validate these findings.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('mutations', 'Var', (108, 117))	('EC', 'Disease', 'MESH:D016889', (135, 137))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('LS', 'Disease', 'MESH:D003123', (42, 44))	('patients', 'Species', '9606', (121, 129))
37989	30612635	The ability to compare patients with both type I and II EC allowed the study to confirm similar rates of LS mutations and low rates of BRCA mutations among patients with both subtypes.	('patients', 'Species', '9606', (156, 164))	('EC', 'Disease', 'MESH:D016889', (56, 58))	('mutations', 'Var', (108, 117))	('patients', 'Species', '9606', (23, 31))	('LS', 'Disease', 'MESH:D003123', (105, 107))	('BRCA', 'Gene', '672', (135, 139))	('BRCA', 'Gene', (135, 139))
37990	30612635	However, the study is limited by a low frequency of cancer predisposition gene mutations and lack of matched controls, which restricted statistical comparisons between patients with type I and type II EC and between specific mutations, and estimation of absolute risks of EC for individual genes.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('EC', 'Disease', 'MESH:D016889', (272, 274))	('EC', 'Disease', 'MESH:D016889', (201, 203))	('type II EC', 'Disease', (193, 203))	('type II EC', 'Disease', 'MESH:D016889', (193, 203))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (79, 88))
37992	30612635	Further study is needed to resolve these issues, to confirm the utility of somatic testing for identification of EC patients with cancer predisposition gene mutations, and to determine the cost-effectiveness of universal or age-related testing.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('patients', 'Species', '9606', (116, 124))	('mutations', 'Var', (157, 166))	('EC', 'Disease', 'MESH:D016889', (113, 115))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
37993	30612635	Overall, our results suggest a clinically significant rate of actionable cancer predisposition gene mutations and LS gene mutations among EC patients.	('mutations', 'Var', (100, 109))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('EC', 'Disease', 'MESH:D016889', (138, 140))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (141, 149))	('LS', 'Disease', 'MESH:D003123', (114, 116))
37995	30612635	These findings suggest that somatic testing for an expanded panel of cancer predisposition gene mutations could identify patients in which germline testing is warranted.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (96, 105))	('patients', 'Species', '9606', (121, 129))	('cancer', 'Disease', (69, 75))
37996	30612635	BRCA1/2 mutations were identified in 0.93% and 0.12% of type I and type II EC, respectively.	('BRCA1/2', 'Gene', '672;675', (0, 7))	('type II EC', 'Disease', (67, 77))	('mutations', 'Var', (8, 17))	('type II EC', 'Disease', 'MESH:D016889', (67, 77))	('BRCA1/2', 'Gene', (0, 7))	('type I', 'Disease', (56, 62))
37998	30612635	Frequency of LS mutations was similar in both type I and type II EC.	('LS', 'Disease', 'MESH:D003123', (13, 15))	('type II EC', 'Disease', 'MESH:D016889', (57, 67))	('mutations', 'Var', (16, 25))	('type II EC', 'Disease', (57, 67))
38024	30627019	MRI features of LMS include nodular borders, flow-void areas, T1 hyperintensity areas, and rapid enhancement at the early phase post-injection of contrast medium; and shared features with that of uterine sarcomas include heterogeneous, intermediate T2 signal, and high signal on DWI with low ADC value, associated with intratumoral hemorrhage and necrosis.	('hemorrhage', 'Disease', 'MESH:D006470', (332, 342))	('os', 'Chemical', 'MESH:D009992', (351, 353))	('enhancement', 'PosReg', (97, 108))	('os', 'Chemical', 'MESH:D009992', (129, 131))	('ADC value', 'MPA', (292, 301))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('sarcomas', 'Disease', 'MESH:D012509', (204, 212))	('necrosis', 'Disease', 'MESH:D009336', (347, 355))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('sarcomas', 'Disease', (204, 212))	('hemorrhage', 'Disease', (332, 342))	('necrosis', 'Disease', (347, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('high signal', 'Var', (264, 275))	('flow-void', 'MPA', (45, 54))	('T2 signal', 'MPA', (249, 258))	('heterogeneous', 'MPA', (221, 234))	('tumor', 'Disease', (324, 329))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (196, 211))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
38033	30627019	Hyperintensity on DWI is reported to have high sensitivity but limited specificity in differentiation between LMS/STUMP and benign leiomyoma.	('benign leiomyoma', 'Disease', 'MESH:D007889', (124, 140))	('benign leiomyoma', 'Disease', (124, 140))	('LMS/STUMP', 'Disease', (110, 119))	('Hyperintensity', 'Var', (0, 14))
38082	30627019	Study shows that similar to the majority of malignant tumors, UCS demonstrates low ADC values on DWI which are significantly higher than that of grade II and III EC, corresponding to the hypocellular regions caused by intratumoral necrosis.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('malignant tumors', 'Disease', (44, 60))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('malignant tumors', 'Disease', 'MESH:D018198', (44, 60))	('ADC values', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('low', 'NegReg', (79, 82))	('necrosis', 'Disease', (231, 239))	('DWI', 'Var', (97, 100))	('higher', 'PosReg', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('intratumoral necrosis', 'Phenotype', 'HP:0010885', (218, 239))	('tumor', 'Disease', (54, 59))	('necrosis', 'Disease', 'MESH:D009336', (231, 239))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
38100	30627019	Meta-analysis conducted in 2014 shows similar pooled sensitivity under DWI and DCE-MRI; although the specificity is slightly higher under DWI versus DCE-MRI, without significance.	('DCE-MRI', 'Var', (79, 86))	('DCE', 'Chemical', '-', (79, 82))	('DCE', 'Chemical', '-', (149, 152))	('specificity', 'MPA', (101, 112))	('higher', 'PosReg', (125, 131))
38106	30627019	In premenopausal patients with EC planning to undergo fertility-preserving treatment, DCE-MRI is superior to DWI in terms of excluding the possibility of the myometrial invasion.	('myometrial invasion', 'CPA', (158, 177))	('DCE-MRI', 'Var', (86, 93))	('DCE', 'Chemical', '-', (86, 89))	('os', 'Chemical', 'MESH:D009992', (140, 142))	('patients', 'Species', '9606', (17, 25))
38159	30057538	Therefore, in December 2017, surgery was performed under the diagnosis of simultaneous endometrial, colon, and breast cancer, which included total abdominal hysterectomy with bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissection, omentectomy, cytology, segmental resection of descending colon with mass excision (by the general surgery team), and incisional biopsy of the right breast (by the general surgery team).	('segmental', 'Var', (271, 280))	('cytology', 'Disease', (261, 269))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('colon', 'Disease', (100, 105))	('breast cancer', 'Disease', (111, 124))	('descending colon', 'Phenotype', 'HP:0012851', (294, 310))	('omentectomy', 'Disease', (248, 259))
38180	30057538	These cancers are known to be associated with obesity, nulliparity, and the use of exogenous estrogen and tamoxifen.	('associated', 'Reg', (30, 40))	('obesity', 'Disease', 'MESH:D009765', (46, 53))	('tamoxifen', 'Chemical', 'MESH:D013629', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('obesity', 'Disease', (46, 53))	('nulliparity', 'Var', (55, 66))	('obesity', 'Phenotype', 'HP:0001513', (46, 53))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))
38223	29643878	In our study, endometrial thickness and EFC were higher in patients with hyperplastic and neoplastic pathology, but this relationship cannot be shown using ROC curve analyses.	('hyperplastic', 'Var', (73, 85))	('endometrial thickness', 'CPA', (14, 35))	('EFC', 'CPA', (40, 43))	('patients', 'Species', '9606', (59, 67))	('neoplastic', 'Var', (90, 100))	('higher', 'PosReg', (49, 55))
38235	29426293	Patients treated with carboplatin/paclitaxel had a statistically significant longer PFS when compared to those receiving ifosfamide/paclitaxel (17.8 vs. 8.0 months, p = 0.025).	('longer', 'PosReg', (77, 83))	('carboplatin', 'Chemical', 'MESH:D016190', (22, 33))	('ifosfamide', 'Chemical', 'MESH:D007069', (121, 131))	('paclitaxel', 'Chemical', 'MESH:D017239', (132, 142))	('Patients', 'Species', '9606', (0, 8))	('paclitaxel', 'Chemical', 'MESH:D017239', (34, 44))	('carboplatin/paclitaxel', 'Var', (22, 44))	('PFS', 'MPA', (84, 87))
38313	29426293	It is known, however, that altered expression of p53 is frequent in gynecologic carcinosarcomas.	('altered', 'Var', (27, 34))	('p53', 'Gene', (49, 52))	('carcinosarcomas', 'Disease', (80, 95))	('p53', 'Gene', '7157', (49, 52))	('expression', 'MPA', (35, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('frequent', 'Reg', (56, 64))	('carcinosarcomas', 'Disease', 'MESH:D002296', (80, 95))
38314	29426293	A recent molecular characterization of an ovarian carcinosarcoma patient-derived xenograft revealed p53 and phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutations, as well as epidermal growth factor receptor overexpression, vascular endothelial growth factor receptor C overexpression and activation of the insulin-like growth factor pathway.	('insulin-like growth factor pathway', 'Pathway', (327, 361))	('ovarian carcinosarcoma', 'Phenotype', 'HP:0025318', (42, 64))	('phosphoinositide-3-kinase, catalytic, alpha polypeptide', 'Gene', '5290', (108, 163))	('overexpression', 'PosReg', (228, 242))	('PIK3CA', 'Gene', (165, 171))	('epidermal growth factor receptor', 'Gene', (195, 227))	('overexpression', 'PosReg', (290, 304))	('mutations', 'Var', (173, 182))	('p53', 'Gene', '7157', (100, 103))	('vascular endothelial growth factor receptor C', 'Pathway', (244, 289))	('epidermal growth factor receptor', 'Gene', '1956', (195, 227))	('PIK3CA', 'Gene', '5290', (165, 171))	('ovarian carcinosarcoma', 'Disease', 'MESH:D002296', (42, 64))	('patient', 'Species', '9606', (65, 72))	('ovarian carcinosarcoma', 'Disease', (42, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('p53', 'Gene', (100, 103))
38318	29426293	In our study, patients treated with carboplatin/paclitaxel have a longer PFS than patients treated with ifosfamide/paclitaxel.	('carboplatin', 'Chemical', 'MESH:D016190', (36, 47))	('patients', 'Species', '9606', (14, 22))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('patients', 'Species', '9606', (82, 90))	('ifosfamide', 'Chemical', 'MESH:D007069', (104, 114))	('PFS', 'CPA', (73, 76))	('carboplatin/paclitaxel', 'Var', (36, 58))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
38342	28531111	CS shares similar risk factors with endometrial carcinomas; both of them are associated with obesity, nulliparity, and the use of exogenous estrogen and tamoxifen.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('obesity', 'Disease', (93, 100))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (36, 58))	('nulliparity', 'Var', (102, 113))	('endometrial carcinomas', 'Disease', (36, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('obesity', 'Phenotype', 'HP:0001513', (93, 100))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (36, 58))	('tamoxifen', 'Chemical', 'MESH:D013629', (153, 162))	('obesity', 'Disease', 'MESH:D009765', (93, 100))	('associated', 'Reg', (77, 87))
38360	28531111	In this model, a number of genetic and epigenetic changes occur over time, with the result that the most aggressive cancer cells are ultimately responsible for driving tumor progression.	('tumor', 'Disease', (168, 173))	('cancer', 'Disease', (116, 122))	('epigenetic', 'Var', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
38361	28531111	Furthermore, through a series of genetic mutations, any cancer cell within the tumor can become invasive, lead to the development of metastases, and contribute to the resistance of therapies and ultimately to the recurrence of disease.	('contribute', 'Reg', (149, 159))	('cancer cell within the tumor', 'Disease', (56, 84))	('genetic mutations', 'Var', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('resistance of therapies', 'CPA', (167, 190))	('lead to', 'Reg', (106, 113))	('metastases', 'Disease', (133, 143))	('cancer cell within the tumor', 'Disease', 'MESH:D001929', (56, 84))	('become', 'PosReg', (89, 95))	('invasive', 'CPA', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('metastases', 'Disease', 'MESH:D009362', (133, 143))
38377	28531111	Further to mutations in cancer genes already observed in uterine and ovarian CS such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, this study identified an excess of mutations in genes encoding histone H2A and H2B, demonstrating a stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line.	('PTEN', 'Gene', (117, 121))	('ovarian CS', 'Disease', (69, 79))	('H2A and H2B', 'Gene', '8337', (210, 221))	('CHD4', 'Gene', (123, 127))	('cancer', 'Disease', (24, 30))	('TP53', 'Gene', '7157', (88, 92))	('rat', 'Species', '10116', (230, 233))	('serous carcinoma', 'Disease', (296, 312))	('H2A and H2B', 'Gene', '8337', (271, 282))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('CHD4', 'Gene', '1108', (123, 127))	('PTEN', 'Gene', '5728', (117, 121))	('mutations', 'Var', (174, 183))	('BCOR', 'Gene', '54880', (133, 137))	('PIK3CA', 'Gene', '5290', (94, 100))	('PPP2R1A', 'Gene', '5518', (102, 109))	('serous carcinoma', 'Disease', 'MESH:D018284', (296, 312))	('KRAS', 'Gene', '3845', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('BCOR', 'Gene', (133, 137))	('TP53', 'Gene', (88, 92))	('PPP2R1A', 'Gene', (102, 109))	('KRAS', 'Gene', (111, 115))	('ovarian CS', 'Disease', 'MESH:D006223', (69, 79))	('PIK3CA', 'Gene', (94, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
38378	28531111	However, the mutant's histones were not wild-type, and they increased the expression of epithelial-mesenchymal markers in addition to the tumors' migratory and invasive properties, indicative of a role in sarcomatous transformation.	('mutant', 'Var', (13, 19))	('expression', 'MPA', (74, 84))	("tumors' migratory", 'Disease', (138, 155))	('epithelial-mesenchymal markers', 'Protein', (88, 118))	('sarcomatous transformation', 'Disease', 'MESH:D018316', (205, 231))	('histones', 'Protein', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('sarcomatous transformation', 'Disease', (205, 231))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (205, 231))	("tumors' migratory", 'Disease', 'MESH:D010146', (138, 155))	('increased', 'PosReg', (60, 69))	('invasive properties', 'CPA', (160, 179))
38438	28531111	Additionally, treatment with MT110 prevented tumor formation in a xenograft model, where mice were inoculated with TICs.	('MT110', 'Var', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', (45, 50))	('prevented', 'NegReg', (35, 44))	('MT110', 'Chemical', 'MESH:C000607229', (29, 34))	('TICs', 'Phenotype', 'HP:0100033', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
38444	28531111	Likewise, the knockdown of FHL2 resulted in an inhibition of EpCAM-specific effects.	('EpCAM-specific effects', 'MPA', (61, 83))	('FHL2', 'Gene', (27, 31))	('inhibition', 'NegReg', (47, 57))	('FHL2', 'Gene', '2274', (27, 31))	('knockdown', 'Var', (14, 23))
38491	28295222	The current investigations identified a subset of HPV-positive HNSCCs with mutations in the genes TRAF3 (tumor necrosis factor receptor-associated factor 3) and CYLD (cylindromatosis lysine 63 deubiquitinase).	('tumor necrosis factor receptor-associated factor 3', 'Gene', '7187', (105, 155))	('TRAF3', 'Gene', (98, 103))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', '1540', (167, 207))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutations', 'Var', (75, 84))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', (167, 207))	('HPV', 'Species', '10566', (50, 53))	('tumor necrosis factor receptor-associated factor 3', 'Gene', (105, 155))
38492	28295222	Defects in TRAF3 and CYLD correlated with the activation of transcriptional factor nuclear factor kappaB, episomal HPV status of tumors, and improved patient survival.	('episomal HPV status of tumors', 'Disease', (106, 135))	('patient', 'Species', '9606', (150, 157))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('activation', 'PosReg', (46, 56))	('Defects', 'Var', (0, 7))	('kappaB', 'Gene', '4790', (98, 104))	('kappaB', 'Gene', (98, 104))	('improved', 'PosReg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('transcriptional', 'MPA', (60, 75))	('episomal HPV status of tumors', 'Disease', 'MESH:D030361', (106, 135))	('TRAF3', 'Gene', (11, 16))	('patient survival', 'CPA', (150, 166))
38497	28295222	Somatic mutations in the genes TRAF3 and CYLD identified in The Cancer Genome Atlas data set are correlated with the activation of nuclear factor-kappaB, define a distinct etiologic subset of head and neck cancers, and will be useful as biomarkers for predicting improved prognosis and selecting patients with human papillomavirus-positive head and neck cancer who may be successfully treated with de-escalating therapy.	('head and neck cancer', 'Phenotype', 'HP:0012288', (340, 360))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('head and neck cancers', 'Phenotype', 'HP:0012288', (192, 213))	('papillomavirus-positive head and neck cancer', 'Disease', 'MESH:D006258', (316, 360))	('neck cancers', 'Disease', (201, 213))	('mutations', 'Var', (8, 17))	('head and neck cancer', 'Disease', 'MESH:D006258', (340, 360))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('nuclear factor-kappaB', 'Gene', '4790', (131, 152))	('neck cancers', 'Disease', 'MESH:D006258', (201, 213))	('head and neck cancer', 'Phenotype', 'HP:0012288', (192, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('nuclear factor-kappaB', 'Gene', (131, 152))	('activation', 'PosReg', (117, 127))	('patients', 'Species', '9606', (296, 304))	('TRAF3', 'Gene', (31, 36))	('Cancer', 'Disease', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('head and neck cancer', 'Disease', 'MESH:D006258', (192, 212))	('human papillomavirus', 'Species', '10566', (310, 330))
38508	28295222	A seminal finding of the TCGA head and neck study identified tumor necrosis factor receptor-associated factor 3 (TRAF3) as 1 of the most commonly mutated genes in HPV-positive HNSCC.12 It is noteworthy that TRAF3 mutations are not described in HPV-negative HNSCC, suggesting that TRAF3 inactivation is required only for HPV-driven carcinogenesis in HNSCC.	('tumor necrosis factor receptor-associated factor 3', 'Gene', (61, 111))	('TRAF3', 'Gene', (207, 212))	('HPV', 'Species', '10566', (244, 247))	('HPV-driven carcinogenesis', 'Disease', (320, 345))	('HPV', 'Species', '10566', (320, 323))	('tumor necrosis factor receptor-associated factor 3', 'Gene', '7187', (61, 111))	('HPV', 'Species', '10566', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('HPV-driven carcinogenesis', 'Disease', 'MESH:D030361', (320, 345))	('HNSCC.12', 'CellLine', 'CVCL:5985', (176, 184))	('mutations', 'Var', (213, 222))
38509	28295222	Receptors that signal through TRAF proteins include those involved in inflammation, innate immune responses, and cell death, most notably: tumor necrosis factor receptors (TNFR), Toll-like receptors (TLRs), RIG-1-like receptors (RLRs), and interleukin-1 receptors (IL-1Rs).14 These receptors initiate signaling that ultimately leads to activation of the innate immune response and nuclear factor-kappaB (NF-kappaB), a potent transcription factor central to the cell's control of apoptosis, inflammation, and several aspects of the immune response.14, 15 It has long been noted that NF-kappaB signaling is activated in many HNSCCs.16, 17, 18, 19 It has been demonstrated that constitutive NF-kappaB activation is induced by carcinogens or oncogenic viruses in patients with head and neck cancer or in cell lines.20, 21 TRAF3 is unique, in that it plays a role in negatively regulating canonical and noncanonical NF-kappaB pathways while simultaneously stimulating a potent antiviral response, which is mediated through type I interferon (IFN) signaling.14, 22 Here, we report that the gene cylindromatosis lysine 63 deubiquitinase (CYLD), which, like TRAF3, inhibits NF-kappaB pathways,23 is also mutated in a subset of HPV-positive HNSCC.	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('nuclear factor-kappaB', 'Gene', (381, 402))	('carcinogens or oncogenic viruses', 'Disease', 'MESH:D000074723', (723, 755))	('inflammation', 'Disease', 'MESH:D007249', (490, 502))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', '1540', (1089, 1129))	('patients', 'Species', '9606', (759, 767))	('carcinogens or oncogenic viruses', 'Disease', (723, 755))	('HPV', 'Species', '10566', (1219, 1222))	('tumor necrosis factor receptors', 'Gene', '7132', (139, 170))	('inhibits', 'NegReg', (1157, 1165))	('inflammation', 'Disease', (70, 82))	('mutated', 'Var', (1196, 1203))	('interferon', 'Gene', (1025, 1035))	('head and neck cancer', 'Phenotype', 'HP:0012288', (773, 793))	('cancer', 'Phenotype', 'HP:0002664', (787, 793))	('inflammation', 'Disease', (490, 502))	('interferon', 'Gene', '3439', (1025, 1035))	('IFN', 'Gene', '3439', (1037, 1040))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor necrosis factor receptors', 'Gene', (139, 170))	('head and neck cancer', 'Disease', 'MESH:D006258', (773, 793))	('TNFR', 'Gene', '7132', (172, 176))	('CYLD', 'Gene', (1131, 1135))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', (1089, 1129))	('nuclear factor-kappaB', 'Gene', '4790', (381, 402))	('IFN', 'Gene', (1037, 1040))	('TNFR', 'Gene', (172, 176))
38510	28295222	Mutations in TRAF3 and CYLD leading to constitutive activation of NF-kappaB have been identified in other cancers, such as multiple myeloma; however, among solid tumors, inactivating TRAF3/CYLD gene defects were most common in HPV-positive HNSCC.	('inactivating', 'Var', (170, 182))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('CYLD gene defects', 'Disease', 'MESH:D025063', (189, 206))	('constitutive', 'MPA', (39, 51))	('solid tumors', 'Disease', (156, 168))	('multiple myeloma', 'Phenotype', 'HP:0006775', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('HPV', 'Species', '10566', (227, 230))	('Mutations', 'Var', (0, 9))	('CYLD gene defects', 'Disease', (189, 206))	('multiple myeloma', 'Disease', 'MESH:D009101', (123, 139))	('common', 'Reg', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('solid tumors', 'Disease', 'MESH:D009369', (156, 168))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('multiple myeloma', 'Disease', (123, 139))	('TRAF3', 'Gene', (13, 18))	('NF-kappaB', 'Gene', (66, 75))	('HPV-positive HNSCC', 'Disease', (227, 245))
38511	28295222	The absence of frequent mutations in uterine cervical cancer24, 25 provides yet another difference between these HPV-associated tumor types.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (128, 133))	('mutations', 'Var', (24, 33))	('HPV', 'Species', '10566', (113, 116))
38512	28295222	In the current report, through in-depth analysis of the TCGA HNSCC data set, we propose that inactivating mutations in TRAF3 or CYLD identify a distinct subset of HPV-positive HNSCC and that this subset has constitutive activation of NF-kappaB signaling.	('HNSCC', 'Disease', (176, 181))	('inactivating mutations', 'Var', (93, 115))	('NF-kappaB', 'MPA', (234, 243))	('HPV', 'Species', '10566', (163, 166))	('TRAF3', 'Gene', (119, 124))	('CYLD', 'Gene', (128, 132))	('activation', 'PosReg', (220, 230))
38513	28295222	This previously undescribed subtype of HPV-positive HNSCC marked by TRAF3 or CYLD mutations is associated with the absence of integrated HPV and improved patient survival.	('absence', 'NegReg', (115, 122))	('HNSCC', 'Disease', (52, 57))	('patient survival', 'CPA', (154, 170))	('patient', 'Species', '9606', (154, 161))	('mutations', 'Var', (82, 91))	('improved', 'PosReg', (145, 153))	('TRAF3', 'Gene', (68, 73))	('HPV', 'Species', '10566', (39, 42))	('HPV', 'Species', '10566', (137, 140))
38517	28295222	3B,C), in the TRAF3/CYLD or PIK3CA wild-type and mutant groups were produced using GraphPad Prism 6 software, and P values were calculated using Fisher exact tests and chi-square tests.	('PIK3CA', 'Gene', (28, 34))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutant', 'Var', (49, 55))
38522	28295222	3; see online supporting information) was performed using software available from The Broad Institute (available at: http://software.broadinstitute.org/gsea/index.jsp).28, 29  One unexpected discovery from TCGA head and neck cancer project was the finding of deletions and/or mutations of TRAF3 in 25% of HPV-associated HNSCCs.12 The majority of TRAF3 alterations were homozygous gene deletions (55%), whereas the remainder were truncating mutations (45%), consistent with TRAF3 inactivation in these tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (501, 506))	('head and neck cancer', 'Disease', 'MESH:D006258', (211, 231))	('tumors', 'Phenotype', 'HP:0002664', (501, 507))	('TRAF3', 'Gene', (346, 351))	('tumors', 'Disease', 'MESH:D009369', (501, 507))	('tumors', 'Disease', (501, 507))	('alterations', 'Var', (352, 363))	('HPV', 'Species', '10566', (305, 308))	('head and neck cancer', 'Phenotype', 'HP:0012288', (211, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
38523	28295222	Notably, 2 mutations, namely, p.R310*/c.928C>T and p.R505*/c.1513C>T, have been reported previously in diffuse large-B cell (DLBC) lymphoma30 and gastric adenocarcinoma, respectively (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('diffuse large-B cell', 'Disease', (103, 123))	('p.R310*', 'Mutation', 'p.R310*', (30, 37))	('p.R505*/c.1513C>T', 'Var', (51, 68))	('p.R505*', 'Mutation', 'p.R505*', (51, 58))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (146, 168))	('p.R310*/c.928C>T', 'Var', (30, 46))	('lymphoma', 'Disease', (131, 139))	('c.1513C>T', 'Mutation', 'rs765227761', (59, 68))	('reported', 'Reg', (80, 88))	('c.928C>T', 'Mutation', 'rs201794033', (38, 46))	('lymphoma', 'Disease', 'MESH:D008223', (131, 139))	('gastric adenocarcinoma', 'Disease', (146, 168))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
38526	28295222	Because the antiviral activity of TRAF3 requires a full-length, wild-type TRAF3 protein,35, 36 alterations in the TRAF3 gene observed in HPV-positive HNSCC most likely result in the loss of TRAF3 antiviral activity.	('loss', 'NegReg', (182, 186))	('TRAF3', 'Gene', (114, 119))	('antiviral activity', 'MPA', (196, 214))	('alterations', 'Var', (95, 106))	('antiviral activity', 'MPA', (12, 30))	('HPV', 'Species', '10566', (137, 140))
38529	28295222	These analyses revealed that the tumor suppressor CYLD, which inhibits NF-kappaB pathways at various steps, was mutated in 11% of HPV-positive HNSCCs (Fig.	('NF-kappaB pathways', 'Pathway', (71, 89))	('inhibits', 'NegReg', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('mutated', 'Var', (112, 119))	('HPV', 'Species', '10566', (130, 133))	('HNSCCs', 'Disease', (143, 149))
38530	28295222	The p.S371*/ c.1112C>A, nonsense substitution, has been described previously in adnexal skin tumors.41 In addition, another amino acid 618 substitution in the CYLD gene, an aspartic acid-to-asparagine substitution at codon 618 (D618N) (identified in HPV-positive HNSCC) has been recently reported in cutaneous squamous cell carcinoma.42 It is noteworthy that, the copy number status of mutated CYLD indicates a shallow loss (a possible heterozygous deletion) in all 4 CYLD-mutant samples (Table 1).	('adnexal skin tumors', 'Disease', (80, 99))	('aspartic acid-to-asparagine substitution at codon 618', 'Mutation', 'p.D618N', (173, 226))	('loss', 'NegReg', (419, 423))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (310, 333))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cutaneous squamous cell carcinoma', 'Disease', (300, 333))	('D618N', 'Mutation', 'p.D618N', (228, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('c.1112C>A', 'Mutation', 'rs886040872', (13, 22))	('mutated', 'Var', (386, 393))	('p.S371*', 'Var', (4, 11))	('p.S371*', 'SUBSTITUTION', 'None', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('CYLD', 'Gene', (394, 398))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (300, 333))	('HPV', 'Species', '10566', (250, 253))	('adnexal skin tumors', 'Disease', 'MESH:D018294', (80, 99))	('CYLD-mutant', 'Var', (468, 479))
38533	28295222	Like TRAF3, CYLD inhibits NF-kappaB pathways at various steps including, binding, deubiquitinating, and inhibiting the NF-kappaB essential modulator (NEMO).	('inhibits', 'NegReg', (17, 25))	('NEMO', 'Gene', (150, 154))	('NF-kappaB pathways', 'Pathway', (26, 44))	('deubiquitinating', 'MPA', (82, 98))	('binding', 'Interaction', (73, 80))	('NEMO', 'Gene', '8517', (150, 154))	('CYLD', 'Var', (12, 16))	('inhibiting', 'NegReg', (104, 114))	('NF-kappaB essential modulator', 'Gene', '8517', (119, 148))	('NF-kappaB essential modulator', 'Gene', (119, 148))
38535	28295222	These findings suggest that up to 36% of HPV-positive HNSCCs harboring defective TRAF3 or CYLD may rely on overactive NF-kappaB and defective innate immunity.	('overactive', 'PosReg', (107, 117))	('HPV', 'Species', '10566', (41, 44))	('NF-kappaB', 'Protein', (118, 127))	('TRAF3', 'Gene', (81, 86))	('defective', 'Var', (71, 80))
38536	28295222	The above data suggest that a portion of HPV-positive HNSCCs may rely on TRAF3 or CYLD mutations.	('HPV', 'Species', '10566', (41, 44))	('HNSCCs', 'Disease', (54, 60))	('rely', 'Reg', (65, 69))	('CYLD', 'Var', (82, 86))	('HPV-positive', 'Gene', (41, 53))	('TRAF3', 'Gene', (73, 78))
38538	28295222	Surprisingly, TRAF3 defects detected in uterine cervical cancer, which is associated with high-risk HPVs in about 93% of cases, were reminiscent of the pattern observed in HPV-negative HNSCCs.	('defects', 'Var', (20, 27))	('HPV', 'Species', '10566', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('HPV', 'Species', '10566', (172, 175))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TRAF3', 'Gene', (14, 19))
38539	28295222	Uterine cervical cancers had infrequent TRAF3 alterations that included both amplifications and deletions (Fig.	('TRAF3', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('amplifications', 'MPA', (77, 91))	('deletions', 'Var', (96, 105))	('cervical cancers', 'Disease', (8, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cervical cancers', 'Disease', 'MESH:D002583', (8, 24))
38540	28295222	Alterations of the CYLD gene in uterine cervical cancer were even less frequent (2%), comprising 1 missense mutation and 2 deletions (Fig.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CYLD gene', 'Gene', (19, 28))	('Alterations', 'Var', (0, 11))	('deletions', 'Var', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('missense mutation', 'Var', (99, 116))	('cancer', 'Disease', (49, 55))
38541	28295222	Compared with HPV-positive HNSCC, in which TRAF3 and CYLD defects were mutually exclusive, TRAF3 and CYLD defects overlapped in 2 of the 9 uterine cervical cancers that had alterations in either gene.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('HPV', 'Species', '10566', (14, 17))	('TRAF3', 'Gene', (91, 96))	('cervical cancers', 'Disease', (147, 163))	('alterations', 'Var', (173, 184))	('CYLD defects', 'Disease', 'MESH:D005128', (101, 113))	('cervical cancers', 'Disease', 'MESH:D002583', (147, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CYLD defects', 'Disease', 'MESH:D005128', (53, 65))	('CYLD defects', 'Disease', (101, 113))	('CYLD defects', 'Disease', (53, 65))
38542	28295222	To extend these analyses, deep-sequencing data from multiple tumor types was queried for mutations in the TRAF3 and CYLD genes.	('CYLD', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TRAF3', 'Gene', (106, 111))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
38543	28295222	Tumor types with > 10% alterations of TRAF/CYLD were: breast (data from xenografted tumors), neuroendocrine prostate cancer (NEPC), DLBC lymphoma, and lung squamous cell carcinoma.	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (93, 123))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 179))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('lung squamous cell carcinoma', 'Disease', (151, 179))	('alterations', 'Var', (23, 34))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('breast', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('DLBC lymphoma', 'Disease', (132, 145))	('DLBC lymphoma', 'Disease', 'MESH:D008223', (132, 145))	('neuroendocrine prostate cancer', 'Disease', (93, 123))
38545	28295222	DLBC lymphoma and lung squamous cancer each had a significant proportion of total TRAF/CYLD alterations (mutations and deletions) and relatively few samples had amplification.	('lymphoma', 'Phenotype', 'HP:0002665', (5, 13))	('DLBC lymphoma', 'Disease', (0, 13))	('deletions', 'Var', (119, 128))	('lung squamous cancer', 'Disease', 'MESH:D008175', (18, 38))	('lung squamous cancer', 'Phenotype', 'HP:0030359', (18, 38))	('DLBC lymphoma', 'Disease', 'MESH:D008223', (0, 13))	('squamous cancer', 'Phenotype', 'HP:0002860', (23, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung squamous cancer', 'Disease', (18, 38))
38547	28295222	A recent study of another EBV-associated cancer, nasopharyngeal carcinoma, identified numerous inactivating mutations in NF-kappaB-negative regulators, including CYLD, NF-kappaB inhibitor alpha (NFKBIA), and tumor necrosis factor alpha-induced protein 3 (TNFAIP3), in 17% of these tumors.46  Across all solid tumor types, frequent inactivating TRAF3 and CYLD alterations, which are predicted to constitutively activate NF-kappaB pathways while inhibiting innate immunity, occur only in HPV-positive HNSCC.	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('nasopharyngeal carcinoma', 'Disease', (49, 73))	('NF-kappaB pathways', 'Pathway', (419, 437))	('innate', 'MPA', (455, 461))	('cancer', 'Disease', (41, 47))	('activate', 'PosReg', (410, 418))	('tumor', 'Disease', (281, 286))	('TRAF3', 'Gene', (344, 349))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (49, 73))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('HPV', 'Species', '10566', (486, 489))	('tumor', 'Disease', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', (309, 314))	('inactivating', 'NegReg', (331, 343))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('alterations', 'Var', (359, 370))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (49, 73))	('tumor necrosis', 'Disease', 'MESH:D009336', (208, 222))	('EBV', 'Species', '10376', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('CYLD', 'Gene', (354, 358))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor necrosis', 'Disease', (208, 222))	('inhibiting', 'NegReg', (444, 454))	('tumors', 'Disease', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
38549	28295222	We and others previously reported that HPV-associated head and neck cancer more frequently, although not exclusively, contained alterations in the PIK3CA gene47, 48 In contrast to TRAF3/CYLD mutations, PIK3CA mutations or amplifications are commonly detected in cervical and head and neck cancers regardless of HPV status (Supporting Fig.	('neck cancers regardless of HPV status', 'Disease', 'MESH:D030361', (284, 321))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('alterations', 'Var', (128, 139))	('head and neck cancer', 'Disease', 'MESH:D006258', (54, 74))	('head and neck cancer', 'Phenotype', 'HP:0012288', (275, 295))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('cervical', 'Disease', (262, 270))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', (147, 153))	('head and neck cancers', 'Phenotype', 'HP:0012288', (275, 296))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('PIK3CA', 'Gene', '5290', (147, 153))	('head and neck cancer', 'Disease', 'MESH:D006258', (275, 295))	('HPV', 'Species', '10566', (311, 314))	('HPV', 'Species', '10566', (39, 42))	('head and neck cancer', 'Phenotype', 'HP:0012288', (54, 74))	('neck cancers regardless of HPV status', 'Disease', (284, 321))
38550	28295222	It is noteworthy that, among 20 HPV-positive head and neck tumors with alterations in PIK3CA gene, 4 samples harbored mutations in TRAF3/CYLD; whereas, among 16 tumors without PIK3CA mutations, 9 contained alterations in TRAF3/CYLD, indicating a tendency toward mutual exclusivity (log odds ratio, -1.1; P = .25) (Supporting Fig.	('alterations', 'Reg', (206, 217))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('neck tumors', 'Disease', (54, 65))	('mutual', 'MPA', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('PIK3CA', 'Gene', (176, 182))	('PIK3CA', 'Gene', '5290', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutations', 'Var', (118, 127))	('neck tumors', 'Disease', 'MESH:D006258', (54, 65))	('alterations', 'Var', (71, 82))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('HPV', 'Species', '10566', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('PIK3CA', 'Gene', (86, 92))	('tumors', 'Disease', (59, 65))	('head and neck tumors', 'Phenotype', 'HP:0012288', (45, 65))	('PIK3CA', 'Gene', '5290', (176, 182))	('TRAF3/CYLD', 'Gene', (131, 141))
38551	28295222	In addition to high-risk HPV infection, several cofactors are associated with uterine cervical tumorigenesis, including alcohol consumption, coinfection with other infectious agents, and smoking.49, 50, 51 In contrast, tobacco smoking is not etiologically implicated in HPV-positive head and neck cancer, but it is associated with decreased survival in patients who have HPV-positive head and neck cancer.4, 52 It is noteworthy that there were relatively high numbers of patients who had a history of smoking in the HPV-positive TCGA cohort.12 Querying the TCGA cohort for TRAF3/CYLD mutations and smoking history revealed a correlation between the absence of smoking and TRAF3/CYLD gene defects, but this association did not reach statistical significance (P = .064) (Fig.	('tobacco', 'Species', '4097', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('head and neck cancer', 'Phenotype', 'HP:0012288', (283, 303))	('head and neck cancer', 'Phenotype', 'HP:0012288', (384, 404))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('HPV infection', 'Disease', 'MESH:D030361', (25, 38))	('patients', 'Species', '9606', (353, 361))	('HPV infection', 'Disease', (25, 38))	('HPV', 'Species', '10566', (25, 28))	('head and neck cancer', 'Disease', 'MESH:D006258', (283, 303))	('head and neck cancer', 'Disease', 'MESH:D006258', (384, 404))	('CYLD gene defects', 'Disease', 'MESH:D025063', (678, 695))	('HPV', 'Species', '10566', (270, 273))	('patients', 'Species', '9606', (471, 479))	('absence', 'Var', (649, 656))	('tumor', 'Disease', (95, 100))	('HPV', 'Species', '10566', (516, 519))	('CYLD gene defects', 'Disease', (678, 695))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('HPV', 'Species', '10566', (371, 374))
38554	28295222	The majority of TRAF3/CYLD mutant tumors (54%) had no HPV integration, whereas only 10% of TRAF3/CYLD wild-type samples lacked HPV integration (Fig.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('mutant', 'Var', (27, 33))	('TRAF3/CYLD', 'Gene', (16, 26))	('HPV integration', 'MPA', (54, 69))	('HPV', 'Species', '10566', (54, 57))	('HPV', 'Species', '10566', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
38555	28295222	These data suggest that defects in TRAF3/CYLD may not be required if tumors contain integrated HPV or, alternatively, that the maintenance of episomal HPV pressures cells to mutate TRAF3/CYLD.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutate', 'Var', (174, 180))	('episomal HPV', 'Disease', (142, 154))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('TRAF3/CYLD', 'Gene', (181, 191))	('episomal HPV', 'Disease', 'MESH:D030361', (142, 154))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('HPV', 'Species', '10566', (95, 98))	('HPV', 'Species', '10566', (151, 154))
38558	28295222	These data led the authors of a previous publication to propose that a subset of HPV-positive HNSCC tumors contain both episomal and integrated HPV DNA.13 The incorporation of tumors suspected to harbor both integrated and episomal forms of HPV into the TRAF3/CYLD mutation analyses revealed that 11 of 13 tumors (85%) with mutant TRAF3/CYLD contained episomal HPV, whereas 6 of 21 (29%) TRAF3/CYLD wild-type tumors harbored episomal HPV DNA (Fig.	('episomal HPV', 'Disease', (352, 364))	('tumors', 'Disease', 'MESH:D009369', (409, 415))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors harbored episomal HPV', 'Disease', 'MESH:D030361', (409, 437))	('HPV', 'Species', '10566', (434, 437))	('HPV', 'Species', '10566', (241, 244))	('contained', 'Reg', (342, 351))	('HPV', 'Species', '10566', (361, 364))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('HPV', 'Species', '10566', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('tumors harbored episomal HPV', 'Disease', (409, 437))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('HPV-positive HNSCC tumors', 'Disease', 'MESH:D000077195', (81, 106))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('mutant', 'Var', (324, 330))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', (306, 312))	('HPV-positive HNSCC tumors', 'Disease', (81, 106))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (409, 415))	('HPV', 'Species', '10566', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('episomal HPV', 'Disease', 'MESH:D030361', (425, 437))	('tumors', 'Disease', (409, 415))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('episomal HPV', 'Disease', 'MESH:D030361', (352, 364))
38560	28295222	Mechanistically, mutations in TRAF3 or CYLD may create a cellular microenvironment needed to support the maintenance of the HPV episome as an alternative to classic HPV carcinogenesis, which that depends on the integration and loss of episomal HPV.	('HPV episome', 'Disease', 'MESH:D030361', (124, 135))	('CYLD', 'Gene', (39, 43))	('HPV episome', 'Disease', (124, 135))	('loss of episomal HPV', 'Disease', 'MESH:D030361', (227, 247))	('TRAF3', 'Gene', (30, 35))	('HPV carcinogenesis', 'Disease', (165, 183))	('mutations', 'Var', (17, 26))	('loss of episomal HPV', 'Disease', (227, 247))	('HPV carcinogenesis', 'Disease', 'MESH:D030361', (165, 183))
38561	28295222	Studies from EBV-related cancers or hepatocellular carcinoma, along with HNSCC, suggest that PIK3CA mutations are common in virally associated cancers and may be mediated by viral infection.	('viral infection', 'Disease', (174, 189))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (36, 60))	('EBV', 'Species', '10376', (13, 16))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('PIK3CA', 'Gene', (93, 99))	('cancers', 'Disease', (25, 32))	('viral infection', 'Disease', 'MESH:D001102', (174, 189))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (36, 60))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('common', 'Reg', (114, 120))	('hepatocellular carcinoma', 'Disease', (36, 60))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('mutations', 'Var', (100, 109))	('PIK3CA', 'Gene', '5290', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
38569	28295222	In contrast, PIK3CA mutations did not influence the overall survival of patients in this cohort (Supporting Fig.	('PIK3CA', 'Gene', '5290', (13, 19))	('mutations', 'Var', (20, 29))	('PIK3CA', 'Gene', (13, 19))	('patients', 'Species', '9606', (72, 80))
38571	28295222	Genes that were highly expressed in tumors with TRAF3/CYLD mutations were enriched for those that shared NF-kappaB or epidermal growth factor 1 (EGR-1) binding sites (Fig.	('EGR-1', 'Gene', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('highly', 'PosReg', (16, 22))	('EGR-1', 'Gene', '1958', (145, 150))	('binding', 'Interaction', (152, 159))	('NF-kappaB', 'Protein', (105, 114))	('epidermal growth factor 1', 'Gene', '1958', (118, 143))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutations', 'Var', (59, 68))	('TRAF3/CYLD', 'Gene', (48, 58))	('tumors', 'Disease', (36, 42))	('epidermal growth factor 1', 'Gene', (118, 143))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
38573	28295222	4B), whereas genes that are highly expressed in tumors with altered PIK3CA are enriched for those that share androgen receptor or hypoxia-inducible factor 1alpha binding sites (Supporting Fig.	('hypoxia', 'Disease', (130, 137))	('PIK3CA', 'Gene', (68, 74))	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('PIK3CA', 'Gene', '5290', (68, 74))	('altered', 'Var', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
38576	28295222	To identify additional biologic functions or pathways associated with TRAF3/CYLD mutations, we ran GSEA using data sets of oncogenic and immunologic signatures as well as hallmark gene sets.	('GSEA', 'Chemical', '-', (99, 103))	('mutations', 'Var', (81, 90))	('TRAF3/CYLD', 'Gene', (70, 80))
38579	28295222	Conversely, mutant tumors were enriched in DNA replication genes,53, 63 in genes that distinguished HPV-positive from HPV-negative HNSCC,53 and in genes that were up-regulated in nasopharyngeal carcinoma compared with normal tissue64 (Fig.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (179, 203))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('HPV', 'Species', '10566', (100, 103))	('nasopharyngeal carcinoma', 'Disease', (179, 203))	('up-regulated', 'PosReg', (163, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (179, 203))	('HPV', 'Species', '10566', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutant', 'Var', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('DNA', 'Gene', (43, 46))
38583	28295222	5C) had a high representation of DNA repair and replication genes.64  Confirming our previous finding that mutant PIK3CA in HPV-positive tumors correlated with activation of the mechanistic target of rapamycin (mTOR) pathway, tumors with altered PIK3CA in the TCGA cohort overexpressed genes that were up-regulated by activation of the mTORC1 complex or during the unfolded protein response (Supporting Fig.	('PIK3CA', 'Gene', '5290', (114, 120))	('HPV-positive tumors', 'Disease', (124, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('up-regulated', 'PosReg', (302, 314))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (124, 143))	('PIK3CA', 'Gene', '5290', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('overexpressed', 'PosReg', (272, 285))	('PIK3CA', 'Gene', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('mTORC1', 'Gene', (336, 342))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('mTORC1', 'Gene', '382056', (336, 342))	('activation', 'PosReg', (160, 170))	('genes', 'Gene', (286, 291))	('PIK3CA', 'Gene', (246, 252))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mutant', 'Var', (107, 113))	('tumors', 'Disease', (226, 232))	('altered', 'Var', (238, 245))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
38585	28295222	The data presented here suggest that, within HPV-positive tumors, there are 2 major subgroups that can be distinguished based on TRAF3 or CYLD mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TRAF3', 'Gene', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (45, 64))	('HPV-positive tumors', 'Disease', (45, 64))	('mutations', 'Var', (143, 152))
38586	28295222	Comparison of HPV-positive tumors with and without TRAF3 or CYLD mutations revealed that mutant tumors had improved survival and expressed genes that were enriched in HPV-positive gene sets, suggesting that the tumors harboring TRAF3 or CYLD defects are the drivers of differences in gene expression between HPV-positive versus HPV-negative HNSCC and contribute significantly to the improved survival of patients with HPV-positive tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('HPV', 'Species', '10566', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('patients', 'Species', '9606', (404, 412))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (418, 437))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (14, 33))	('improved', 'PosReg', (383, 391))	('mutant', 'Var', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (431, 437))	('HPV', 'Species', '10566', (418, 421))	('gene expression', 'MPA', (284, 299))	('mutations', 'Var', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('differences', 'Reg', (269, 280))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('HPV', 'Species', '10566', (328, 331))	('CYLD defects', 'Disease', 'MESH:D005128', (237, 249))	('CYLD defects', 'Disease', (237, 249))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (431, 437))	('HPV', 'Species', '10566', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('improved', 'PosReg', (107, 115))	('TRAF3', 'Gene', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (27, 33))	('HPV-positive tumors', 'Disease', (418, 437))	('tumor', 'Phenotype', 'HP:0002664', (431, 436))	('tumors', 'Disease', (431, 437))	('HPV', 'Species', '10566', (308, 311))	('HPV-positive tumors', 'Disease', (14, 33))
38587	28295222	Our data also suggest that TRAF3 or CYLD mutations harbor episomal HPV and have activated NF-kappaB, which may be required for episomal maintenance.	('mutations', 'Var', (41, 50))	('harbor', 'Reg', (51, 57))	('NF-kappaB', 'Protein', (90, 99))	('episomal HPV', 'Disease', 'MESH:D030361', (58, 70))	('TRAF3', 'Gene', (27, 32))	('CYLD', 'Gene', (36, 40))	('activated', 'PosReg', (80, 89))	('episomal HPV', 'Disease', (58, 70))
38589	28295222	It is noteworthy that the transcriptome of tumors with altered TRAF3/CYLD is highly enriched in genes that are overexpressed in well differentiated squamous cells (Fig.	('altered', 'Var', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('TRAF3/CYLD', 'Gene', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
38593	28295222	We observed that patients who had wild-type TRAF3 and CYLD tumors had worse survival, which may implicate IFN signaling in therapeutic resistance (Fig.	('worse', 'NegReg', (70, 75))	('survival', 'MPA', (76, 84))	('IFN', 'Gene', '3439', (106, 109))	('TRAF3', 'Gene', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('IFN', 'Gene', (106, 109))	('CYLD tumors', 'Disease', (54, 65))	('patients', 'Species', '9606', (17, 25))	('wild-type', 'Var', (34, 43))	('CYLD tumors', 'Disease', 'MESH:D009369', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
38595	28295222	Further profiling of HPV-associated head and neck samples is needed to confirm the significance of TRAF3/CYLD mutations in HNSCC and to determine whether additional regulators of NF-kappaB, which is known to be mutated in human cancer (Fig.	('HPV', 'Species', '10566', (21, 24))	('cancer', 'Disease', (228, 234))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('HNSCC', 'Gene', (123, 128))	('human', 'Species', '9606', (222, 227))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
38596	28295222	Although additional data may improve biomarker selection for predicting prognosis, these studies suggest that TRAF3 and CYLD mutations are useful for selecting patients who have HPV-positive HNSCC with an improved outcome and suggest that these patients may be most appropriate for trials of therapeutic de-escalation.	('TRAF3', 'Gene', (110, 115))	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (245, 253))	('CYLD', 'Gene', (120, 124))	('HNSCC', 'Disease', (191, 196))	('HPV', 'Species', '10566', (178, 181))
38598	28295222	These groups are distinguished by the presence or absence of TRAF3/CYLD mutations, which are associated with the presence of HPV episomes and a lack of HPV genome integration.	('mutations', 'Var', (72, 81))	('TRAF3/CYLD', 'Gene', (61, 71))	('HPV', 'Species', '10566', (152, 155))	('HPV', 'Species', '10566', (125, 128))	('HPV episomes', 'Disease', 'MESH:D030361', (125, 137))	('HPV episomes', 'Disease', (125, 137))
38599	28295222	The presence of HPV episomes is not well described in other HPV-associated cancers, and uterine cervical cancers do not have frequent mutations in TRAF3 or CYLD.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', (75, 82))	('cervical cancers', 'Disease', (96, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('HPV', 'Species', '10566', (16, 19))	('cervical cancers', 'Disease', 'MESH:D002583', (96, 112))	('HPV episomes', 'Disease', 'MESH:D030361', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('HPV', 'Species', '10566', (60, 63))	('mutations', 'Var', (134, 143))	('TRAF3', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HPV episomes', 'Disease', (16, 28))
38600	28295222	The co-occurrence of episomal HPV with TRAF3 or CYLD mutations suggests an alternative route of HPV carcinogenesis based on selection for HPV integration and high levels of HPV E6 and E7 expression (classic) or for TRAF3 or CYLD mutations with low HPV oncogene expression (alternative).	('HPV', 'Species', '10566', (96, 99))	('episomal HPV', 'Disease', 'MESH:D030361', (21, 33))	('HPV carcinogenesis', 'Disease', (96, 114))	('TRAF3', 'Gene', (39, 44))	('HPV', 'Species', '10566', (138, 141))	('HPV', 'Species', '10566', (248, 251))	('HPV', 'Species', '10566', (173, 176))	('mutations', 'Var', (53, 62))	('HPV', 'Species', '10566', (30, 33))	('episomal HPV', 'Disease', (21, 33))	('HPV carcinogenesis', 'Disease', 'MESH:D030361', (96, 114))	('E6 and E7', 'Gene', '25479186', (177, 186))
38602	28295222	In the classic pathway, HPV integrates to avoid recognition by PRR; whereas, in the alternative pathway, episomal HPV can be recognized, but somatic mutations that block innate immune response while activating NF-kappaB to promote cell survival are selected.	('block', 'NegReg', (164, 169))	('NF-kappaB', 'Protein', (210, 219))	('mutations', 'Var', (149, 158))	('activating', 'PosReg', (199, 209))	('HPV', 'Species', '10566', (24, 27))	('HPV', 'Species', '10566', (114, 117))	('episomal HPV', 'Disease', (105, 117))	('cell survival', 'CPA', (231, 244))	('episomal HPV', 'Disease', 'MESH:D030361', (105, 117))	('promote', 'PosReg', (223, 230))
38603	28295222	Significantly, HNSCC with defects in the TRAF3/CYLD genes have a better prognosis compared with tumors that lack mutations (Fig.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('HNSCC', 'Disease', (15, 20))	('defects', 'Var', (26, 33))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('TRAF3/CYLD', 'Gene', (41, 51))
38605	28295222	Our data suggest that constitutively active NF-kappaB resulting from somatic mutations in TRAF3 or CYLD may serve as a biomarker to predict an improved prognosis for patients with HPV-positive head and neck cancer.	('TRAF3', 'Gene', (90, 95))	('improved', 'PosReg', (143, 151))	('HPV', 'Species', '10566', (180, 183))	('head and neck cancer', 'Phenotype', 'HP:0012288', (193, 213))	('mutations', 'Var', (77, 86))	('NF-kappaB', 'Protein', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (166, 174))	('head and neck cancer', 'Disease', 'MESH:D006258', (193, 213))
38781	26558647	A subset of uLMS shows a loss of PTEN, resulting in aberrant signaling and increased activation of the AKT-mTOR pathway, which leads to unregulated cell proliferation.	('AKT', 'Gene', '207', (103, 106))	('signaling', 'MPA', (61, 70))	('leads to', 'Reg', (127, 135))	('mTOR', 'Gene', (107, 111))	('mTOR', 'Gene', '2475', (107, 111))	('PTEN', 'Gene', (33, 37))	('AKT', 'Gene', (103, 106))	('PTEN', 'Gene', '5728', (33, 37))	('aberrant', 'Var', (52, 60))	('increased activation', 'PosReg', (75, 95))	('loss', 'NegReg', (25, 29))	('unregulated', 'MPA', (136, 147))	('uLMS', 'Phenotype', 'HP:0002891', (12, 16))
38796	26558647	The combination of rapamycin and MLN8237 (an Aurora-A kinase inhibitor) resulted in synergistic inhibition of cell growth in both in vitro and in vivo models.	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('MLN8237', 'Var', (33, 40))	('rapamycin', 'Chemical', 'MESH:D020123', (19, 28))	('inhibition', 'NegReg', (96, 106))	('cell growth', 'CPA', (110, 121))
38823	26793763	Uterine CS is considered a Type II epithelial endometrial malignancy with high rates of p53 mutations, like other high-grade endometrial cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Uterine CS', 'Disease', (0, 10))	('endometrial cancer', 'Phenotype', 'HP:0012114', (125, 143))	('mutations', 'Var', (92, 101))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('endometrial cancers', 'Disease', 'MESH:D016889', (125, 144))	('Type II epithelial endometrial malignancy', 'Disease', (27, 68))	('endometrial cancers', 'Disease', (125, 144))	('Type II epithelial endometrial malignancy', 'Disease', 'MESH:D002277', (27, 68))
38848	26793763	The maternal cousin with breast and ovarian cancer was diagnosed with a 5677insA BRCA-1 mutation.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (25, 50))	('5677insA', 'Var', (72, 80))	('5677insA', 'Mutation', 'c.5677insA', (72, 80))	('BRCA-1', 'Gene', (81, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('BRCA-1', 'Gene', '672', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
38851	26793763	Mutations in KRAS, PTEN, and ARID1A were detected in the sarcomatous component.	('KRAS', 'Gene', '3845', (13, 17))	('PTEN', 'Gene', (19, 23))	('KRAS', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (19, 23))	('ARID1A', 'Gene', '8289', (29, 35))	('Mutations', 'Var', (0, 9))	('sarcomatous component', 'Disease', 'MESH:D018316', (57, 78))	('sarcomatous component', 'Disease', (57, 78))	('ARID1A', 'Gene', (29, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('detected', 'Reg', (41, 49))
38853	26793763	In the carcinomatous component, PTEN and NFE2L2 (nuclear-factor (erythroid-derived 2)-like 2) missense mutations were detected.	('NFE2L2 (nuclear-factor (erythroid-derived 2)-like 2', 'Gene', '4780', (41, 92))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('carcinomatous component', 'Disease', 'MESH:D055756', (7, 30))	('carcinomatous component', 'Disease', (7, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('missense mutations', 'Var', (94, 112))
38871	26793763	Uterine CS is considered a type II endometrial cancer, with high rates of p53, FBXW7, and PIK3CA mutations such as those found in serous endometrial cancers.	('PIK3CA', 'Gene', '5290', (90, 96))	('mutations', 'Var', (97, 106))	('type II endometrial cancer', 'Disease', 'MESH:D016889', (27, 53))	('endometrial cancer', 'Phenotype', 'HP:0012114', (137, 155))	('FBXW7', 'Gene', '55294', (79, 84))	('Uterine CS', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('FBXW7', 'Gene', (79, 84))	('PIK3CA', 'Gene', (90, 96))	('serous endometrial cancers', 'Disease', (130, 156))	('p53', 'Gene', (74, 77))	('endometrial cancer', 'Phenotype', 'HP:0012114', (35, 53))	('p53', 'Gene', '7157', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('serous endometrial cancers', 'Disease', 'MESH:D016889', (130, 156))	('type II endometrial cancer', 'Disease', (27, 53))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
38872	26793763	In contrast, low proliferative endometrioid endometrial carcinomas commonly have somatic mutations in PTEN, PIK3CA, ARID1A, KRAS, and ARID5B.	('ARID1A', 'Gene', '8289', (116, 122))	('ARID1A', 'Gene', (116, 122))	('low proliferative', 'CPA', (13, 30))	('KRAS', 'Gene', (124, 128))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (44, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('ARID5B', 'Gene', (134, 140))	('KRAS', 'Gene', '3845', (124, 128))	('endometrial carcinomas', 'Disease', (44, 66))	('ARID5B', 'Gene', '84159', (134, 140))	('PIK3CA', 'Gene', (108, 114))	('mutations', 'Var', (89, 98))	('PTEN', 'Gene', (102, 106))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (44, 66))	('PTEN', 'Gene', '5728', (102, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('PIK3CA', 'Gene', '5290', (108, 114))
38884	26428316	A Survey of DICER1 Hotspot Mutations in Ovarian and Testicular Sex Cord-Stromal Tumors Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations.	('Testicular Sex Cord-Stromal Tumors', 'Disease', 'MESH:D018312', (52, 86))	('Mutations', 'Var', (27, 36))	('Ovarian', 'Disease', (40, 47))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (95, 113))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (95, 112))	('Sertoli-Leydig cell tumors', 'Disease', (87, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('DICER1', 'Gene', (12, 18))	('DICER1', 'Gene', '192119', (12, 18))	('Testicular Sex Cord-Stromal Tumors', 'Phenotype', 'HP:0031918', (52, 86))	('mutations', 'Var', (174, 183))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (87, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Testicular Sex Cord-Stromal Tumors', 'Disease', (52, 86))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (87, 113))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (87, 113))	('DICER1', 'Gene', (159, 165))	('DICER1', 'Gene', '192119', (159, 165))	('Tumors', 'Phenotype', 'HP:0002664', (80, 86))
38885	26428316	In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('DICER1', 'Gene', (59, 65))	('ovarian Sertoli-Leydig cell tumors', 'Disease', (122, 156))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (130, 155))	('mutations', 'Var', (74, 83))	('ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (122, 156))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (130, 156))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (138, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (138, 156))	('association', 'Interaction', (39, 50))
38886	26428316	Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation.	('occur', 'Reg', (65, 70))	('genital tract tumors', 'Phenotype', 'HP:0010787', (165, 185))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (80, 110))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('rhabdomyosarcomatous', 'Disease', 'None', (191, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors', 'Disease', 'MESH:D018312', (80, 147))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (80, 111))	('testicular sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (113, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (124, 146))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (88, 111))	('mutations', 'Var', (55, 64))	('hotspot', 'PosReg', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('rhabdomyosarcomatous', 'Disease', (191, 211))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (191, 207))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (88, 110))	('genital tract tumors', 'Disease', (165, 185))	('genital tract tumors', 'Disease', 'MESH:D060737', (165, 185))	('testicular sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (113, 147))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (124, 147))	('DICER1', 'Gene', (40, 46))
38888	26428316	We also tested 2 gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G).	('tested', 'Reg', (8, 14))	('FOXL2', 'Gene', (55, 60))	('c.402C>G', 'Mutation', 'rs1057519865', (89, 97))	('gynandroblastomas', 'Disease', 'MESH:D018312', (17, 34))	('gynandroblastomas', 'Disease', (17, 34))	('p.C134W', 'SUBSTITUTION', 'None', (80, 87))	('p.C134W', 'Var', (80, 87))	('FOXL2', 'Gene', '26927', (55, 60))
38889	26428316	Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation.	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (19, 45))	('p.E1705K', 'Mutation', 'p.E1705K', (103, 111))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (19, 45))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (19, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('DICER1', 'Gene', (57, 63))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (27, 44))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (27, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('Sertoli-Leydig cell tumors', 'Disease', (19, 45))	('p.E1705K', 'Var', (103, 111))
38890	26428316	No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors.	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (128, 146))	('mutation', 'Var', (40, 48))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Sertoli-Leydig cell tumors', 'Disease', (120, 146))	('retiform differentiation', 'CPA', (92, 116))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (120, 146))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (120, 146))	('DICER1', 'Gene', (33, 39))	('heterologous', 'CPA', (76, 88))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (120, 145))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (128, 145))
38891	26428316	DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; p>0.1), and all mutated tumors harbored a p.E1705K mutation.	('DICER1', 'Gene', (0, 6))	('gynandroblastoma', 'Disease', (54, 70))	('p.E1705K', 'Var', (167, 175))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (94, 112))	('ovarian Sertoli cell tumors', 'Disease', 'MESH:D012707', (86, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ovarian Sertoli cell tumors', 'Disease', (86, 113))	('tumors', 'Disease', (149, 155))	('p.E1705K', 'Mutation', 'p.E1705K', (167, 175))	('mutations', 'Var', (7, 16))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (94, 113))	('tumors', 'Disease', (107, 113))	('gynandroblastoma', 'Disease', 'MESH:D018312', (54, 70))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('harbored', 'Reg', (156, 164))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
38892	26428316	DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma.	('DICER1', 'Gene', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('mutations', 'Var', (15, 24))	('rhabdomyosarcomatous component', 'Disease', 'MESH:C562869', (95, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('carcinosarcoma', 'Disease', 'MESH:D002296', (139, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (67, 83))	('cervical rhabdomyosarcoma', 'Disease', 'MESH:D012208', (58, 83))	('cervical rhabdomyosarcoma', 'Disease', (58, 83))	('carcinosarcoma', 'Disease', (139, 153))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (131, 153))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (95, 111))	('rhabdomyosarcomatous component', 'Disease', (95, 125))
38893	26428316	No DICER1 mutations were detected in testicular sex cord-stromal tumors.	('testicular sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (37, 70))	('testicular sex cord-stromal tumors', 'Disease', (37, 71))	('testicular sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (37, 71))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (48, 70))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('testicular sex cord-stromal tumors', 'Disease', 'MESH:D018312', (37, 71))	('mutations', 'Var', (10, 19))	('DICER1', 'Gene', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
38894	26428316	Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components.	('p.C134W', 'Var', (50, 57))	('DICER1', 'Gene', (4, 10))	('gynandroblastomas', 'Disease', (21, 38))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('gynandroblastomas', 'Disease', 'MESH:D018312', (21, 38))	('FOXL2', 'Gene', (58, 63))	('p.C134W', 'SUBSTITUTION', 'None', (50, 57))	('FOXL2', 'Gene', '26927', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('harbored', 'Reg', (39, 47))
38895	26428316	In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation.	('hotspot', 'PosReg', (39, 46))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (87, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (95, 113))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (95, 112))	('ovarian Sertoli-Leydig cell tumors', 'Disease', (79, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (79, 113))	('DICER1', 'Gene', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (87, 113))	('tumor', 'Disease', (136, 141))
38896	26428316	We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas.	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (32, 63))	('mutations', 'Var', (114, 123))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (40, 62))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (32, 62))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (32, 63))	('DICER1', 'Gene', (107, 113))	('gynandroblastomas', 'Disease', (179, 196))	('ovarian sex cord-stromal tumors', 'Disease', (32, 63))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (155, 173))	('Sertoli cell tumors', 'Disease', 'MESH:D012707', (155, 174))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (40, 63))	('gynandroblastomas', 'Disease', 'MESH:D018312', (179, 196))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (155, 174))	('Sertoli cell tumors', 'Disease', (155, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('sertoliform differentiation', 'Phenotype', 'HP:0100619', (69, 96))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
38897	26428316	Our results suggest that DICER1 mutations may not play a role in testicular sex cord-stromal tumorigenesis.	('testicular sex cord-stromal tumorigenesis', 'Phenotype', 'HP:0031918', (65, 106))	('DICER1', 'Gene', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('sex cord-stromal tumor', 'Disease', (76, 98))	('testicular sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (65, 98))	('mutations', 'Var', (32, 41))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (76, 98))	('sex cord-stromal tumor', 'Disease', 'MESH:D018312', (76, 98))
38908	26428316	The majority of ovarian adult granulosa cell tumors have been shown to harbor somatic FOXL2 mutations, while somatic DICER1 mutations have been identified in approximately 60% of Sertoli-Leydig cell tumors and, more rarely, in other tumor types including embryonal rhabdomyosarcomas and ovarian and testicular germ cell tumors, such as yolk sac tumors and teratomas.	('FOXL2', 'Gene', '26927', (86, 91))	('teratomas', 'Phenotype', 'HP:0009792', (356, 365))	('FOXL2', 'Gene', (86, 91))	('tumors', 'Disease', (199, 205))	('tumor', 'Disease', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (320, 326))	('tumor', 'Disease', (345, 350))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (179, 205))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (179, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (265, 282))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('teratomas', 'Disease', 'MESH:D013724', (356, 365))	('tumor', 'Disease', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (265, 281))	('tumors', 'Phenotype', 'HP:0002664', (345, 351))	('tumor', 'Disease', (320, 325))	('ovarian adult granulosa cell tumors', 'Disease', 'MESH:D006106', (16, 51))	('germ cell tumors', 'Phenotype', 'HP:0100728', (310, 326))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('teratomas', 'Disease', (356, 365))	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (255, 282))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumors', 'Disease', (345, 351))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (187, 205))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (255, 281))	('embryonal rhabdomyosarcomas and ovarian and testicular germ cell tumors', 'Disease', 'MESH:C563236', (255, 326))	('Sertoli-Leydig cell tumors', 'Disease', (179, 205))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (187, 204))	('ovarian adult granulosa cell tumors', 'Disease', (16, 51))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumors', 'Disease', (320, 326))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (345, 351))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (179, 204))	('ovarian adult granulosa cell tumors', 'Phenotype', 'HP:0031919', (16, 51))
38909	26428316	These somatic DICER1 missense mutations affect several 'hotspots' in the metal-binding domain of the RNase IIIb subunit of the gene.	("'hotspots' in the metal-binding domain", 'MPA', (55, 93))	('DICER1', 'Gene', (14, 20))	('missense mutations', 'Var', (21, 39))	('metal', 'Chemical', 'MESH:D008670', (73, 78))	('affect', 'Reg', (40, 46))
38910	26428316	In contrast, germline DICER1 mutations associated with the DICER1 syndrome, which confers risk for multiple tumor types including pleuropulmonary blastoma, cystic nephroma, ovarian Sertoli-Leydig cell tumor and childhood embryonal rhabdomyosarcoma, are mainly truncating and spread across the gene.	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('associated', 'Reg', (39, 49))	('cystic nephroma, ovarian Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (156, 206))	('DICER1', 'Gene', (22, 28))	('DICER1 syndrome', 'Disease', (59, 74))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (221, 247))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (130, 154))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (189, 206))	('multiple tumor', 'Disease', 'MESH:D009369', (99, 113))	('embryonal rhabdomyosarcoma', 'Disease', (221, 247))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutations', 'Var', (29, 38))	('multiple tumor', 'Disease', (99, 113))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (181, 206))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (231, 247))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (221, 247))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (130, 154))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('pleuropulmonary blastoma', 'Disease', (130, 154))
38911	26428316	To date, the association between morphologic subtypes of ovarian Sertoli-Leydig cell tumor and the presence of somatic DICER1 mutations remains unclear, and it has yet to be established whether other ovarian sex cord-stromal tumors such as Sertoli cell tumor, gynandroblastoma and sex cord tumor with annular tubules may also harbor DICER1 hotspot mutations.	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (200, 231))	('ovarian sex cord-stromal tumors', 'Disease', (200, 231))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('Sertoli cell tumor', 'Disease', 'MESH:D012707', (240, 258))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (65, 90))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (208, 231))	('gynandroblastoma and sex cord tumor', 'Disease', 'MESH:D018312', (260, 295))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('mutations', 'Var', (348, 357))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (240, 258))	('Sertoli cell tumor', 'Disease', (240, 258))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (200, 231))	('ovarian Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (57, 90))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (208, 230))	('ovarian Sertoli-Leydig cell tumor', 'Disease', (57, 90))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (200, 230))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (73, 90))	('DICER1', 'Gene', (333, 339))
38912	26428316	In addition, only 4 testicular Sertoli cell tumors and a single testicular sex cord-stromal tumor not otherwise specified have been analyzed for the presence of somatic DICER1 mutations to date, all of which were reported to be wild-type.	('sex cord-stromal tumor', 'Disease', 'MESH:D018312', (75, 97))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('mutations', 'Var', (176, 185))	('testicular Sertoli cell tumors', 'Disease', 'MESH:D012707', (20, 50))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (31, 50))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (75, 97))	('testicular sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (64, 97))	('testicular Sertoli cell', 'Phenotype', 'HP:0100619', (20, 43))	('DICER1', 'Gene', (169, 175))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (31, 49))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('testicular Sertoli cell tumors', 'Disease', (20, 50))	('sex cord-stromal tumor', 'Disease', (75, 97))
38913	26428316	In this study, we aimed to define i) the association between DICER1 hotspot mutations and ovarian Sertoli-Leydig cell tumor morphology, ii) whether DICER1 hotspot mutations occur in other subtypes of ovarian sex cord-stromal tumor or in testicular sex cord-stromal tumors, iii) whether FOXL2 mutations occur in DICER1 wild-type gynandroblastomas, and iv) whether other female genital tract tumors with rhabdomyosarcomatous morphology harbor DICER1 hotspot mutations.	('genital tract tumors', 'Disease', (376, 396))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (98, 123))	('tumor', 'Phenotype', 'HP:0002664', (390, 395))	('testicular sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (237, 271))	('genital tract tumors', 'Disease', 'MESH:D060737', (376, 396))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (402, 418))	('DICER1', 'Gene', (441, 447))	('testicular sex cord-stromal tumors', 'Disease', (237, 271))	('genital tract tumors', 'Phenotype', 'HP:0010787', (376, 396))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (248, 271))	('mutations', 'Var', (292, 301))	('gynandroblastomas', 'Disease', (328, 345))	('sarcoma', 'Phenotype', 'HP:0100242', (411, 418))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (248, 270))	('ovarian Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (90, 123))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('rhabdomyosarcomatous morphology harbor', 'Disease', (402, 440))	('ovarian Sertoli-Leydig cell tumor', 'Disease', (90, 123))	('ovarian sex cord-stromal tumor', 'Disease', 'MESH:D018312', (200, 230))	('gynandroblastomas', 'Disease', 'MESH:D018312', (328, 345))	('rhabdomyosarcomatous morphology harbor', 'Disease', 'MESH:C537062', (402, 440))	('FOXL2', 'Gene', '26927', (286, 291))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (208, 230))	('FOXL2', 'Gene', (286, 291))	('mutations', 'Var', (76, 85))	('testicular sex cord-stromal tumors', 'Disease', 'MESH:D018312', (237, 271))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (106, 123))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (200, 230))	('ovarian sex cord-stromal tumor', 'Disease', (200, 230))	('rhabdomyosarcomatous morphology', 'Phenotype', 'HP:0002859', (402, 433))	('testicular sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (237, 270))	('tumors', 'Phenotype', 'HP:0002664', (390, 396))
38921	26428316	In addition, two gynandroblastomas were tested for the presence of the c.402C>G (p.C134W) FOXL2 hotspot mutation utilizing a primer pair that amplifies a 279bp fragment encompassing the site of the c.402C>G mutation of the FOXL2 gene (5'CCTCAACGAGTGCTTCATCA3' (forward), 5'AGGAAGCCAGACTGCAGGTAC3' (reverse)).	('c.402C', 'Var', (71, 77))	('p.C134W', 'Var', (81, 88))	('FOXL2', 'Gene', '26927', (90, 95))	('FOXL2', 'Gene', '26927', (223, 228))	('c.402C>G', 'Mutation', 'rs1057519865', (71, 79))	('FOXL2', 'Gene', (90, 95))	('c.402C>G', 'Var', (198, 206))	('gynandroblastomas', 'Disease', 'MESH:D018312', (17, 34))	('gynandroblastomas', 'Disease', (17, 34))	('p.C134W', 'SUBSTITUTION', 'None', (81, 88))	('c.402C>G', 'Mutation', 'rs1057519865', (198, 206))	('FOXL2', 'Gene', (223, 228))
38922	26428316	In these two cases, the morphologically distinct tumor components were microdissected, and the extracted DNA was subjected to FOXL2 mutation testing separately.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('FOXL2', 'Gene', (126, 131))	('FOXL2', 'Gene', '26927', (126, 131))	('mutation', 'Var', (132, 140))
38926	26428316	DICER1 mutations were found at similar frequencies in poorly-differentiated Sertoli-Leydig cell tumors (6/10, 60%) and Sertoli-Leydig cell tumors with intermediate differentiation (14/20, 70%; two-tailed Fisher's exact test p=0.7).	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (76, 102))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (84, 102))	('Sertoli-Leydig cell tumors', 'Disease', (119, 145))	('DICER1', 'Gene', (0, 6))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (76, 102))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (84, 101))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (76, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (119, 144))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (119, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (119, 145))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (127, 145))	('Sertoli-Leydig cell tumors', 'Disease', (76, 102))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (7, 16))
38928	26428316	Furthermore, DICER1 hotspot mutations were identified at similar frequencies in tumors showing heterologous or retiform elements (9/14, 64%) and tumors without these features (11/18, 61%; two-tailed Fisher's exact test p=1).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('p=1', 'Gene', (219, 222))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('p=1', 'Gene', '22673', (219, 222))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('DICER1', 'Gene', (13, 19))	('mutations', 'Var', (28, 37))
38929	26428316	No statistically significant difference in the prevalence of DICER1 mutations was found between tumors with heterologous (rhabdomyosarcoma or gastrointestinal-epithelium) or retiform morphology (two-tailed Fisher's exact test, p=1) (Table 1), and DICER1-mutant and wild-type examples of each of these Sertoli-Leydig cell tumor subtypes could not be differentiated on morphologic review (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('rhabdomyosarcoma', 'Disease', (122, 138))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (309, 326))	('DICER1', 'Gene', (61, 67))	('gastrointestinal-epithelium', 'Disease', 'MESH:D005767', (142, 169))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (122, 138))	('p=1', 'Gene', (227, 230))	('p=1', 'Gene', '22673', (227, 230))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (122, 138))	('Sertoli-Leydig cell tumor', 'Disease', (301, 326))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (301, 326))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (301, 326))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('gastrointestinal-epithelium', 'Disease', (142, 169))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('mutations', 'Var', (68, 77))
38930	26428316	The most frequent DICER1 hotspot mutation identified in the ovarian Sertoli-Leydig cell tumors analyzed was the p.E1705K (c.5113G>A) mutation (16/20 cases, 80%).	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('p.E1705K (c.5113G>A', 'Var', (112, 131))	('ovarian Sertoli-Leydig cell tumors', 'Disease', (60, 94))	('ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (60, 94))	('c.5113G>A', 'Var', (122, 131))	('DICER1', 'Gene', (18, 24))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (68, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('c.5113G>A', 'Mutation', 'c.5113G>A', (122, 131))	('p.E1705K', 'Mutation', 'p.E1705K', (112, 120))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (68, 94))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (76, 93))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (76, 94))
38932	26428316	One neoplasm with both heterologous morphology and intermediately-differentiated classical Sertoli-Leydig cell tumor morphology had a p.E1705K DICER1 mutation in the heterologous component only, while in the other tumor with mixed morphology, the retiform component harbored a p.E1705K DICER1 mutation whereas the rhabdomyosarcoma component was DICER1 wild-type.	('rhabdomyosarcoma component', 'Disease', (314, 340))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (91, 116))	('Sertoli-Leydig cell tumor', 'Disease', (91, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (91, 116))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('neoplasm', 'Phenotype', 'HP:0002664', (4, 12))	('rhabdomyosarcoma component', 'Disease', 'MESH:D012208', (314, 340))	('p.E1705K', 'Var', (277, 285))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (314, 330))	('p.E1705K', 'Var', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (323, 330))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (214, 219))	('p.E1705K', 'Mutation', 'p.E1705K', (134, 142))	('p.E1705K', 'Mutation', 'p.E1705K', (277, 285))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('neoplasm', 'Disease', 'MESH:D009369', (4, 12))	('DICER1', 'Gene', (286, 292))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (99, 116))	('neoplasm', 'Disease', (4, 12))	('DICER1', 'Gene', (143, 149))
38933	26428316	Sanger sequencing analysis revealed that 5 of 8 (63%) Sertoli cell tumors and 2 of 5 (40%) gynandroblastomas harbored a DICER1 hotspot mutation (Table 1).	('gynandroblastomas', 'Disease', (91, 108))	('gynandroblastomas', 'Disease', 'MESH:D018312', (91, 108))	('hotspot', 'PosReg', (127, 134))	('Sertoli cell tumors', 'Disease', 'MESH:D012707', (54, 73))	('Sertoli cell tumors', 'Disease', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (54, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('DICER1', 'Gene', (120, 126))	('mutation', 'Var', (135, 143))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (54, 72))
38934	26428316	Akin to the ovarian Sertoli-Leydig cell tumors, of which 80% harbored a p.E1705K DICER1 hotspot mutation, all 7 DICER1-mutant gynandroblastomas and Sertoli cell tumors had a p.E1705K mutation.	('ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (12, 46))	('gynandroblastomas', 'Disease', (126, 143))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (20, 46))	('p.E1705K', 'Var', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('p.E1705K', 'Var', (72, 80))	('gynandroblastomas', 'Disease', 'MESH:D018312', (126, 143))	('DICER1-mutant', 'Gene', (112, 125))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (148, 166))	('p.E1705K', 'Mutation', 'p.E1705K', (174, 182))	('Sertoli cell tumors', 'Disease', 'MESH:D012707', (148, 167))	('ovarian Sertoli-Leydig cell tumors', 'Disease', (12, 46))	('p.E1705K', 'Mutation', 'p.E1705K', (72, 80))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (28, 45))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('DICER1', 'Gene', (81, 87))	('Sertoli cell tumors', 'Disease', (148, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (148, 167))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (20, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
38937	26428316	In the single lipid-rich variant Sertoli cell tumor tested, a DICER1 p.E1705K mutation was identified.	('p.E1705K', 'Mutation', 'p.E1705K', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Sertoli cell tumor', 'Disease', (33, 51))	('Sertoli cell tumor', 'Disease', 'MESH:D012707', (33, 51))	('lipid', 'Chemical', 'MESH:D008055', (14, 19))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (33, 51))	('variant Sertoli', 'CellLine', 'CVCL:7204', (25, 40))	('p.E1705K', 'Var', (69, 77))	('DICER1', 'Gene', (62, 68))
38938	26428316	FOXL2 mutation testing was performed on 2 of the 3 gynandroblastomas with wild-type DICER1; one case did not have sufficient material available for testing.	('performed', 'Reg', (27, 36))	('mutation', 'Var', (6, 14))	('FOXL2', 'Gene', '26927', (0, 5))	('gynandroblastomas', 'Disease', 'MESH:D018312', (51, 68))	('FOXL2', 'Gene', (0, 5))	('gynandroblastomas', 'Disease', (51, 68))
38939	26428316	For this analysis, both tumor components, the granulosa cell-like and Sertoli-Leydig cell tumor-like areas, were separately microdissected and subjected to FOXL2 mutation analysis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (78, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutation', 'Var', (162, 170))	('FOXL2', 'Gene', '26927', (156, 161))	('subjected', 'Reg', (143, 152))	('FOXL2', 'Gene', (156, 161))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (70, 95))	('Sertoli-Leydig cell tumor', 'Disease', (70, 95))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (70, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
38940	26428316	A p.C134W (c.402C>G) FOXL2 hotspot mutation was identified in both the granulosa cell tumor-like components and the Sertoli-Leydig cell tumor-like areas of the two DICER1 wild-type gynandroblastomas.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Sertoli-Leydig cell tumor', 'Disease', (116, 141))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (116, 141))	('gynandroblastomas', 'Disease', (181, 198))	('c.402C>G', 'Mutation', 'rs1057519865', (11, 19))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (116, 141))	('gynandroblastomas', 'Disease', 'MESH:D018312', (181, 198))	('p.C134W', 'SUBSTITUTION', 'None', (2, 9))	('granulosa cell tumor', 'Disease', 'MESH:D006106', (71, 91))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (124, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('p.C134W', 'Var', (2, 9))	('granulosa cell tumor-', 'Phenotype', 'HP:0031919', (71, 92))	('FOXL2', 'Gene', (21, 26))	('granulosa cell tumor', 'Disease', (71, 91))	('FOXL2', 'Gene', '26927', (21, 26))
38942	26428316	Two of the ten female genital tract tumors with rhabdomyosarcomatous differentiation (20%) studied here harbored a DICER1 hotspot mutation: a p.D1709N (c.5125G>A) mutation in a metastasis from a primary cervical rhabdomyosarcoma in an adult patient, and a p.E1813Q (c.5437G>C) mutation in a rhabdomyosarcoma arising in a uterine carcinosarcoma (Table 1).	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (212, 228))	('genital tract tumors', 'Phenotype', 'HP:0010787', (22, 42))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (291, 307))	('c.5125G>A', 'Mutation', 'c.5125G>A', (152, 161))	('cervical rhabdomyosarcoma', 'Disease', 'MESH:D012208', (203, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (291, 307))	('p.E1813Q (c.5437G>C', 'Var', (256, 275))	('carcinosarcoma', 'Disease', (329, 343))	('sarcoma', 'Phenotype', 'HP:0100242', (300, 307))	('DICER1', 'Gene', (115, 121))	('rhabdomyosarcomatous', 'Disease', 'None', (48, 68))	('p.E1813Q', 'Mutation', 'p.E1813Q', (256, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('rhabdomyosarcoma', 'Disease', (48, 64))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('carcinosarcoma', 'Disease', 'MESH:D002296', (329, 343))	('p.D1709N', 'Mutation', 'p.D1709N', (142, 150))	('genital tract tumors', 'Disease', (22, 42))	('rhabdomyosarcoma', 'Disease', (212, 228))	('cervical rhabdomyosarcoma', 'Disease', (203, 228))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (48, 64))	('genital tract tumors', 'Disease', 'MESH:D060737', (22, 42))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (321, 343))	('p.D1709N (c.5125G>A', 'Var', (142, 161))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (48, 64))	('rhabdomyosarcoma', 'Disease', (291, 307))	('patient', 'Species', '9606', (241, 248))	('rhabdomyosarcomatous', 'Disease', (48, 68))	('c.5437G>C', 'Mutation', 'c.5437G>C', (266, 275))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (212, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))
38944	26428316	Neither of the 2 pediatric embryonal rhabdomyosarcomas tested was found to harbor a DICER1 hotspot mutation.	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (37, 54))	('embryonal rhabdomyosarcomas', 'Disease', (27, 54))	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (27, 54))	('mutation', 'Var', (99, 107))	('DICER1', 'Gene', (84, 90))	('embryonal rhabdomyosarcomas', 'Disease', 'MESH:D018233', (27, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (27, 53))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (37, 53))
38946	26428316	We have shown herein that approximately 60% of the Sertoli-Leydig cell tumors analyzed harbor DICER1 hotspot mutations, and demonstrated that there is no clear association between either the degree of tumor differentiation or the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumor and DICER1 hotspot mutation status.	('DICER1', 'Gene', (94, 100))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (294, 311))	('tumor', 'Disease', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Sertoli-Leydig cell tumors', 'Disease', (51, 77))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('Sertoli-Leydig cell tumor', 'Disease', (286, 311))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (51, 77))	('tumor', 'Disease', (201, 206))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (51, 77))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (286, 311))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (286, 311))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (59, 76))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (51, 76))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (51, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (59, 77))
38947	26428316	We have further shown that DICER1 hotspot mutations occur at similar frequencies in ovarian Sertoli cell tumors and gynandroblastomas, providing additional evidence to demonstrate that DICER1 hotspot mutation is a frequent genomic event across the spectrum of ovarian sex cord-stromal tumors with Sertoliform differentiation.	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (268, 290))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (92, 110))	('ovarian Sertoli cell tumors', 'Disease', 'MESH:D012707', (84, 111))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('gynandroblastomas', 'Disease', (116, 133))	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (260, 291))	('Sertoliform differentiation', 'Phenotype', 'HP:0100619', (297, 324))	('ovarian Sertoli cell tumors', 'Disease', (84, 111))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (260, 290))	('mutation', 'Var', (200, 208))	('DICER1', 'Gene', (27, 33))	('gynandroblastomas', 'Disease', 'MESH:D018312', (116, 133))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (260, 291))	('ovarian sex cord-stromal tumors', 'Disease', (260, 291))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('DICER1', 'Gene', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (92, 111))	('mutations', 'Var', (42, 51))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (268, 291))
38948	26428316	In contrast, we have observed that testicular Sertoli cell tumors appear to lack hotspot mutations in DICER1.	('testicular Sertoli cell', 'Phenotype', 'HP:0100619', (35, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (46, 65))	('testicular Sertoli cell tumors', 'Disease', 'MESH:D012707', (35, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (89, 98))	('DICER1', 'Gene', (102, 108))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (46, 64))	('testicular Sertoli cell tumors', 'Disease', (35, 65))
38949	26428316	Finally, we have shown that DICER1 hotspot mutations do occur in female genital tract tumors with rhabdomyosarcomatous differentiation, although the true prevalence of this mutation in these tumors remains to be defined.	('rhabdomyosarcomatous', 'Disease', 'None', (98, 118))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('rhabdomyosarcomatous', 'Disease', (98, 118))	('DICER1', 'Gene', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('genital tract tumors', 'Disease', (72, 92))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('mutations', 'Var', (43, 52))	('hotspot', 'PosReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('genital tract tumors', 'Phenotype', 'HP:0010787', (72, 92))	('tumors', 'Disease', (191, 197))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (98, 114))	('genital tract tumors', 'Disease', 'MESH:D060737', (72, 92))
38950	26428316	The overall frequency of DICER1 mutations in Sertoli-Leydig cell tumor in this cohort (63%) is similar to that reported by Heravi-Moussavi (26/43, 60%), but distinct from the recent findings by Goulvent et al, who reported the presence of DICER1 mutations in only one third of the Sertoli-Leydig cell tumors tested (6/19, 32%).	('DICER1', 'Gene', (25, 31))	('Sertoli-Leydig cell tumors', 'Disease', (281, 307))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (289, 306))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (53, 70))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (281, 306))	('Sertoli-Leydig cell tumor', 'Disease', (45, 70))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (281, 306))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (281, 307))	('mutations', 'Var', (246, 255))	('mutations', 'Var', (32, 41))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (45, 70))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (281, 307))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (45, 70))	('DICER1', 'Gene', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (289, 307))
38951	26428316	It should be noted, however, that although the prevalence of DICER1 hotspot mutations in the ovarian Sertoli-Leydig cell tumors studied here and those reported by Heravi-Moussavi et al was similar, there was a difference in the prevalence of the residues in the Dicer RNase IIIb domain affected by mutations.	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (101, 127))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (101, 126))	('mutations', 'Var', (76, 85))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (109, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (109, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('ovarian Sertoli-Leydig cell tumors', 'Disease', (93, 127))	('mutations', 'Var', (298, 307))	('ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (93, 127))	('DICER1', 'Gene', (61, 67))
38952	26428316	While Heravi-Moussavi et al found the p.D1709N (c.5125G>A) DICER1 hotpot mutation to be most common in ovarian Sertoli-Leydig cell tumors (10/26, 38%), in our study this mutation was identified in only 2 cases (2/20, 10%), whereas the p.E1705K (c.5113G>A) mutation was seen in the majority (80%) of DICER1-mutant tumors.	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (119, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (119, 137))	('ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (103, 137))	('c.5125G>A', 'Mutation', 'c.5125G>A', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (111, 136))	('DICER1', 'Gene', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('tumors', 'Disease', (131, 137))	('p.D1709N (c.5125G>A', 'Var', (38, 57))	('DICER1-mutant', 'Gene', (299, 312))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (111, 137))	('p.D1709N', 'Mutation', 'p.D1709N', (38, 46))	('c.5113G>A', 'Mutation', 'c.5113G>A', (245, 254))	('ovarian Sertoli-Leydig cell tumors', 'Disease', (103, 137))	('tumors', 'Disease', (313, 319))	('p.E1705K', 'Mutation', 'p.E1705K', (235, 243))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
38954	26428316	Larger studies will be required to determine the true prevalence of DICER1 mutations in well-differentiated Sertoli-Leydig cell tumors.	('DICER1', 'Gene', (68, 74))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (108, 133))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (116, 134))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutations', 'Var', (75, 84))	('Sertoli-Leydig cell tumors', 'Disease', (108, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (108, 134))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (108, 134))
38955	26428316	The absence of a clear association between the presence of rhabdomyosarcoma within Sertoli-Leydig cell tumor and DICER1 mutation status may be somewhat unexpected given the reported frequency of rhabdomyosarcomtous tumors in the familial DICER1 mutation syndrome, and the identification of two DICER1 hotspot mutations in the female genital tract tumors with rhabdomyosarcomatous elements (2/10, 20%), including one uterine carcinosarcoma, reported here.	('rhabdomyosarcomtous tumors', 'Disease', 'MESH:D009369', (195, 221))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('rhabdomyosarcoma within Sertoli-Leydig cell tumor', 'Disease', 'MESH:D001929', (59, 108))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('rhabdomyosarcomatous', 'Disease', 'None', (359, 379))	('rhabdomyosarcomtous tumors', 'Phenotype', 'HP:0002859', (195, 221))	('mutations', 'Var', (309, 318))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('carcinosarcoma', 'Disease', (424, 438))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (59, 75))	('carcinosarcoma', 'Disease', 'MESH:D002296', (424, 438))	('genital tract tumors', 'Disease', (333, 353))	('genital tract tumors', 'Disease', 'MESH:D060737', (333, 353))	('rhabdomyosarcomatous', 'Disease', (359, 379))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (359, 375))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (83, 108))	('genital tract tumors', 'Phenotype', 'HP:0010787', (333, 353))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (91, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (368, 375))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (416, 438))	('rhabdomyosarcoma within Sertoli-Leydig cell tumor', 'Disease', (59, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (431, 438))	('rhabdomyosarcomtous tumors', 'Disease', (195, 221))	('DICER1', 'Gene', (294, 300))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
38956	26428316	Studies to date have suggested that the acquisition of somatic DICER1 mutation is a markedly rare event in epithelial cancer.	('DICER1', 'Gene', (63, 69))	('epithelial cancer', 'Disease', (107, 124))	('epithelial cancer', 'Disease', 'MESH:D000077216', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutation', 'Var', (70, 78))	('epithelial cancer', 'Phenotype', 'HP:0031492', (107, 124))
38957	26428316	Review of databases such as 1000 Genomes, The Cancer Genome Atlas (TCGA) and COSMIC by Heravi-Moussavi et al showed no DICER1 hotspot mutations, while Slade et al found DICER1 mutations in only 4 of 781 cancer cell lines, all of which occurred in microsatellite unstable tumors, where it was unlikely to constitute a driver mutation.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (46, 65))	('mutations', 'Var', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('unstable tumors', 'Disease', (262, 277))	('occurred', 'Reg', (235, 243))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (134, 143))	('unstable tumors', 'Disease', 'MESH:D000789', (262, 277))	('DICER1', 'Gene', (119, 125))	('Cancer Genome Atlas', 'Disease', (46, 65))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('microsatellite', 'Var', (247, 261))
38958	26428316	Heravi-Moussavi et al identified a single somatic DICER1 mutation in only one carcinosarcoma of ovarian origin among 266 female genital tract (ovarian and endometrial) cancers.	('mutation', 'Var', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('genital tract (ovarian and endometrial) cancers', 'Disease', 'MESH:D016889', (128, 175))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('carcinosarcoma of ovarian', 'Disease', 'MESH:D002296', (78, 103))	('carcinosarcoma of ovarian', 'Disease', (78, 103))	('DICER1', 'Gene', (50, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
38960	26428316	We performed a re-analysis of the endometrial cancer TCGA dataset and found that among 248 endometrial cancers subjected to massively parallel sequencing, 6 (2.4%) harbored mutations affecting DICER1 hotspot residues (www.cBioPortal.org, accessed May 2015; Supplementary Figure 1).	('endometrial cancer', 'Phenotype', 'HP:0012114', (34, 52))	('endometrial cancers', 'Disease', (91, 110))	('endometrial cancer', 'Disease', 'MESH:D016889', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('endometrial cancer', 'Disease', 'MESH:D016889', (34, 52))	('mutations', 'Var', (173, 182))	('harbored', 'Reg', (164, 172))	('DICER1', 'Gene', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('endometrial cancer', 'Disease', (34, 52))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('endometrial cancers', 'Disease', 'MESH:D016889', (91, 110))
38962	26428316	In the remaining two cases, a somatic p.E1813A DICER1 hotspot mutation was found in a copy-number high TP53-mutant serous carcinoma, and a somatic p.L539fs mutation and p.D1810A DICER1 hotspot mutation was also seen in an endometrioid carcinoma of copy-number low genomic subtype (low microsatellite instability), which also harbored characteristic PTEN and CTNNB1 mutations (Supplementary Figure 1).	('TP53', 'Gene', '22059', (103, 107))	('serous carcinoma', 'Disease', (115, 131))	('CTNNB1', 'Gene', '12387', (358, 364))	('PTEN', 'Gene', '19211', (349, 353))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (222, 244))	('serous carcinoma', 'Disease', 'MESH:D018284', (115, 131))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (222, 244))	('p.E1813A', 'Var', (38, 46))	('p.E1813A', 'Mutation', 'p.E1813A', (38, 46))	('p.D1810A', 'Mutation', 'p.D1810A', (169, 177))	('p.L539fs', 'Var', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('PTEN', 'Gene', (349, 353))	('CTNNB1', 'Gene', (358, 364))	('endometrioid carcinoma', 'Disease', (222, 244))	('p.D1810A', 'Var', (169, 177))	('TP53', 'Gene', (103, 107))	('p.L539fs', 'Mutation', 'p.L539fsX', (147, 155))	('DICER1', 'Gene', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
38964	26428316	We have observed that several subtypes of ovarian sex cord-stromal tumors (including Sertoli cell tumor and gynandroblastoma) harbored a DICER1 hotspot mutation, which may be expected given their postulated common cell lineage.	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (42, 72))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (50, 73))	('gynandroblastoma', 'Disease', 'MESH:D018312', (108, 124))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (85, 103))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (50, 72))	('hotspot', 'PosReg', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Sertoli cell tumor', 'Disease', 'MESH:D012707', (85, 103))	('Sertoli cell tumor', 'Disease', (85, 103))	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (42, 73))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('DICER1', 'Gene', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (42, 73))	('gynandroblastoma', 'Disease', (108, 124))	('ovarian sex cord-stromal tumors', 'Disease', (42, 73))	('mutation', 'Var', (152, 160))
38965	26428316	Prior to this study, the DICER1 mutation status of only two ovarian Sertoli cell tumors had been reported and both were DICER1 wild-type.	('DICER1', 'Gene', (25, 31))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (68, 86))	('ovarian Sertoli cell tumors', 'Disease', 'MESH:D012707', (60, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (68, 87))	('mutation', 'Var', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('ovarian Sertoli cell tumors', 'Disease', (60, 87))
38966	26428316	In contrast, we have observed that ovarian Sertoli cell tumors and Sertoli-Leydig cell tumors harbor DICER1 mutations at similar frequencies (63% in both tumor categories).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (67, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (43, 62))	('tumor', 'Disease', (154, 159))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (67, 93))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (67, 93))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('DICER1', 'Gene', (101, 107))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (43, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (87, 92))	('ovarian Sertoli cell tumors', 'Disease', 'MESH:D012707', (35, 62))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (75, 93))	('mutations', 'Var', (108, 117))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (75, 92))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian Sertoli cell tumors', 'Disease', (35, 62))	('Sertoli-Leydig cell tumors', 'Disease', (67, 93))
38967	26428316	In the five gynandroblastomas tested, only 2 harbored a DICER1 hotspot mutation.	('mutation', 'Var', (71, 79))	('gynandroblastomas', 'Disease', 'MESH:D018312', (12, 29))	('DICER1', 'Gene', (56, 62))	('gynandroblastomas', 'Disease', (12, 29))
38969	26428316	These results suggest that the gynandroblastoma category may encompass two distinct entities at the genetic level - those with a granulosa cell tumor-like genotype characterized by FOXL2 hotspot mutations and those with a Sertoli-Leydig cell tumor-like DICER1-mutant genotype.	('granulosa cell tumor', 'Disease', (129, 149))	('Sertoli-Leydig cell tumor', 'Disease', (222, 247))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (222, 247))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (222, 247))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (230, 247))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('gynandroblastoma', 'Disease', 'MESH:D018312', (31, 47))	('FOXL2', 'Gene', (181, 186))	('mutations', 'Var', (195, 204))	('FOXL2', 'Gene', '26927', (181, 186))	('granulosa cell tumor', 'Disease', 'MESH:D006106', (129, 149))	('gynandroblastoma', 'Disease', (31, 47))	('granulosa cell tumor-', 'Phenotype', 'HP:0031919', (129, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
38970	26428316	These findings are consistent with those of Goulvent et al, who demonstrated that DICER1 and FOXL2 mutations appear to be mutually exclusive in ovarian sex cord-stromal tumors.	('FOXL2', 'Gene', (93, 98))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (152, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (144, 175))	('mutations', 'Var', (99, 108))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (144, 175))	('DICER1', 'Gene', (82, 88))	('ovarian sex cord-stromal tumors', 'Disease', (144, 175))	('FOXL2', 'Gene', '26927', (93, 98))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (144, 174))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (152, 175))
38971	26428316	In the current study, however, DICER1-mutant gynandroblastomas could not be distinguished from those harboring FOXL2 mutations based on morphologic grounds, and further studies are warranted to establish the clinical significance of the molecular findings.	('FOXL2', 'Gene', '26927', (111, 116))	('mutations', 'Var', (117, 126))	('FOXL2', 'Gene', (111, 116))	('gynandroblastomas', 'Disease', (45, 62))	('gynandroblastomas', 'Disease', 'MESH:D018312', (45, 62))	('DICER1-mutant', 'Gene', (31, 44))
38973	26428316	Yuan et al demonstrated that loss of Dicer expression in the developing oocyte leads to compromised folliculogenesis, infertility and loss of ovarian function.	('infertility and loss of ovarian function', 'Disease', 'MESH:D007247', (118, 158))	('infertility', 'Phenotype', 'HP:0000789', (118, 129))	('Dicer', 'Gene', (37, 42))	('loss', 'Var', (29, 33))	('compromised folliculogenesis', 'CPA', (88, 116))
38974	26428316	In light of the importance of Dicer in gonadal function in both sexes and following the recent discoveries in ovarian sex cord-stromal tumors, we hypothesized that mutations affecting DICER1 would play a role in testicular Sertoli cell tumor oncogenesis.	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (110, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('ovarian sex cord-stromal tumors', 'Disease', (110, 141))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (223, 241))	('testicular Sertoli cell', 'Phenotype', 'HP:0100619', (212, 235))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (110, 140))	('DICER1', 'Gene', (184, 190))	('role', 'Reg', (204, 208))	('play', 'Reg', (197, 201))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('Sertoli cell tumor', 'Disease', (223, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('oncogenesis', 'CPA', (242, 253))	('Sertoli cell tumor', 'Disease', 'MESH:D012707', (223, 241))	('mutations', 'Var', (164, 173))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (118, 140))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (118, 141))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (110, 141))
38977	26428316	Combining the results of the mutational analysis of the current 15 testicular Sertoli cell tumors with those reported by Heravi-Moussavi et al, 20 testicular Sertoli cell tumors and sex cord-stromal tumors not otherwise specified have now been tested for the presence of DICER1 hotspot mutations, and all have been found to be DICER1 wild-type.	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (158, 176))	('testicular Sertoli cell tumors', 'Disease', (67, 97))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (182, 204))	('testicular Sertoli cell', 'Phenotype', 'HP:0100619', (67, 90))	('sex cord-stromal tumors', 'Disease', 'MESH:D018312', (182, 205))	('testicular Sertoli cell tumors', 'Disease', (147, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (78, 96))	('testicular Sertoli cell', 'Phenotype', 'HP:0100619', (147, 170))	('sex cord-stromal tumors', 'Disease', (182, 205))	('mutations', 'Var', (286, 295))	('testicular Sertoli cell tumors', 'Disease', 'MESH:D012707', (67, 97))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (158, 177))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('testicular Sertoli cell tumors', 'Disease', 'MESH:D012707', (147, 177))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (182, 205))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (78, 97))	('DICER1', 'Gene', (271, 277))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
38979	26428316	More recently, Perrone et al have demonstrated the presence of CTNNB1 (beta-catenin) mutations in 71% (10 of 14) of testicular Sertoli cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (127, 145))	('CTNNB1', 'Gene', '12387', (63, 69))	('beta-catenin', 'Gene', '12387', (71, 83))	('testicular Sertoli cell tumors', 'Disease', (116, 146))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (127, 146))	('CTNNB1', 'Gene', (63, 69))	('mutations', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('beta-catenin', 'Gene', (71, 83))	('testicular Sertoli cell tumors', 'Disease', 'MESH:D012707', (116, 146))	('testicular Sertoli cell', 'Phenotype', 'HP:0100619', (116, 139))
38980	26428316	Based on these observations, further studies are required to define the molecular underpinning of testicular Sertoli cell tumors, and to establish whether Dicer or other members of the miRNA machinery may be deregulated by mechanisms other than DICER1 hotspot mutations in this disease.	('testicular Sertoli cell', 'Phenotype', 'HP:0100619', (98, 121))	('Dicer', 'Gene', (155, 160))	('testicular Sertoli cell tumors', 'Disease', (98, 128))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('DICER1', 'Gene', (245, 251))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (109, 128))	('mutations', 'Var', (260, 269))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('underpinning of testicular', 'Phenotype', 'HP:0008734', (82, 108))	('testicular Sertoli cell tumors', 'Disease', 'MESH:D012707', (98, 128))
38981	26428316	In summary, our study has confirmed the presence of DICER1 hotspot mutations in the majority of ovarian Sertoli-Leydig cell tumors.	('DICER1', 'Gene', (52, 58))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (104, 130))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (112, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (112, 130))	('mutations', 'Var', (67, 76))	('hotspot', 'PosReg', (59, 66))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('ovarian Sertoli-Leydig cell tumors', 'Disease', (96, 130))	('ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (96, 130))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (104, 129))
38983	26428316	In addition, we have shown that DICER1 hotspot mutations are also present in ovarian Sertoli cell tumors and gynandroblastomas, and that a proportion of DICER1 wild-type gynandroblastomas may harbor FOXL2 hotspot mutations.	('ovarian Sertoli cell tumors', 'Disease', (77, 104))	('gynandroblastomas', 'Disease', 'MESH:D018312', (109, 126))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('ovarian Sertoli cell tumors', 'Disease', 'MESH:D012707', (77, 104))	('mutations', 'Var', (47, 56))	('gynandroblastomas', 'Disease', (109, 126))	('DICER1', 'Gene', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('gynandroblastomas', 'Disease', 'MESH:D018312', (170, 187))	('DICER1', 'Gene', (32, 38))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (85, 104))	('FOXL2', 'Gene', '26927', (199, 204))	('mutations', 'Var', (213, 222))	('FOXL2', 'Gene', (199, 204))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (85, 103))	('gynandroblastomas', 'Disease', (170, 187))
38984	26428316	Finally, our results provide evidence to suggest that testicular sex cord-stromal tumors lack hotspot mutations in DICER1.	('lack', 'NegReg', (89, 93))	('testicular sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (54, 87))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('testicular sex cord-stromal tumors', 'Disease', (54, 88))	('testicular sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (54, 88))	('DICER1', 'Gene', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutations', 'Var', (102, 111))	('testicular sex cord-stromal tumors', 'Disease', 'MESH:D018312', (54, 88))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (65, 87))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (65, 88))
38985	26428316	While the recognition of recurrent DICER1 mutations in various subtypes of ovarian sex cord-stromal tumors represents a major advance in our understanding of these tumors, the mechanisms underlying tumorigenesis in the presence of DICER1 mutations remain to be elucidated.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (83, 106))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (83, 105))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('DICER1', 'Gene', (35, 41))	('tumors', 'Disease', (164, 170))	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (75, 106))	('tumors', 'Disease', (100, 106))	('tumor', 'Disease', (198, 203))	('ovarian sex cord-stromal tumor', 'Phenotype', 'HP:0031918', (75, 105))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (75, 106))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('ovarian sex cord-stromal tumors', 'Disease', (75, 106))	('mutations', 'Var', (42, 51))
39001	26260909	The dysregulation of a number of pathways commonly associated with high grade endometrial cancer including PIK3CA, PTEN, and KRAS have been suggested to influence EMT and maybe precursor molecular alterations prior to the development of carcinosarcoma.	('KRAS', 'Gene', '16653', (125, 129))	('carcinosarcoma', 'Disease', 'MESH:D002296', (237, 251))	('endometrial cancer', 'Disease', 'MESH:D016889', (78, 96))	('KRAS', 'Gene', (125, 129))	('PIK3CA', 'Gene', '18706', (107, 113))	('PTEN', 'Gene', (115, 119))	('dysregulation', 'Var', (4, 17))	('PTEN', 'Gene', '19211', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carcinosarcoma', 'Disease', (237, 251))	('EMT', 'Gene', (163, 166))	('PIK3CA', 'Gene', (107, 113))	('EMT', 'Gene', '16428', (163, 166))	('endometrial cancer', 'Disease', (78, 96))	('influence', 'Reg', (153, 162))	('endometrial cancer', 'Phenotype', 'HP:0012114', (78, 96))
39005	26260909	The dysregulation of the ErbB family of tyrosine kinases has been implicated in the development of a number of tumors including breast, colorectal, anal, gastric, bladder, prostate, esophageal, head and neck, endometrial and non-small cell lung cancers.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (229, 252))	('ErbB', 'Gene', '13649', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('dysregulation', 'Var', (4, 17))	('esophageal', 'Disease', (182, 192))	('tumors', 'Disease', (111, 117))	('colorectal', 'Disease', (136, 146))	('ErbB', 'Gene', (25, 29))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (225, 252))	('implicated', 'Reg', (66, 76))	('bladder', 'Disease', (163, 170))	('anal', 'Disease', (148, 152))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (240, 251))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (225, 251))	('lung cancers', 'Phenotype', 'HP:0100526', (240, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('non-small cell lung cancers', 'Disease', (225, 252))	('prostate', 'Disease', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (225, 252))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('breast', 'Disease', (128, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (229, 251))	('endometrial', 'Disease', (209, 220))	('gastric', 'Disease', (154, 161))
39006	26260909	It is well known that amplification or mutation of the ErbB pathways can lead to increased metabolic rate, proliferation and oncogenesis.	('metabolic rate', 'CPA', (91, 105))	('mutation', 'Var', (39, 47))	('proliferation', 'CPA', (107, 120))	('ErbB', 'Gene', '13649', (55, 59))	('amplification', 'Var', (22, 35))	('oncogenesis', 'CPA', (125, 136))	('increased', 'PosReg', (81, 90))	('ErbB', 'Gene', (55, 59))
39008	26260909	The amplification of HER2/neu has been reported to occur in 20-25% of uterine carcinosarcomas while the frequency of amplification in ovarian carcinosarcomas has not yet been reported.	('ovarian carcinosarcomas', 'Disease', (134, 157))	('carcinosarcomas', 'Disease', (142, 157))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (134, 157))	('carcinosarcomas', 'Disease', 'MESH:D002296', (78, 93))	('occur', 'Reg', (51, 56))	('HER2/neu', 'Gene', '13866', (21, 29))	('amplification', 'Var', (4, 17))	('carcinosarcomas', 'Disease', (78, 93))	('ovarian carcinosarcoma', 'Phenotype', 'HP:0025318', (134, 156))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (70, 92))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (134, 157))	('carcinosarcomas', 'Disease', 'MESH:D002296', (142, 157))	('HER2/neu', 'Gene', (21, 29))
39022	26260909	Serial dilutions of the drug were made using DMSO to reach final concentrations of 1mM, 0.1mM, 0.05mM and 0.005mM.	('0.005mM', 'Var', (106, 113))	('DMSO', 'Chemical', 'MESH:D004121', (45, 49))	('0.1mM', 'Var', (88, 93))
39026	26260909	They were exposed to neratinib at concentrations of 0.01 muM, 0.065 muM, or 0.133 muM.	('0.065 muM', 'Var', (62, 71))	('neratinib', 'Chemical', 'MESH:C487932', (21, 30))	('0.133 muM', 'Var', (76, 85))	('0.01 muM', 'Var', (52, 60))
39048	26260909	Overall survival in mice harboring HER2 amplified uterine carcinosarcoma xenografts, treated with neratinib or vehicle, was compared using a Kaplan Meier curve and log rank test.	('neratinib', 'Chemical', 'MESH:C487932', (98, 107))	('carcinosarcoma xenografts', 'Disease', 'MESH:D002296', (58, 83))	('HER2', 'Protein', (35, 39))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (50, 72))	('mice', 'Species', '10090', (20, 24))	('carcinosarcoma xenografts', 'Disease', (58, 83))	('amplified', 'Var', (40, 49))
39052	26260909	Of the currently available carcinosarcoma cell lines SARARK6 and SARARK 9 were the only cell lines that displayed amplification in the HER2/neu pathway.	('amplification', 'Var', (114, 127))	('HER2/neu', 'Gene', '13866', (135, 143))	('carcinosarcoma', 'Disease', 'MESH:D002296', (27, 41))	('SARARK6', 'Chemical', '-', (53, 60))	('HER2/neu', 'Gene', (135, 143))	('carcinosarcoma', 'Disease', (27, 41))
39055	26260909	Comparisons of the overall mean IC50 values for the HER2/neu amplified and non-amplified cell lines revealed a significant difference between the means of the two groups mean+-SEM IC50:0.014muM+-0.004 vs. 0.164muM+-0.019 p=0.0003 (Figure 1B).	('HER2/neu', 'Gene', '13866', (52, 60))	('HER2/neu', 'Gene', (52, 60))	('IC50:0.014muM+-0.004', 'Var', (180, 200))
39057	26260909	The differential effect of neratinib on the proliferation of HER2/neu amplified compared to non-amplified carcinosarcoma suggests that the amplification of HER2/neu confers sensitivity to the cell line.	('HER2/neu', 'Gene', '13866', (156, 164))	('carcinosarcoma', 'Disease', 'MESH:D002296', (106, 120))	('carcinosarcoma', 'Disease', (106, 120))	('amplified', 'Var', (70, 79))	('HER2/neu', 'Gene', (156, 164))	('HER2/neu', 'Gene', '13866', (61, 69))	('HER2/neu', 'Gene', (61, 69))	('neratinib', 'Chemical', 'MESH:C487932', (27, 36))
39072	26260909	Results show that with neratinib treatment at both 0.065 muM (p=0.03) and 0.133 muM (p=0.02) there was significant buildup in the G0/G1 phase of the cell cycle (Figure 3).	('0.065 muM', 'Var', (51, 60))	('neratinib', 'Chemical', 'MESH:C487932', (23, 32))	('0.133 muM', 'Var', (74, 83))	('buildup', 'PosReg', (115, 122))	('G0/G1 phase of the cell cycle', 'CPA', (130, 159))
39091	26260909	In vivo data further support these conclusions with a significant inhibition of tumor growth and ultimately improved overall survival in mice harboring HER2/neu amplified carcinosarcoma xenografts.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('carcinosarcoma xenografts', 'Disease', (171, 196))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('HER2/neu', 'Gene', (152, 160))	('overall survival', 'CPA', (117, 133))	('improved', 'PosReg', (108, 116))	('tumor', 'Disease', (80, 85))	('carcinosarcoma xenografts', 'Disease', 'MESH:D002296', (171, 196))	('amplified', 'Var', (161, 170))	('inhibition', 'NegReg', (66, 76))	('mice', 'Species', '10090', (137, 141))	('HER2/neu', 'Gene', '13866', (152, 160))
39107	26260909	Given the results of these studies and others a number of phase III trials are planned or underway in colon (NCT0196002), breast (NCT01808573, NCT01111825, NCT01008150, NCT01042379, NCT01494662, NCT01670877) and non-small cell lung cancer (NCT01827267).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (212, 238))	('NCT01008150', 'Var', (156, 167))	('NCT01494662', 'Var', (182, 193))	('colon', 'Disease', (102, 107))	('NCT01042379', 'Var', (169, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (212, 238))	('NCT01670877', 'Var', (195, 206))	('NCT01808573', 'Var', (130, 141))	('non-small cell lung cancer', 'Disease', (212, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('NCT0196002', 'Var', (109, 119))	('breast', 'Disease', (122, 128))	('NCT01111825', 'Var', (143, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (216, 238))
39139	24561247	For patients who did not have specific chemotherapy HCPCS codes, we used HCPCS codes (J8510, J9999, 964XX, 965XX, Q0083-85, Q0163-Q0185, G0355-G0363), ICD-9-CM diagnostic codes (V581, V662, V672), procedure or surgery codes (9925), and codes from the 2005 Medicare oncology demonstration project to capture any evidence that an unspecified chemotherapeutic drug was administered.	('unspecified', 'Species', '32644', (328, 339))	('Q0083-85', 'Var', (114, 122))	('Q0163-Q0185', 'Var', (124, 135))	('9925', 'Var', (225, 229))	('J9999', 'Var', (93, 98))	('V581', 'Var', (178, 182))	('J9999', 'CellLine', 'CVCL:M891', (93, 98))	('G0355-G0363', 'Var', (137, 148))	('oncology', 'Phenotype', 'HP:0002664', (265, 273))	('patients', 'Species', '9606', (4, 12))	('V672', 'Var', (190, 194))	('J8510', 'Var', (86, 91))	('V662', 'Var', (184, 188))
39251	19903572	Other trials are closed, however the data are not yet mature enough for presentation (GOG 188 [faslodex], GOG 229-F [VEGF-TRAP]).	('VEGF', 'Gene', (117, 121))	('GOG', 'Chemical', '-', (106, 109))	('VEGF', 'Gene', '7422', (117, 121))	('GOG', 'Chemical', '-', (86, 89))	('TRAP', 'Gene', '100187907', (122, 126))	('TRAP', 'Gene', (122, 126))	('GOG', 'Var', (106, 109))
39263	19903572	These cancers tend to be of an endometrioid histology, are often estrogen-mediated and are associated with a high rate of PTEN (phosphatase and tensine homologue) tumor suppressor gene loss or mutation, as well as defects in mismatch repair that lead to microsatellite instability.	('loss', 'NegReg', (185, 189))	('microsatellite instability', 'MPA', (254, 280))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mismatch repair', 'Protein', (225, 240))	('defects', 'Var', (214, 221))	('tumor', 'Disease', (163, 168))	('cancers', 'Disease', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('PTEN', 'Gene', (122, 126))	('mutation', 'Var', (193, 201))	('endometrioid', 'Disease', (31, 43))	('PTEN', 'Gene', '5728', (122, 126))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('lead to', 'Reg', (246, 253))
39329	19903572	Similar to the antiangiogenic agents, it may be that the mTOR inhibitors may potentiate the activity of and act synergistically with chemotherapeutic agents.	('potentiate', 'PosReg', (77, 87))	('mTOR', 'Gene', (57, 61))	('inhibitors', 'Var', (62, 72))	('mTOR', 'Gene', '2475', (57, 61))	('activity', 'MPA', (92, 100))
39336	19903572	In an in vitro model of endometrial stromal sarcoma, SAHA, a distone deacetylase inhibitor, treated cells exhibited decreased expression of mTOR and phospho-S6 ribosomal protein, which is a downstream target of mTOR.	('phospho-S6', 'Var', (149, 159))	('SAHA', 'Disease', 'None', (53, 57))	('endometrial stromal sarcoma', 'Disease', (24, 51))	('expression', 'MPA', (126, 136))	('SAHA', 'Disease', (53, 57))	('mTOR', 'Gene', '2475', (211, 215))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (24, 51))	('mTOR', 'Gene', (211, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('mTOR', 'Gene', (140, 144))	('mTOR', 'Gene', '2475', (140, 144))	('decreased', 'NegReg', (116, 125))
39337	19903572	There are two drugs in development, enzastaurin (LY 317615, Eli Lilly) and bryostatin-1, which can selectively inhibit specific serine/threonine kinase iso-forms.	('LY 317615', 'Chemical', 'MESH:C504878', (49, 58))	('inhibit', 'NegReg', (111, 118))	('specific serine/threonine kinase iso-forms', 'MPA', (119, 161))	('LY 317615', 'Var', (49, 58))	('enzastaurin', 'Chemical', 'MESH:C504878', (36, 47))
39378	19903572	There is epidemiological evidence to suggest that metformin use lowers cancer risk and reduces the rate of cancer deaths among diabetic patients.	('metformin', 'Chemical', 'MESH:D008687', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer deaths', 'Disease', 'MESH:D003643', (107, 120))	('diabetic', 'Disease', 'MESH:D003920', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (71, 77))	('reduces', 'NegReg', (87, 94))	('diabetic', 'Disease', (127, 135))	('patients', 'Species', '9606', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('metformin', 'Var', (50, 59))	('cancer', 'Disease', (107, 113))	('cancer deaths', 'Disease', (107, 120))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('lowers', 'NegReg', (64, 70))
39384	19903572	Ixabepilone (BMS-2474550, Bristol-Myers Squibb) is an epothi-lone B analog that induces microtubule stabilization and due to their different mechanism of action, can provide activity even in those tumors deemed taxane resistant.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('BMS-2474550', 'Var', (13, 24))	('taxane', 'Chemical', 'MESH:C080625', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('Ixabepilone', 'Chemical', 'MESH:C430592', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('microtubule stabilization', 'MPA', (88, 113))	('tumors', 'Disease', (197, 203))	('activity', 'MPA', (174, 182))	('induces', 'Reg', (80, 87))
39405	24753854	Nevertheless a basal expression of WT1 in monocytes and in vitro cultured unloaded DC was observed, the electroporation of in vitro cultured DC with WT1-mRNA resulted in a higher expression of WT1 by the DC.	('electroporation', 'Var', (104, 119))	('expression', 'MPA', (179, 189))	('WT1', 'Gene', '7490', (35, 38))	('higher', 'PosReg', (172, 178))	('WT1', 'Gene', '7490', (149, 152))	('WT1', 'Gene', (149, 152))	('WT1', 'Gene', (35, 38))	('WT1', 'Gene', '7490', (193, 196))	('WT1', 'Gene', (193, 196))
39473	24753854	In conclusion, WT1 is overexpressed in the majority of uterine sarcomas and the presence of WT1 worsens their prognosis, suggesting a role for WT1 in the tumourigenesis of uterine sarcoma.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('WT1', 'Gene', (92, 95))	('sarcoma', 'Disease', (63, 70))	('sarcomas', 'Disease', (63, 71))	('WT1', 'Gene', '7490', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcoma', 'Disease', (180, 187))	('presence', 'Var', (80, 88))	('tumour', 'Disease', (154, 160))	('prognosis', 'MPA', (110, 119))	('WT1', 'Gene', (143, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('worsens', 'NegReg', (96, 103))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (55, 70))	('WT1', 'Gene', (15, 18))	('WT1', 'Gene', '7490', (143, 146))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (172, 187))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('WT1', 'Gene', '7490', (15, 18))	('sarcomas', 'Disease', 'MESH:D012509', (63, 71))
39482	24753854	Pooled data (mean results) revealed WT1 positivity in 7/36 samples (19%) in the tumour cells, while 22/35 samples (63%) were positive if only WT1 positivity in the blood vessels was taken into account.	('tumour', 'Disease', (80, 86))	('WT1', 'Gene', '7490', (142, 145))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('WT1', 'Gene', (142, 145))	('WT1', 'Gene', '7490', (36, 39))	('WT1', 'Gene', (36, 39))	('positivity', 'Var', (40, 50))
39528	24753854	Immunohistochemical staining, which was performed as described before (Coosemans et al., 2007), showed WT1 positivity in 10% of the tumour cells and the intratumoural endothelial cells showed widely distributed WT1 positivity (Coosemans et al., 2008).	('WT1', 'Gene', (211, 214))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('positivity', 'Var', (107, 117))	('WT1', 'Gene', '7490', (103, 106))	('tumour', 'Disease', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('WT1', 'Gene', (103, 106))	('WT1', 'Gene', '7490', (211, 214))	('tumour', 'Disease', 'MESH:D009369', (132, 138))
39575	24753854	Electroporation of DCs with WT1-RNA resulted in an increase of WT1 in the DCs compared to the unloaded state.	('increase', 'PosReg', (51, 59))	('WT1', 'Gene', '7490', (63, 66))	('WT1', 'Gene', '7490', (28, 31))	('WT1', 'Gene', (28, 31))	('Electroporation', 'Var', (0, 15))	('WT1', 'Gene', (63, 66))
39629	23533892	Based on the result of the histological examination, using a punch biopsy specimen, SCC was diagnosed, and neoadjuvant chemotherapy with BOAI was performed twice with cisplatin (100 mg), mitomycin C (10 mg), and pirarubicin (50 mg).	('SCC', 'Gene', '6317', (84, 87))	('pirarubicin', 'Chemical', 'MESH:C027260', (212, 223))	('SCC', 'Gene', (84, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('mitomycin C', 'Chemical', 'MESH:D016685', (187, 198))	('100 mg', 'Var', (178, 184))
39636	23533892	The pathological stage of the tumor was ypT1b1 N1 M0.	('ypT1b1 N1 M0', 'Var', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))
39711	22247807	Adjusting for stage and age, the recurrence rate was 21% lower for CIM patients than for WAI patients (relative hazard [RH], 0.789; 95% confidence interval [CI], 0.530 to 1.176; p=0.245; 2-tail test).	('patients', 'Species', '9606', (71, 79))	('CIM', 'Var', (67, 70))	('patients', 'Species', '9606', (93, 101))	('lower', 'NegReg', (57, 62))
39766	21437229	If the TP53 gene is damaged, tumor suppression is severely reduced.	('damaged', 'Var', (20, 27))	('reduced', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('TP53 gene', 'Gene', (7, 16))
39768	21437229	More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('human', 'Species', '9606', (24, 29))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('deletion', 'Var', (59, 67))	('TP53', 'Gene', (75, 79))
39771	21437229	The correlation of defective TP53 function with uterine LMS tumorigenesis is not clearly understood.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('uterine LMS', 'Disease', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('defective', 'Var', (19, 28))	('tumor', 'Disease', (60, 65))	('TP53', 'Protein', (29, 33))
39786	21437229	Thus, a lowered level of IRF1 resulting from a deficiency in LMP2 seemed to be a risk factor for uterine LMS in mice.	('LMP2', 'Gene', (61, 65))	('IRF1', 'Gene', (25, 29))	('IRF1', 'Gene', '16362', (25, 29))	('mice', 'Species', '10090', (112, 116))	('lowered', 'NegReg', (8, 15))	('level', 'MPA', (16, 21))	('uterine LMS', 'Disease', (97, 108))	('deficiency', 'Var', (47, 57))
39793	21437229	In the case of uterine LMS in LMP2-deficient mice, defective IRF1 is considered to be involved in cellular transformation and cell proliferation (Figure 3).	('mice', 'Species', '10090', (45, 49))	('IRF1', 'Gene', (61, 65))	('cell proliferation', 'CPA', (126, 144))	('defective', 'Var', (51, 60))	('IRF1', 'Gene', '16362', (61, 65))	('involved', 'Reg', (86, 94))	('cellular transformation', 'CPA', (98, 121))
39801	21437229	A recent study showed that re-expression of human calponin h1 suppressed cell proliferation and tumorigenesis in uterine LMS cells.	('human', 'Species', '9606', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('calponin h1', 'Gene', (50, 61))	('suppressed', 'NegReg', (62, 72))	('cell proliferation', 'CPA', (73, 91))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('re-expression', 'Var', (27, 40))
39802	21437229	Since no spontaneous development of uterine LMS is observed in IRF1-, calponin h1-deficient mice or heterozygous Rb mice, the lack of LMP2 is largely associated with the expression of other known or unknown cell-cycle regulatory factors.	('associated', 'Reg', (150, 160))	('mice', 'Species', '10090', (116, 120))	('LMP2', 'Gene', (134, 138))	('lack', 'Var', (126, 130))	('IRF1', 'Gene', (63, 67))	('IRF1', 'Gene', '16362', (63, 67))	('mice', 'Species', '10090', (92, 96))
39832	33299884	Another study revealed that high body mass index (BMI) was positively associated with the incidence of several types of cancer, while patients with high BMI at the time of initial diagnosis had higher two/five-year survival rates than those with low BMI.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('higher', 'PosReg', (194, 200))	('high BMI', 'Var', (148, 156))	('low BMI', 'Phenotype', 'HP:0045082', (246, 253))	('cancer', 'Disease', (120, 126))	('patients', 'Species', '9606', (134, 142))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('high body mass index', 'Phenotype', 'HP:0031418', (28, 48))	('two/five-year survival rates', 'CPA', (201, 229))
39846	33299884	The patients were divided into four groups based on BMI: normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI<40 kg/m2), and extremely obese (BMI >= 40 kg/m2).	('obese', 'Disease', 'MESH:D009765', (191, 196))	('25 kg/m2 <=', 'Var', (114, 125))	('30 kg/m2 <= BMI', 'Var', (150, 165))	('obese', 'Disease', 'MESH:D009765', (143, 148))	('obese', 'Disease', (191, 196))	('patients', 'Species', '9606', (4, 12))	('obese', 'Disease', (143, 148))
39856	33299884	Mutations, copy number variations (CNVs), and controlling expression levels of obesity-related genes were downloaded from TCGA.	('Mutations', 'Var', (0, 9))	('obesity', 'Disease', (79, 86))	('obesity', 'Disease', 'MESH:D009765', (79, 86))	('obesity', 'Phenotype', 'HP:0001513', (79, 86))
39883	33299884	As displayed in Figure 2(c), for each of the five obesity-related genes (LEPR, MTCH2, MC4R, LEP, and KCTD15), the patients in a high-expression group had a greater cancer survival rate than those in the low/medium-expression groups (P < 0.05).	('KCTD15', 'Gene', '79047', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('LEP', 'Gene', '3952', (92, 95))	('KCTD15', 'Gene', (101, 107))	('obesity', 'Disease', (50, 57))	('greater', 'PosReg', (156, 163))	('patients', 'Species', '9606', (114, 122))	('LEP', 'Gene', (92, 95))	('obesity', 'Disease', 'MESH:D009765', (50, 57))	('LEPR', 'Gene', '3953', (73, 77))	('cancer', 'Disease', (164, 170))	('LEP', 'Gene', '3952', (73, 76))	('LEPR', 'Gene', (73, 77))	('MC4R', 'Gene', (86, 90))	('high-expression', 'Var', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MTCH2', 'Gene', '23788', (79, 84))	('LEP', 'Gene', (73, 76))	('obesity', 'Phenotype', 'HP:0001513', (50, 57))	('MC4R', 'Gene', '4160', (86, 90))	('MTCH2', 'Gene', (79, 84))
39886	33299884	For patients with six types of cancer (KIRC, LUAD, LGG, GBM, UCEC, and BLCA), those in the PCSK1 low/medium-expression group had higher survival probability than those in the high-expression group.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('LGG', 'Disease', (51, 54))	('PCSK1', 'Gene', '5122', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('survival', 'CPA', (136, 144))	('higher', 'PosReg', (129, 135))	('GBM', 'Disease', (56, 59))	('UCEC', 'Disease', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (4, 12))	('PCSK1', 'Gene', (91, 96))	('cancer', 'Disease', (31, 37))	('low/medium-expression', 'Var', (97, 118))
39887	33299884	However, for patients with SKCM, patients with high expression level of PCSK1 may benefit from a superior survival probability than those with low/medium expression level.	('patients', 'Species', '9606', (33, 41))	('PCSK1', 'Gene', (72, 77))	('survival', 'CPA', (106, 114))	('patients', 'Species', '9606', (13, 21))	('high expression level', 'Var', (47, 68))	('PCSK1', 'Gene', '5122', (72, 77))	('benefit', 'PosReg', (82, 89))
39897	33299884	However, the mutation rates of five obesity-related genes in few cancer tissues were >0.05 (i.e., LEPR in SKCM (0.11), UCEC (0.07), and LUSC (0.07) and PCSK1 in SKCM (0.09) and UCEC (0.06)).	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('mutation', 'Var', (13, 21))	('LEPR', 'Gene', (98, 102))	('PCSK1', 'Gene', (152, 157))	('obesity', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PCSK1', 'Gene', '5122', (152, 157))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('LEPR', 'Gene', '3953', (98, 102))
39902	33299884	Then, for each of the 33 types of cancer, the expression levels of the 13 obesity-related genes were divided into different groups based on the seven factors as follows: (1) patients' gender (male or female), (2) patients' race (African-American, Caucasian, and Asian), (3) menopausal status (premenopause, perimenopause, and postmenopause), (4) history of smoking (smoker, nonsmoker, reformed smoker #1 (<=15 years), and reformed smoker #2 (>15 years)), (5) tumor grade (grade 1, grade 2, grade 3, and grade 4), (6) BMI (normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI < 40 kg/m2), and extremely obese (BMI >= 40 kg/m2)), and (7) history of drinking (occasional drinker, social drinker, daily drinker, weekly drinker, and nondrinker).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('menopausal status', 'Phenotype', 'HP:0008209', (274, 291))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('patients', 'Species', '9606', (213, 221))	('obese', 'Disease', (658, 663))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('obesity', 'Disease', (74, 81))	('obese', 'Disease', 'MESH:D009765', (658, 663))	('30 kg/m2 <= BMI < 40 kg/m2', 'Var', (615, 641))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('tumor', 'Disease', (459, 464))	('obese', 'Disease', (608, 613))	('25 kg/m2 <= BMI < 30 kg/m2', 'Var', (579, 605))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('3 obesity', 'Phenotype', 'HP:0025501', (72, 81))	('obese', 'Disease', 'MESH:D009765', (608, 613))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', (34, 40))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))
39949	33299884	For the majority of obesity-related genes, cancer patients who were in low/medium-expression level group had a superior prognosis than those in the high-expression level group.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (43, 49))	('obesity', 'Phenotype', 'HP:0001513', (20, 27))	('low/medium-expression level', 'Var', (71, 98))	('obesity', 'Disease', 'MESH:D009765', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('obesity', 'Disease', (20, 27))
39952	33299884	However, for three types of cancer (SKCM, ACC, and LUAD), patients in the high-expression group for GPR120 gene could benefit from a greater prognosis as compared to those in the low/medium-expression level group.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high-expression', 'Var', (74, 89))	('benefit', 'PosReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('GPR120', 'Gene', '338557', (100, 106))	('GPR120', 'Gene', (100, 106))	('cancer', 'Disease', (28, 34))
39953	33299884	Moreover, for four types of cancer (KIRP, UVM, CESC, and LUSC), patients in the high-expression level group for SH2B1 gene experienced a better prognosis than those in the low/medium-expression level group.	('SH2B1', 'Gene', (112, 117))	('better', 'PosReg', (137, 143))	('high-expression level', 'Var', (80, 101))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('UVM', 'Disease', (42, 45))	('CESC', 'Disease', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('SH2B1', 'Gene', '25970', (112, 117))
39958	33299884	According to the Kaplan-Meier survival curves, patients with kidney cancer in the low/medium-expression level group for each of LEPR and NEGR1 genes had a long-time life expectancy in comparison to those in the high-expression level group.	('NEGR1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('kidney cancer', 'Disease', (61, 74))	('LEPR', 'Gene', '3953', (128, 132))	('patients', 'Species', '9606', (47, 55))	('low/medium-expression level', 'Var', (82, 109))	('kidney cancer', 'Disease', 'MESH:D007680', (61, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (61, 74))	('LEPR', 'Gene', (128, 132))	('NEGR1', 'Gene', '257194', (137, 142))
39959	33299884	However, patients with kidney cancer in the high-expression level group for each of TMEM18 and SH2B1 genes had a long life expectancy than those who in the low/medium-expression level group.	('patients', 'Species', '9606', (9, 17))	('kidney cancer', 'Disease', (23, 36))	('TMEM18', 'Gene', '129787', (84, 90))	('SH2B1', 'Gene', '25970', (95, 100))	('SH2B1', 'Gene', (95, 100))	('TMEM18', 'Gene', (84, 90))	('high-expression level', 'Var', (44, 65))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
39966	33299884	Once mutations or modify alterations occur for obesity gene, microenvironment probably impacts behavior and adaptive evolution of cancer cells.	('behavior', 'CPA', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('obesity', 'Disease', 'MESH:D009765', (47, 54))	('mutations', 'Var', (5, 14))	('obesity', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('impacts', 'Reg', (87, 94))	('obesity', 'Phenotype', 'HP:0001513', (47, 54))
40001	32551237	A 46-year-old woman, G0P0, presented to the emergency department with chronic vaginal bleeding that had started 5 months previously and acute heavy vaginal bleeding over the past 2 days.	('vaginal bleeding', 'Disease', (78, 94))	('vaginal bleeding', 'Disease', 'MESH:D014592', (78, 94))	('woman', 'Species', '9606', (14, 19))	('vaginal bleeding', 'Disease', 'MESH:D014592', (148, 164))	('G0P0', 'Var', (21, 25))	('vaginal bleeding', 'Disease', (148, 164))
40029	32551237	Compared with undifferentiated endometrial carcinomas, SDUS more frequently shows phyllodiform architecture, and less frequently expresses TP53 mutations, microsatellite instability, and is characterized only by inactivating mutations in SMARCA4.	('SMARCA4', 'Gene', '6597', (238, 245))	('inactivating mutations', 'Var', (212, 234))	('microsatellite instability', 'Var', (155, 181))	('less', 'NegReg', (113, 117))	('undifferentiated endometrial carcinomas', 'Disease', (14, 53))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (31, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('TP53', 'Gene', '7157', (139, 143))	('undifferentiated endometrial carcinomas', 'Disease', 'MESH:D016889', (14, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('SMARCA4', 'Gene', (238, 245))	('TP53', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('phyllodiform architecture', 'CPA', (82, 107))
40030	32551237	SDUS and small cell carcinoma of the ovary (hypercalcemic type) both affect young women, are fatal with aggressive clinical behavior and share inactivation of SMARCA4.	('small cell carcinoma', 'Phenotype', 'HP:0030357', (9, 29))	('inactivation', 'Var', (143, 155))	('affect', 'Reg', (69, 75))	('small cell carcinoma of the ovary', 'Disease', (9, 42))	('women', 'Species', '9606', (82, 87))	('SMARCA4', 'Gene', (159, 166))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (104, 132))	('SMARCA4', 'Gene', '6597', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('SDUS', 'Disease', (0, 4))	('small cell carcinoma of the ovary', 'Disease', 'MESH:D010051', (9, 42))
40069	31741845	Tumor markers for epithelial ovarian cancer were elevated as follows: Carbohydrate antigen (CA) 125, 150 U/ml; CA 19-9, 220 IU/ml.	('epithelial ovarian cancer', 'Disease', (18, 43))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (18, 43))	('Carbohydrate', 'Chemical', 'MESH:D002241', (70, 82))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (18, 43))	('CA 19-9', 'Var', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (29, 43))	('elevated', 'PosReg', (49, 57))	('Tumor markers', 'MPA', (0, 13))
40093	31741845	The formation of ovarian, endometrial cysts is caused by metaplasia of the coelomic epithelium, which then invaginates into the ovarian cortex.	('ovarian', 'Disease', (17, 24))	('metaplasia', 'Var', (57, 67))	('ovarian', 'Disease', (128, 135))	('caused by', 'Reg', (47, 56))	('ovarian', 'Disease', 'MESH:D010049', (128, 135))	('endometrial cysts', 'Disease', (26, 43))	('endometrial cysts', 'Disease', 'MESH:D016889', (26, 43))	('ovarian', 'Disease', 'MESH:D010049', (17, 24))
40103	31741845	Several risk factors for ERONs have been reported, and a recent review article demonstrated that older age at endometriosis diagnosis (>=45 years), large size (>9-cm diameter), solid endometrial cysts component, nulliparity, hyperestrogenism (endogenous or exogenous), and postmenopausal status were all associated with an increased risk of malignant transformation of ovarian endometrioma, whereas complete surgical excision of endometriotic tissue with concomitant unilateral oophorectomy and use of oral contraceptives may be associated with a lower risk of ovarian cancer in women with endometriosis.	('solid endometrial cysts component', 'Disease', 'MESH:D016889', (177, 210))	('endometriosis', 'Disease', 'MESH:D004715', (110, 123))	('endometriosis', 'Disease', (110, 123))	('malignant transformation of ovarian endometrioma', 'Disease', (341, 389))	('nulliparity', 'Var', (212, 223))	('ovarian cancer', 'Disease', (561, 575))	('women', 'Species', '9606', (579, 584))	('ovarian cancer', 'Phenotype', 'HP:0100615', (561, 575))	('postmenopausal status', 'Phenotype', 'HP:0008209', (273, 294))	('endometriosis', 'Phenotype', 'HP:0030127', (110, 123))	('malignant transformation of ovarian endometrioma', 'Disease', 'MESH:D010051', (341, 389))	('endometriosis', 'Disease', 'MESH:D004715', (590, 603))	('endometriosis', 'Disease', (590, 603))	('solid endometrial cysts component', 'Disease', (177, 210))	('cancer', 'Phenotype', 'HP:0002664', (569, 575))	('hyperestrogenism', 'Var', (225, 241))	('concomitant unilateral oophorectomy', 'Disease', (455, 490))	('endometriosis', 'Phenotype', 'HP:0030127', (590, 603))	('oral contraceptives', 'Chemical', 'MESH:D003276', (502, 521))	('concomitant unilateral oophorectomy', 'Disease', 'MESH:C567079', (455, 490))	('ovarian cancer', 'Disease', 'MESH:D010051', (561, 575))
40130	31467958	Prolonged use of pegylated liposomal doxorubicin in gynecologic malignancies Pegylated liposomal doxorubicin (PLD) is a palliative treatment option for patients with recurrent gynecologic malignancies.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('malignancies', 'Disease', (64, 76))	('malignancies', 'Disease', (188, 200))	('doxorubicin', 'Chemical', 'MESH:D004317', (37, 48))	('recurrent gynecologic malignancies', 'Phenotype', 'HP:0000771', (166, 200))	('patients', 'Species', '9606', (152, 160))	('Pegylated', 'Var', (77, 86))	('doxorubicin', 'Chemical', 'MESH:D004317', (97, 108))	('malignancies', 'Disease', 'MESH:D009369', (188, 200))
40213	31467958	Cardiomyocytes have non-chelated intracellular iron which also increases the production of oxygen free radicals by doxorubicin.	('non-chelated', 'Var', (20, 32))	('increases', 'PosReg', (63, 72))	('oxygen free radicals', 'Chemical', '-', (91, 111))	('iron', 'Chemical', 'MESH:D007501', (47, 51))	('production of oxygen free radicals', 'MPA', (77, 111))	('doxorubicin', 'Chemical', 'MESH:D004317', (115, 126))
40220	31467958	Theodoulou and Hudis state that use of PLD vs. conventional doxorubicin reduced incidence of cardiotoxicity by 5-fold even in doses >=500 mg/m2.	('reduced', 'NegReg', (72, 79))	('doxorubicin', 'Chemical', 'MESH:D004317', (60, 71))	('cardiotoxicity', 'Disease', 'MESH:D066126', (93, 107))	('PLD', 'Var', (39, 42))	('cardiotoxicity', 'Disease', (93, 107))
40276	31101846	Six of them: HSPA2, DNAJC20, HSP90AA1, CCT1, CCT2 and CCT6A were statistically significant in both datasets (TCGA and KM plotter) and they were selected for further validation (Table 1).	('HSP90AA1', 'Gene', (29, 37))	('CCT1', 'Gene', (39, 43))	('HSP90AA1', 'Gene', '3320', (29, 37))	('CCT1', 'Gene', '6950', (39, 43))	('DNAJC20', 'Gene', '150274', (20, 27))	('CCT6A', 'Gene', (54, 59))	('CCT2', 'Gene', (45, 49))	('CCT6A', 'Gene', '908', (54, 59))	('HSPA2', 'Var', (13, 18))	('CCT2', 'Gene', '10576', (45, 49))	('DNAJC20', 'Gene', (20, 27))
40280	31101846	Interestingly, high expression of HSPA2 and DNAJC20 was significantly associated with better prognosis for breast cancer patients from TCGA cohort (p = 6,4e-03 and p = 4,3e-02, respectively), longer overall survival in KM plotter cohort (p = 4,5e-04 and p = 5,3e-03, respectively) and longer relapse-free survival in KM plotter cohort (p = 1,5e-07 and p = 5,3e-12, respectively) (Figs 1A, S3).	('HSPA2', 'Gene', (34, 39))	('overall survival', 'CPA', (199, 215))	('high expression', 'Var', (15, 30))	('longer', 'PosReg', (192, 198))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('better', 'PosReg', (86, 92))	('DNAJC20', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('relapse-free survival', 'CPA', (292, 313))	('DNAJC20', 'Gene', '150274', (44, 51))	('patients', 'Species', '9606', (121, 129))
40287	31101846	We have observed that patients with high expression of HSPA2 (better prognosis) were associated with smaller tumors (p = 0,0162), ER-positive and PR-positive cancers (p < 0,0001 and p < 0,0001, respectively).	('high expression', 'Var', (36, 51))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('PR', 'Gene', '5241', (146, 148))	('HSPA2', 'Gene', (55, 60))	('patients', 'Species', '9606', (22, 30))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ER', 'Gene', '2099', (130, 132))	('smaller', 'NegReg', (101, 108))	('tumors', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
40292	31101846	Moreover, mutated TP53 lose the oncosuppressive role and acquire new oncogenic functions.	('mutated', 'Var', (10, 17))	('oncogenic functions', 'CPA', (69, 88))	('TP53', 'Gene', '7157', (18, 22))	('lose', 'NegReg', (23, 27))	('TP53', 'Gene', (18, 22))	('oncosuppressive role', 'CPA', (32, 52))
40304	31101846	Risk score was constructed with the formula: Risk score = (-0,4181 x HSPA2 0/1) + (-0,1813 x DNAJC20 0/1) + (0,6861 x HSP90AA1 0/1) + (0,0824 x CCT1 0/1) + (0,11 x CCT2 0/1) + (0,8427 x Stage 1/2/3/4).	('DNAJC20', 'Gene', (93, 100))	('HSP90AA1', 'Gene', (118, 126))	('HSP90AA1', 'Gene', '3320', (118, 126))	('CCT2', 'Gene', '10576', (164, 168))	('CCT2', 'Gene', (164, 168))	('CCT1', 'Gene', (144, 148))	('DNAJC20', 'Gene', '150274', (93, 100))	('-0,4181', 'Var', (59, 66))	('CCT1', 'Gene', '6950', (144, 148))
40341	31101846	High expression of HSPA2 have been associated with shorter overall survival in stage I-II of non-small cell lung carcinoma patients.	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (93, 122))	('High', 'Var', (0, 4))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (103, 122))	('shorter', 'NegReg', (51, 58))	('patients', 'Species', '9606', (123, 131))	('HSPA2', 'Gene', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (97, 122))	('cell lung carcinoma', 'Disease', (103, 122))	('overall survival', 'MPA', (59, 75))
40357	31101846	HSP90 is also involved in many cancer-associated processes like cellular transformation, DNA double-strand break repair, apoptosis, invasion, genetic variation.	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('genetic variation', 'Var', (142, 159))	('cellular transformation', 'CPA', (64, 87))	('apoptosis', 'CPA', (121, 130))	('involved', 'Reg', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('invasion', 'CPA', (132, 140))
40361	31101846	Additionally, overexpression of HSP90AA1 was observed in tumors containing mutation in TP53, one of the most frequent genetic alteration in cancer that is often associated with accelerated tumor progression.	('associated', 'Reg', (161, 171))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('overexpression', 'PosReg', (14, 28))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('TP53', 'Gene', '7157', (87, 91))	('mutation', 'Var', (75, 83))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('HSP90AA1', 'Gene', (32, 40))	('tumor', 'Disease', (189, 194))	('TP53', 'Gene', (87, 91))	('HSP90AA1', 'Gene', '3320', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Disease', (57, 63))
40370	31101846	Moreover, high expression of identified CCT subunits was associated with aggressive clinical features including the high stage and grade of cancer.	('high', 'Disease', (116, 120))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('high', 'Var', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('associated', 'Reg', (57, 67))
40406	30194005	In addition to TP53, other recurrently mutated genes harboring putative driver or loss-offunction mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS.	('CTNNB1', 'Gene', (154, 160))	('FBXW7', 'Gene', '55294', (123, 128))	('UCS', 'Phenotype', 'HP:0002891', (192, 195))	('PTEN', 'Gene', (117, 121))	('loss-offunction', 'NegReg', (82, 97))	('PTEN', 'Gene', '5728', (117, 121))	('PIK3CA', 'Gene', (143, 149))	('FBXW7', 'Gene', (123, 128))	('mutations', 'Var', (98, 107))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('CTNNB1', 'Gene', '1499', (154, 160))	('KRAS', 'Gene', (137, 141))	('FGFR2', 'Gene', (130, 135))	('PIK3CA', 'Gene', '5290', (143, 149))	('FGFR2', 'Gene', '2263', (130, 135))	('KRAS', 'Gene', '3845', (137, 141))
40424	30194005	Other studies have shown consistent patterns of deletions, preserved across carcinoma and sarcoma components, also suggesting monoclonal origin.	('sarcoma', 'Disease', (90, 97))	('carcinoma', 'Disease', 'MESH:D002277', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('carcinoma', 'Disease', (76, 85))	('deletions', 'Var', (48, 57))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
40434	30194005	Separately in both tissue types in each patient, using paired adjacent normal tissue as a contrast, we performed genome-wide SCA and targeted point mutation profiling, using SNP DNA microarrays and deep next-generation sequencing (NGS).	('patient', 'Species', '9606', (40, 47))	('SCA', 'Disease', (125, 128))	('point mutation', 'Var', (142, 156))
40448	30194005	To profile SCAs, we applied a haplotype-aware hidden Markov model (HMM), hapLOH, designed to detect acquired allelic imbalance, including those at low mutant cell fractions or exhibited in tumor samples of low cellularity.	('tumor', 'Disease', (189, 194))	('mutant', 'Var', (151, 157))	('imbalance', 'Phenotype', 'HP:0002172', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
40463	30194005	Mutations in TP53 were the most prevalent, detected in 12 of 18 (67%) samples from 6 of 9 patients (Figure 3).	('TP53', 'Gene', (13, 17))	('prevalent', 'Reg', (32, 41))	('Mutations', 'Var', (0, 9))	('detected', 'Reg', (43, 51))	('TP53', 'Gene', '7157', (13, 17))	('patients', 'Species', '9606', (90, 98))
40465	30194005	Mutations identified in the sarcomas were identical to those identified in their carcinoma counterparts with the exception of one mutation identified (18 of 19).	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('carcinoma', 'Disease', (81, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sarcomas', 'Disease', (28, 36))	('carcinoma', 'Disease', 'MESH:D002277', (81, 90))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))
40466	30194005	A highly recurrent COSMIC PIK3CA E542K mutation was unique to subject 0609's sarcoma component.	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('E542K', 'Var', (33, 38))	('PIK3CA', 'Gene', '5290', (26, 32))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('PIK3CA', 'Gene', (26, 32))	('E542K', 'Mutation', 'p.E542K', (33, 38))
40467	30194005	Other highly recurrent COSMIC and putative driver mutations were identified in PIK3CA (E545K), KRAS (G12A and G12S), CTNBB1 (D32A) and TP53 (R175H and R273C), identified in both UCS component samples of 5 subjects.	('KRAS', 'Gene', '3845', (95, 99))	('CTNBB1', 'Gene', (117, 123))	('E545K', 'Mutation', 'p.E545K', (87, 92))	('R273C', 'SUBSTITUTION', 'None', (151, 156))	('TP53', 'Gene', '7157', (135, 139))	('D32A', 'Mutation', 'p.D32A', (125, 129))	('R175H', 'Var', (141, 146))	('G12A', 'Mutation', 'c.12G>A', (101, 105))	('E545K', 'Var', (87, 92))	('PIK3CA', 'Gene', (79, 85))	('D32A', 'Var', (125, 129))	('TP53', 'Gene', (135, 139))	('KRAS', 'Gene', (95, 99))	('G12S', 'Mutation', 'p.G12S', (110, 114))	('UCS', 'Phenotype', 'HP:0002891', (178, 181))	('PIK3CA', 'Gene', '5290', (79, 85))	('R273C', 'Var', (151, 156))	('R175H', 'Mutation', 'p.R175H', (141, 146))
40472	30194005	Where a mutation difference existed within components of a single patient, the sarcoma component harbored the additional mutation (a highly recurrent PIK3CA E542K mutation), hinting that in this case, the sarcoma may have evolved from the carcinoma.	('PIK3CA', 'Gene', (150, 156))	('E542K mutation', 'Var', (157, 171))	('sarcoma', 'Disease', (79, 86))	('sarcoma component harbored', 'Disease', 'MESH:C537062', (79, 105))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('E542K', 'Mutation', 'p.E542K', (157, 162))	('carcinoma', 'Disease', 'MESH:D002277', (239, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Disease', (205, 212))	('PIK3CA', 'Gene', '5290', (150, 156))	('sarcoma component harbored', 'Disease', (79, 105))	('patient', 'Species', '9606', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('carcinoma', 'Disease', (239, 248))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
40605	29625055	In the LGG marker paper, analysis of OS showed that patients diagnosed with an IDH1 and IDH2 (two very similar genes, hereafter referred to collectively as IDH) mutation with or without 1p/19q codeletion had substantially longer OS than did patients who had wild-type IDH, proving that IDH-1p/19q status represents a more robust survival predictor than LGG histologic subtype.	('IDH-1p', 'Gene', (286, 292))	('IDH', 'Gene', (88, 91))	('IDH1', 'Gene', (79, 83))	('IDH', 'Gene', (79, 82))	('mutation', 'Var', (161, 169))	('IDH', 'Gene', (286, 289))	('IDH', 'Gene', '3417', (88, 91))	('patients', 'Species', '9606', (52, 60))	('IDH1', 'Gene', '3417', (79, 83))	('IDH', 'Gene', (268, 271))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', (156, 159))	('OS', 'Chemical', '-', (229, 231))	('OS', 'Chemical', '-', (37, 39))	('IDH', 'Gene', '3417', (286, 289))	('patients', 'Species', '9606', (241, 249))	('longer', 'PosReg', (222, 228))	('IDH2', 'Gene', (88, 92))	('IDH-1p', 'Gene', '3417', (286, 292))	('IDH2', 'Gene', '3418', (88, 92))	('IDH', 'Gene', '3417', (268, 271))	('IDH', 'Gene', '3417', (156, 159))
40788	29773071	Patients with lymph node metastasis have significant lower median survival rates compared to patients with a tumor confined to the uterus.	('patients', 'Species', '9606', (93, 101))	('median survival', 'MPA', (59, 74))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('lymph node metastasis', 'Var', (14, 35))	('tumor confined to the uterus', 'Phenotype', 'HP:0010784', (109, 137))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('lower', 'NegReg', (53, 58))	('tumor', 'Disease', (109, 114))
40809	29773071	In patients with short history of postmenopausal vaginal bleeding, inconspicuous ultrasound findings, good differentiation after D/C, lack of lymphovascular space invasion, or atypical hyperplasia with transition into a well differentiated carcinoma, a great probability of a low-risk situation was to assume.	('carcinoma', 'Disease', (240, 249))	('hyperplasia', 'Disease', 'MESH:D006965', (185, 196))	('lack of lymphovascular space', 'Phenotype', 'HP:0045006', (134, 162))	('patients', 'Species', '9606', (3, 11))	('vaginal bleeding', 'Disease', 'MESH:D014592', (49, 65))	('carcinoma', 'Disease', 'MESH:D002277', (240, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('vaginal bleeding', 'Disease', (49, 65))	('hyperplasia', 'Disease', (185, 196))	('atypical', 'Var', (176, 184))
40810	29773071	In patient with supposed uterine risk factors "higher than low risk" (e.g., suspected MI > 50% in ultrasound diagnostic, G3/type2/LVSI in the D/C specimen), consecutive lymph node assessment was performed within the same operation.	('MI > 50%', 'Var', (86, 94))	('G3/type2/LVSI', 'Var', (121, 134))	('patient', 'Species', '9606', (3, 10))
40897	28882536	The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]).	('doxorubicin', 'Var', (203, 214))	('fever', 'Phenotype', 'HP:0001945', (310, 315))	('docetaxel', 'Chemical', 'MESH:D000077143', (299, 308))	('neutropenia', 'Disease', 'MESH:D009503', (126, 137))	('neutropenia', 'Phenotype', 'HP:0001875', (126, 137))	('neutropenia', 'Disease', (345, 356))	('neutropenia', 'Disease', 'MESH:D009503', (345, 356))	('gemcitabine', 'Chemical', 'MESH:C056507', (283, 294))	('fever', 'Disease', 'MESH:D005334', (310, 315))	('doxorubicin', 'Chemical', 'MESH:D004317', (203, 214))	('febrile neutropenia', 'Disease', (118, 137))	('febrile neutropenia', 'Disease', 'MESH:D009503', (118, 137))	('patients', 'Species', '9606', (261, 269))	('patients', 'Species', '9606', (181, 189))	('neutropenia', 'Disease', (126, 137))	('neutropenia', 'Phenotype', 'HP:0001875', (345, 356))	('fever', 'Disease', (310, 315))
40933	28882536	A pharmacogenomics study was also done to investigate the influence of single-nucleotide polymorphisms (SNPs) on treatment efficacy and toxicity.	('single-nucleotide polymorphisms', 'Var', (71, 102))	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))
40936	28882536	Patients were required to have adequate organ function (absolute neutrophil count >=1 0 x 109 per L; platelet count >=100 x 109 per L; bilirubin <=1 5 x upper limit of normal [ULN]; aspartate transaminase, alanine transaminase, or both <=3 0 x ULN; alkaline phosphatase <=3 0 x ULN [patients were eligible with a higher alkaline phosphatase concentration if this was shown to be due to bone isoenzyme]; measured or calculated creatinine clearance >=30 mL/min; and cardiac ejection fraction within local normal limits).	('cardiac', 'MPA', (464, 471))	('alkaline', 'MPA', (249, 257))	('creatinine clearance', 'MPA', (426, 446))	('higher alkaline phosphatase concentration', 'Phenotype', 'HP:0003155', (313, 354))	('alkaline phosphatase concentration', 'MPA', (320, 354))	('>=100', 'Var', (116, 121))	('patients', 'Species', '9606', (283, 291))	('Patients', 'Species', '9606', (0, 8))	('bilirubin', 'Chemical', 'MESH:D001663', (135, 144))
41021	28882536	Within the doxorubicin group, three of the four SNPs in the SLC22A16 gene, all in linkage disequilibrium with each other, were associated with a worse progression-free survival (appendix pp 12, 15), as was the minor allele of the SLC29A1 SNP (rs9394992, in both heterozygotes and homozygotes; appendix p 14).	('progression-free survival', 'CPA', (151, 176))	('p 14', 'Gene', (302, 306))	('rs9394992', 'Mutation', 'rs9394992', (243, 252))	('p 14', 'Gene', '1029', (302, 306))	('rs9394992', 'Var', (243, 252))	('SLC29A1', 'Gene', (230, 237))	('SLC29A1', 'Gene', '2030', (230, 237))	('worse', 'NegReg', (145, 150))	('SLC22A16', 'Gene', '85413', (60, 68))	('appendix p 14', 'Phenotype', 'HP:0002825', (293, 306))	('doxorubicin', 'Chemical', 'MESH:D004317', (11, 22))	('p 12', 'Gene', (188, 192))	('SLC22A16', 'Gene', (60, 68))	('p 12', 'Gene', '56655', (188, 192))
41022	28882536	By contrast, the PRDX4 SNP (rs518329) minor allele was associated with improved overall survival in the doxorubicin group in both heterozygotes and homozygotes (appendix p 13).	('overall survival', 'MPA', (80, 96))	('PRDX4', 'Gene', '10549', (17, 22))	('rs518329', 'Var', (28, 36))	('doxorubicin', 'Chemical', 'MESH:D004317', (104, 115))	('p 13', 'Gene', '440926', (170, 174))	('PRDX4', 'Gene', (17, 22))	('rs518329', 'Mutation', 'rs518329', (28, 36))	('p 13', 'Gene', (170, 174))	('improved', 'PosReg', (71, 79))
41023	28882536	Analysis of the gemcitabine and docetaxel treatment group indicated a possible association of the ABCB1 rs1045642 minor allele with worse progression-free survival in both heterozygotes and homozygotes (appendix p 12); the CDA rs2072671 SNP was associated with worse overall survival (appendix p 14), and the CMPK1 rs4492666 SNP was associated with improved overall survival in both heterozygotes and homozygotes (appendix p 14).	('ABCB1', 'Gene', (98, 103))	('ABCB1', 'Gene', '5243', (98, 103))	('overall survival', 'MPA', (358, 374))	('CMPK1', 'Gene', '51727', (309, 314))	('p 14', 'Gene', (423, 427))	('improved', 'PosReg', (349, 357))	('p 14', 'Gene', '1029', (423, 427))	('p 14', 'Gene', (294, 298))	('p 14', 'Gene', '1029', (294, 298))	('docetaxel', 'Chemical', 'MESH:D000077143', (32, 41))	('appendix p 14', 'Phenotype', 'HP:0002825', (414, 427))	('gemcitabine', 'Chemical', 'MESH:C056507', (16, 27))	('p 12', 'Gene', (212, 216))	('p 12', 'Gene', '56655', (212, 216))	('rs4492666 SNP', 'Var', (315, 328))	('rs2072671 SNP', 'Var', (227, 240))	('rs1045642', 'Var', (104, 113))	('rs2072671', 'Mutation', 'rs2072671', (227, 236))	('rs1045642', 'Mutation', 'rs1045642', (104, 113))	('rs4492666', 'Mutation', 'rs4492666', (315, 324))	('CMPK1', 'Gene', (309, 314))	('appendix p 14', 'Phenotype', 'HP:0002825', (285, 298))	('overall', 'MPA', (267, 274))
41024	28882536	The SLC22A16 rs723685 minor allele was associated with a reduced frequency of grade 3-4 adverse events compared with wild type (ten [48%] of 21 patients vs 69 [71%] of 97 patients) in the doxorubicin treatment group but not in the gemcitabine and docetaxel group.	('docetaxel', 'Chemical', 'MESH:D000077143', (247, 256))	('SLC22A16', 'Gene', (4, 12))	('gemcitabine', 'Chemical', 'MESH:C056507', (231, 242))	('doxorubicin', 'Chemical', 'MESH:D004317', (188, 199))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (144, 152))	('reduced', 'NegReg', (57, 64))	('rs723685 minor', 'Var', (13, 27))	('SLC22A16', 'Gene', '85413', (4, 12))	('rs723685', 'Mutation', 'rs723685', (13, 21))	('grade 3-4 adverse events', 'MPA', (78, 102))
41073	28882536	The pharmacogenomics data obtained in the current study suggest that SNPs in the organic cation transporter SLC22A16 are associated with reduced efficacy and decreased toxicity following doxorubicin treatment.	('efficacy', 'MPA', (145, 153))	('doxorubicin', 'Chemical', 'MESH:D004317', (187, 198))	('decreased', 'NegReg', (158, 167))	('toxicity', 'Disease', 'MESH:D064420', (168, 176))	('toxicity', 'Disease', (168, 176))	('SLC22A16', 'Gene', (108, 116))	('SNPs', 'Var', (69, 73))	('SLC22A16', 'Gene', '85413', (108, 116))	('reduced', 'NegReg', (137, 144))
41076	28882536	Two other SNPs, SLC29A1 rs9394992 and PRDX4 rs518329, were also associated with outcomes in the doxorubicin group; however, these genes are not known to be involved in the pharmacology of doxorubicin, so further investigation is required to understand these effects.	('associated', 'Reg', (64, 74))	('rs518329', 'Mutation', 'rs518329', (44, 52))	('doxorubicin', 'Chemical', 'MESH:D004317', (188, 199))	('PRDX4', 'Gene', '10549', (38, 43))	('SLC29A1', 'Gene', '2030', (16, 23))	('rs9394992', 'Var', (24, 33))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('PRDX4', 'Gene', (38, 43))	('rs9394992', 'Mutation', 'rs9394992', (24, 33))	('SLC29A1', 'Gene', (16, 23))	('rs518329', 'Var', (44, 52))
41077	28882536	There were indications that three SNPs predicted to affect gemcitabine pharmacokinetics were associated with an effect on overall survival, most notably the CDA rs2072671 SNP, which was associated with reduced overall survival in the gemcitabine and docetaxel group, with worse survival in patients homozygous (rather than heterozygous) for the minor allele (this is referred to as a gene-dose effect).	('overall survival', 'MPA', (210, 226))	('reduced', 'NegReg', (202, 209))	('gemcitabine', 'MPA', (59, 70))	('patients', 'Species', '9606', (290, 298))	('gemcitabine', 'Chemical', 'MESH:C056507', (234, 245))	('gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('overall survival', 'MPA', (122, 138))	('docetaxel', 'Chemical', 'MESH:D000077143', (250, 259))	('rs2072671', 'Mutation', 'rs2072671', (161, 170))	('rs2072671', 'Var', (161, 170))	('affect', 'Reg', (52, 58))
41135	28913066	Genetic tests in molecular pathology can identify translocations that help distinguish peripheral PNETs from other round cell tumors.	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('translocations', 'Var', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('peripheral PNETs', 'Disease', (87, 103))	('PNET', 'Phenotype', 'HP:0030065', (98, 102))
41148	28657223	Although the presence of pathological necrosis was not a poor prognostic factor (p=0.704), unenhanced regions on MRI correlated with poor prognosis when the unenhanced regions in the tumor accounted for more than 10% of the total tumor (p=0.019).	('tumor', 'Disease', (230, 235))	('necrosis', 'Disease', (38, 46))	('unenhanced regions', 'Var', (91, 109))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('poor', 'NegReg', (133, 137))	('necrosis', 'Disease', 'MESH:D009336', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
41252	28139702	However, the same 'actionable mutation' impacts distinct context-specific gene regulatory programs and signalling networks:and interacts with different genetic backgrounds of co-occurring alterations:in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('impacts', 'Reg', (40, 47))	('context-specific', 'MPA', (57, 73))	('mutation', 'Var', (30, 38))	('signalling networks', 'Pathway', (103, 122))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancers', 'Disease', (213, 220))	('interacts', 'Reg', (127, 136))
41254	28139702	Our analysis predicts distinct dysregulated transcriptional regulators downstream of somatic alterations in different cancers, and we validate the context-specific differential activity of TFs associated to mutant PIK3CA in isogenic cancer cell line models.	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (233, 239))	('mutant', 'Var', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('dysregulated transcriptional regulators', 'MPA', (31, 70))	('PIK3CA', 'Gene', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('PIK3CA', 'Gene', '5290', (214, 220))
41257	28139702	Large-scale cancer genomics projects such as The Cancer Genome Atlas (TCGA) have generated a comprehensive catalogue of somatic mutations and copy number aberrations across many tumour types.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (12, 18))	('copy number aberrations', 'Var', (142, 165))	('tumour type', 'Disease', (178, 189))	('tumour type', 'Disease', 'MESH:D009369', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))
41262	28139702	To this end, we applied a computational strategy for exploiting parallel (phospho)proteomic and mRNA sequencing data for large tumour sets by linking the dysregulation of upstream signalling pathways with altered transcriptional response through the transcriptional circuitry.	('dysregulation', 'Var', (154, 167))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('upstream signalling pathways', 'Pathway', (171, 199))	('transcriptional response', 'MPA', (213, 237))	('tumour', 'Disease', (127, 133))
41266	28139702	By stratifying tumours by inferred TF activities rather than gene expression patterns, we identified known and previously unlinked TFs that are differentially active in HPV(+) versus HPV(-) head and neck squamous cancer, and we uncovered a subtype of endometrioid uterine cancer harbouring mutant beta-catenin with altered TF activities.	('uterine cancer', 'Phenotype', 'HP:0010784', (264, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('squamous cancer', 'Phenotype', 'HP:0002860', (204, 219))	('neck squamous cancer', 'Disease', 'MESH:D006258', (199, 219))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (190, 219))	('HPV', 'Species', '10566', (169, 172))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('activities', 'MPA', (326, 336))	('cancer', 'Disease', (213, 219))	('HPV', 'Disease', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('expression', 'Species', '29278', (66, 76))	('tumours', 'Disease', (15, 22))	('HPV', 'Species', '10566', (183, 186))	('neck squamous cancer', 'Disease', (199, 219))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('beta-catenin', 'Gene', (297, 309))	('cancer', 'Disease', (272, 278))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('mutant', 'Var', (290, 296))	('beta-catenin', 'Gene', '1499', (297, 309))
41268	28139702	This analysis identified key regulators associated with the major mutations in renal clear-cell carcinoma.	('mutations', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('renal clear-cell carcinoma', 'Phenotype', 'HP:0006770', (79, 105))	('renal clear-cell carcinoma', 'Disease', 'MESH:C538614', (79, 105))	('renal clear-cell carcinoma', 'Disease', (79, 105))
41270	28139702	In particular, we associated PIK3CA activating mutations with altered activities of distinct sets of TFs in different cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('activities', 'MPA', (70, 80))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TFs', 'Gene', (101, 104))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('activating', 'PosReg', (36, 46))
41271	28139702	Notably, in isogenic cell line models of breast cancer and head and neck cancer, we validated the altered activity of several TFs in the presence of mutant PIK3CA by measuring promoter occupancy and expression of target genes, confirming the context-specific predictions of our model.	('expression', 'Species', '29278', (199, 209))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('promoter occupancy', 'MPA', (176, 194))	('head and neck cancer', 'Phenotype', 'HP:0012288', (59, 79))	('expression', 'MPA', (199, 209))	('PIK3CA', 'Gene', '5290', (156, 162))	('breast cancer', 'Disease', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutant', 'Var', (149, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('head and neck cancer', 'Disease', 'MESH:D006258', (59, 79))	('activity', 'MPA', (106, 114))	('altered', 'Reg', (98, 105))	('PIK3CA', 'Gene', (156, 162))
41300	28139702	Head and neck squamous cancer is frequently associated with human papillomavirus (HPV) infection and mutations in TP53.	('associated', 'Reg', (44, 54))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (66, 96))	('neck squamous cancer', 'Disease', (9, 29))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', '7157', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('neck squamous cancer', 'Disease', 'MESH:D006258', (9, 29))	('TP53', 'Gene', (114, 118))	('squamous cancer', 'Phenotype', 'HP:0002860', (14, 29))	('human', 'Species', '9606', (60, 65))
41309	28139702	As described previously, mutant TP53 tends to be mutually exclusive with HPV(+) status, but inferred TP53 TF activity and inferred p53 protein activity were not significantly different between HPV(+) and HPV(-) patients (t-test P=0.477 and P=0.741, respectively).	('mutant', 'Var', (25, 31))	('patients', 'Species', '9606', (211, 219))	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', '7157', (32, 36))	('HPV', 'Species', '10566', (73, 76))	('p53', 'Gene', (131, 134))	('HPV', 'Species', '10566', (193, 196))	('p53', 'Gene', '7157', (131, 134))	('HPV', 'Species', '10566', (204, 207))	('TP53', 'Gene', (101, 105))	('TP53', 'Gene', (32, 36))
41314	28139702	Serous-like endometrial tumours are hormone receptor negative, mostly copy number high, and harbour mutations in TP53, whereas endometrioid tumours are hormone receptor positive, copy number low, and have a high frequency of PI3K-AKT (phosphatidylinositol 3-kinase-AKT) pathway alterations.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('AKT', 'Gene', (230, 233))	('alterations', 'Reg', (278, 289))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('hormone receptor', 'Gene', (152, 168))	('endometrioid tumours', 'Disease', 'MESH:D016889', (127, 147))	('hormone receptor', 'Gene', '3164', (36, 52))	('AKT', 'Gene', '207', (230, 233))	('TP53', 'Gene', (113, 117))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('endometrial tumours', 'Disease', (12, 31))	('AKT', 'Gene', (265, 268))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('hormone receptor', 'Gene', (36, 52))	('endometrioid tumours', 'Disease', (127, 147))	('hormone receptor', 'Gene', '3164', (152, 168))	('mutations', 'Var', (100, 109))	('endometrial tumours', 'Disease', 'MESH:D016889', (12, 31))	('TP53', 'Gene', '7157', (113, 117))	('AKT', 'Gene', '207', (265, 268))
41316	28139702	Importantly, clustering by TF activities revealed subclasses of tumours within each histological subtype that sometimes correlated with mutation status.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('mutation', 'Var', (136, 144))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('correlated', 'Reg', (120, 130))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
41317	28139702	In particular, endometrioid tumours with a CTNNB1 mutation form a distinct cluster based on inferred TF activity profiles that was not observed by clustering TF mRNA expression levels directly (Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('CTNNB1', 'Gene', (43, 49))	('endometrioid tumours', 'Disease', (15, 35))	('endometrioid tumours', 'Disease', 'MESH:D016889', (15, 35))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('CTNNB1', 'Gene', '1499', (43, 49))	('expression', 'Species', '29278', (166, 176))	('mutation', 'Var', (50, 58))
41318	28139702	Moreover, clustering based on inferred TF activity was better able to stratify patients by CTNNB1 mutation status (P<10-17, two-sided chi2 test for all tests) compared to reported TCGA mRNA clusters (P<0.01) and TCGA integrated clusters (P<10-6) (Supplementary Tables 9 and 10).	('CTNNB1', 'Gene', '1499', (91, 97))	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (79, 87))	('CTNNB1', 'Gene', (91, 97))
41319	28139702	Significant inferred TF activity differences between CTNNB1 mutant and WT patients (satisfying FDR-corrected P<0.01, t-test) associated CTNNB1 mutant status with altered activity of TFs involved in WNT signalling, epithelial-mesenchymal transition and cancer stem cell transition including TCF4 (transcriptional factor 4), NFATC4, JUN, TP53, MAX, MYC, STAT3 and KLF12 (Fig.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('KLF12', 'Gene', (362, 367))	('STAT3', 'Gene', '6774', (352, 357))	('NFATC4', 'Gene', (323, 329))	('CTNNB1', 'Gene', '1499', (136, 142))	('KLF12', 'Gene', '11278', (362, 367))	('MYC', 'Gene', '4609', (347, 350))	('TP53', 'Gene', '7157', (336, 340))	('TCF4', 'Gene', '6925', (290, 294))	('TP53', 'Gene', (336, 340))	('mutant', 'Var', (143, 149))	('CTNNB1', 'Gene', (136, 142))	('cancer', 'Disease', (252, 258))	('patients', 'Species', '9606', (74, 82))	('CTNNB1', 'Gene', '1499', (53, 59))	('transcriptional factor 4', 'Gene', (296, 320))	('transcriptional factor 4', 'Gene', '6925', (296, 320))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('TCF4', 'Gene', (290, 294))	('epithelial-mesenchymal transition', 'CPA', (214, 247))	('MYC', 'Gene', (347, 350))	('activity', 'MPA', (170, 178))	('altered', 'Reg', (162, 169))	('STAT3', 'Gene', (352, 357))	('NFATC4', 'Gene', '4776', (323, 329))	('mutant', 'Var', (60, 66))	('CTNNB1', 'Gene', (53, 59))
41320	28139702	We confirmed these results in an independent data set of 203 endometrial RPPA profiles along with mutation and clinical data compiled by MDACC, using the UCEC TCGA-trained AR model to infer TF activities, and replicated many of the TFs associated with mutant CTNBB1 (P<10-5, Mann-Whitney test; Fig.	('CTNBB1', 'Gene', (259, 265))	('mutant', 'Var', (252, 258))	('P<10-5', 'Gene', (267, 273))	('P<10-5', 'Gene', '4790', (267, 273))
41321	28139702	Interestingly, another study performed customized consensus clustering on TCGA UCEC expression data and did identify a cluster enriched with beta-catenin mutations, and GSEA (gene set enrichment analysis) suggested an association with WNT signalling, consistent with our analysis.	('association', 'Interaction', (218, 229))	('WNT signalling', 'Pathway', (235, 249))	('beta-catenin', 'Gene', (141, 153))	('GSEA', 'Chemical', '-', (169, 173))	('expression', 'Species', '29278', (84, 94))	('beta-catenin', 'Gene', '1499', (141, 153))	('mutations', 'Var', (154, 163))
41322	28139702	Encouraged by our findings for mutant CTNBB1 endometrioid tumours, we developed a systematic statistical approach for modelling the impact of somatic alterations on regulator activity in each tumour type, with the eventual goal of deciphering cancer-specific downstream effects of targeted therapies and potentially discovering secondary targets for combination drug strategies.	('CTNBB1', 'Gene', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mutant', 'Var', (31, 37))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (243, 249))	('tumour type', 'Disease', (192, 203))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('tumour type', 'Disease', 'MESH:D009369', (192, 203))	('endometrioid tumours', 'Disease', (45, 65))	('endometrioid tumours', 'Disease', 'MESH:D016889', (45, 65))
41325	28139702	Combining these results identified a set of regulators predicted to be significantly dysregulated by each somatic alteration in each TCGA cancer study.	('cancer', 'Disease', (138, 144))	('TCGA', 'Disease', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('alteration', 'Var', (114, 124))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
41326	28139702	Our model identified mutations in VHL (von Hippel-Lindau), PBMR1, BAP1, MTOR, ATM, SETD2, KDM5C and PTEN (phosphatase and tensin homolog), as well as copy number changes in MLH1, DUSP1 and RANDBP17 as significantly associated with various TF activity changes across tumours.	('PTEN', 'Gene', (100, 104))	('DUSP1', 'Gene', '1843', (179, 184))	('tumours', 'Disease', 'MESH:D009369', (266, 273))	('BAP1', 'Gene', (66, 70))	('SETD2', 'Gene', '29072', (83, 88))	('ATM', 'Gene', '472', (78, 81))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('associated', 'Reg', (215, 225))	('PTEN', 'Gene', '5728', (100, 104))	('MLH1', 'Gene', (173, 177))	('KDM5C', 'Gene', '8242', (90, 95))	('von Hippel-Lindau', 'Gene', '7428', (39, 56))	('PBMR1', 'Gene', (59, 64))	('copy number changes', 'Var', (150, 169))	('DUSP1', 'Gene', (179, 184))	('MLH1', 'Gene', '4292', (173, 177))	('MTOR', 'Gene', (72, 76))	('ATM', 'Gene', (78, 81))	('activity', 'MPA', (242, 250))	('MTOR', 'Gene', '2475', (72, 76))	('VHL', 'Gene', (34, 37))	('mutations', 'Var', (21, 30))	('KDM5C', 'Gene', (90, 95))	('BAP1', 'Gene', '8314', (66, 70))	('tumours', 'Disease', (266, 273))	('RANDBP17', 'Gene', (189, 197))	('SETD2', 'Gene', (83, 88))	('von Hippel-Lindau', 'Gene', (39, 56))	('VHL', 'Gene', '7428', (34, 37))	('tumours', 'Phenotype', 'HP:0002664', (266, 273))
41327	28139702	KIRC is characterized by a high-frequency inactivating mutation in the VHL gene found in ~54% of tumours in TCGA and likely more prevalent.	('tumours', 'Disease', (97, 104))	('VHL', 'Gene', (71, 74))	('inactivating mutation', 'Var', (42, 63))	('VHL', 'Gene', '7428', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
41328	28139702	Mutually exclusive mutations in PBRM1, a subunit of the PBAF SWI/SNF chromatin remodelling complex, and in histone deubiquitinase BAP1 define two genetic subtypes of KIRC, while recurrent mutations in the histone methyltransferase SETD2 also occur.	('PBRM1', 'Gene', (32, 37))	('BAP1', 'Gene', (130, 134))	('PBRM1', 'Gene', '55193', (32, 37))	('SETD2', 'Gene', (231, 236))	('mutations', 'Var', (19, 28))	('BAP1', 'Gene', '8314', (130, 134))	('SETD2', 'Gene', '29072', (231, 236))
41329	28139702	KIRC samples with PBMR1 and BAP1 mutations showed distinct patterns of TF and protein activities (Fig.	('BAP1', 'Gene', '8314', (28, 32))	('PBMR1', 'Gene', (18, 23))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
41330	28139702	PBMR1 mutant tumours are associated with increased activity of TFs/(phospho)proteins that have roles in interleukin signalling and MYC, while regulators with increased activity in BAP1 mutant tumours are involved in DNA damage response, apoptosis, insulin signalling and mTOR signalling.	('TFs/', 'Protein', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('MYC', 'Gene', (131, 134))	('tumours', 'Disease', (192, 199))	('mTOR', 'Gene', (271, 275))	('insulin', 'Gene', '3630', (248, 255))	('tumours', 'Phenotype', 'HP:0002664', (192, 199))	('BAP1', 'Gene', '8314', (180, 184))	('tumours', 'Disease', 'MESH:D009369', (192, 199))	('mTOR', 'Gene', '2475', (271, 275))	('MYC', 'Gene', '4609', (131, 134))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumours', 'Disease', (13, 20))	('BAP1', 'Gene', (180, 184))	('insulin', 'Gene', (248, 255))	('activity', 'MPA', (51, 59))	('mutant', 'Var', (6, 12))	('increased', 'PosReg', (41, 50))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('PBMR1', 'Gene', (0, 5))	('tumours', 'Disease', 'MESH:D009369', (13, 20))
41331	28139702	Notably, NFE2L2 TF activity was significantly higher in BAP1 mutant tumours than PBMR1 mutant tumours.	('tumours', 'Disease', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('higher', 'PosReg', (46, 52))	('BAP1', 'Gene', '8314', (56, 60))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('activity', 'MPA', (19, 27))	('tumours', 'Disease', (68, 75))	('BAP1', 'Gene', (56, 60))	('NFE2L2', 'Gene', '4780', (9, 15))	('mutant', 'Var', (61, 67))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('NFE2L2', 'Gene', (9, 15))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
41333	28139702	Mutations in KEAP1, NFE2L2 (Nrf2), CUL3 or RBX1 are the most common mechanisms that impair KEAP1-mediated degradation of NFE2L2 and thereby activate the transcriptional effects of NFE2L2.	('KEAP1', 'Gene', (91, 96))	('NFE2L2', 'Gene', '4780', (20, 26))	('RBX1', 'Gene', '9978', (43, 47))	('Nrf2', 'Gene', (28, 32))	('impair', 'NegReg', (84, 90))	('NFE2L2', 'Gene', (180, 186))	('activate', 'PosReg', (140, 148))	('NFE2L2', 'Gene', '4780', (121, 127))	('NFE2L2', 'Gene', (20, 26))	('Mutations', 'Var', (0, 9))	('CUL3', 'Gene', (35, 39))	('RBX1', 'Gene', (43, 47))	('NFE2L2', 'Gene', (121, 127))	('degradation', 'MPA', (106, 117))	('KEAP1', 'Gene', '9817', (13, 18))	('transcriptional effects', 'MPA', (153, 176))	('KEAP1', 'Gene', (13, 18))	('Nrf2', 'Gene', '4780', (28, 32))	('NFE2L2', 'Gene', '4780', (180, 186))	('KEAP1', 'Gene', '9817', (91, 96))	('CUL3', 'Gene', '8452', (35, 39))
41334	28139702	Inferred TF activity of NFE2L2 was increased in mutant versus WT KEAP1 or NFE2L2 lung cancers; these differences are not observed at the gene expression level (Supplementary Fig.	('NFE2L2', 'Gene', '4780', (74, 80))	('increased', 'PosReg', (35, 44))	('mutant', 'Var', (48, 54))	('TF activity', 'MPA', (9, 20))	('NFE2L2', 'Gene', '4780', (24, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('KEAP1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancers', 'Disease', 'MESH:D008175', (81, 93))	('NFE2L2', 'Gene', (74, 80))	('NFE2L2', 'Gene', (24, 30))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('expression', 'Species', '29278', (142, 152))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('lung cancers', 'Disease', (81, 93))	('KEAP1', 'Gene', '9817', (65, 70))
41335	28139702	In samples where VHL was comutated with PBMR1, SMAD1 (interaction P<0.0003) and KLF12 (interaction P<0.05) activity were significantly decreased.	('SMAD1', 'Gene', (47, 52))	('PBMR1', 'Gene', (40, 45))	('activity', 'MPA', (107, 115))	('comutated', 'Var', (25, 34))	('KLF12', 'Gene', '11278', (80, 85))	('VHL', 'Gene', (17, 20))	('decreased', 'NegReg', (135, 144))	('VHL', 'Gene', '7428', (17, 20))	('KLF12', 'Gene', (80, 85))	('SMAD1', 'Gene', '4086', (47, 52))
41337	28139702	The PI3K pathway controls proliferation, metabolism, survival and motility and is frequently activated in many cancers, often via mutations in PIK3CA, which encodes the alpha-isoform of the p110 catalytic subunit of PI3K (PI3Kalpha); loss of PTEN, which antagonizes PI3K function; and overexpression of membrane-bound receptor tyrosine kinase.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('loss', 'Var', (234, 238))	('cancers', 'Disease', (111, 118))	('PI3Kalpha', 'Gene', (222, 231))	('PIK3CA', 'Gene', (143, 149))	('PTEN', 'Gene', (242, 246))	('motility', 'CPA', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PTEN', 'Gene', '5728', (242, 246))	('expression', 'Species', '29278', (289, 299))	('activated', 'PosReg', (93, 102))	('mutations', 'Var', (130, 139))	('PI3Kalpha', 'Gene', '5290', (222, 231))	('PIK3CA', 'Gene', '5290', (143, 149))	('PI3K pathway', 'Pathway', (4, 16))	('proliferation', 'CPA', (26, 39))	('overexpression', 'PosReg', (285, 299))
41341	28139702	Mutations often occur in one of three hotspot locations (E545K, E542K and H1047) and promote constitutive signalling though the pathway.	('E542K', 'Mutation', 'rs121913273', (64, 69))	('E545K', 'Var', (57, 62))	('promote', 'PosReg', (85, 92))	('H1047', 'Var', (74, 79))	('E542K', 'Var', (64, 69))	('E545K', 'Mutation', 'rs104886003', (57, 62))	('constitutive signalling', 'MPA', (93, 116))
41342	28139702	In UCEC, ~66% of tumours have PTEN inactivating mutations, ~50% have PIK3CA activating mutations and ~35% have a comutation of PTEN and PIK3CA.	('PIK3CA', 'Gene', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('activating', 'PosReg', (76, 86))	('PIK3CA', 'Gene', '5290', (136, 142))	('PIK3CA', 'Gene', '5290', (69, 75))	('inactivating', 'NegReg', (35, 47))	('PIK3CA', 'Gene', (69, 75))	('tumours', 'Disease', (17, 24))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', (30, 34))	('comutation', 'Var', (113, 123))	('PTEN', 'Gene', '5728', (127, 131))	('PTEN', 'Gene', '5728', (30, 34))
41344	28139702	Notably, the number of TFs dysregulated by PI3K pathway alterations varied widely across different cancers (9 in HNSC, 65 in BRCA and 63 in UCEC), with striking changes in ErbB/MAPK, mTOR, HIF-1, VEGF and PI3K-Akt pathways.	('PI3K', 'Gene', (43, 47))	('BRCA', 'Gene', '672', (125, 129))	('HNSC', 'Disease', (113, 117))	('mTOR', 'Gene', (183, 187))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('BRCA', 'Gene', (125, 129))	('ErbB', 'Gene', '1956', (172, 176))	('Akt', 'Gene', (210, 213))	('HIF-1', 'Gene', (189, 194))	('mTOR', 'Gene', '2475', (183, 187))	('HIF-1', 'Gene', '29072', (189, 194))	('Akt', 'Gene', '207', (210, 213))	('VEGF', 'Gene', '7422', (196, 200))	('alterations', 'Var', (56, 67))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('changes', 'Reg', (161, 168))	('cancers', 'Disease', (99, 106))	('VEGF', 'Gene', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ErbB', 'Gene', (172, 176))
41345	28139702	Only ELK1, a TF downstream of the MAPK/ERK pathway, is dysregulated by PIK3CA or PTEN mutations in all three cancers.	('mutations', 'Var', (86, 95))	('PIK3CA', 'Gene', '5290', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('PTEN', 'Gene', '5728', (81, 85))	('ELK1', 'Gene', (5, 9))	('cancers', 'Disease', (109, 116))	('ERK', 'Gene', '2048', (39, 42))	('ELK1', 'Gene', '2002', (5, 9))	('ERK', 'Gene', (39, 42))	('PTEN', 'Gene', (81, 85))	('dysregulated', 'Reg', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PIK3CA', 'Gene', (71, 77))
41348	28139702	Interestingly, many TF activities were associated with mutant PTEN irrespective of PIK3CA status in endometrial cancer (Supplementary Fig.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('mutant', 'Var', (55, 61))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('associated', 'Reg', (39, 49))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('activities', 'MPA', (23, 33))
41349	28139702	19), consistent with a recent preclinical study, while PIK3CA mutations were only significantly associated with a single TF, CREB1.	('CREB1', 'Gene', '1385', (125, 130))	('CREB1', 'Gene', (125, 130))	('associated', 'Reg', (96, 106))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (55, 61))	('mutations', 'Var', (62, 71))
41350	28139702	Therefore, PTEN and PIK3CA appear to have distinct consequences for PI3K activation in UCEC.	('PTEN', 'Gene', (11, 15))	('activation', 'PosReg', (73, 83))	('PTEN', 'Gene', '5728', (11, 15))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))	('PI3K', 'Var', (68, 72))	('UCEC', 'Disease', (87, 91))
41351	28139702	PI3K pathway inhibition is known to alter STAT5 (ref.	('inhibition', 'Var', (13, 23))	('PI3K pathway', 'Pathway', (0, 12))	('STAT5', 'Gene', '6776', (42, 47))	('STAT5', 'Gene', (42, 47))
41355	28139702	We also examined protein microarray-based AKT1 kinase assay and SILAC-based phosphoproteomic data from isogenic knock-in breast cell lines harbouring mutations of PIK3CA (see Methods section).	('AKT1', 'Gene', '207', (42, 46))	('AKT1', 'Gene', (42, 46))	('PIK3CA', 'Gene', (163, 169))	('mutations', 'Var', (150, 159))	('PIK3CA', 'Gene', '5290', (163, 169))
41356	28139702	Of 11 TFs represented in the phosphoproteomic data and associated with mutant PIK3CA in BRCA, eight of them:ADD1, FOXO3, HMGA1, HSF1, JUND, NF1, POU2F1, STAT3:showed protein abundance change in isogenic cell line systems (see Methods section and Supplementary Table 12).	('PIK3CA', 'Gene', (78, 84))	('STAT3', 'Gene', '6774', (153, 158))	('ADD1', 'Gene', (108, 112))	('POU2F1', 'Gene', (145, 151))	('HMGA1', 'Gene', (121, 126))	('FOXO3', 'Gene', '2309', (114, 119))	('ADD1', 'Gene', '118', (108, 112))	('mutant', 'Var', (71, 77))	('HSF1', 'Gene', '3297', (128, 132))	('NF1', 'Gene', '4763', (140, 143))	('HSF1', 'Gene', (128, 132))	('HMGA1', 'Gene', '3159', (121, 126))	('JUND', 'Gene', (134, 138))	('PIK3CA', 'Gene', '5290', (78, 84))	('NF1', 'Gene', (140, 143))	('JUND', 'Gene', '3727', (134, 138))	('change', 'Reg', (184, 190))	('BRCA', 'Gene', '672', (88, 92))	('STAT3', 'Gene', (153, 158))	('POU2F1', 'Gene', '5451', (145, 151))	('FOXO3', 'Gene', (114, 119))	('BRCA', 'Gene', (88, 92))	('protein abundance', 'MPA', (166, 183))
41357	28139702	Moreover, of the six TFs represented in the AKT1 kinase assay and associated with mutant PIK3CA in BRCA, four of them:ETS1, ATF6, SOX9 and TEAD1:were identified as AKT substrates (Supplementary Table 13).	('PIK3CA', 'Gene', '5290', (89, 95))	('AKT1', 'Gene', '207', (44, 48))	('ETS1', 'Gene', (118, 122))	('mutant', 'Var', (82, 88))	('AKT', 'Gene', (164, 167))	('AKT', 'Gene', (44, 47))	('BRCA', 'Gene', '672', (99, 103))	('SOX9', 'Gene', (130, 134))	('AKT1', 'Gene', (44, 48))	('PIK3CA', 'Gene', (89, 95))	('ATF6', 'Gene', (124, 128))	('AKT', 'Gene', '207', (164, 167))	('TEAD1', 'Gene', (139, 144))	('BRCA', 'Gene', (99, 103))	('SOX9', 'Gene', '6662', (130, 134))	('AKT', 'Gene', '207', (44, 47))	('TEAD1', 'Gene', '7003', (139, 144))	('ETS1', 'Gene', '2113', (118, 122))	('ATF6', 'Gene', '22926', (124, 128))
41358	28139702	Our analysis associated mutant PIK3CA with ELK1 and TCF4 activity in both breast and head and neck cancer, and with FOXO1 activity in BRCA but not in head and neck cancer.	('BRCA', 'Gene', '672', (134, 138))	('head and neck cancer', 'Disease', 'MESH:D006258', (150, 170))	('ELK1', 'Gene', (43, 47))	('activity', 'MPA', (57, 65))	('mutant', 'Var', (24, 30))	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('FOXO1', 'Gene', '2308', (116, 121))	('BRCA', 'Gene', (134, 138))	('PIK3CA', 'Gene', '5290', (31, 37))	('FOXO1', 'Gene', (116, 121))	('TCF4', 'Gene', '6925', (52, 56))	('head and neck cancer', 'Disease', 'MESH:D006258', (85, 105))	('ELK1', 'Gene', '2002', (43, 47))	('breast', 'Disease', (74, 80))	('head and neck cancer', 'Phenotype', 'HP:0012288', (150, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('TCF4', 'Gene', (52, 56))	('PIK3CA', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('activity', 'MPA', (122, 130))
41360	28139702	First, we used the parental MCF7 cell line carrying the PIK3CA E545K mutation and an MCF7 PIK3CA WT cell line in which the mutation was corrected using gene targeting.	('MCF7', 'CellLine', 'CVCL:0031', (28, 32))	('E545K', 'Mutation', 'rs104886003', (63, 68))	('E545K', 'Var', (63, 68))	('PIK3CA', 'Gene', (56, 62))	('PIK3CA', 'Gene', (90, 96))	('MCF7', 'CellLine', 'CVCL:0031', (85, 89))	('PIK3CA', 'Gene', '5290', (56, 62))	('PIK3CA', 'Gene', '5290', (90, 96))
41363	28139702	), WNK1, PAPLN, FOXP4 and DDX27 confirmed significant increases in mRNA levels in the parental PIK3CA mutant cells compared to PIK3CA WT cells, with the exception of PAPLN, where we observed a significant decrease (Fig.	('mutant', 'Var', (102, 108))	('PAPLN', 'Gene', (166, 171))	('WNK1', 'Gene', (3, 7))	('PIK3CA', 'Gene', (95, 101))	('DDX27', 'Gene', '55661', (26, 31))	('PAPLN', 'Gene', (9, 14))	('PIK3CA', 'Gene', '5290', (95, 101))	('DDX27', 'Gene', (26, 31))	('mRNA levels', 'MPA', (67, 78))	('PIK3CA', 'Gene', (127, 133))	('FOXP4', 'Gene', '116113', (16, 21))	('PIK3CA', 'Gene', '5290', (127, 133))	('increases', 'PosReg', (54, 63))	('FOXP4', 'Gene', (16, 21))	('WNK1', 'Gene', '65125', (3, 7))	('PAPLN', 'Gene', '89932', (166, 171))	('PAPLN', 'Gene', '89932', (9, 14))
41364	28139702	Moreover, ChIP-qPCR experiments confirmed that ELK1 binding to all five target gene promoters was significantly increased in the PIK3CA mutant MCF7 compared to WT cells, showing that mutant PIK3CA enhances ELK1 transcriptional activity in BRCA cells (Fig.	('enhances', 'PosReg', (197, 205))	('PIK3CA', 'Gene', '5290', (190, 196))	('PIK3CA', 'Gene', (129, 135))	('BRCA', 'Gene', '672', (239, 243))	('mutant', 'Var', (183, 189))	('PIK3CA', 'Gene', '5290', (129, 135))	('binding', 'Interaction', (52, 59))	('ELK1', 'Gene', (47, 51))	('increased', 'PosReg', (112, 121))	('transcriptional activity', 'MPA', (211, 235))	('MCF7', 'CellLine', 'CVCL:0031', (143, 147))	('PIK3CA', 'Gene', (190, 196))	('ELK1', 'Gene', '2002', (47, 51))	('ELK1', 'Gene', (206, 210))	('mutant', 'Var', (136, 142))	('ELK1', 'Gene', '2002', (206, 210))	('BRCA', 'Gene', (239, 243))
41365	28139702	Well-known TCF4 target genes such as WNT10B, APC, FBXW11 and PPP2R5E were differentially regulated by the PIK3CA E545K mutation in MCF7 cells (Fig.	('WNT10B', 'Gene', (37, 43))	('PPP2R5E', 'Gene', '5529', (61, 68))	('E545K', 'Mutation', 'rs104886003', (113, 118))	('E545K', 'Var', (113, 118))	('FBXW11', 'Gene', (50, 56))	('WNT10B', 'Gene', '7480', (37, 43))	('PIK3CA', 'Gene', (106, 112))	('PPP2R5E', 'Gene', (61, 68))	('TCF4', 'Gene', (11, 15))	('PIK3CA', 'Gene', '5290', (106, 112))	('MCF7', 'CellLine', 'CVCL:0031', (131, 135))	('TCF4', 'Gene', '6925', (11, 15))	('FBXW11', 'Gene', '23291', (50, 56))	('regulated', 'Reg', (89, 98))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))
41366	28139702	21b), and ChIP-qPCR analysis confirmed enhanced binding of TCF4 to their promoters in mutant PIK3CA cells (Fig.	('TCF4', 'Gene', (59, 63))	('TCF4', 'Gene', '6925', (59, 63))	('PIK3CA', 'Gene', '5290', (93, 99))	('mutant', 'Var', (86, 92))	('binding', 'Interaction', (48, 55))	('PIK3CA', 'Gene', (93, 99))	('enhanced', 'PosReg', (39, 47))
41368	28139702	mRNA confirmed that their mRNA levels were differentially regulated by the PIK3CA E545K mutation (Fig.	('PIK3CA', 'Gene', (75, 81))	('E545K', 'Var', (82, 87))	('PIK3CA', 'Gene', '5290', (75, 81))	('mRNA levels', 'MPA', (26, 37))	('regulated', 'Reg', (58, 67))	('E545K', 'Mutation', 'rs104886003', (82, 87))
41371	28139702	Control, PIK3CA WT or PIK3CA E545K vectors were overexpressed in Cal27, and ChIP-qPCR and RT-qPCR expression experiments were performed to investigate the activity of ELK1, TCF4 and FOXO1.	('PIK3CA', 'Gene', '5290', (22, 28))	('PIK3CA', 'Gene', '5290', (9, 15))	('FOXO1', 'Gene', (182, 187))	('FOXO1', 'Gene', '2308', (182, 187))	('ELK1', 'Gene', (167, 171))	('TCF4', 'Gene', '6925', (173, 177))	('ELK1', 'Gene', '2002', (167, 171))	('PIK3CA', 'Gene', (9, 15))	('Cal27', 'CellLine', 'CVCL:1107', (65, 70))	('expression', 'Species', '29278', (98, 108))	('TCF4', 'Gene', (173, 177))	('PIK3CA', 'Gene', (22, 28))	('E545K', 'Mutation', 'rs104886003', (29, 34))	('E545K', 'Var', (29, 34))
41373	28139702	Like in the MCF7 BRCA model, RT-qPCR analysis demonstrated an increase in the mRNA levels of four known ELK1 target genes, ACTR3, PSMB4, WNK1 and DDX27, in Cal27 cells transfected with PIK3CA E545K compared to Cal27 cells transfected with WT PIK3CA and control cells (Fig.	('E545K', 'Var', (192, 197))	('PIK3CA', 'Gene', '5290', (185, 191))	('PIK3CA', 'Gene', (242, 248))	('ELK1', 'Gene', (104, 108))	('increase', 'PosReg', (62, 70))	('PSMB4', 'Gene', (130, 135))	('MCF7', 'CellLine', 'CVCL:0031', (12, 16))	('ACTR3', 'Gene', (123, 128))	('BRCA', 'Gene', '672', (17, 21))	('Cal27', 'CellLine', 'CVCL:1107', (156, 161))	('mRNA levels', 'MPA', (78, 89))	('PIK3CA', 'Gene', (185, 191))	('WNK1', 'Gene', (137, 141))	('DDX27', 'Gene', (146, 151))	('PSMB4', 'Gene', '5692', (130, 135))	('ELK1', 'Gene', '2002', (104, 108))	('BRCA', 'Gene', (17, 21))	('E545K', 'Mutation', 'rs104886003', (192, 197))	('Cal27', 'CellLine', 'CVCL:1107', (210, 215))	('ACTR3', 'Gene', '10096', (123, 128))	('PIK3CA', 'Gene', '5290', (242, 248))	('WNK1', 'Gene', '65125', (137, 141))	('DDX27', 'Gene', '55661', (146, 151))
41374	28139702	Increased occupancy of ELK1 at target promoters was confirmed by ChIP-qPCR assays only when cells were transfected with the PIK3CA E545K vector (Fig.	('ELK1', 'Gene', (23, 27))	('PIK3CA', 'Gene', (124, 130))	('E545K', 'Mutation', 'rs104886003', (131, 136))	('ELK1', 'Gene', '2002', (23, 27))	('E545K', 'Var', (131, 136))	('PIK3CA', 'Gene', '5290', (124, 130))
41375	28139702	Thus, ELK1 transcriptional activity is enhanced by mutant PIK3CA in both head and neck and BRCA models.	('transcriptional activity', 'MPA', (11, 35))	('BRCA', 'Gene', (91, 95))	('mutant', 'Var', (51, 57))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('ELK1', 'Gene', (6, 10))	('BRCA', 'Gene', '672', (91, 95))	('ELK1', 'Gene', '2002', (6, 10))	('enhanced', 'PosReg', (39, 47))
41376	28139702	RT-qPCR analysis demonstrated an increase in the mRNA levels of four TCF4 target genes in Cal27 cells with PIK3CA E545K compared to WT Cal27 and control cells (Fig.	('mRNA levels of', 'MPA', (49, 63))	('Cal27', 'CellLine', 'CVCL:1107', (90, 95))	('TCF4', 'Gene', '6925', (69, 73))	('Cal27', 'CellLine', 'CVCL:1107', (135, 140))	('TCF4', 'Gene', (69, 73))	('increase', 'PosReg', (33, 41))	('PIK3CA', 'Gene', (107, 113))	('PIK3CA', 'Gene', '5290', (107, 113))	('E545K', 'Mutation', 'rs104886003', (114, 119))	('E545K', 'Var', (114, 119))
41377	28139702	Increased occupancy of TCF4 at the promoters of these genes was confirmed by ChIP assays only when cells were transfected with the PIK3CA E545K vector (Fig.	('E545K', 'Mutation', 'rs104886003', (138, 143))	('E545K', 'Var', (138, 143))	('PIK3CA', 'Gene', (131, 137))	('PIK3CA', 'Gene', '5290', (131, 137))	('TCF4', 'Gene', (23, 27))	('TCF4', 'Gene', '6925', (23, 27))
41378	28139702	Thus, mutant PIK3CA enhances TCF4 transcriptional activity in head and neck as well as BRCA models.	('mutant', 'Var', (6, 12))	('PIK3CA', 'Gene', (13, 19))	('BRCA', 'Gene', '672', (87, 91))	('transcriptional activity', 'MPA', (34, 58))	('BRCA', 'Gene', (87, 91))	('enhances', 'PosReg', (20, 28))	('PIK3CA', 'Gene', '5290', (13, 19))	('TCF4', 'Gene', (29, 33))	('TCF4', 'Gene', '6925', (29, 33))
41379	28139702	FOXO1 activity was not associated with mutant PIK3CA in our HNSC model.	('activity', 'MPA', (6, 14))	('PIK3CA', 'Gene', '5290', (46, 52))	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('mutant', 'Var', (39, 45))	('PIK3CA', 'Gene', (46, 52))
41381	28139702	Further, no change in occupancy of FOXO1 at the promoters of TNFSF10 and RUNX1 was shown by ChIP assays when cells were transfected with the PIK3CA E545K vector (Fig.	('PIK3CA', 'Gene', '5290', (141, 147))	('RUNX1', 'Gene', (73, 78))	('occupancy', 'MPA', (22, 31))	('RUNX1', 'Gene', '861', (73, 78))	('FOXO1', 'Gene', '2308', (35, 40))	('PIK3CA', 'Gene', (141, 147))	('E545K', 'Mutation', 'rs104886003', (148, 153))	('E545K', 'Var', (148, 153))	('TNFSF10', 'Gene', (61, 68))	('FOXO1', 'Gene', (35, 40))	('TNFSF10', 'Gene', '8743', (61, 68))
41384	28139702	Our computational and experimental results suggest that a potential mechanism for ELK1 activation is through an activating PIK3CA mutation.	('activation', 'PosReg', (87, 97))	('mutation', 'Var', (130, 138))	('PIK3CA', 'Gene', (123, 129))	('PIK3CA', 'Gene', '5290', (123, 129))	('ELK1', 'Gene', (82, 86))	('ELK1', 'Gene', '2002', (82, 86))	('activating', 'PosReg', (112, 122))
41386	28139702	Our analyses confirm that TCF4 activation may result from an activating PIK3CA mutation.	('PIK3CA', 'Gene', (72, 78))	('mutation', 'Var', (79, 87))	('activation', 'PosReg', (31, 41))	('PIK3CA', 'Gene', '5290', (72, 78))	('TCF4', 'Gene', (26, 30))	('TCF4', 'Gene', '6925', (26, 30))	('activating', 'PosReg', (61, 71))
41388	28139702	Since we demonstrated altered transcriptional activity of TCF4 downstream of mutant PIK3CA in breast and head and neck cancer cells, targeting TCF4 might be new therapeutic strategy in PIK3CA mutant patients.	('PIK3CA', 'Gene', '5290', (84, 90))	('head and neck cancer', 'Disease', 'MESH:D006258', (105, 125))	('TCF4', 'Gene', (58, 62))	('TCF4', 'Gene', (143, 147))	('TCF4', 'Gene', '6925', (58, 62))	('PIK3CA', 'Gene', (185, 191))	('altered', 'Reg', (22, 29))	('head and neck cancer', 'Phenotype', 'HP:0012288', (105, 125))	('PIK3CA', 'Gene', (84, 90))	('patients', 'Species', '9606', (199, 207))	('PIK3CA', 'Gene', '5290', (185, 191))	('mutant', 'Var', (77, 83))	('transcriptional activity', 'MPA', (30, 54))	('TCF4', 'Gene', '6925', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
41391	28139702	Specifically, we showed that an activating PIK3CA mutation altered FOXO1 activity in the BRCA model but not in the head and neck cancer model, consistent with the context-specific predictions of our algorithm.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('FOXO1', 'Gene', (67, 72))	('FOXO1', 'Gene', '2308', (67, 72))	('PIK3CA', 'Gene', '5290', (43, 49))	('BRCA', 'Gene', (89, 93))	('activity', 'MPA', (73, 81))	('head and neck cancer', 'Disease', 'MESH:D006258', (115, 135))	('head and neck cancer', 'Phenotype', 'HP:0012288', (115, 135))	('BRCA', 'Gene', '672', (89, 93))	('activating', 'PosReg', (32, 42))	('mutation', 'Var', (50, 58))	('PIK3CA', 'Gene', (43, 49))
41392	28139702	This shows one example of how a clinically relevant 'actionable mutation' impacts regulatory programs in a cancer-specific manner, giving clues about druggability across tumour types.	('tumour type', 'Disease', 'MESH:D009369', (170, 181))	('tumour type', 'Disease', (170, 181))	('regulatory programs', 'MPA', (82, 101))	('impacts', 'Reg', (74, 81))	("mutation'", 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('clues', 'Reg', (138, 143))	('cancer', 'Disease', (107, 113))
41394	28139702	For example, activating mutations and amplifications of PIK3CA are targetable by PI3K inhibitors, which are in active clinical assessment in combination therapies with RTK inhibitors and antioestrogen therapies in BRCA, antiandrogen therapy in PRAD and MEK inhibitors in many solid tumours.	('solid tumours', 'Disease', 'MESH:D009369', (276, 289))	('tumour', 'Phenotype', 'HP:0002664', (282, 288))	('amplifications', 'Var', (38, 52))	('activating', 'PosReg', (13, 23))	('solid tumours', 'Disease', (276, 289))	('MEK', 'Gene', '5604;5605', (253, 256))	('PIK3CA', 'Gene', (56, 62))	('BRCA', 'Gene', '672', (214, 218))	('tumours', 'Phenotype', 'HP:0002664', (282, 289))	('BRCA', 'Gene', (214, 218))	('MEK', 'Gene', (253, 256))	('PIK3CA', 'Gene', '5290', (56, 62))
41401	28139702	Linking mutant beta-catenin to putative downstream TF effectors could inform future mechanistic studies:for example, short hairpin RNA or CRISPR/Cas screening to identify TFs whose deletion/knockdown leads to changes in proliferation:to develop new therapeutic strategies.	('proliferation', 'MPA', (220, 233))	('changes', 'Reg', (209, 216))	('mutant', 'Var', (8, 14))	('beta-catenin', 'Gene', (15, 27))	('beta-catenin', 'Gene', '1499', (15, 27))	('deletion/knockdown', 'Var', (181, 199))
41402	28139702	Several recent studies have integrated TF binding site or occupancy data to identify cancer-associated TFs, for example, combining tumour-specific DNA methylation changes in distal enhancers, mRNA sequencing and cis-regulatory sequences mediating effects on target genes or integrating ENCODE TF ChIP-seq profiles with the pancancer TCGA expression data.	('changes', 'Var', (163, 170))	('tumour', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('expression', 'Species', '29278', (338, 348))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('cancer', 'Disease', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', (326, 332))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
41416	28139702	We obtained SILAC-based quantitative phosphoproteomic data set of a spontaneously immortalized non-tumorigenic breast epithelial cell line MCF10A along with two isogenic derivatives generated by knock-in of mutant alleles:one bearing the E545K mutation and the other bearing the H1047R mutation of the PIK3CA gene:from the originally published Supplementary Data.	('MCF10A', 'CellLine', 'CVCL:0598', (139, 145))	('H1047R', 'Mutation', 'rs121913279', (279, 285))	('PIK3CA', 'Gene', (302, 308))	('PIK3CA', 'Gene', '5290', (302, 308))	('H1047R', 'Var', (279, 285))	('E545K', 'Var', (238, 243))	('E545K', 'Mutation', 'rs104886003', (238, 243))
41442	28139702	The BRCA cell line, MCF7, which has a PIK3CA E545K mutation, and the targeted correction of the E545K mutation to WT PIK3CA were obtained from the Lauring Lab.	('BRCA', 'Gene', '672', (4, 8))	('BRCA', 'Gene', (4, 8))	('PIK3CA', 'Gene', (38, 44))	('E545K mutation', 'Var', (45, 59))	('PIK3CA', 'Gene', (117, 123))	('E545K', 'Mutation', 'rs104886003', (96, 101))	('E545K', 'Var', (96, 101))	('PIK3CA', 'Gene', '5290', (38, 44))	('E545K', 'Mutation', 'rs104886003', (45, 50))	('PIK3CA', 'Gene', '5290', (117, 123))	('MCF7', 'CellLine', 'CVCL:0031', (20, 24))
41446	28139702	Cal27 cell lines were transfected with pbabe control vector, pbabe WT PIK3CA and pbabe E545K PIK3CA vectors (Addgene) using Lipofectamine 3000 according to the manufacturer's instructions.	('PIK3CA', 'Gene', '5290', (93, 99))	('E545K', 'Mutation', 'rs104886003', (87, 92))	('E545K', 'Var', (87, 92))	('PIK3CA', 'Gene', (70, 76))	('Cal27', 'CellLine', 'CVCL:1107', (0, 5))	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (70, 76))	('Lipofectamine', 'Chemical', 'MESH:C086724', (124, 137))
41451	28139702	Sheared chromatin was incubated overnight with 2 mug of rabbit monoclonal ChIP grade antibody to ELK1 (E277, ab32106; Abcam) as has been previously used by Zhang et al.	('rabbit', 'Species', '9986', (56, 62))	('E277', 'Var', (103, 107))	('ELK1', 'Gene', '2002', (97, 101))	('ELK1', 'Gene', (97, 101))
41467	27822490	Some have a chromosomal translocation of the Ewing sarcoma (EWS) gene on chromosome 22, which 90% of the time creates the EWSR1/FLI1 fusion product t(11;22)q24q12.	('EWSR1', 'Gene', '2130', (122, 127))	('t(11;22)q24q12', 'Var', (148, 162))	('EWS', 'Gene', '2130', (122, 125))	('FLI1', 'Gene', '2313', (128, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('FLI1', 'Gene', (128, 132))	('EWS', 'Gene', '2130', (60, 63))	('EWS', 'Gene', (60, 63))	('EWS', 'Phenotype', 'HP:0012254', (60, 63))	('Ewing sarcoma', 'Disease', (45, 58))	('creates', 'Reg', (110, 117))	('EWS', 'Phenotype', 'HP:0012254', (122, 125))	('EWSR1', 'Gene', (122, 127))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))	('EWS', 'Gene', (122, 125))
41513	27822490	The presence of endothelial proliferation and VEGF positivity within the tumor provides a rational explanation to the effectiveness of this novel chemotherapy modality against uterine cPNET.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('uterine cPNET', 'Disease', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('positivity', 'Var', (51, 61))	('VEGF', 'Gene', (46, 50))	('endothelial proliferation', 'CPA', (16, 41))	('tumor', 'Disease', (73, 78))	('VEGF', 'Gene', '7422', (46, 50))
41672	27499896	These were screened for ALT telomere maintenance by the presence of ALT-associated PML bodies (APBs) and for changes associated with the ALT phenotype, namely aberrant p53 expression, isocitrate dehydrogenase 1 mutation (R132H substitution) expression, mutant ATRX (alphathalassemia/mental retardation syndrome X-linked) expression and mutant DAXX (death-domain-associated protein) expression by immunohistochemistry (IHC).	('R132H substitution', 'Var', (221, 239))	('PML', 'Gene', (83, 86))	('mental retardation', 'Phenotype', 'HP:0001249', (283, 301))	('alphathalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:D038901', (266, 319))	('APBs', 'Chemical', '-', (95, 99))	('ALT', 'Chemical', '-', (24, 27))	('p53', 'Gene', (168, 171))	('mutant', 'Var', (336, 342))	('ATRX', 'Gene', (260, 264))	('death', 'Disease', (349, 354))	('PML', 'Gene', '5371', (83, 86))	('ATRX', 'Gene', '546', (260, 264))	('R132H', 'Mutation', 'rs121913500', (221, 226))	('isocitrate dehydrogenase 1', 'Gene', (184, 210))	('isocitrate dehydrogenase 1', 'Gene', '3417', (184, 210))	('DAXX', 'Gene', (343, 347))	('ALT', 'Chemical', '-', (68, 71))	('DAXX', 'Gene', '1616', (343, 347))	('mutant', 'Var', (253, 259))	('death', 'Disease', 'MESH:D003643', (349, 354))	('ALT', 'Chemical', '-', (137, 140))	('p53', 'Gene', '7157', (168, 171))	('expression', 'MPA', (321, 331))
41687	27499896	ALT maintenance in pancreatic neuroendocrine tumours and pediatric glioblastoma multiforme has been shown to closely correlate with the presence of a mutation in ATRX and DAXX genes 12, 13.	('DAXX', 'Gene', (171, 175))	('pediatric glioblastoma multiforme', 'Disease', (57, 90))	('mutation', 'Var', (150, 158))	('pancreatic neuroendocrine tumours', 'Disease', 'MESH:D010190', (19, 52))	('pediatric glioblastoma multiforme', 'Disease', 'MESH:D005909', (57, 90))	('pancreatic neuroendocrine tumours', 'Disease', (19, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('DAXX', 'Gene', '1616', (171, 175))	('ATRX', 'Gene', (162, 166))	('ALT', 'Chemical', '-', (0, 3))	('ATRX', 'Gene', '546', (162, 166))
41688	27499896	In glioblastoma multiforme ALT tumours were associated with simultaneous mutations in ATRX-DAXX, p53 and H3F3A 14.	('associated', 'Reg', (44, 54))	('ATRX', 'Gene', '546', (86, 90))	('glioblastoma multiforme ALT tumours', 'Disease', (3, 38))	('p53', 'Gene', (97, 100))	('DAXX', 'Gene', (91, 95))	('H3F3A', 'Gene', (105, 110))	('glioblastoma multiforme ALT tumours', 'Disease', 'MESH:D005909', (3, 38))	('p53', 'Gene', '7157', (97, 100))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('ATRX', 'Gene', (86, 90))	('DAXX', 'Gene', '1616', (91, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('H3F3A', 'Gene', '3020', (105, 110))	('mutations', 'Var', (73, 82))
41691	27499896	Isocitrate dehydrogenase (IDH) mutations have also been identified in association with ALT activation in tumours 15, 16.	('ALT', 'Chemical', '-', (87, 90))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('mutations', 'Var', (31, 40))	('identified', 'Reg', (56, 66))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('tumours 15', 'Disease', 'MESH:C567447', (105, 115))	('IDH', 'Gene', '3417', (26, 29))	('IDH', 'Gene', (26, 29))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('ALT activation', 'MPA', (87, 101))	('tumours 15', 'Disease', (105, 115))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('association', 'Reg', (70, 81))
41694	27499896	The profile of the ALT associated R132H IDH1 mutation was studied to provide a biological basis for its application as a radiological diagnostic and therapeutic tool.	('R132H', 'Mutation', 'rs121913500', (34, 39))	('IDH1', 'Gene', (40, 44))	('ALT', 'Chemical', '-', (19, 22))	('IDH1', 'Gene', '3417', (40, 44))	('ALT', 'Disease', (19, 22))	('R132H', 'Var', (34, 39))
41710	27499896	Mutant IDH1 was detected using the anti-Human IDH1 R132H specific mouse monoclonal antibody HO-9 (Dianova, Hamburg, Germany) diluted 1 in 50.	('IDH1', 'Gene', '3417', (7, 11))	('Human', 'Species', '9606', (40, 45))	('IDH1', 'Gene', (46, 50))	('mouse', 'Species', '10090', (66, 71))	('R132H', 'Var', (51, 56))	('HO-9', 'CellLine', 'CVCL:M698', (92, 96))	('R132H', 'Mutation', 'rs121913500', (51, 56))	('IDH1', 'Gene', '3417', (46, 50))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))
41711	27499896	ATRX was detected using HPA001906 (Sigma-Aldrich, St Louis, MO) diluted 1 in 700.	('ATRX', 'Gene', '546', (0, 4))	('HPA001906', 'Var', (24, 33))	('ATRX', 'Gene', (0, 4))
41740	27499896	All tumours were screened for APB presence, p53 aberrant expression (a surrogate for p53 mutation), IDH1 R132H mutation expression and ATRX or DAXX expression loss to determine the ALT phenotype.	('ATRX', 'Gene', '546', (135, 139))	('aberrant expression', 'Var', (48, 67))	('tumours', 'Disease', (4, 11))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('R132H', 'Mutation', 'rs121913500', (105, 110))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('IDH1', 'Gene', (100, 104))	('ALT', 'Chemical', '-', (181, 184))	('p53', 'Gene', '7157', (85, 88))	('R132H mutation', 'Var', (105, 119))	('p53', 'Gene', '7157', (44, 47))	('p53', 'Gene', (85, 88))	('DAXX', 'Gene', (143, 147))	('IDH1', 'Gene', '3417', (100, 104))	('loss', 'NegReg', (159, 163))	('p53', 'Gene', (44, 47))	('APB', 'Gene', (30, 33))	('DAXX', 'Gene', '1616', (143, 147))	('ATRX', 'Gene', (135, 139))	('APB', 'Gene', '6051', (30, 33))
41748	27499896	No STUMP and 14% (6/43) of LMS cases showed IDH1 R132H mutation expression.	('R132H', 'Var', (49, 54))	('IDH1', 'Gene', (44, 48))	('R132H', 'Mutation', 'rs121913500', (49, 54))	('IDH1', 'Gene', '3417', (44, 48))	('LMS', 'Disease', (27, 30))	('LMS', 'Phenotype', 'HP:0100243', (27, 30))
41759	27499896	Univariate Cox regression showed that, for overall survival in the LMS group, loss of ATRX or DAXX expression identified poor prognosis (CI 2.1 to 40, p < 0.003) and, for progression free survival, loss of ATRX or DAXX expression was statistically significant (CI 2.2 to 25, p = 0.001).	('DAXX', 'Gene', (214, 218))	('ATRX', 'Gene', '546', (86, 90))	('ATRX', 'Gene', (206, 210))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('DAXX', 'Gene', '1616', (94, 98))	('LMS', 'Phenotype', 'HP:0100243', (67, 70))	('DAXX', 'Gene', '1616', (214, 218))	('DAXX', 'Gene', (94, 98))	('ATRX', 'Gene', (86, 90))	('ATRX', 'Gene', '546', (206, 210))	('loss', 'Var', (78, 82))	('poor', 'NegReg', (121, 125))
41761	27499896	Aberrant p53 expression did not reach significance.	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))
41770	27499896	This does not prove mutation and is less sensitive on small-sized tissue microarrays compared to sequence based methods to identify ATRX mutations directly 22.	('ATRX', 'Gene', (132, 136))	('mutations', 'Var', (137, 146))	('ATRX', 'Gene', '546', (132, 136))
41775	27499896	However, for patients with ATRX or DAXX expression loss, the associated mutant p53 in their tumours may make such treatment ineffective.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('mutant', 'Var', (72, 78))	('DAXX', 'Gene', '1616', (35, 39))	('patients', 'Species', '9606', (13, 21))	('ATRX', 'Gene', (27, 31))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('ATRX', 'Gene', '546', (27, 31))	('DAXX', 'Gene', (35, 39))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
41776	27499896	The acquisition of the R132H IDH1 mutation leads to an alteration in catalytic ability and the production of an oncometabolite, R(-)-2-hydroxyglutarate (2-HG) that inhibits histone demethylases and indirectly affects H3F3A methylation 23, 24, 25.	('alteration', 'Reg', (55, 65))	('inhibits', 'NegReg', (164, 172))	('IDH1', 'Gene', (29, 33))	('affects', 'Reg', (209, 216))	('H3F3A', 'Gene', '3020', (217, 222))	('catalytic ability', 'MPA', (69, 86))	('IDH1', 'Gene', '3417', (29, 33))	('H3F3A', 'Gene', (217, 222))	('histone demethylases', 'Enzyme', (173, 193))	('R132H', 'Var', (23, 28))	('R132H', 'Mutation', 'rs121913500', (23, 28))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (128, 151))	('methylation 23', 'MPA', (223, 237))
41777	27499896	Furthermore, 2-HG has been identified by noninvasive imaging 26, and tumours with the mutant enzyme may be susceptible to chemotherapy 27.	('tumours', 'Disease', (69, 76))	('mutant', 'Var', (86, 92))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
41778	27499896	The R132H IDH1 mutation precedes mutation of p53, which appears to be the lynch pin facilitating recombination and the emergence of the gross deregulated ALT telomere length phenotype 28.	('p53', 'Gene', (45, 48))	('ALT telomere length phenotype', 'MPA', (154, 183))	('p53', 'Gene', '7157', (45, 48))	('IDH1', 'Gene', '3417', (10, 14))	('ALT', 'Chemical', '-', (154, 157))	('IDH1', 'Gene', (10, 14))	('R132H', 'Var', (4, 9))	('R132H', 'Mutation', 'rs121913500', (4, 9))
41779	27499896	IDH1(R132H) status by IHC was not informative in our cohort, but our analysis did not capture all mutations in IDH.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (111, 114))	('mutations', 'Var', (98, 107))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('IDH', 'Gene', '3417', (111, 114))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
41781	27499896	The R132H IDH1 mutation is the most prominent IDH1 mutation in glioma 29, 30, but in cartilaginous tumours other mutations in IDH1 were more frequent than R132H 31, 32.	('IDH1', 'Gene', '3417', (126, 130))	('IDH1', 'Gene', '3417', (10, 14))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('IDH1', 'Gene', (46, 50))	('cartilaginous tumours', 'Disease', 'MESH:D015831', (85, 106))	('R132H', 'Mutation', 'rs121913500', (155, 160))	('IDH1', 'Gene', '3417', (46, 50))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', (126, 130))	('IDH1', 'Gene', (10, 14))	('R132H', 'Mutation', 'rs121913500', (4, 9))	('R132H', 'Var', (4, 9))	('cartilaginous tumours', 'Disease', (85, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('glioma', 'Disease', (63, 69))
41782	27499896	We identified IDH1 R132H mutation in a LM, which has not been previously reported.	('IDH1', 'Gene', (14, 18))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('R132H', 'Var', (19, 24))	('IDH1', 'Gene', '3417', (14, 18))
41785	27499896	In the absence of a known viral oncogene, overexpression in these tumours probably reflects the mutational or epigenetic status of the retinoblastoma gene.	('mutational', 'Var', (96, 106))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('retinoblastoma', 'Disease', 'MESH:D012175', (135, 149))	('retinoblastoma', 'Disease', (135, 149))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('epigenetic status', 'Var', (110, 127))	('overexpression', 'PosReg', (42, 56))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('retinoblastoma', 'Phenotype', 'HP:0009919', (135, 149))
41786	27499896	Indeed, alterations of the retinoblastoma gene locus play an important role in the pathogenesis of LMS 35.	('alterations', 'Var', (8, 19))	('LMS 35', 'Disease', (99, 105))	('retinoblastoma', 'Phenotype', 'HP:0009919', (27, 41))	('LMS', 'Phenotype', 'HP:0100243', (99, 102))	('retinoblastoma', 'Disease', 'MESH:D012175', (27, 41))	('retinoblastoma', 'Disease', (27, 41))
41794	27499896	These tumours highlight the importance of identifying specific criteria for a specific tumour, in different anatomical sites, but also suggest loss of ATRX or DAXX expression may prove similarly prognostic as in uterine tumours.	('tumour', 'Disease', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('DAXX', 'Gene', '1616', (159, 163))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour', 'Disease', 'MESH:D009369', (220, 226))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('tumour', 'Disease', (220, 226))	('tumour', 'Disease', (6, 12))	('tumours', 'Disease', (220, 227))	('tumours', 'Disease', (6, 13))	('ATRX', 'Gene', (151, 155))	('ATRX', 'Gene', '546', (151, 155))	('tumours', 'Phenotype', 'HP:0002664', (220, 227))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('DAXX', 'Gene', (159, 163))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('loss', 'Var', (143, 147))	('tumours', 'Disease', 'MESH:D009369', (220, 227))
41863	25398397	The HER2/neu oncogene has been reported as overexpressed and/or amplified in various human tumor types including CS of the female genital tract.	('CS of the female genital tract', 'Disease', (113, 143))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('HER2/neu', 'Gene', '2064', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('HER2/neu', 'Gene', (4, 12))	('overexpressed', 'PosReg', (43, 56))	('amplified', 'Var', (64, 73))	('human', 'Species', '9606', (85, 90))
41925	25398397	Indeed, all animals treated with T-DM-1 (i.e., 5 out of 5) remained free of detectable tumor for the entire duration of the study period (i.e., over 90 days) with a P value of P=0.008 and P=0.0001 when compared to T and vehicle group respectively (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (87, 92))	('T-DM-1', 'Var', (33, 39))
41965	18755503	After adjusting for stage and age, the recurrence rate at 5 years was 21% lower for CIM v WAI (relative hazard [RH] = 0.789, 95% confidence interval [CI]: (0.530-1.176), P = 0.245, 2-tail test).	('lower', 'NegReg', (74, 79))	('CIM', 'Var', (84, 87))	('CIM', 'Chemical', '-', (84, 87))
41966	18755503	The death rate was 29% lower for CIM v WAI (RH = 0.712, 95% CI: 0.484-1.048, P = 0.085, 2-tail test).	('CIM', 'Chemical', '-', (33, 36))	('death', 'Disease', 'MESH:D003643', (4, 9))	('death', 'Disease', (4, 9))	('CIM v WAI', 'Var', (33, 42))	('lower', 'NegReg', (23, 28))
42018	18755503	This study did, however, show that after adjusting for age and stage, the recurrence rate was 21% lower for CIM versus WAI.	('recurrence', 'MPA', (74, 84))	('CIM', 'Chemical', '-', (108, 111))	('CIM', 'Var', (108, 111))	('lower', 'NegReg', (98, 103))
42021	18755503	In prior single-agent GOG phase II and III trials, response rates have been as follows: etoposide (7%), topotecan (10%), doxorubicin (10%), cisplatin (18%) and ifosfamide (32%).	('doxorubicin', 'MPA', (121, 132))	('topotecan', 'Chemical', 'MESH:D019772', (104, 113))	('cisplatin', 'Var', (140, 149))	('etoposide', 'Chemical', 'MESH:D005047', (88, 97))	('doxorubicin', 'Chemical', 'MESH:D004317', (121, 132))	('ifosfamide', 'Chemical', 'MESH:D007069', (160, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('GOG', 'Chemical', '-', (22, 25))
42035	23585021	Impact of tubulin-beta-III knockdown on IC50 was assessed with siRNAs.	('tubulin-beta-III', 'Gene', '10381', (10, 26))	('knockdown', 'Var', (27, 36))	('tubulin-beta-III', 'Gene', (10, 26))
42037	23585021	Tubulin-beta-III immunohistochemistry reflected qRT-PCR copy number and overexpression stratified patients by overall survival (copy number <=400: 615 days; copy number >400: 165 days, p=0.049); p-glycoprotein did not predict clinical outcome.	('Tubulin-beta-III', 'Gene', '10381', (0, 16))	('patients', 'Species', '9606', (98, 106))	('copy number >400', 'Var', (157, 173))	('p-glycoprotein', 'Gene', (195, 209))	('Tubulin-beta-III', 'Gene', (0, 16))	('p-glycoprotein', 'Gene', '5243', (195, 209))
42038	23585021	USC remained exquisitely sensitive to patupilone in vitro despite tubulin-beta-III overexpression (IC50, USC 0.245+-0.11 nM versus IC50, OSC 1.01+-0.13 nM, p=0.006).	('OSC', 'Phenotype', 'HP:0012887', (137, 140))	('0.245+-0.11', 'Var', (109, 120))	('tubulin-beta-III', 'Gene', '10381', (66, 82))	('tubulin-beta-III', 'Gene', (66, 82))	('overexpression', 'PosReg', (83, 97))	('patupilone', 'Chemical', 'MESH:C093788', (38, 48))	('OS', 'Chemical', '-', (137, 139))
42070	23585021	Tubulin-beta-III (Hs00964962_g1) and p-glycoprotein (Hs00184491_m1) specific primers were obtained (Assay-On-Demand, Carlsbad, CA), with GAPDH (Hs99999905_m1) as an internal control.	('Tubulin-beta-III', 'Gene', '10381', (0, 16))	('p-glycoprotein', 'Gene', (37, 51))	('GAPDH', 'Gene', (137, 142))	('Hs99999905_m1', 'Var', (144, 157))	('Hs00184491_m1', 'Var', (53, 66))	('Hs00964962_g1', 'Var', (18, 31))	('Tubulin-beta-III', 'Gene', (0, 16))	('p-glycoprotein', 'Gene', '5243', (37, 51))	('GAPDH', 'Gene', '2597', (137, 142))
42104	23585021	Transfection successfully produced reductions in tubulin-beta-III of 83-93%, and efficiency was not affected by addition of chemotherapy (Figure 5b).	('tubulin-beta-III', 'Gene', '10381', (49, 65))	('reductions', 'NegReg', (35, 45))	('tubulin-beta-III', 'Gene', (49, 65))	('Transfection', 'Var', (0, 12))
42114	23585021	Using a cutoff of 400, median OS among patients with low and high tubulin-beta-III was 615 and 165 days, respectively (Figure 6b; p=0.049).	('low', 'NegReg', (53, 56))	('patients', 'Species', '9606', (39, 47))	('high', 'Var', (61, 65))	('tubulin-beta-III', 'Gene', '10381', (66, 82))	('tubulin-beta-III', 'Gene', (66, 82))	('OS', 'Chemical', '-', (30, 32))
42115	23585021	Of patients with high tubulin-beta-III expression, 71% demonstrated pure histology compared to 44% in those with low expression but this difference was not statistically different (p=0.33).	('tubulin-beta-III', 'Gene', '10381', (22, 38))	('tubulin-beta-III', 'Gene', (22, 38))	('high', 'Var', (17, 21))	('patients', 'Species', '9606', (3, 11))
42118	23585021	Among the USC cohort, mean tubulin-beta-III and p-glycoprotein copy numbers were 643.31 (range: 150-2837) and 72.63 (range: 9-304), respectively (Figure 6d/e).	('tubulin-beta-III', 'Gene', '10381', (27, 43))	('p-glycoprotein', 'Gene', '5243', (48, 62))	('tubulin-beta-III', 'Gene', (27, 43))	('643.31', 'Var', (81, 87))	('p-glycoprotein', 'Gene', (48, 62))
42135	23585021	Among patients with advanced-stage disease, we have shown for the first time in USC that tubulin-beta-III copy number may identify patients who are at risk of poorer OS.	('poorer', 'Disease', (159, 165))	('patients', 'Species', '9606', (131, 139))	('tubulin-beta-III', 'Gene', (89, 105))	('copy number', 'Var', (106, 117))	('patients', 'Species', '9606', (6, 14))	('OS', 'Chemical', '-', (166, 168))	('tubulin-beta-III', 'Gene', '10381', (89, 105))
42146	23585021	Epothilones warrant further clinical investigation in the treatment of these aggressive, chemoresistant tumors, especially in the setting of recurrent or persistent disease and high tubulin-beta-III expression.	('tubulin-beta-III', 'Gene', '10381', (182, 198))	('tubulin-beta-III', 'Gene', (182, 198))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('expression', 'MPA', (199, 209))	('high', 'Var', (177, 181))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('Epothilones', 'Chemical', 'MESH:D034261', (0, 11))
42149	23346316	For the development of genomic study in gynecologic cancers, BRCA and DICER1 mutations were covered in epithelial and nonepithelial ovarian cancer, respectively.	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (121, 146))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('DICER1', 'Gene', (70, 76))	('ovarian cancer', 'Disease', (132, 146))	('DICER1', 'Gene', '23405', (70, 76))	('epithelial ovarian', 'Disease', 'MESH:D000077216', (121, 139))	('mutations', 'Var', (77, 86))	('epithelial ovarian', 'Disease', (121, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('epithelial', 'Disease', (103, 113))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('BRCA', 'Gene', '672', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))	('BRCA', 'Gene', (61, 65))
42186	23346316	By contrast, a multicenter retrospective analysis of patients with EOC who progressed on bevacizumab therapy showed that PFS was statistically higher in no-bevacizumab beyond progression (BBP) group than that of BBP groups.	('bevacizumab', 'Chemical', 'MESH:D000068258', (156, 167))	('patients', 'Species', '9606', (53, 61))	('no-bevacizumab', 'Var', (153, 167))	('BBP', 'Chemical', '-', (188, 191))	('BBP', 'Chemical', '-', (212, 215))	('PFS', 'MPA', (121, 124))	('higher', 'PosReg', (143, 149))	('bevacizumab', 'Chemical', 'MESH:D000068258', (89, 100))
42192	23346316	PARP plays an important role in the repair of single-stranded DNA breaks, through the base excision repair pathway, keeping low-fidelity nonhomologous-end-joining DNA repair machinery in check.	('PARP', 'Gene', (0, 4))	('PARP', 'Gene', '142', (0, 4))	('single-stranded DNA', 'Var', (46, 65))
42193	23346316	Patients with EOC who harbor germ-line mutations in BRCA1/2 genes, approximately 10% of cases of EOC, exhibit defects in homologous recombination DNA repair.	('defects', 'NegReg', (110, 117))	('BRCA1/2', 'Gene', (52, 59))	('homologous recombination DNA repair', 'MPA', (121, 156))	('mutations', 'Var', (39, 48))	('BRCA1/2', 'Gene', '672;675', (52, 59))	('Patients', 'Species', '9606', (0, 8))	('EOC', 'Disease', (14, 17))
42196	23346316	reported the results of a phase II study in patients with recurrent ovarian cancer with germ-line BRCA mutations, in which the efficacy and safety of olaparib were compared with those of PLD.	('BRCA', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('patients', 'Species', '9606', (44, 52))	('olaparib', 'Chemical', 'MESH:C531550', (150, 158))	('ovarian cancer', 'Disease', 'MESH:D010051', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ovarian cancer', 'Disease', (68, 82))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (58, 82))	('BRCA', 'Gene', '672', (98, 102))
42197	23346316	A total of 97 patients with platinum-resistant recurrent ovarian cancer were randomly assigned in a 1:1:1 ratio to olaparib 200 mg bid or 400 mg bid continuously or PLD 50 mg/m2 intravenously q 4wks.	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('ovarian cancer', 'Disease', (57, 71))	('platinum', 'Chemical', 'MESH:D010984', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('olaparib', 'Gene', (115, 123))	('olaparib', 'Chemical', 'MESH:C531550', (115, 123))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (47, 71))	('patients', 'Species', '9606', (14, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('PLD', 'Var', (165, 168))
42202	23346316	Second, the predominance of BRCA1 mutation over BRCA2 mutation in each group could be one of the possible explanations for unsatisfactory activity of olaparib, considering known higher chemo-sensitivity of EOC patients with BRCA2 mutations than with BRCA1 mutations.	('BRCA1', 'Gene', '672', (28, 33))	('BRCA1', 'Gene', (250, 255))	('olaparib', 'Chemical', 'MESH:C531550', (150, 158))	('BRCA2', 'Gene', '675', (48, 53))	('BRCA2', 'Gene', '675', (224, 229))	('BRCA1', 'Gene', (28, 33))	('mutation', 'Var', (34, 42))	('mutations', 'Var', (230, 239))	('patients', 'Species', '9606', (210, 218))	('BRCA1', 'Gene', '672', (250, 255))	('BRCA2', 'Gene', (48, 53))	('BRCA2', 'Gene', (224, 229))
42203	23346316	Lastly, higher proportion of more heavily pretreated patients in the olaparib 400 mg group than PLD group (78.2% vs. 51.5%) may contribute to the development of secondary somatic mutations that restore BRCA1/2 function and may confer resistance to olaparib.	('patients', 'Species', '9606', (53, 61))	('function', 'MPA', (210, 218))	('BRCA1/2', 'Gene', '672;675', (202, 209))	('olaparib', 'Chemical', 'MESH:C531550', (69, 77))	('olaparib', 'Chemical', 'MESH:C531550', (248, 256))	('mutations', 'Var', (179, 188))	('BRCA1/2', 'Gene', (202, 209))	('resistance', 'MPA', (234, 244))	('restore', 'PosReg', (194, 201))
42241	23346316	Those who reap the greatest benefit from routine complete genome sequencing would be individuals who inherited mutations conferring high cancer risks such as BRCA mutation carriers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (111, 120))	('BRCA', 'Gene', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('BRCA', 'Gene', '672', (158, 162))
42243	23346316	Nevertheless, K. Claes indicated that bioinformatics and quality control metrics must be addressed in order to dispel the concern about great uncertainty caused by BRCA1/2 variants of unknown clinical significance and extract diagnostic value from whole-genome sequencing for hereditary cancers.	('BRCA1/2', 'Gene', '672;675', (164, 171))	('variants', 'Var', (172, 180))	('hereditary cancers', 'Disease', (276, 294))	('cancers', 'Phenotype', 'HP:0002664', (287, 294))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('BRCA1/2', 'Gene', (164, 171))	('hereditary cancers', 'Disease', 'MESH:D009369', (276, 294))
42244	23346316	Regarding the association between BRCA1 and BRCA2 mutations and survival in women with EOC, a pooled analysis of 26 observational studies was reported to try to provide definitive evidence of the relative effect of germline BRCA1 and BRCA2 mutations on prognosis.	('BRCA2', 'Gene', '675', (234, 239))	('BRCA1', 'Gene', '672', (34, 39))	('mutations', 'Var', (50, 59))	('BRCA1', 'Gene', '672', (224, 229))	('BRCA1', 'Gene', (34, 39))	('association', 'Interaction', (14, 25))	('BRCA1', 'Gene', (224, 229))	('BRCA2', 'Gene', (44, 49))	('BRCA2', 'Gene', (234, 239))	('BRCA2', 'Gene', '675', (44, 49))	('women', 'Species', '9606', (76, 81))
42245	23346316	Despite the recent report of favorable outcome for BRCA2 mutation carriers compared with noncarriers, the results of many other relevant studies are not consistent, most of which had a weakness of small sample size less than 250 carriers, resulting in unreliable survival estimates.	('weakness', 'Disease', (185, 193))	('BRCA2', 'Gene', (51, 56))	('weakness', 'Disease', 'MESH:D018908', (185, 193))	('carriers', 'Var', (66, 74))	('BRCA2', 'Gene', '675', (51, 56))	('mutation carriers', 'Var', (57, 74))
42246	23346316	included data from 1,213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2,666 noncarriers.	('BRCA2', 'Gene', (90, 95))	('BRCA1', 'Gene', '672', (73, 78))	('pathogenic', 'Reg', (40, 50))	('BRCA2', 'Gene', '675', (90, 95))	('BRCA1', 'Gene', (73, 78))	('germline mutations', 'Var', (51, 69))
42247	23346316	After adjusting for the year of study and diagnosis, BRCA1 (HR, 0.78; 95% CI, 0.68 to 0.89; p<0.001) and BRCA2 (HR, 0.61; 95% CI, 0.50 to 0.76; p<0.001) mutation carriers showed a more favorable 5-year OS than noncarriers.	('OS', 'Chemical', '-', (202, 204))	('HR', 'Gene', '3164', (60, 62))	('BRCA2', 'Gene', (105, 110))	('BRCA1', 'Gene', '672', (53, 58))	('BRCA2', 'Gene', '675', (105, 110))	('BRCA1', 'Gene', (53, 58))	('mutation', 'Var', (153, 161))	('HR', 'Gene', '3164', (112, 114))
42249	23346316	Thus, they concluded that a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year OS, with that of BRCA2 carriers being the best.	('BRCA2', 'Gene', '675', (58, 63))	('BRCA2', 'Gene', '675', (117, 122))	('OS', 'Chemical', '-', (100, 102))	('BRCA1', 'Gene', '672', (49, 54))	('improved', 'PosReg', (84, 92))	('BRCA1', 'Gene', (49, 54))	('germline mutation', 'Var', (28, 45))	('BRCA2', 'Gene', (58, 63))	('BRCA2', 'Gene', (117, 122))	('5-year OS', 'CPA', (93, 102))
42251	23346316	Although little is known about the pathogenesis of ovarian sex cord-stromal tumors because of their rare incidence, less than 3-5% of ovarian cancers, germline mutation carriers of DICER1 are known to be at risk for these rare tumors.	('DICER1', 'Gene', '23405', (181, 187))	('ovarian sex cord-stromal tumors', 'Disease', (51, 82))	('ovarian cancers', 'Disease', (134, 149))	('ovarian cancers', 'Disease', 'MESH:D010051', (134, 149))	('DICER1', 'Gene', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('ovarian cancers', 'Phenotype', 'HP:0100615', (134, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('germline mutation carriers', 'Var', (151, 177))	('tumors', 'Disease', (76, 82))	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (51, 82))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (51, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))
42252	23346316	In this study, however, somatic, rather than germline, DICER1 mutations were found in 29% (30/102) of nonepithelial ovarian tumors, predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%).	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (149, 175))	('epithelial ovarian', 'Disease', 'MESH:D000077216', (105, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('DICER1', 'Gene', (55, 61))	('epithelial ovarian', 'Disease', (105, 123))	('found', 'Reg', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ovarian tumors', 'Disease', (116, 130))	('DICER1', 'Gene', '23405', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('Sertoli-Leydig cell tumors', 'Disease', (149, 175))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (157, 175))	('ovarian tumors', 'Phenotype', 'HP:0100615', (116, 130))	('ovarian tumors', 'Disease', 'MESH:D010051', (116, 130))	('mutations', 'Var', (62, 71))
42253	23346316	Based on the fact that these mutations change DICER1 function in specific cell types rather than obliterating it, they concluded that aberrant miRNA processing resulting from DICER1 hot-spot mutations might be a key oncogenic event in a certain type of nonepithelial ovarian cancers.	('aberrant', 'Var', (134, 142))	('type of nonepithelial ovarian cancers', 'Disease', 'MESH:D010051', (245, 282))	('ovarian cancers', 'Phenotype', 'HP:0100615', (267, 282))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('type of nonepithelial ovarian cancers', 'Disease', (245, 282))	('mutations', 'Var', (29, 38))	('mutations', 'Var', (191, 200))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (256, 281))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('DICER1', 'Gene', (46, 52))	('DICER1', 'Gene', '23405', (46, 52))	('DICER1', 'Gene', (175, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (267, 281))	('miRNA processing', 'MPA', (143, 159))	('change', 'Reg', (39, 45))	('DICER1', 'Gene', '23405', (175, 181))	('function', 'MPA', (53, 61))
42254	23346316	Last genetic study we review here is regarding the mutations in the p110alpha subunit of phosphatidylinositol 3-kinase (PI3K), which is called PIK3CA.	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', (143, 149))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (89, 118))	('PIK3CA', 'Gene', '5290', (143, 149))	('phosphatidylinositol 3-kinase', 'Gene', (89, 118))	('p110alpha', 'Gene', (68, 77))	('p110alpha', 'Gene', '5290', (68, 77))
42255	23346316	PIK3CA mutations are known to be common in gynecologic and breast cancers ranged from 12% of ovarian cancer to 39% of endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('endometrial cancer', 'Phenotype', 'HP:0012114', (118, 136))	('ovarian cancer', 'Disease', (93, 107))	('endometrial cancer', 'Disease', (118, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('breast cancers', 'Disease', 'MESH:D001943', (59, 73))	('breast cancers', 'Disease', (59, 73))	('PIK3CA', 'Gene', '5290', (0, 6))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('endometrial cancer', 'Disease', 'MESH:D016889', (118, 136))	('mutations', 'Var', (7, 16))	('breast cancers', 'Phenotype', 'HP:0003002', (59, 73))	('common', 'Reg', (33, 39))	('gynecologic', 'Disease', (43, 54))	('PIK3CA', 'Gene', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
42256	23346316	Based on the results of preclinical studies that suggested that PIK3CA mutations could predict response to PI3K/AKT/the mammalian target of rapamycin (mTOR) inhibitors, Janku et al.	('PIK3CA', 'Gene', (64, 70))	('predict', 'Reg', (87, 94))	('PIK3CA', 'Gene', '5290', (64, 70))	('mammalian target of rapamycin', 'Gene', '2475', (120, 149))	('mammalian target of rapamycin', 'Gene', (120, 149))	('AKT', 'Gene', '207', (112, 115))	('mutations', 'Var', (71, 80))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('AKT', 'Gene', (112, 115))
42257	23346316	investigated PIK3CA mutation status of 140 patients with advanced breast (n=29), cervical (n=22), endometrial (n=29), and ovarian (n=60) cancers and found PIK3CA mutations in 25 patients (18%).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (162, 171))	('cervical', 'Disease', (81, 89))	('PIK3CA', 'Gene', (13, 19))	('patients', 'Species', '9606', (43, 51))	('PIK3CA', 'Gene', '5290', (155, 161))	('patients', 'Species', '9606', (178, 186))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('PIK3CA', 'Gene', '5290', (13, 19))	('PIK3CA', 'Gene', (155, 161))	('cancers', 'Disease', (137, 144))	('endometrial', 'Disease', (98, 109))	('ovarian', 'Disease', (122, 129))
42258	23346316	Of the 25 patients with PIK3CA mutations who experienced treatment failure with standard therapies, 23 were treated on a protocol that included a PI3K/AKT/mTOR inhibitor and 7 (30%) showed a partial response compared with a 10% response rate in patients with the same disease but wild-type PIK3CA treated on the same protocol (p=0.04).	('AKT', 'Gene', (151, 154))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (290, 296))	('mTOR', 'Gene', '2475', (155, 159))	('PIK3CA', 'Gene', (24, 30))	('PIK3CA', 'Gene', '5290', (290, 296))	('mTOR', 'Gene', (155, 159))	('patients', 'Species', '9606', (245, 253))	('PIK3CA', 'Gene', '5290', (24, 30))	('AKT', 'Gene', '207', (151, 154))	('patients', 'Species', '9606', (10, 18))
42259	23346316	They suggested that screening for PIK3CA mutations might support the use of PI3K/AKT/mTOR inhibitors in gynecologic and breast cancers.	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (34, 40))	('breast cancers', 'Disease', 'MESH:D001943', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancers', 'Disease', (120, 134))	('AKT', 'Gene', '207', (81, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('gynecologic', 'Disease', (104, 115))	('PIK3CA', 'Gene', '5290', (34, 40))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('AKT', 'Gene', (81, 84))	('mTOR', 'Gene', '2475', (85, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (120, 134))	('mTOR', 'Gene', (85, 89))
42262	23346316	Although they failed to demonstrate the correlation of molecular markers of PI3K/AKT/mTOR pathway such as p-mTOR, p-AKT, and p-S6, with the clinical outcomes, they showed encouraging single-agent activity, especially in chemotherapy-naive patients, 14% of partial response and 69% of stable disease.	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', '2475', (108, 112))	('AKT', 'Gene', '207', (81, 84))	('p-S6', 'Var', (125, 129))	('patients', 'Species', '9606', (239, 247))	('partial', 'Disease', (256, 263))	('AKT', 'Gene', '207', (116, 119))	('AKT', 'Gene', (81, 84))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))	('AKT', 'Gene', (116, 119))
42286	23346316	Thus, the authors concluded that LND increased morbidity without discernible benefits in low-risk EEC as defined by the "Mayo criteria" and hysterectomy with salpingo-oophorectomy alone, therefore, might be appropriate surgical management.	('LND', 'Var', (33, 36))	('morbidity', 'MPA', (47, 56))	('EEC', 'Disease', (98, 101))	('Mayo', 'Species', '162683', (121, 125))
42325	23346316	This suggests that women with primary tumors <4 cm who met the eligibility criteria for this trial can be preoperatively counseled that if SLN is negative, the groin relapse risk due to a false-negative SLN would be less than 3%.	('SLN', 'Chemical', '-', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('primary tumors', 'Disease', 'MESH:D009369', (30, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('women', 'Species', '9606', (19, 24))	('primary tumors', 'Disease', (30, 44))	('groin relapse', 'CPA', (160, 173))	('SLN', 'Chemical', '-', (203, 206))	('SLN', 'Var', (203, 206))
42334	23346316	Recently, recommendations for 3D insulated gate bipolar transistor (IGBT) were released by the Groupe Europeen de Curietherapie and the European Society for Therapeutic Radiology and Oncology (GEC-ESTRO), which use D90 and D100 for prescription instead of A point doses and include new concepts such as high-risk clinical target volume (HR CTV) and intermediate-risk CTV (IR CTV).	('CTV', 'Chemical', '-', (367, 370))	('CTV', 'Chemical', '-', (340, 343))	('CTV', 'Chemical', '-', (375, 378))	('D100', 'Var', (223, 227))	('D90', 'Var', (215, 218))	('HR', 'Gene', '3164', (337, 339))	('Oncology', 'Phenotype', 'HP:0002664', (183, 191))
42336	23346316	Supporting the trend of image based brachytherapy in cervical cancer, there is accumulating evidence that favor HDR brachytherapy vs. LDR in terms of an improvement in late toxicity, and CT-based 3D planning vs. conventional 2D imaging based planning with regard to conformity of target coverage and reduction of dose to OARs.	('cervical cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('improvement', 'PosReg', (153, 164))	('HDR', 'Var', (112, 115))	('toxicity', 'Disease', 'MESH:D064420', (173, 181))	('cervical cancer', 'Disease', 'MESH:D002583', (53, 68))	('toxicity', 'Disease', (173, 181))
42422	32957442	The protein products of individual CGB genes show amino acid differences at position 117.	('amino acid differences', 'Var', (50, 72))	('CGB', 'Gene', (35, 38))	('CGB', 'Gene', '93659', (35, 38))
42429	32957442	The insertion led to the deletion of a 52-base long segment of the proximal promoter, as well as the entire 5' untranslated region (5'UTR) region of the CGB gene.	(', as', 'Gene', '112935892', (84, 88))	('CGB', 'Gene', (153, 156))	('to', 'Gene', '6999', (18, 20))	('deletion', 'Var', (25, 33))	('CGB', 'Gene', '93659', (153, 156))
42430	32957442	The consequence of this mutation was the creation of a new promoter sequence for CGB1 and CGB2, a new 5'UTR region with an alternative start codon, and a new first exon.	('CGB2', 'Gene', (90, 94))	('CGB1', 'Gene', (81, 85))	('CGB1', 'Gene', '114335', (81, 85))	('mutation', 'Var', (24, 32))	('CGB2', 'Gene', '114336', (90, 94))
42464	32957442	It was also demonstrated that specific targeting of CGB1 and CGB2 with siRNA was much more effective in reducing cancer cell numbers than silencing other CGB genes.	('CGB', 'Gene', '93659', (154, 157))	('CGB', 'Gene', (52, 55))	('targeting', 'Var', (39, 48))	('CGB2', 'Gene', '114336', (61, 65))	('CGB', 'Gene', '93659', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CGB', 'Gene', (154, 157))	('CGB', 'Gene', (61, 64))	('cancer', 'Disease', (113, 119))	('reducing', 'NegReg', (104, 112))	('CGB', 'Gene', '93659', (52, 55))	('CGB2', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CGB1', 'Gene', (52, 56))	('CGB1', 'Gene', '114335', (52, 56))
42554	32274663	showed that FDG-PET/CT had higher diagnostic accuracy than PET or CT alone in detecting tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('FDG', 'Chemical', 'MESH:D019788', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('FDG-PET/CT', 'Var', (12, 22))
42587	32884852	A 52-year-old G4P3 female presented to the gynecology outpatient clinic with complaints of heavy irregular menstrual bleeding for several years and new right elbow pain and swelling.	('menstrual bleeding', 'Disease', 'MESH:D008595', (107, 125))	('outpatient', 'Species', '9606', (54, 64))	('elbow pain', 'Phenotype', 'HP:0030835', (158, 168))	('right elbow pain', 'Disease', (152, 168))	('irregular menstrual', 'Phenotype', 'HP:0000858', (97, 116))	('menstrual bleeding', 'Disease', (107, 125))	('G4P3', 'Var', (14, 18))	('right elbow pain', 'Disease', 'MESH:D010146', (152, 168))	('pain', 'Phenotype', 'HP:0012531', (164, 168))	('swelling', 'Disease', 'MESH:D004487', (173, 181))	('menstrual bleeding', 'Phenotype', 'HP:0100608', (107, 125))	('swelling', 'Disease', (173, 181))
42595	32884852	The mutation pattern studied by molecular pathology study suggested an endometrioid differentiation with ARID1A mutation and lack of p53 mutation.	('ARID1A', 'Gene', '8289', (105, 111))	('ARID1A', 'Gene', (105, 111))	('mutation', 'Var', (112, 120))	('p53', 'Gene', '7157', (133, 136))	('endometrioid', 'Disease', (71, 83))	('p53', 'Gene', (133, 136))
42609	32884852	Other risk factors include obesity, nulliparity, exogenous estrogen, tamoxifen, and exposure to pelvic radiation, while progestin-containing contraceptives are thought to have protective effects.	('exogenous', 'Var', (49, 58))	('obesity', 'Phenotype', 'HP:0001513', (27, 34))	('tamoxifen', 'Chemical', 'MESH:D013629', (69, 78))	('obesity', 'Disease', 'MESH:D009765', (27, 34))	('obesity', 'Disease', (27, 34))	('tamoxifen', 'Disease', (69, 78))	('nulliparity', 'Var', (36, 47))
42619	32884852	The lack of p53 mutation is against serous, and the presence of ARID1A mutations is suggestive of endometrioid carcinomas, although only seen in up to 20% of carcinosarcomas.	('endometrioid carcinomas', 'Disease', (98, 121))	('ARID1A', 'Gene', '8289', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('ARID1A', 'Gene', (64, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('presence', 'Var', (52, 60))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (98, 121))	('carcinosarcomas', 'Disease', 'MESH:D002296', (158, 173))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (98, 121))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('mutations', 'Var', (71, 80))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (98, 120))	('carcinosarcomas', 'Disease', (158, 173))
42620	32884852	Commonly associated mutations include TP53 mutations (91%) and PI3K pathway genes (50%, specifically PIK3CA comprising 35%), providing potential targets for therapies.	('PIK3CA', 'Gene', '5290', (101, 107))	('TP53', 'Gene', (38, 42))	('associated', 'Reg', (9, 19))	('mutations', 'Var', (43, 52))	('PI3K pathway', 'Pathway', (63, 75))	('mutations', 'Var', (20, 29))	('PIK3CA', 'Gene', (101, 107))	('TP53', 'Gene', '7157', (38, 42))
42621	32884852	Other genetic associations include mutations in PTEN, KRAS, PPP2R1A, CHD4, and BCOR, as well as abnormalities in histone H2A/H2B expression.	('CHD4', 'Gene', (69, 73))	('PTEN', 'Gene', (48, 52))	('H2B', 'Gene', '8349', (125, 128))	('abnormalities', 'Var', (96, 109))	('BCOR', 'Gene', '54880', (79, 83))	('expression', 'MPA', (129, 139))	('associations', 'Reg', (14, 26))	('PTEN', 'Gene', '5728', (48, 52))	('CHD4', 'Gene', '1108', (69, 73))	('KRAS', 'Gene', (54, 58))	('mutations', 'Var', (35, 44))	('H2B', 'Gene', (125, 128))	('KRAS', 'Gene', '3845', (54, 58))	('PPP2R1A', 'Gene', '5518', (60, 67))	('PPP2R1A', 'Gene', (60, 67))	('BCOR', 'Gene', (79, 83))
42711	32227579	Considering tumour mutations can result in immunogenic neo-antigens, which have also been correlated with responsiveness to a more effective response to immune therapy, we analysed IDO1 expression with TMB status and grouped patients into IDO1-high and IDO1-low and analysed their TMB status.	('TMB', 'Chemical', '-', (281, 284))	('IDO1', 'Gene', (181, 185))	('patients', 'Species', '9606', (225, 233))	('IDO1', 'Gene', (253, 257))	('TMB', 'Chemical', '-', (202, 205))	('result in', 'Reg', (33, 42))	('tumour', 'Disease', (12, 18))	('mutations', 'Var', (19, 28))	('IDO1', 'Gene', '3620', (239, 243))	('IDO1', 'Gene', '3620', (253, 257))	('IDO1', 'Gene', '3620', (181, 185))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('IDO1', 'Gene', (239, 243))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
42715	32227579	Then, we combined group analysis with IDO1 and TMB, and it showed that patients with low IDO1 expression and high TMB have the worse OS than IDO-high/TMB-low (P = .0347) and IDO-high/TMB-high (P = .0085) groups in BRCA.	('TMB', 'Chemical', '-', (47, 50))	('TMB', 'MPA', (114, 117))	('BRCA', 'Disease', (214, 218))	('IDO1', 'Gene', (38, 42))	('IDO', 'Gene', (89, 92))	('patients', 'Species', '9606', (71, 79))	('IDO', 'Gene', '3620', (38, 41))	('high', 'Var', (109, 113))	('IDO', 'Gene', (174, 177))	('TMB', 'Chemical', '-', (114, 117))	('IDO1', 'Gene', '3620', (89, 93))	('IDO', 'Gene', (141, 144))	('IDO', 'Gene', '3620', (89, 92))	('low', 'NegReg', (85, 88))	('BRCA', 'Phenotype', 'HP:0003002', (214, 218))	('TMB', 'Chemical', '-', (183, 186))	('expression', 'MPA', (94, 104))	('IDO1', 'Gene', '3620', (38, 42))	('TMB', 'Chemical', '-', (150, 153))	('IDO', 'Gene', (38, 41))	('IDO1', 'Gene', (89, 93))	('IDO', 'Gene', '3620', (174, 177))	('IDO', 'Gene', '3620', (141, 144))
42743	32227579	Other studies indicated reversely that high IDO1 expression levels are correlated with a favourable survival, which include renal cell carcinoma, 28  breast cancer 29  and hepatocellular carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (124, 144))	('expression levels', 'MPA', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('high', 'Var', (39, 43))	('renal cell carcinoma', 'Disease', (124, 144))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 144))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (172, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (172, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('hepatocellular carcinoma', 'Disease', (172, 196))	('IDO1', 'Gene', '3620', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('IDO1', 'Gene', (44, 48))
42746	32227579	Actually, IDO1 is expressed in two compartments, TCs and TILs, respectively, and the tumour microenvironment may be changed by their interaction, leading to variant outcomes of tumour prognosis.	('interaction', 'Interaction', (133, 144))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('leading to', 'Reg', (146, 156))	('tumour', 'Disease', (177, 183))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('IDO1', 'Gene', (10, 14))	('tumour', 'Disease', (85, 91))	('variant', 'Var', (157, 164))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('IDO1', 'Gene', '3620', (10, 14))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
42752	32227579	Riesenberg et al 28  investigated that the immunogenic RCC tumours especially benefit from the presence of IDO1.	('immunogenic RCC tumours', 'Disease', 'MESH:C538614', (43, 66))	('immunogenic RCC tumours', 'Disease', (43, 66))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('IDO1', 'Gene', (107, 111))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('presence', 'Var', (95, 103))	('benefit', 'PosReg', (78, 85))	('IDO1', 'Gene', '3620', (107, 111))
42761	32227579	Their data showed that tumours with a high level of IDO1 expression were more likely accompanied by abundant CD8+ T cell infiltration.	('IDO1', 'Gene', '3620', (52, 56))	('expression', 'MPA', (57, 67))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('CD8', 'Gene', (109, 112))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('CD8', 'Gene', '925', (109, 112))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('high', 'Var', (38, 42))	('IDO1', 'Gene', (52, 56))	('tumours', 'Disease', (23, 30))
42772	32227579	Since tumours with a higher mutation burden have been hypothesized to have more chance to produce neoantigens and these neoantigens can be recognized by the immune system.	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('produce neoantigens', 'MPA', (90, 109))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('mutation', 'Var', (28, 36))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
42774	32227579	We also observed that high IDO1 expression and high TMB had a better clinical outcome than other IDO1/TMB expression patterns in female cancer except uterine carcinosarcoma.	('IDO1', 'Gene', '3620', (97, 101))	('IDO1', 'Gene', (27, 31))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (150, 172))	('high', 'Var', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('carcinosarcoma', 'Disease', (158, 172))	('IDO1', 'Gene', (97, 101))	('cancer', 'Disease', (136, 142))	('IDO1', 'Gene', '3620', (27, 31))	('TMB', 'Chemical', '-', (52, 55))	('expression', 'MPA', (32, 42))	('carcinosarcoma', 'Disease', 'MESH:D002296', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('TMB', 'Chemical', '-', (102, 105))
42775	32227579	This point may be contrary to the routine study and conclusions, in which patients with high TMB usually display poor clinical outcome, but nothing is absolute.	('high', 'Var', (88, 92))	('TMB', 'Chemical', '-', (93, 96))	('TMB', 'Gene', (93, 96))	('patients', 'Species', '9606', (74, 82))
42787	32227579	Previous studies indicated the correlations between PD-L1 and reduced prognosis, but some other studies 38 ,  39 ,  40  found that PD-L1 expression is paradoxically associated with improved patients' survival.	('PD-L1', 'Gene', '29126', (52, 57))	('improved', 'PosReg', (181, 189))	('patients', 'Species', '9606', (190, 198))	('PD-L1', 'Gene', '29126', (131, 136))	('prognosis', 'MPA', (70, 79))	('expression', 'Var', (137, 147))	('PD-L1', 'Gene', (52, 57))	('PD-L1', 'Gene', (131, 136))
42788	32227579	Lee et al 38  investigated that PD-L1, LAG3 and IDO1 expressions in tumour-infiltrating immune cells were significantly associated with a better disease-free survival.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('associated', 'Reg', (120, 130))	('PD-L1', 'Gene', (32, 37))	('expressions', 'Var', (53, 64))	('LAG3', 'Gene', (39, 43))	('IDO1', 'Gene', (48, 52))	('LAG3', 'Gene', '3902', (39, 43))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('PD-L1', 'Gene', '29126', (32, 37))	('better', 'PosReg', (138, 144))	('disease-free survival', 'CPA', (145, 166))	('IDO1', 'Gene', '3620', (48, 52))
42814	31635323	Upregulation of class III beta-tubulin confers taxane resistance in colon, prostate, breast, and ovarian/uterine carcinosarcoma and serous carcinoma, among others, in part due to alterations in the binding pocket conferring reduced affinity of paclitaxel and docetaxel.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (105, 127))	('serous carcinoma', 'Disease', 'MESH:D018284', (132, 148))	('taxane resistance', 'MPA', (47, 64))	('affinity', 'MPA', (232, 240))	('paclitaxel', 'Chemical', 'MESH:D017239', (244, 254))	('ovarian', 'Disease', 'MESH:D010049', (97, 104))	('taxane', 'Chemical', 'MESH:C080625', (47, 53))	('breast', 'Disease', (85, 91))	('alterations', 'Var', (179, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('reduced', 'NegReg', (224, 231))	('class III beta-tubulin', 'Gene', (16, 38))	('colon', 'Disease', (68, 73))	('carcinosarcoma', 'Disease', (113, 127))	('ovarian', 'Disease', (97, 104))	('carcinosarcoma', 'Disease', 'MESH:D002296', (113, 127))	('binding pocket', 'Interaction', (198, 212))	('Upregulation', 'PosReg', (0, 12))	('serous carcinoma', 'Disease', (132, 148))	('class III beta-tubulin', 'Gene', '10381', (16, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('prostate', 'Disease', (75, 83))	('docetaxel', 'Chemical', 'MESH:C067311', (259, 268))
42816	31635323	Overexpression of class III beta-tubulin has robustly been associated with chemoresistance and poor clinical outcome.	('associated', 'Reg', (59, 69))	('chemoresistance', 'CPA', (75, 90))	('class III beta-tubulin', 'Gene', '10381', (18, 40))	('class III beta-tubulin', 'Gene', (18, 40))	('Overexpression', 'Var', (0, 14))
42827	31635323	Pharmacologic targeting of the EP4 receptor can halt this cascade.	('EP4', 'Gene', '5734', (31, 34))	('EP4', 'Gene', (31, 34))	('Pharmacologic targeting', 'Var', (0, 23))
42831	31635323	In osteosarcoma, a recent meta-analysis found that COX-2 expression predicted reduced 2-year overall and disease-free survival, without significant association with age, gender, tumor location, histology, stage, metastasis, or necrosis.	('COX-2', 'Gene', (51, 56))	('tumor', 'Disease', (178, 183))	('osteosarcoma', 'Disease', (3, 15))	('COX-2', 'Gene', '5743', (51, 56))	('expression', 'Var', (57, 67))	('necrosis', 'Disease', (227, 235))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('necrosis', 'Disease', 'MESH:D009336', (227, 235))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('reduced', 'NegReg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('disease-free survival', 'CPA', (105, 126))
42861	31635323	As measured by densitometry, EP4 was significantly overexpressed in SK-UT-1 and SK-UT-1B by approximately 9- and 8-fold higher, respectively, compared to PHM1-41 cells (Figure 4B).	('EP4', 'Gene', '5734', (29, 32))	('SK-UT-1B', 'Var', (80, 88))	('higher', 'PosReg', (120, 126))	('overexpressed', 'PosReg', (51, 64))	('EP4', 'Gene', (29, 32))
42868	31635323	Similarly, expression for both class III beta-tubulin and EP4 was significantly increased in the cytoplasmic portions of SK-UT-1 and SK-UT-1B, replicating what was observed for the total protein Western blots.	('expression', 'MPA', (11, 21))	('increased', 'PosReg', (80, 89))	('SK-UT-1B', 'Var', (133, 141))	('EP4', 'Gene', '5734', (58, 61))	('class III beta-tubulin', 'Gene', '10381', (31, 53))	('SK-UT-1', 'Var', (121, 128))	('EP4', 'Gene', (58, 61))	('class III beta-tubulin', 'Gene', (31, 53))
42877	31635323	The EP4 antagonist RQ15986 also lead to a decrease in the migration of SK-UT-1 by 75%; however, for unknown reasons, we did not observe inhibition in a dose responsive manner (10 microM and 3 microM, p < 0.05) (Figure 5A).	('RQ15986', 'Chemical', 'MESH:C043461', (19, 26))	('decrease', 'NegReg', (42, 50))	('EP4', 'Gene', (4, 7))	('EP4', 'Gene', '5734', (4, 7))	('RQ15986', 'Var', (19, 26))	('migration', 'CPA', (58, 67))
42878	31635323	For SK-UT-1B, migration was decreased by up to 50% in a dose-dependent response with either AH23848 or RQ15986; however, we did not reach statistical significance compared to the positive control (Figure 5B).	('migration', 'CPA', (14, 23))	('decreased', 'NegReg', (28, 37))	('AH23848', 'Var', (92, 99))	('RQ15986', 'Var', (103, 110))	('AH23848', 'Chemical', 'MESH:C046926', (92, 99))	('SK-UT-1B', 'Var', (4, 12))	('RQ15986', 'Chemical', 'MESH:C043461', (103, 110))
42880	31635323	Using a DNA content-based assay, we observed negligible effects on proliferation in SK-UT-1 and SK-UT-1B when treated with AH23848 or RQ15986 (Figure 6A,B).	('AH23848', 'Var', (123, 130))	('RQ15986', 'Var', (134, 141))	('AH23848', 'Chemical', 'MESH:C046926', (123, 130))	('RQ15986', 'Chemical', 'MESH:C043461', (134, 141))
42884	31635323	Pre-treatment with EP4 antagonists AH23848 or RQ15986 resulted in a significant increase in sensitivity to treatment with docetaxel in SK-UT-1 cells (Figure 6D).	('sensitivity to treatment with docetaxel', 'MPA', (92, 131))	('docetaxel', 'Chemical', 'MESH:C067311', (122, 131))	('AH23848', 'Chemical', 'MESH:C046926', (35, 42))	('RQ15986', 'Chemical', 'MESH:C043461', (46, 53))	('increase', 'PosReg', (80, 88))	('EP4', 'Gene', (19, 22))	('EP4', 'Gene', '5734', (19, 22))	('RQ15986', 'Var', (46, 53))	('AH23848', 'Var', (35, 42))
42885	31635323	A 2-fold sensitization occurred when cells were treated with AH23848 with a decrease in the IC50 from 1.47 nM for docetaxel as a single agent to 0.6 nM (p < 0.01) when combined with 10 microM AH23848 and 0.46 nM (p < 0.001) when combined with 0.5 microM AH23848.	('AH23848', 'Chemical', 'MESH:C046926', (254, 261))	('AH23848', 'Var', (61, 68))	('IC50', 'MPA', (92, 96))	('AH23848', 'Chemical', 'MESH:C046926', (61, 68))	('decrease', 'NegReg', (76, 84))	('docetaxel', 'Chemical', 'MESH:C067311', (114, 123))	('AH23848', 'Chemical', 'MESH:C046926', (192, 199))
42887	31635323	when treated with 30 microM RQ15986 and 0.66 nM (p < 0.01) when treated with 3 microM RQ15986 compared to an IC50 of 1.47 nM for single agent docetaxel (Figure 6D).	('RQ15986', 'Var', (86, 93))	('RQ15986', 'Var', (28, 35))	('docetaxel', 'Chemical', 'MESH:C067311', (142, 151))	('RQ15986', 'Chemical', 'MESH:C043461', (86, 93))	('RQ15986', 'Chemical', 'MESH:C043461', (28, 35))
42888	31635323	The difference in chemosensitization between SK-UT-1 and SK-UT-1B when pre-treated with EP4 antagonists may be due to differences in EP4 protein expression since SK-UT-1 has higher EP4 expression compared to SK-UT-1B (Figure 6E).	('expression', 'MPA', (185, 195))	('EP4', 'Gene', (88, 91))	('EP4', 'Gene', '5734', (88, 91))	('EP4', 'Gene', '5734', (133, 136))	('higher', 'PosReg', (174, 180))	('EP4', 'Gene', (133, 136))	('EP4', 'Gene', '5734', (181, 184))	('SK-UT-1', 'Var', (162, 169))	('EP4', 'Gene', (181, 184))
42901	31635323	SK-UT-1 and SK-UT-1B represent the malignant mesenchymal and epithelial components from a uterine grade III mesodermal mixed tumor consistent with leiomyosarcoma (carcinosarcoma) derived from a 75-year-old, female, Caucasian patient.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('SK-UT-1B', 'Var', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('carcinosarcoma', 'Disease', 'MESH:D002296', (163, 177))	('tumor', 'Disease', (125, 130))	('leiomyosarcoma', 'Disease', (147, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('patient', 'Species', '9606', (225, 232))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (147, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (147, 161))	('carcinosarcoma', 'Disease', (163, 177))
42904	31635323	Two EP4 antagonists were used AH23848 (Cayman Chemical) and RQ15986 (AskAt, Inc., Japan).	('AH23848', 'Var', (30, 37))	('RQ15986', 'Chemical', 'MESH:C043461', (60, 67))	('EP4', 'Gene', '5734', (4, 7))	('EP4', 'Gene', (4, 7))	('AH23848', 'Chemical', 'MESH:C046926', (30, 37))	('RQ15986', 'Var', (60, 67))
42930	31635323	However, knockdown of TUBB3 only partially recovered sensitivity to eribulin which suggests that class III beta-tubulin is not solely responsible for the observed eribulin resistance in SK-LMS-1.	('knockdown', 'Var', (9, 18))	('LMS', 'Phenotype', 'HP:0100243', (189, 192))	('sensitivity', 'MPA', (53, 64))	('TUBB3', 'Gene', (22, 27))	('TUBB3', 'Gene', '10381', (22, 27))	('class III beta-tubulin', 'Gene', '10381', (97, 119))	('SK-LMS-1', 'CellLine', 'CVCL:7020', (186, 194))	('class III beta-tubulin', 'Gene', (97, 119))
42957	31635323	In the present study of LMS, low (<1+) cytoplasmic EP4 staining was associated with improved crude overall survival.	('LMS', 'Disease', (24, 27))	('crude overall survival', 'MPA', (93, 115))	('LMS', 'Phenotype', 'HP:0100243', (24, 27))	('LMS', 'Disease', 'MESH:D007890', (24, 27))	('low (<1+', 'Var', (29, 37))	('improved', 'PosReg', (84, 92))	('EP4', 'Gene', '5734', (51, 54))	('EP4', 'Gene', (51, 54))
42958	31635323	Overall, our findings suggest that cytoplasmic EP4 could serve as a biomarker for aggressive LMS.	('LMS', 'Disease', (93, 96))	('EP4', 'Gene', '5734', (47, 50))	('LMS', 'Phenotype', 'HP:0100243', (93, 96))	('LMS', 'Disease', 'MESH:D007890', (93, 96))	('EP4', 'Gene', (47, 50))	('cytoplasmic', 'Var', (35, 46))
42967	31635323	demonstrated in pre-clinical models that treatment with EP4 antagonist GW627368X reduces tumor chemoresistance of breast cancer and colorectal tumors in vivo when used in combination with paclitaxel, thus demonstrating that EP4 antagonists could be a viable addition to chemotherapeutic treatment for a variety of cancers including LMS.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Disease', (314, 321))	('colorectal tumors', 'Disease', (132, 149))	('EP4', 'Gene', '5734', (224, 227))	('EP4', 'Gene', (224, 227))	('reduces', 'NegReg', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('GW627368X', 'Chemical', 'MESH:C515270', (71, 80))	('tumor', 'Disease', (89, 94))	('EP4', 'Gene', '5734', (56, 59))	('EP4', 'Gene', (56, 59))	('colorectal tumors', 'Disease', 'MESH:D015179', (132, 149))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('LMS', 'Disease', 'MESH:D007890', (332, 335))	('tumor', 'Disease', (143, 148))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('LMS', 'Disease', (332, 335))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('paclitaxel', 'Chemical', 'MESH:D017239', (188, 198))	('LMS', 'Phenotype', 'HP:0100243', (332, 335))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('GW627368X', 'Var', (71, 80))	('breast cancer', 'Disease', (114, 127))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
42969	31635323	The potentially interesting finding is that, in spite of this, EP4 antagonists sensitize cells to docetaxel and other chemotherapeutics.	('antagonists', 'Var', (67, 78))	('EP4', 'Gene', '5734', (63, 66))	('sensitize', 'Reg', (79, 88))	('EP4', 'Gene', (63, 66))	('docetaxel', 'Chemical', 'MESH:C067311', (98, 107))
43101	30659312	SK-UT-1, SK-UT-1B, MES-SA, ESS-1 (3 x 104 cells/ml) and HSF (1 x 105 cells/ml) cells were platted on 96-well microplates.	('SK-UT-1', 'CellLine', 'CVCL:0533', (0, 7))	('HSF', 'Gene', (56, 59))	('ESS-1', 'Gene', (27, 32))	('SK-UT-1B', 'Var', (9, 17))	('SK-UT-1', 'CellLine', 'CVCL:0533', (9, 16))	('MES-SA', 'Chemical', '-', (19, 25))	('HSF', 'Gene', '3569', (56, 59))	('ESS-1', 'Gene', '7046', (27, 32))
43146	30659312	Taking into consideration the results obtained in this study we can state that fucoidan express not only cytostatic activity but cytotoxic as well (by inducing apoptosis).	('apoptosis', 'CPA', (160, 169))	('inducing', 'PosReg', (151, 159))	('fucoidan', 'Var', (79, 87))	('fucoidan', 'Chemical', 'MESH:C007789', (79, 87))
43179	30514387	However, in a more recent meta-analysis including 15 studies and 849 patients, the specificity of T2w images plus DWI was superior to that of DCE MR imaging.	('patients', 'Species', '9606', (69, 77))	('DCE', 'Chemical', '-', (142, 145))	('T2w', 'Var', (98, 101))	('specificity', 'MPA', (83, 94))
43206	30514387	In stage IB tumours, disruption or irregularity of the low T2-w signal junctional zone and/or of sub-endometrial enhancement in post-contrast T1 images with myometrial invasion > 50% can be demonstrated (Fig.	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('irregularity', 'Var', (35, 47))	('tumours', 'Disease', (12, 19))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))
43229	28292439	Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7 and KRAS, similar to endometrioid and serous uterine carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('carcinomas', 'Disease', 'MESH:D002277', (121, 131))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (33, 37))	('PIK3CA', 'Gene', (45, 51))	('PTEN', 'Gene', '5728', (39, 43))	('PPP2R1A', 'Gene', '5518', (53, 60))	('FBXW7', 'Gene', (62, 67))	('carcinomas', 'Disease', (121, 131))	('KRAS', 'Gene', '3845', (72, 76))	('PPP2R1A', 'Gene', (53, 60))	('endometrioid', 'Disease', (89, 101))	('PIK3CA', 'Gene', '5290', (45, 51))	('TP53', 'Gene', (33, 37))	('serous uterine carcinomas', 'Phenotype', 'HP:0012887', (106, 131))	('KRAS', 'Gene', (72, 76))	('FBXW7', 'Gene', '55294', (62, 67))	('PTEN', 'Gene', (39, 43))	('tri', 'Chemical', '-', (95, 98))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (113, 131))
43230	28292439	Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters.	('tri', 'Chemical', '-', (135, 138))	('epithelial-to-mesenchymal', 'CPA', (45, 70))	('epigenetic alterations', 'Var', (149, 171))
43238	28292439	Heterologous differentiation is a prognostic feature associated with a higher risk of tumor recurrence, particularly when present in early-stage disease.	('Heterologous', 'Var', (0, 12))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
43243	28292439	Prior work that included 13 non-hypermutated UCS tumors found a high frequency of TP53 mutations and lower frequencies of FBXW7, PIK3CA and PPP2R1A mutations.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('PPP2R1A', 'Gene', '5518', (140, 147))	('FBXW7', 'Gene', '55294', (122, 127))	('PIK3CA', 'Gene', (129, 135))	('PPP2R1A', 'Gene', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('UCS', 'Phenotype', 'HP:0002891', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('FBXW7', 'Gene', (122, 127))	('PIK3CA', 'Gene', '5290', (129, 135))	('UCS tumors', 'Disease', 'MESH:D009369', (45, 55))	('UCS tumors', 'Disease', (45, 55))	('mutations', 'Var', (87, 96))
43244	28292439	Many of the mutations in chromatin-remodeling genes were found in hypermutated UCS samples or in carcinosarcoma tumors of ovarian origin.	('tumors of ovarian origin', 'Phenotype', 'HP:0100615', (112, 136))	('carcinosarcoma tumors of ovarian', 'Disease', 'MESH:D002296', (97, 129))	('carcinosarcoma tumors of ovarian', 'Disease', (97, 129))	('UCS', 'Phenotype', 'HP:0002891', (79, 82))	('chromatin-remodeling genes', 'Gene', (25, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('mutations', 'Var', (12, 21))	('found', 'Reg', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
43245	28292439	A recent publication of 24 non-hypermutated UCS tumor-normal exomes found lower frequencies of TP53 and FBXW7 mutations.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (110, 119))	('FBXW7', 'Gene', '55294', (104, 109))	('UCS', 'Phenotype', 'HP:0002891', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TP53', 'Gene', '7157', (95, 99))	('FBXW7', 'Gene', (104, 109))	('TP53', 'Gene', (95, 99))
43252	28292439	From this set of mutations, we selected 492 sites for independent hybrid-capture validation, representing 161 genes from lists of significantly mutated genes in this study (below and Supplemental Experimental Procedures) as well as The Cancer Genome Atlas (TCGA) endometrioid endometrial cancer (UCEC) study.	('Cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tri', 'Chemical', '-', (269, 272))	('Cancer Genome Atlas', 'Disease', (236, 255))	('tri', 'Chemical', '-', (282, 285))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (236, 255))	('endometrial cancer', 'Disease', (276, 294))	('endometrial cancer', 'Phenotype', 'HP:0012114', (276, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('mutations', 'Var', (17, 26))	('endometrial cancer', 'Disease', 'MESH:D016889', (276, 294))
43254	28292439	Analysis of mutational signatures also identified an APOBEC signature with C>T and TC>AA/T substitutions in a single tumor that had elevated expression of several APOBEC3 genes (Figure S1B).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('elevated', 'PosReg', (132, 140))	('tumor', 'Disease', (117, 122))	('APOBEC3 genes', 'Gene', (163, 176))	('expression', 'MPA', (141, 151))	('substitutions', 'Var', (91, 104))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('C>T', 'Var', (75, 78))	('TC>AA/T substitutions', 'Var', (83, 104))
43255	28292439	Combined analysis using multiple versions of MutSig identified 14 significantly recurring mutations, many of which were also recurrent mutations in uterine endometrial cancer (Figure 1B and Table S3).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (90, 99))	('endometrial cancer', 'Disease', (156, 174))	('endometrial cancer', 'Phenotype', 'HP:0012114', (156, 174))	('endometrial cancer', 'Disease', 'MESH:D016889', (156, 174))
43256	28292439	Most prominent were TP53 mutations, which were found in all but five tumors (91%).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('TP53', 'Gene', '7157', (20, 24))
43257	28292439	Approximately half of the UCS tumors had mutations in one or more of the PI3-kinase pathway genes:PIK3CA (35%), PTEN (19%) or PIK3R1 (11%).	('mutations', 'Var', (41, 50))	('UCS tumors', 'Disease', 'MESH:D009369', (26, 36))	('PIK3R1', 'Gene', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('PIK3CA', 'Gene', (98, 104))	('UCS tumors', 'Disease', (26, 36))	('PIK3CA', 'Gene', '5290', (98, 104))	('PI3-kinase pathway', 'Pathway', (73, 91))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PTEN', 'Gene', (112, 116))	('UCS', 'Phenotype', 'HP:0002891', (26, 29))	('PTEN', 'Gene', '5728', (112, 116))	('PIK3R1', 'Gene', '5295', (126, 132))
43258	28292439	However, unlike previous studies of endometrial tumors where PTEN and TP53 mutations tended to be mutually exclusive and confined to one of the two common histologic subtypes (endometrioid or serous), eight (73%) of 11 tumors with PTEN mutations also had a TP53 mutation.	('tumors', 'Disease', (48, 54))	('TP53', 'Gene', (70, 74))	('PTEN', 'Gene', (61, 65))	('endometrial tumors', 'Disease', 'MESH:D016889', (36, 54))	('TP53', 'Gene', (257, 261))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('endometrial tumors', 'Disease', (36, 54))	('PTEN', 'Gene', '5728', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('TP53', 'Gene', '7157', (70, 74))	('PTEN', 'Gene', (231, 235))	('mutations', 'Var', (236, 245))	('TP53', 'Gene', '7157', (257, 261))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tri', 'Chemical', '-', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('PTEN', 'Gene', '5728', (231, 235))	('tri', 'Chemical', '-', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
43260	28292439	Genes that were significantly mutated in UCS but not in endometrial carcinomas include the tumor suppressor RB1 (11%) and the splicing factor U2AF1 (4%), which was twice mutated at a hotspot (p.S34F) also found in lung adenocarcinoma and acute myeloid leukemia tumors.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (214, 233))	('p.S34F', 'Var', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (56, 78))	('tumor', 'Disease', (91, 96))	('RB1', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (56, 78))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (244, 260))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (238, 260))	('leukemia', 'Phenotype', 'HP:0001909', (252, 260))	('U2AF1', 'Gene', (142, 147))	('lung adenocarcinoma', 'Disease', (214, 233))	('RB1', 'Gene', '5925', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('endometrial carcinomas', 'Disease', (56, 78))	('UCS', 'Phenotype', 'HP:0002891', (41, 44))	('acute myeloid leukemia tumors', 'Disease', 'MESH:D015470', (238, 267))	('U2AF1', 'Gene', '7307', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('tumor', 'Disease', (261, 266))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (214, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (56, 77))	('p.S34F', 'Mutation', 'rs371769427', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('acute myeloid leukemia tumors', 'Disease', (238, 267))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
43263	28292439	The PIK3CA hotspots p.E545K and p.H1047R are the two most commonly reported mutated PIK3CA sites in this study and in cancer overall (COSMIC v78), both leading to a constitutively active enzyme.	('PIK3CA', 'Gene', '5290', (84, 90))	('cancer', 'Disease', (118, 124))	('constitutively active enzyme', 'MPA', (165, 193))	('leading to', 'Reg', (152, 162))	('p.H1047R', 'Mutation', 'rs121913279', (32, 40))	('p.E545K', 'Var', (20, 27))	('PIK3CA', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('p.E545K', 'Mutation', 'rs104886003', (20, 27))	('p.H1047R', 'Var', (32, 40))	('PIK3CA', 'Gene', (84, 90))	('PIK3CA', 'Gene', '5290', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
43264	28292439	PTEN and ARHGAP35 mutations were more common in the few tumors without identified TP53 mutations.	('TP53', 'Gene', (82, 86))	('ARHGAP35', 'Gene', '2909', (9, 17))	('mutations', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ARHGAP35', 'Gene', (9, 17))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('TP53', 'Gene', '7157', (82, 86))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('common', 'Reg', (38, 44))
43267	28292439	The APOBEC signature was characterized by C>T/G at TCW (W=A/T), the POLE signature had a predominance of C>A at TCT and C>T at TCG, the microsatellite instability (MSI) signature had a significant enrichment of one-base indels, and the spontaneous deamination signature was dominated by C>T at CpG di-nucleotides.	('MSI', 'Disease', 'None', (164, 167))	('C>T', 'Var', (120, 123))	('C>T/G', 'Var', (42, 47))	('C>A', 'Var', (105, 108))	('MSI', 'Disease', (164, 167))	('di-nucleotides', 'Chemical', 'MESH:D015226', (298, 312))
43276	28292439	These alterations included somatic mutations in PIK3CA, PIK3R1 and PTEN, in addition to homozygous deletions of PTEN and NF1.	('NF1', 'Gene', '4763', (121, 124))	('deletions', 'Var', (99, 108))	('PIK3CA', 'Gene', (48, 54))	('PIK3R1', 'Gene', '5295', (56, 62))	('PIK3R1', 'Gene', (56, 62))	('mutations', 'Var', (35, 44))	('PTEN', 'Gene', (67, 71))	('PTEN', 'Gene', (112, 116))	('PIK3CA', 'Gene', '5290', (48, 54))	('PTEN', 'Gene', '5728', (67, 71))	('PTEN', 'Gene', '5728', (112, 116))	('NF1', 'Gene', (121, 124))
43277	28292439	Alterations were also identified in AKT/mTOR targets in 32% of patients, including frequent mutations in FBXW7, AKT2 and STK11.	('FBXW7', 'Gene', (105, 110))	('AKT', 'Gene', '207', (36, 39))	('mTOR', 'Gene', (40, 44))	('mutations', 'Var', (92, 101))	('AKT', 'Gene', '207', (112, 115))	('mTOR', 'Gene', '2475', (40, 44))	('AKT', 'Gene', (36, 39))	('STK11', 'Gene', (121, 126))	('AKT2', 'Gene', (112, 116))	('AKT2', 'Gene', '208', (112, 116))	('patients', 'Species', '9606', (63, 71))	('FBXW7', 'Gene', '55294', (105, 110))	('AKT', 'Gene', (112, 115))	('STK11', 'Gene', '6794', (121, 126))
43279	28292439	Recurrent hotspot mutations were seen in PIK3CA and PPP2R1A (Figure 2B).	('PIK3CA', 'Gene', (41, 47))	('PPP2R1A', 'Gene', (52, 59))	('PPP2R1A', 'Gene', '5518', (52, 59))	('hotspot', 'PosReg', (10, 17))	('PIK3CA', 'Gene', '5290', (41, 47))	('mutations', 'Var', (18, 27))
43280	28292439	Potentially clinically relevant alterations in cell cycle genes were found in 22.8% of patients, including somatic mutations in CCND1, CDKN2B; high-level amplification of CCNE1; and homozygous deletion of CDKN2A and CDKN2B.	('CDKN2B', 'Gene', '1030', (216, 222))	('mutations', 'Var', (115, 124))	('CCND1', 'Gene', (128, 133))	('CDKN2A', 'Gene', (205, 211))	('CCNE1', 'Gene', (171, 176))	('alterations', 'Reg', (32, 43))	('CCNE1', 'Gene', '898', (171, 176))	('CDKN2B', 'Gene', '1030', (135, 141))	('homozygous deletion', 'Var', (182, 201))	('CDKN2A', 'Gene', '1029', (205, 211))	('CCND1', 'Gene', '595', (128, 133))	('cell cycle genes', 'Gene', (47, 63))	('CDKN2B', 'Gene', (216, 222))	('patients', 'Species', '9606', (87, 95))	('CDKN2B', 'Gene', (135, 141))
43281	28292439	Potentially actionable alterations were also found in multiple cases for somatic mutations in ERBB2, ERBB3, BRCA2, and homozygous deletion of ATM.	('BRCA2', 'Gene', (108, 113))	('ATM', 'Gene', '472', (142, 145))	('BRCA2', 'Gene', '675', (108, 113))	('ERBB2', 'Gene', (94, 99))	('ERBB3', 'Gene', (101, 106))	('ERBB3', 'Gene', '2065', (101, 106))	('mutations', 'Var', (81, 90))	('ERBB2', 'Gene', '2064', (94, 99))	('ATM', 'Gene', (142, 145))
43282	28292439	Mutations in chromatin remodeling genes including ARID1A and CHD4 were common and are becoming potentially actionable (Figure 2B).	('CHD4', 'Gene', '1108', (61, 65))	('Mutations', 'Var', (0, 9))	('CHD4', 'Gene', (61, 65))	('ARID1A', 'Gene', '8289', (50, 56))	('ARID1A', 'Gene', (50, 56))
43283	28292439	Single cases with FGFR2 and SMARCA4 mutations and an in-frame fusion with ALK were identified.	('ALK', 'Gene', (74, 77))	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('SMARCA4', 'Gene', (28, 35))	('mutations', 'Var', (36, 45))	('SMARCA4', 'Gene', '6597', (28, 35))	('ALK', 'Gene', '238', (74, 77))
43285	28292439	Seventy-three percent of all mutations (Figure 3B) and 82% of those in significantly mutated genes (Figure 3C) were found to be clonal, which is similar to the frequencies seen in most other solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (197, 202))
43286	28292439	The high clonal proportion of UCS mutations is consistent with mutations from bladder urothelial carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, and stomach adenocarcinoma.	('lung adenocarcinoma', 'Disease', (108, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 182))	('UCS', 'Phenotype', 'HP:0002891', (30, 33))	('skin cutaneous melanoma', 'Disease', (159, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 157))	('lung squamous cell carcinoma', 'Disease', (129, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('stomach adenocarcinoma', 'Disease', (188, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('bladder urothelial carcinoma', 'Disease', (78, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (164, 182))	('UCS', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (78, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (188, 210))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (129, 157))	('mutations', 'Var', (34, 43))
43315	28292439	One group of tumors from the DNA methylation clustering exhibited a hypermethylation pattern similar to that of endometrioid UCEC, whereas the others were much more similar to the serous subtype (Figure S5B).	('endometrioid UCEC', 'Disease', (112, 129))	('exhibited', 'Reg', (56, 65))	('methylation', 'Var', (33, 44))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('S5B', 'Gene', '5711', (203, 206))	('hypermethylation', 'MPA', (68, 84))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tri', 'Chemical', '-', (118, 121))	('S5B', 'Gene', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
43318	28292439	This subset of tumors had frequent PTEN mutations, which were almost exclusive to the endometrioid subtype of UCEC, suggesting an independent molecular mechanism underlying the development of this histologic subtype.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('PTEN', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('PTEN', 'Gene', '5728', (35, 39))	('mutations', 'Var', (40, 49))	('tri', 'Chemical', '-', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
43319	28292439	Tumors with PTEN mutations had frequent amplification of chromosome 8p (p = 0.001, Fisher's exact test), whereas chromosome 8q was amplified in most tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('amplification', 'MPA', (40, 53))	('chromosome 8p', 'Protein', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('PTEN', 'Gene', (12, 16))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('PTEN', 'Gene', '5728', (12, 16))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (17, 26))
43322	28292439	The mismatch repair gene MLH1 was epigenetically silenced in two tumors that were independently identified by PCR as having high microsatellite instability (Figure S5A).	('epigenetically', 'Var', (34, 48))	('high microsatellite instability', 'MPA', (124, 155))	('MLH1', 'Gene', '4292', (25, 29))	('MLH1', 'Gene', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
43325	28292439	This contrasts with serous ovarian tumors, in which 12% have epigenetic silencing and 3% have BRCA1 somatic mutations.	('epigenetic silencing', 'Var', (61, 81))	('ovarian tumors', 'Phenotype', 'HP:0100615', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('serous ovarian tumors', 'Phenotype', 'HP:0012887', (20, 41))	('BRCA1', 'Gene', '672', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (20, 41))	('BRCA1', 'Gene', (94, 99))	('serous ovarian tumors', 'Disease', (20, 41))
43336	28292439	However, UCS showed higher activity of the cell cycle and DNA damage response pathways than either the gynecologic carcinomas or sarcomas, with elevated levels of Cyclin E1 and FOXM1 (cell cycle pathway), and phospho-CHK2, MRE11, RAD50 and RAD51 (DNA damage response pathway), delineating additional future targets for therapy (Figure 7B).	('RAD51', 'Gene', (240, 245))	('cell cycle', 'Pathway', (43, 53))	('RAD50', 'Gene', (230, 235))	('higher', 'PosReg', (20, 26))	('carcinomas', 'Disease', (115, 125))	('DNA damage response pathways', 'Pathway', (58, 86))	('Cyclin E1', 'MPA', (163, 172))	('FOXM1', 'Gene', (177, 182))	('elevated', 'PosReg', (144, 152))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('elevated levels of Cyclin', 'Phenotype', 'HP:0003236', (144, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('activity', 'MPA', (27, 35))	('sarcomas', 'Disease', (129, 137))	('phospho-CHK2', 'Var', (209, 221))	('MRE11', 'Gene', (223, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('carcinomas', 'Disease', 'MESH:D002277', (115, 125))	('levels', 'MPA', (153, 159))	('UCS', 'Phenotype', 'HP:0002891', (9, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
43341	28292439	Additionally, more than three-quarters of the cases also had mutation in FBXW7, amplification of CCNE1 or RB1 loss, suggesting deregulated cell cycle function.	('loss', 'NegReg', (110, 114))	('RB1', 'Gene', '5925', (106, 109))	('mutation', 'Var', (61, 69))	('deregulated', 'PosReg', (127, 138))	('FBXW7', 'Gene', '55294', (73, 78))	('cell cycle function', 'CPA', (139, 158))	('CCNE1', 'Gene', '898', (97, 102))	('CCNE1', 'Gene', (97, 102))	('RB1', 'Gene', (106, 109))	('FBXW7', 'Gene', (73, 78))
43344	28292439	A number of reports indicate that inactivation of chromatin remodeling genes such as ARID1A and CHD4 results in susceptibility to various targeted therapies including PARP and EZH2 inhibition.	('susceptibility', 'Reg', (112, 126))	('PARP', 'Gene', (167, 171))	('ARID1A', 'Gene', (85, 91))	('inactivation', 'Var', (34, 46))	('CHD4', 'Gene', '1108', (96, 100))	('EZH2', 'Gene', '2146', (176, 180))	('PARP', 'Gene', '142', (167, 171))	('EZH2', 'Gene', (176, 180))	('CHD4', 'Gene', (96, 100))	('ARID1A', 'Gene', '8289', (85, 91))
43346	28292439	PI3K inhibition has been successful in advanced endometrial cancers with responses seen in patients with pathway alterations despite some limitations due to tolerability.	('PI3K', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('patients', 'Species', '9606', (91, 99))	('endometrial cancer', 'Phenotype', 'HP:0012114', (48, 66))	('endometrial cancers', 'Disease', 'MESH:D016889', (48, 67))	('endometrial cancers', 'Disease', (48, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
43348	28292439	A minority of UCS tumors has molecular features consistent with an endometrioid subtype, including PTEN and KRAS mutations and corresponding gene expression profiles.	('KRAS', 'Gene', (108, 112))	('UCS', 'Phenotype', 'HP:0002891', (14, 17))	('tri', 'Chemical', '-', (73, 76))	('KRAS', 'Gene', '3845', (108, 112))	('endometrioid', 'Disease', (67, 79))	('UCS tumors', 'Disease', 'MESH:D009369', (14, 24))	('mutations', 'Var', (113, 122))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))	('UCS tumors', 'Disease', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
43355	28292439	In addition, molecular features including DNA methylation, copy number and gene expression recapitulate the endometrial versus serous dichotomy observed in endometrial carcinomas, which was in line with a previous report studying genetic mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('tri', 'Chemical', '-', (114, 117))	('endometrial carcinomas', 'Disease', (156, 178))	('endometrial versus serous dichotomy', 'Disease', (108, 143))	('tri', 'Chemical', '-', (162, 165))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (156, 178))	('copy number', 'Var', (59, 70))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (156, 178))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))
43359	28292439	In comparison to prior work where many of the mutations in chromatin-remodeling genes, including CHD4 and ARID1A, were found in hypermutated UCS samples or in carcinosarcoma tumors of ovarian origin, the present study identifies these mutations in more than one-third of non-hypermutated UCS samples.	('CHD4', 'Gene', (97, 101))	('carcinosarcoma tumors of ovarian', 'Disease', 'MESH:D002296', (159, 191))	('tumors of ovarian origin', 'Phenotype', 'HP:0100615', (174, 198))	('UCS', 'Phenotype', 'HP:0002891', (141, 144))	('mutations', 'Var', (46, 55))	('ARID1A', 'Gene', '8289', (106, 112))	('ARID1A', 'Gene', (106, 112))	('UCS', 'Phenotype', 'HP:0002891', (288, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('found', 'Reg', (119, 124))	('CHD4', 'Gene', '1108', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('carcinosarcoma tumors of ovarian', 'Disease', (159, 191))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
43371	28292439	Each candidate mutation site was assessed in the matched RNA-seq tumor data to identify candidate mutations with independent confirmation from RNA.	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
43372	28292439	35.6% of the candidate mutations occurred at expressed sites in the RNA-seq with sufficient coverage for >90% power to detect the mutation observed in the tumor DNA.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))
43384	28292439	We identify multiple somatic mutations and copy number alterations that offer expanded therapeutic options including potential use of PARP, EZH2, cell cycle and PI3K pathway inhibitors.	('copy number alterations', 'Var', (43, 66))	('EZH2', 'Gene', '2146', (140, 144))	('PARP', 'Gene', (134, 138))	('EZH2', 'Gene', (140, 144))	('PI3K pathway', 'Pathway', (161, 173))	('PARP', 'Gene', '142', (134, 138))
43386	28292439	Uterine carcinosarcomas (UCS) have frequent TP53 mutations UCS demonstrate a strong and varied degree of epithelial-mesenchymal transition MicroRNA expression in UCS is under epigenetic control Multiple alterations are present in UCS in genes that are therapeutic targets	('UCS', 'Phenotype', 'HP:0002891', (59, 62))	('UCS', 'Phenotype', 'HP:0002891', (25, 28))	('carcinosarcomas', 'Disease', (8, 23))	('mutations', 'Var', (49, 58))	('UCS', 'Phenotype', 'HP:0002891', (162, 165))	('TP53', 'Gene', '7157', (44, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('UCS', 'Phenotype', 'HP:0002891', (230, 233))	('TP53', 'Gene', (44, 48))	('carcinosarcomas', 'Disease', 'MESH:D002296', (8, 23))
43393	28620240	Finally, by treatment of UCS-xenografted mice with miR-200c incorporated in DOPC nanoliposomes, we demonstrate anti-tumor activities.	('DOPC', 'Chemical', '-', (76, 80))	('S', 'Chemical', 'MESH:D013455', (27, 28))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('miR-200c', 'Var', (51, 59))
43394	28620240	These findings suggest that ectopic miR-200 expression using advanced microRNA therapeutics may be a potential treatment approach for patients with UCS.	('patients', 'Species', '9606', (134, 142))	('ectopic', 'Var', (28, 35))	('S', 'Chemical', 'MESH:D013455', (150, 151))	('miR-200', 'Gene', (36, 43))	('miR-200', 'Chemical', '-', (36, 43))	('UCS', 'Disease', (148, 151))
43398	28620240	Recent data has shown that UCSs share mutational features similar to serous uterine carcinomas more commonly than endometrioid histologies, have extensive copy number alterations, and almost all harbor somatic TP53 mutations.	('serous uterine carcinomas', 'Disease', (69, 94))	('serous uterine carcinomas', 'Phenotype', 'HP:0012887', (69, 94))	('TP53', 'Gene', (210, 214))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (76, 94))	('S', 'Chemical', 'MESH:D013455', (29, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('serous uterine carcinomas', 'Disease', 'MESH:D014594', (69, 94))	('mutations', 'Var', (215, 224))	('harbor', 'Reg', (195, 201))	('TP53', 'Gene', '7157', (210, 214))
43400	28620240	This theory is supported by multiple levels of evidence, including the co-expression of cytokeratins and epithelial membrane antigens in carcinomatous and sarcomatous cells, as well as concordance of TP53 and K-ras mutations, identical patterns of X chromosome inactivation, and similar losses of heterozygosity between carcinomatous and sarcomatous components.	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (320, 349))	('inactivation', 'NegReg', (261, 273))	('losses', 'NegReg', (287, 293))	('TP53', 'Gene', '7157', (200, 204))	('TP53', 'Gene', (200, 204))	('mutations', 'Var', (215, 224))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (137, 166))	('K-ras', 'Gene', (209, 214))	('K-ras', 'Gene', '3845', (209, 214))
43415	28620240	We show that while EAC cell lines are resistant to full EMT, UCSs readily undergo miR-200-induced MET.	('undergo', 'Reg', (74, 81))	('S', 'Chemical', 'MESH:D013455', (63, 64))	('miR-200-induced', 'Var', (82, 97))	('miR-200', 'Chemical', '-', (82, 89))
43443	28620240	Proliferation for either miR-200 knockdown or miR-200 expressing cells was calculated relative to negative controls.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('miR-200', 'Gene', (25, 32))	('miR-200', 'Chemical', '-', (25, 32))	('knockdown', 'Var', (33, 42))	('miR-200', 'Chemical', '-', (46, 53))
43463	28620240	One week after JHUCS-1 wild-type cells (5 x 106) were injected subcutaneously over the posterior flank of 5-6 week old NSG mice, the mice were randomly assigned to treatment with control miRNA-DOPC or miR-200c-DOPC.	('mice', 'Species', '10090', (133, 137))	('-DOPC', 'Chemical', '-', (192, 197))	('S', 'Chemical', 'MESH:D013455', (19, 20))	('miR-200c-DOPC', 'Var', (201, 214))	('S', 'Chemical', 'MESH:D013455', (120, 121))	('-DOPC', 'Chemical', '-', (209, 214))	('JHUCS-1', 'CellLine', 'CVCL:4652', (15, 22))	('mice', 'Species', '10090', (123, 127))	('miRNA-DOPC', 'Var', (187, 197))
43468	28620240	Data was analyzed to identify single nucleotide variants (SNVs), small indels, and copy number alterations.	('copy number alterations', 'Var', (83, 106))	('S', 'Chemical', 'MESH:D013455', (58, 59))	('single nucleotide variants', 'Var', (30, 56))
43486	28620240	Alterations in PIK3CA are frequently found in both endometrioid and serous histologies, whereas PTEN, PIK3R1, CTNNB1 and KRAS are often mutated in endometrioid but rarely in serous histologies.	('PIK3R1', 'Gene', '5295', (102, 108))	('PTEN', 'Gene', '5728', (96, 100))	('KRAS', 'Gene', (121, 125))	('PIK3R1', 'Gene', (102, 108))	('CTNNB1', 'Gene', (110, 116))	('PIK3CA', 'Gene', '5290', (15, 21))	('Alterations', 'Var', (0, 11))	('found', 'Reg', (37, 42))	('KRAS', 'Gene', '3845', (121, 125))	('CTNNB1', 'Gene', '1499', (110, 116))	('serous', 'Disease', (68, 74))	('endometrioid', 'Disease', (51, 63))	('PTEN', 'Gene', (96, 100))	('PIK3CA', 'Gene', (15, 21))
43488	28620240	Given that UCSs are proposed to arise from carcinomatous subclones that are predominately p53-mutant, we chose 3 model cell lines with TP53 mutations: Ishikawa, MFE-280 and HEC-251.	('carcinomatous', 'Disease', 'MESH:D055756', (43, 56))	('p53', 'Gene', (90, 93))	('carcinomatous', 'Disease', (43, 56))	('p53', 'Gene', '7157', (90, 93))	('TP53', 'Gene', '7157', (135, 139))	('TP53', 'Gene', (135, 139))	('HEC-251', 'CellLine', 'CVCL:2927', (173, 180))	('mutations', 'Var', (140, 149))	('S', 'Chemical', 'MESH:D013455', (13, 14))
43492	28620240	Mutations consistent with UCSs were identified in both cell lines.	('UCSs', 'Disease', (26, 30))	('Mutations', 'Var', (0, 9))	('S', 'Chemical', 'MESH:D013455', (28, 29))
43493	28620240	JHUCS-1 cells were found to have an overlapping mutational landscape with mutations in genes seen in both endometrioid and serous adenocarcinomas, including TP53, FBXW7, PPP2R1A, PIK3CA, ARID1A, PTEN, and CTNNB1.	('TP53', 'Gene', (157, 161))	('serous adenocarcinomas', 'Disease', 'MESH:D000230', (123, 145))	('PPP2R1A', 'Gene', (170, 177))	('FBXW7', 'Gene', '55294', (163, 168))	('ARID1A', 'Gene', '8289', (187, 193))	('PTEN', 'Gene', (195, 199))	('JHUCS-1', 'CellLine', 'CVCL:4652', (0, 7))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('PIK3CA', 'Gene', (179, 185))	('endometrioid', 'Disease', (106, 118))	('PTEN', 'Gene', '5728', (195, 199))	('serous adenocarcinomas', 'Disease', (123, 145))	('TP53', 'Gene', '7157', (157, 161))	('CTNNB1', 'Gene', '1499', (205, 211))	('FBXW7', 'Gene', (163, 168))	('mutations', 'Var', (74, 83))	('PPP2R1A', 'Gene', '5518', (170, 177))	('PIK3CA', 'Gene', '5290', (179, 185))	('ARID1A', 'Gene', (187, 193))	('CTNNB1', 'Gene', (205, 211))
43494	28620240	SNU-685 cells were found to have mutations in TP53 and PPP2R1A, similar to serous adenocarcinomas.	('PPP2R1A', 'Gene', (55, 62))	('TP53', 'Gene', '7157', (46, 50))	('PPP2R1A', 'Gene', '5518', (55, 62))	('mutations', 'Var', (33, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('TP53', 'Gene', (46, 50))	('serous adenocarcinomas', 'Disease', 'MESH:D000230', (75, 97))	('serous adenocarcinomas', 'Disease', (75, 97))	('S', 'Chemical', 'MESH:D013455', (0, 1))
43498	28620240	In UCS cell lines, we also observed increased expression of ZEB1 and ZEB2, transcription factors upstream in the EMT pathway that are targeted by miR-200 for degradation (Fig.	('ZEB2', 'Gene', '9839', (69, 73))	('ZEB1', 'Gene', (60, 64))	('ZEB1', 'Gene', '6935', (60, 64))	('miR-200', 'Var', (146, 153))	('increased', 'PosReg', (36, 45))	('miR-200', 'Chemical', '-', (146, 153))	('S', 'Chemical', 'MESH:D013455', (5, 6))	('expression', 'MPA', (46, 56))	('ZEB2', 'Gene', (69, 73))
43506	28620240	Levels of miR-200b and miR-200c remained decreased over 10 transfection cycles.	('miR-200c', 'Var', (23, 31))	('miR-200b', 'Gene', '406984', (10, 18))	('miR-200b', 'Gene', (10, 18))
43507	28620240	As expected, constitutive miR-200b/c depletion resulted in increased expression of ZEB1 and ZEB2 in both cell lines by 1.4- to 5.9-fold and 1.9- to 3.5-fold, respectively (Fig.	('ZEB2', 'Gene', '9839', (92, 96))	('miR-200b', 'Gene', '406984', (26, 34))	('depletion', 'Var', (37, 46))	('ZEB2', 'Gene', (92, 96))	('miR-200b', 'Gene', (26, 34))	('expression', 'MPA', (69, 79))	('increased', 'PosReg', (59, 68))	('ZEB1', 'Gene', (83, 87))	('ZEB1', 'Gene', '6935', (83, 87))
43515	28620240	Our data show that, despite miR-200 depletion and subsequent increases in ZEB1/2 expression in EACs, there is no evidence of complete EMT induction.	('ZEB1/2', 'Gene', '6935;9839', (74, 80))	('depletion', 'Var', (36, 45))	('miR-200', 'Gene', (28, 35))	('miR-200', 'Chemical', '-', (28, 35))	('ZEB1/2', 'Gene', (74, 80))	('increases', 'PosReg', (61, 70))	('expression', 'MPA', (81, 91))
43520	28620240	In conclusion, although miR-200 depletion and increase in ZEB1/2 expression resulted in a modest decrease in cellular adhesion, there was no evidence of molecular or functional complete EMT.	('increase', 'PosReg', (46, 54))	('depletion', 'Var', (32, 41))	('ZEB1/2', 'Gene', '6935;9839', (58, 64))	('cellular', 'CPA', (109, 117))	('miR-200', 'Gene', (24, 31))	('miR-200', 'Chemical', '-', (24, 31))	('expression', 'MPA', (65, 75))	('decrease', 'NegReg', (97, 105))	('ZEB1/2', 'Gene', (58, 64))
43524	28620240	Taken together, our data suggest that the only consistent EMT-like changes achievable in EAC cells, either by constitutive miR-200 depletion or exogenous TGF-beta treatment, are increases in ZEB1 and ZEB2 expression.	('TGF-beta', 'Gene', (154, 162))	('ZEB2', 'Gene', (200, 204))	('miR-200', 'Gene', (123, 130))	('miR-200', 'Chemical', '-', (123, 130))	('ZEB1', 'Gene', '6935', (191, 195))	('ZEB1', 'Gene', (191, 195))	('TGF-beta', 'Gene', '7040', (154, 162))	('depletion', 'Var', (131, 140))	('ZEB2', 'Gene', '9839', (200, 204))	('expression', 'MPA', (205, 215))	('increases', 'PosReg', (178, 187))
43531	28620240	The expression levels of miR200c in miR-200c-overexpressing SNU-685 were comparable to the EAC cell lines, whereas miR-200c-overexpressing JHUCS-1 cells had approximately a 14-fold increased expression when compared to EAC cell lines (Supplementary Fig.	('S', 'Chemical', 'MESH:D013455', (143, 144))	('S', 'Chemical', 'MESH:D013455', (60, 61))	('miR-200c-overexpressing', 'Var', (115, 138))	('miR-200c-overexpressing', 'Var', (36, 59))	('JHUCS-1', 'CellLine', 'CVCL:4652', (139, 146))	('miR200c', 'Gene', (25, 32))	('increased', 'PosReg', (181, 190))	('S', 'Chemical', 'MESH:D013455', (235, 236))	('expression', 'MPA', (191, 201))	('miR200c', 'Gene', '406985', (25, 32))
43533	28620240	Vimentin mRNA levels decreased by 71% in JHUCS-1 cells with miR-200c OE, while no significant changes were observed in SNU-685 cells.	('Vimentin', 'Gene', '7431', (0, 8))	('S', 'Chemical', 'MESH:D013455', (45, 46))	('decreased', 'NegReg', (21, 30))	('JHUCS-1', 'CellLine', 'CVCL:4652', (41, 48))	('mRNA levels', 'MPA', (9, 20))	('S', 'Chemical', 'MESH:D013455', (119, 120))	('miR-200c OE', 'Var', (60, 71))	('Vimentin', 'Gene', (0, 8))
43537	28620240	UCSs with miR-200 OE exhibited significantly decreased cellular proliferation compared to control cells (Fig.	('cellular proliferation', 'CPA', (55, 77))	('miR-200', 'Chemical', '-', (10, 17))	('decreased', 'NegReg', (45, 54))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('miR-200 OE', 'Var', (10, 20))
43539	28620240	JHUCS-1 cells overexpressing miR-200c demonstrated increased adhesion as well as decreased migration and invasion, suggestive of biological MET changes (Fig.	('decreased', 'NegReg', (81, 90))	('JHUCS-1', 'CellLine', 'CVCL:4652', (0, 7))	('increased', 'PosReg', (51, 60))	('miR-200c', 'Var', (29, 37))	('adhesion', 'CPA', (61, 69))
43540	28620240	Unexpectedly, SNU-685 cells with miR2-200c OE showed decreased adhesion and non-statistically significant differences in migration or invasion, compared to SNU-685 NTCs.	('miR2-200c OE', 'Var', (33, 45))	('migration', 'CPA', (121, 130))	('adhesion', 'CPA', (63, 71))	('invasion', 'CPA', (134, 142))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('decreased', 'NegReg', (53, 62))	('S', 'Chemical', 'MESH:D013455', (14, 15))
43541	28620240	Altogether, our data show that increased miR-200c is sufficient to evoke molecular and biological changes consistent with MET, fully in JHUCS-1, and partially in SNU-685 cell lines.	('S', 'Chemical', 'MESH:D013455', (162, 163))	('evoke', 'Reg', (67, 72))	('increased', 'PosReg', (31, 40))	('S', 'Chemical', 'MESH:D013455', (140, 141))	('miR-200c', 'Var', (41, 49))	('JHUCS-1', 'CellLine', 'CVCL:4652', (136, 143))
43542	28620240	To further characterize the molecular effects of miR-200 modulation, we performed whole transcriptome sequencing (RNA-seq) on EAC cell lines with miR200b/c KD and UCS cell lines with miR-200c OE.	('miR-200', 'Chemical', '-', (49, 56))	('miR200b', 'Gene', '406984', (146, 153))	('miR-200', 'Chemical', '-', (183, 190))	('miR200b', 'Gene', (146, 153))	('miR-200c OE', 'Var', (183, 194))	('S', 'Chemical', 'MESH:D013455', (165, 166))
43545	28620240	However, stable miR-200c OE in JHUCS-1 and SNU-685 cells led to robust upregulation of epithelial genes and downregulation of mesenchymal genes.	('S', 'Chemical', 'MESH:D013455', (35, 36))	('epithelial genes', 'Gene', (87, 103))	('JHUCS-1', 'CellLine', 'CVCL:4652', (31, 38))	('upregulation', 'PosReg', (71, 83))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('downregulation', 'NegReg', (108, 122))	('miR-200c OE', 'Var', (16, 27))	('mesenchymal genes', 'Gene', (126, 143))
43547	28620240	Consistent with our prior findings, this suggests that miR-200c OE drives a more complete MET in JHUCS-1 cells than in SNU-685 cells.	('S', 'Chemical', 'MESH:D013455', (101, 102))	('miR-200c OE', 'Var', (55, 66))	('JHUCS-1', 'CellLine', 'CVCL:4652', (97, 104))	('S', 'Chemical', 'MESH:D013455', (119, 120))	('MET', 'MPA', (90, 93))
43549	28620240	Notably, 913 differentially expressed genes were identified in UCS cells with miR-200c OE, whereas only 185 genes were identified in EAC cells with miR-200b/c KD.	('miR-200b', 'Gene', (148, 156))	('S', 'Chemical', 'MESH:D013455', (65, 66))	('differentially expressed genes', 'MPA', (13, 43))	('miR-200b', 'Gene', '406984', (148, 156))	('miR-200c OE', 'Var', (78, 89))
43550	28620240	In UCS cells that underwent miR-200c OE, GO, KEGG pathway analysis and functional annotation clustering all showed enrichment in MET-related genes (e.g.	('MET-related genes', 'Gene', (129, 146))	('miR-200c OE', 'Var', (28, 39))	('S', 'Chemical', 'MESH:D013455', (5, 6))
43555	28620240	To test whether miR-200c OE leads to decreased tumor growth in vivo, we developed murine UCS xenograft models.	('decreased tumor', 'Disease', 'MESH:D009369', (37, 52))	('murine', 'Species', '10090', (82, 88))	('S', 'Chemical', 'MESH:D013455', (91, 92))	('decreased tumor', 'Disease', (37, 52))	('miR-200c OE', 'Var', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))
43558	28620240	Similar to our in vitro cell proliferation results, mice bearing miR-200c-overexpressed cells had substantially smaller tumors compared to mice bearing control cells (Fig.	('smaller', 'NegReg', (112, 119))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mice', 'Species', '10090', (52, 56))	('miR-200c-overexpressed cells', 'Var', (65, 93))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('S', 'Chemical', 'MESH:D013455', (0, 1))
43560	28620240	Relative to controls, miR-200c OE resulted in increased length of time from injection of cells until formation of measurable tumors (31 days in JHUCS-1; 14 days in SNU-685) and decreased tumor growth (Fig.	('decreased tumor', 'Disease', 'MESH:D009369', (177, 192))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('increased', 'PosReg', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('decreased tumor', 'Disease', (177, 192))	('JHUCS-1', 'CellLine', 'CVCL:4652', (144, 151))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('S', 'Chemical', 'MESH:D013455', (148, 149))	('miR-200c OE', 'Var', (22, 33))	('S', 'Chemical', 'MESH:D013455', (164, 165))
43561	28620240	The effects were more prominent in JHUCS-1 cells versus SNU-685, consistent with our observation that upon miR-200c OE, JHUCS-1 cells exhibit more pronounced biological MET characteristics.	('S', 'Chemical', 'MESH:D013455', (56, 57))	('S', 'Chemical', 'MESH:D013455', (124, 125))	('JHUCS-1', 'CellLine', 'CVCL:4652', (120, 127))	('JHUCS-1', 'CellLine', 'CVCL:4652', (35, 42))	('biological MET characteristics', 'CPA', (158, 188))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('miR-200c OE', 'Var', (107, 118))	('more', 'PosReg', (142, 146))
43565	28620240	In contrast, tumors overexpressing miR-200c showed distinct morphologic changes.	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('miR-200c', 'Var', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
43568	28620240	In comparison, tumors with miR-200c OE demonstrated significant IHC differences: ZEB1 staining was absent, E-cadherin demonstrated strong, patchy membranous staining, and vimentin staining was minimal.	('E-cadherin', 'Gene', (107, 117))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('ZEB1', 'Gene', '6935', (81, 85))	('ZEB1', 'Gene', (81, 85))	('absent', 'NegReg', (99, 105))	('vimentin', 'Gene', '7431', (171, 179))	('miR-200c', 'Var', (27, 35))	('vimentin', 'Gene', (171, 179))	('tumors', 'Disease', (15, 21))	('E-cadherin', 'Gene', '999', (107, 117))
43569	28620240	These findings are consistent with our mRNA and protein expression results, and further confirm that JHUCS-1 cells readily undergo complete MET upon miR-200c overexpression.	('overexpression', 'PosReg', (158, 172))	('JHUCS-1', 'CellLine', 'CVCL:4652', (101, 108))	('miR-200c', 'Var', (149, 157))
43578	28620240	Our results suggest that while UCSs do not appear to develop from EACs by miR-200-dependent EMT, UCS cell lines readily undergo miR-200-induced MET resulting in decreased tumor growth and aggressiveness.	('decreased tumor', 'Disease', (161, 176))	('MET', 'Var', (144, 147))	('aggressiveness', 'Disease', (188, 202))	('undergo', 'Reg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('S', 'Chemical', 'MESH:D013455', (33, 34))	('miR-200-induced', 'Gene', (128, 143))	('aggressiveness', 'Phenotype', 'HP:0000718', (188, 202))	('miR-200', 'Chemical', '-', (128, 135))	('decreased tumor', 'Disease', 'MESH:D009369', (161, 176))	('S', 'Chemical', 'MESH:D013455', (99, 100))	('aggressiveness', 'Disease', 'MESH:D001523', (188, 202))	('miR-200', 'Chemical', '-', (74, 81))
43579	28620240	Recent data has shown that 91% of UCSs harbor TP53 mutations, and many share mutational features with endometrioid and serous uterine carcinomas.	('serous uterine carcinomas', 'Disease', 'MESH:D014594', (119, 144))	('mutations', 'Var', (51, 60))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (126, 144))	('TP53', 'Gene', '7157', (46, 50))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('endometrioid', 'Disease', (102, 114))	('TP53', 'Gene', (46, 50))	('serous uterine carcinomas', 'Disease', (119, 144))	('serous uterine carcinomas', 'Phenotype', 'HP:0012887', (119, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('UCSs', 'Disease', (34, 38))
43587	28620240	Firstly, we used miR-200b and miR-200c inhibitors to ensure knockdown of both miR-200 gene clusters.	('miR-200', 'Gene', (78, 85))	('miR-200', 'Chemical', '-', (78, 85))	('miR-200', 'Chemical', '-', (17, 24))	('miR-200b', 'Gene', '406984', (17, 25))	('miR-200b', 'Gene', (17, 25))	('knockdown', 'Var', (60, 69))	('miR-200', 'Chemical', '-', (30, 37))
43588	28620240	Secondly, the miR-200 knockdown we achieved was sufficient to increase expression of ZEB1 and ZEB2, which are direct targets of miR-200c.	('ZEB2', 'Gene', (94, 98))	('expression', 'MPA', (71, 81))	('miR-200', 'Gene', (14, 21))	('miR-200', 'Chemical', '-', (14, 21))	('knockdown', 'Var', (22, 31))	('ZEB1', 'Gene', (85, 89))	('miR-200', 'Chemical', '-', (128, 135))	('ZEB1', 'Gene', '6935', (85, 89))	('ZEB2', 'Gene', '9839', (94, 98))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('increase', 'PosReg', (62, 70))
43596	28620240	This is likely due to a lack of significantly decreased vimentin expression in miR-200c-overexpressed compared to control SNU-685 cells.	('vimentin', 'Gene', '7431', (56, 64))	('miR-200c-overexpressed', 'Var', (79, 101))	('vimentin', 'Gene', (56, 64))	('expression', 'MPA', (65, 75))	('decreased', 'NegReg', (46, 55))	('S', 'Chemical', 'MESH:D013455', (122, 123))
43598	28620240	For miR-200c-overexpressed JHUCS-1 cells, decreased vimentin expression and readiness to undergo a complete MET may partly be attributed to the mutational profile of this cell line.	('vimentin', 'Gene', '7431', (52, 60))	('decreased', 'NegReg', (42, 51))	('miR-200c-overexpressed', 'Var', (4, 26))	('vimentin', 'Gene', (52, 60))	('JHUCS-1', 'CellLine', 'CVCL:4652', (27, 34))	('expression', 'MPA', (61, 71))
43599	28620240	JHUCS-1 cells harbor a mutation in CTNNB1, a gene that encodes for beta-catenin.	('CTNNB1', 'Gene', '1499', (35, 41))	('JHUCS-1', 'CellLine', 'CVCL:4652', (0, 7))	('mutation', 'Var', (23, 31))	('CTNNB1', 'Gene', (35, 41))	('beta-catenin', 'Gene', (67, 79))	('beta-catenin', 'Gene', '1499', (67, 79))
43603	28620240	Xenografting studies further confirmed that miR-200c overexpression in JHUCS-1 cells results in MET.	('overexpression', 'PosReg', (53, 67))	('MET', 'MPA', (96, 99))	('JHUCS-1', 'CellLine', 'CVCL:4652', (71, 78))	('miR-200c', 'Var', (44, 52))
43607	28620240	Taken together, our in vitro and in vivo data strongly support the conclusion that JHUCS-1 cells readily undergo miR-200 driven MET, leading to decreased tumor aggressiveness.	('miR-200', 'Var', (113, 120))	('aggressiveness', 'Phenotype', 'HP:0000718', (160, 174))	('decreased tumor aggressiveness', 'Disease', (144, 174))	('decreased tumor aggressiveness', 'Disease', 'MESH:D009369', (144, 174))	('JHUCS-1', 'CellLine', 'CVCL:4652', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('miR-200', 'Chemical', '-', (113, 120))
43612	28620240	Specifically, ectopic miR-200 expression was shown to decrease metastasis, inhibit angiogenesis, and induce normal vascularization.	('decrease', 'NegReg', (54, 62))	('metastasis', 'CPA', (63, 73))	('inhibit', 'NegReg', (75, 82))	('normal vascularization', 'CPA', (108, 130))	('ectopic', 'Var', (14, 21))	('miR-200', 'Chemical', '-', (22, 29))	('miR-200', 'Gene', (22, 29))	('angiogenesis', 'CPA', (83, 95))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('induce', 'PosReg', (101, 107))
43613	28620240	normal vs. pathologic) are ultimately determined by a complex interplay between pro-angiogenic and anti-angiogenic factors, it appears that miR-200 is associated with inhibition of angiogenesis.	('miR-200', 'Var', (140, 147))	('inhibition', 'NegReg', (167, 177))	('miR-200', 'Chemical', '-', (140, 147))	('angiogenesis', 'CPA', (181, 193))
43616	28620240	Ectopic expression of miR-200 has been shown to increase sensitivity of ovarian, breast and endometrial cancer cells to chemotherapeutic agents and enhance radiosensitivity in lung cancer.	('ovarian, breast and endometrial cancer', 'Disease', 'MESH:D010051', (72, 110))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Ectopic expression', 'Var', (0, 18))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (148, 172))	('radiosensitivity', 'CPA', (156, 172))	('enhance', 'PosReg', (148, 155))	('sensitivity', 'MPA', (57, 68))	('miR-200', 'Chemical', '-', (22, 29))	('endometrial cancer', 'Phenotype', 'HP:0012114', (92, 110))	('miR-200', 'Gene', (22, 29))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('increase', 'PosReg', (48, 56))
43617	28620240	DOPC-nanoliposomes carrying siRNAs against multiple genes were shown to be active in xenograft models of various tumors without any detectable distress or toxicity.	('siRNAs', 'Var', (28, 34))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('toxicity', 'Disease', 'MESH:D064420', (155, 163))	('toxicity', 'Disease', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('active', 'MPA', (75, 81))	('DOPC', 'Chemical', '-', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
43620	28620240	Here, we demonstrate that systemic miR-200c DOPC nanoliposome treatment in a murine xenograft UCS model can effectively reach the target tissue, increase intra-tumoral miR-200c expression, and decrease UCS tumor growth.	('increase intra-tumoral', 'Disease', (145, 167))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('S', 'Chemical', 'MESH:D013455', (96, 97))	('tumor', 'Disease', (206, 211))	('murine', 'Species', '10090', (77, 83))	('expression', 'MPA', (177, 187))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('DOPC', 'Chemical', '-', (44, 48))	('S', 'Chemical', 'MESH:D013455', (204, 205))	('increase intra-tumoral', 'Disease', 'MESH:D009369', (145, 167))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('miR-200c', 'Protein', (168, 176))	('miR-200c', 'Var', (35, 43))	('tumor', 'Disease', (160, 165))	('decrease', 'NegReg', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
43622	28620240	miR-200c decreases tumor growth, and may affect angiogenesis and chemosensitivity.	('decreases tumor', 'Disease', 'MESH:D009369', (9, 24))	('decreases tumor', 'Disease', (9, 24))	('chemosensitivity', 'CPA', (65, 81))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('miR-200c', 'Var', (0, 8))	('affect', 'Reg', (41, 47))	('angiogenesis', 'CPA', (48, 60))
43646	27374098	PCs are a family of serine proteases, seven of which (furin, PC1/3, PC2, PC4, PACE4, PC5/6 and PC7/8) share a consensus cleavage motif of (K/R-(X)n-(KR) (n = 2, 4 or 6, X is any other amino acid).	('PC4', 'Gene', (73, 76))	('PACE4', 'Gene', '5046', (78, 83))	('K/R-(X)n-(KR', 'Var', (139, 151))	('PC4', 'Gene', '3854', (73, 76))	('PC5', 'Gene', (85, 88))	('PC2', 'Gene', '3854', (68, 71))	('PC7/8', 'Gene', (95, 100))	('PC5', 'Gene', '5125', (85, 88))	('PACE4', 'Gene', (78, 83))	('PC1/3', 'Gene', (61, 66))	('furin', 'Gene', '5045', (54, 59))	('PC2', 'Gene', (68, 71))	('furin', 'Gene', (54, 59))	('PC1/3', 'Gene', '5122', (61, 66))	('PC7/8', 'Gene', '9159', (95, 100))
43672	27374098	Sample collection was approved by appropriate Institutional Ethics Committees (MMCB02031B and MMC06032C) and written informed consent was obtained from individual patients.	('patients', 'Species', '9606', (163, 171))	('MMC06032C', 'Var', (94, 103))	('MMCB02031B', 'Var', (79, 89))
43829	26841870	Anti-p21waf1, anti-cyclin D1, and anti-CD44s antibodies were purchased from Dako (Copenhagen, Denmark).	('Anti-p21waf1', 'Var', (0, 12))	('cyclin D1', 'Gene', '595', (19, 28))	('CD44', 'Gene', '960', (39, 43))	('cyclin D1', 'Gene', (19, 28))	('CD44', 'Gene', (39, 43))
43858	26841870	In addition, the Sox4 promoter activity was increased by 20-50 folds following transfection of Sox7, while changes in the promoter activity of both Sox7 and Sox9 in response to other Sox factors were relatively minor (Fig.	('Sox9', 'Gene', (157, 161))	('Sox7', 'Gene', '83595', (95, 99))	('Sox4', 'Gene', (17, 21))	('Sox7', 'Gene', (95, 99))	('increased', 'PosReg', (44, 53))	('Sox4', 'Gene', '6659', (17, 21))	('transfection', 'Var', (79, 91))	('Sox7', 'Gene', '83595', (148, 152))	('Sox7', 'Gene', (148, 152))	('Sox9', 'Gene', '6662', (157, 161))
43862	26841870	Cultured Hec6 cells had a low cell proliferation rate, particularly in the exponential growth phase, which correlated with increased p21waf1 but not p27Kip1 expression, and a decreased S-fraction during cell cycle progression (Fig.	('increased', 'PosReg', (123, 132))	('Hec6', 'CellLine', 'CVCL:0293', (9, 13))	('low', 'NegReg', (26, 29))	('S-fraction', 'MPA', (185, 195))	('p27Kip1', 'Gene', '1027', (149, 156))	('cell proliferation rate', 'CPA', (30, 53))	('p27Kip1', 'Gene', (149, 156))	('decreased', 'NegReg', (175, 184))	('p21waf1', 'Var', (133, 140))
43875	26841870	Using a series of 5'-truncated promoter constructs, we found that deletion from -2125 to -1587 bp had little effect on induction of the promoter activity by Sox4, as well as Sox7 and Sox9, whereas the -813/-235 bp deletion appeared to have prevented binding of the Sox factors and reduced the promoter activity to a very low level (Fig.	('promoter activity', 'MPA', (293, 310))	('prevented', 'NegReg', (240, 249))	('Sox4', 'Gene', (157, 161))	('Sox7', 'Gene', '83595', (174, 178))	('Sox9', 'Gene', '6662', (183, 187))	('Sox9', 'Gene', (183, 187))	('Sox7', 'Gene', (174, 178))	('promoter activity', 'MPA', (136, 153))	('binding', 'Interaction', (250, 257))	('Sox4', 'Gene', '6659', (157, 161))	('reduced', 'NegReg', (281, 288))	('deletion', 'Var', (66, 74))
43900	26841870	Interestingly, the Sox4 promoter activity was drastically increased by transfection of Sox7, in line with the IHC data showing significant positive correlation between the two in UCS tissues.	('increased', 'PosReg', (58, 67))	('transfection', 'Var', (71, 83))	('Sox7', 'Gene', '83595', (87, 91))	('Sox4', 'Gene', '6659', (19, 23))	('Sox7', 'Gene', (87, 91))	('Sox4', 'Gene', (19, 23))
43910	26841870	The effects were further enhanced by cotransfection of Sox9 and/or Sox7.	('Sox7', 'Gene', (67, 71))	('enhanced', 'PosReg', (25, 33))	('Sox9', 'Gene', '6662', (55, 59))	('Sox9', 'Gene', (55, 59))	('cotransfection', 'Var', (37, 51))	('Sox7', 'Gene', '83595', (67, 71))
43911	26841870	Interestingly, it has been recently reported that ectopic Sox4 expression in human mammary epithelial cells could induce a mesenchymal phenotype, which was associated with increased stem cell properties, cellular migration, and invasion in vitro.	('Sox4', 'Gene', '6659', (58, 62))	('increased', 'PosReg', (172, 181))	('ectopic', 'Var', (50, 57))	('invasion', 'CPA', (228, 236))	('mesenchymal phenotype', 'CPA', (123, 144))	('Sox4', 'Gene', (58, 62))	('cellular migration', 'CPA', (204, 222))	('induce', 'PosReg', (114, 120))	('stem cell properties', 'CPA', (182, 202))	('human', 'Species', '9606', (77, 82))
43934	26293576	P53 gene mutations occur in approximately one-half of all tumors in a wide range of human malignancies and overexpression is associated with poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('malignancies', 'Disease', (90, 102))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('P53', 'Gene', (0, 3))	('human', 'Species', '9606', (84, 89))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('P53', 'Gene', '7157', (0, 3))	('occur', 'Reg', (19, 24))
43944	26293576	AA98 inhibits human umbilical vein endothelial cell proliferation and migration as well as angiogenesis, validating CD146 as a novel target for antiangiogenic agents.	('AA98', 'Var', (0, 4))	('angiogenesis', 'CPA', (91, 103))	('migration', 'CPA', (70, 79))	('human', 'Species', '9606', (14, 19))	('inhibits', 'NegReg', (5, 13))	('CD146', 'Gene', '4162', (116, 121))	('CD146', 'Gene', (116, 121))
43999	26293576	On multivariate analyses, CD146 positivity varied statistically significantly with clinicopathological parameters, P53, and Ki-67 expression (P = 0.01).	('P53', 'Gene', '7157', (115, 118))	('P53', 'Gene', (115, 118))	('CD146', 'Gene', '4162', (26, 31))	('positivity', 'Var', (32, 42))	('CD146', 'Gene', (26, 31))	('varied', 'Reg', (43, 49))
44002	26293576	CD146 positivity also tended to be associated with poor prognosis in ESS, though the difference was not significant (P = 0.1).	('positivity', 'Var', (6, 16))	('ESS', 'Disease', (69, 72))	('CD146', 'Gene', '4162', (0, 5))	('CD146', 'Gene', (0, 5))
44027	26293576	CD146 positivity in the epithelial compartment showed a significant association with poor prognosis in ESS (P = 0.1).	('positivity', 'Var', (6, 16))	('CD146', 'Gene', '4162', (0, 5))	('ESS', 'Disease', (103, 106))	('CD146', 'Gene', (0, 5))
44032	26293576	WHO World Health Organization LMS leiomyosarcoma ESS endometrial stromal sarcoma UD undifferentiated sarcoma MMMT malignant mixed Mullerian tumor SYSUCC Sun Yat-Sen University Cancer Center FIGO International Federation of Obstetrics and Gynecology PE paraffin-embedded TAH total abdominal hysterectomy BSO bilateral salpingo-oophorectomy PL pelvic lymphadenectomy MI mitotic index HPF high-power field OS overall survival DFS disease-free survival LVSI lymphovascular space invasion	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (53, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('LMS', 'Phenotype', 'HP:0100243', (30, 33))	('leiomyosarcoma', 'Disease', (34, 48))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (84, 108))	('OS', 'Chemical', '-', (403, 405))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (34, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('undifferentiated sarcoma', 'Disease', (84, 108))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('paraffin', 'Chemical', 'MESH:D010232', (252, 260))	('endometrial stromal sarcoma', 'Disease', (53, 80))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (34, 48))	('MI mitotic index HPF', 'Var', (365, 385))	('tumor', 'Disease', (140, 145))
44255	24126219	The authors found 4 endometrial cancer types: DNA polymerase epsilon (POLE) ultramutated, microsatellite instability hypermutated, copy number low, and copy number high.	('endometrial cancer', 'Disease', 'MESH:D016889', (20, 38))	('endometrial cancer', 'Phenotype', 'HP:0012114', (20, 38))	('microsatellite', 'MPA', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('copy number high', 'Var', (152, 168))	('copy number low', 'Var', (131, 146))	('endometrial cancer', 'Disease', (20, 38))
44256	24126219	The copy number high group (serous-like), which was composed of mostly serous tumors and grade 3 endometrioid tumors, had the worst prognosis.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('endometrioid tumors', 'Disease', 'MESH:D016889', (97, 116))	('copy number high', 'Var', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mostly serous tumors', 'Disease', 'MESH:D018284', (64, 84))	('mostly serous tumors', 'Disease', (64, 84))	('endometrioid tumors', 'Disease', (97, 116))
44305	24126219	This work has also provided outcomes data that emphasize the distinctive and aggressive nature of serous carcinomas and related tumors that mapped to the copy number high cluster.	('serous carcinomas', 'Disease', 'MESH:D018284', (98, 115))	('serous carcinomas', 'Disease', (98, 115))	('copy number', 'Var', (154, 165))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))
44325	25426405	Tumor markers were as follows: CA 125 = 127 U/ml, CEA = 0.7 ng/ml, and CA 19-9 = 52 U/ml.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CA 19-9 = 52 U/ml', 'Var', (71, 88))	('CEA', 'Gene', (50, 53))	('CEA', 'Gene', '5670', (50, 53))	('CA 125 = 127 U/ml', 'Var', (31, 48))
44443	22802879	Routinely, the diagnosis is made without a stromal cell mitotic count (that in adenosarcoma is more than 1-2 per 10 HPFs), immunohistochemical determinations (ER, PR, CD10, WT1, p53) or DNA aneuploidia/diploidia determination.	('aneuploidia/diploidia determination', 'Disease', (190, 225))	('CD10', 'Gene', '4311', (167, 171))	('ER', 'Var', (159, 161))	('adenosarcoma', 'Disease', (79, 91))	('adenosarcoma', 'Disease', 'MESH:D018195', (79, 91))	('WT1', 'Gene', '7490', (173, 176))	('CD10', 'Gene', (167, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('WT1', 'Gene', (173, 176))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))	('aneuploidia/diploidia determination', 'Disease', 'MESH:D003643', (190, 225))
44475	20642852	Exposure to radiation, excessive estrogen exposure, obesity, and nulliparity are believed to be associated with MMMT development.	('obesity', 'Disease', (52, 59))	('MMMT development', 'Disease', (112, 128))	('associated', 'Reg', (96, 106))	('obesity', 'Phenotype', 'HP:0001513', (52, 59))	('nulliparity', 'Var', (65, 76))	('obesity', 'Disease', 'MESH:D009765', (52, 59))
44525	20642852	Mutations in the p53 gene (tumor suppresser and gatekeeper) remain one of the commonest genetic lesions found in human cancers.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('human', 'Species', '9606', (113, 118))	('cancers', 'Disease', (119, 126))	('Mutations', 'Var', (0, 9))	('gatekeeper', 'Species', '111938', (48, 58))	('p53', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('p53', 'Gene', '7157', (17, 20))
44528	20642852	The average survival time in p53 positive cases was 3.56 years as opposed to 8.94 years in the negatively stained cases.	('p53', 'Gene', '7157', (29, 32))	('positive', 'Var', (33, 41))	('p53', 'Gene', (29, 32))
44530	20642852	Overexpression of p53 has been linked to decreased survival in several other malignancies.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('decreased', 'NegReg', (41, 50))	('malignancies', 'Disease', (77, 89))	('Overexpression', 'Var', (0, 14))	('survival', 'MPA', (51, 59))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
44539	20642852	Overexpression of p16 is believed to be the result of mutated p16 gene product and/or an accumulation due to decreased turnover of the protein.	('decreased', 'NegReg', (109, 118))	('p16', 'Gene', '1029', (18, 21))	('accumulation', 'PosReg', (89, 101))	('p16', 'Gene', (62, 65))	('mutated', 'Var', (54, 61))	('p16', 'Gene', (18, 21))	('protein', 'Protein', (135, 142))	('p16', 'Gene', '1029', (62, 65))	('turnover', 'MPA', (119, 127))
44565	20642852	P53 is known to regulate Bax expression, with inactivation of p53 leading to reduced Bax protein levels.	('Bax', 'Gene', '581', (25, 28))	('p53', 'Gene', '7157', (62, 65))	('Bax', 'Gene', (85, 88))	('P53', 'Gene', (0, 3))	('Bax', 'Gene', (25, 28))	('reduced', 'NegReg', (77, 84))	('P53', 'Gene', '7157', (0, 3))	('inactivation', 'Var', (46, 58))	('p53', 'Gene', (62, 65))	('Bax', 'Gene', '581', (85, 88))
44566	20642852	Bax mutations and resistance to apoptosis have been described in stomach, pancreas, endometrium, hemopoietic malignancies, and a subset of colon and lung cancers indicating that inactivating Bax mutations may play an important role in tumor progression in these cancers.	('lung cancers', 'Phenotype', 'HP:0100526', (149, 161))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('hemopoietic malignancies', 'Disease', 'MESH:D009369', (97, 121))	('Bax', 'Gene', (191, 194))	('hemopoietic malignancies', 'Disease', (97, 121))	('described', 'Reg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('Bax', 'Gene', (0, 3))	('Bax', 'Gene', '581', (191, 194))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('cancers', 'Disease', (262, 269))	('stomach', 'Disease', (65, 72))	('pancreas', 'Disease', (74, 82))	('Bax', 'Gene', '581', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('mutations', 'Var', (195, 204))	('mutations', 'Var', (4, 13))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('pancreas', 'Disease', 'MESH:D010190', (74, 82))	('colon and lung cancers', 'Disease', 'MESH:D008175', (139, 161))	('tumor', 'Disease', (235, 240))	('inactivating', 'Var', (178, 190))	('endometrium', 'Disease', (84, 95))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Disease', 'MESH:D009369', (262, 269))
44571	20642852	Our study supports that cell cycle and apoptotic regulatory protein dysregulation is an important pathway for tumorigenesis.	('dysregulation', 'Var', (68, 81))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cell', 'CPA', (24, 28))	('apoptotic regulatory protein', 'Protein', (39, 67))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
44588	33670088	On a molecular basis, MA and MLA share KRAS mutations, but in MLA, concurrent PIK3CA mutations are described in nearly half of the cases, a mutation not found in MA and present among the genetic alterations in endometrioid adenocarcinoma.	('MLA', 'Chemical', '-', (29, 32))	('PIK3CA', 'Gene', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('MLA', 'Chemical', '-', (62, 65))	('mutations', 'Var', (85, 94))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (210, 237))	('endometrioid adenocarcinoma', 'Disease', (210, 237))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (210, 237))
44610	33670088	Additional molecular analysis showed a pathogenic KRAS c.38G > A variant (p.Gly13Asp) and two probable pathogenic variants of PTEN (c.388C > T and c.634 + 2T > G).	('2T > G', 'SUBSTITUTION', 'None', (155, 161))	('c.388C > T', 'Var', (132, 142))	('KRAS c.38G > A', 'Var', (50, 64))	('p.Gly13Asp', 'Mutation', 'rs112445441', (74, 84))	('pathogenic', 'Reg', (39, 49))	('c.388C > T', 'Mutation', 'rs121909224', (132, 142))	('c.38G > A', 'Mutation', 'rs112445441', (55, 64))	('PTEN', 'Gene', (126, 130))	('2T > G', 'Var', (155, 161))
44622	33670088	could prove clonality between the Mullerian lesions (endometrioid endometrial carcinoma, serous borderline tumor and low-grade serous carcinoma of the ovary) since they share mutations in the KRAS and NRAS gene.	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 87))	('endometrioid endometrial carcinoma', 'Disease', (53, 87))	('NRAS', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (66, 87))	('mutations', 'Var', (175, 184))	('KRAS', 'Gene', (192, 196))	('serous carcinoma of the ovary', 'Disease', 'MESH:D010051', (127, 156))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('serous carcinoma of the ovary', 'Disease', (127, 156))
44631	33670088	ER/PR negativity in endometrioid endometrial adenocarcinoma (EEC) is an independent risk factor for recurrence and death in FIGO grade I-II EEC.	('endometrioid endometrial adenocarcinoma', 'Disease', (20, 59))	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (20, 59))	('EEC', 'Chemical', '-', (61, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('ER/PR negativity', 'Var', (0, 16))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (33, 59))	('EEC', 'Chemical', '-', (140, 143))	('EEC', 'Phenotype', 'HP:0012114', (61, 64))	('EEC', 'Phenotype', 'HP:0012114', (140, 143))	('death', 'Disease', 'MESH:D003643', (115, 120))	('negativity', 'Var', (6, 16))	('death', 'Disease', (115, 120))
44641	33670088	The majority of MLA harbor KRAS mutations, suggesting KRAS mutation is involved in MLA development.	('KRAS', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('MLA', 'Chemical', '-', (16, 19))	('MLA', 'Chemical', '-', (83, 86))
44642	33670088	The KRAS mutation G12V and G12D are the most common, G12A and G12C are respectively 4 and 3 times reported.	('G12C', 'Var', (62, 66))	('G12C', 'Mutation', 'rs121913530', (62, 66))	('G12A', 'Var', (53, 57))	('G12V', 'Mutation', 'rs121913529', (18, 22))	('G12D', 'Var', (27, 31))	('G12V', 'Var', (18, 22))	('G12A', 'Mutation', 'rs121913529', (53, 57))	('G12D', 'Mutation', 'rs121913529', (27, 31))	('KRAS', 'Var', (4, 8))
44643	33670088	PTEN mutation, also frequent in EEC, was found as an additional mutation in three MLA cases.	('EEC', 'Phenotype', 'HP:0012114', (32, 35))	('MLA', 'Chemical', '-', (82, 85))	('mutation', 'Var', (5, 13))	('PTEN', 'Gene', (0, 4))	('EEC', 'Chemical', '-', (32, 35))
44646	33670088	On the other hand, PIK3CA and PTEN mutations, which are common in EEC but have not been described in MA of the cervix are rather indicative of Mullerian origin with subsequent differentiation along mesonephric lines.	('PIK3CA', 'Gene', (19, 25))	('EEC', 'Chemical', '-', (66, 69))	('EEC', 'Phenotype', 'HP:0012114', (66, 69))	('PTEN', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
44652	33670088	Compared with other endometrial adenocarcinomas, MLAs have better overall survival than malignant mixed Mullerian tumors and serous carcinoma has equal overall survival to endometrioid grade 3 and has worse overall survival than endometrioid grade 1-2 carcinomas.	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (20, 47))	('overall', 'MPA', (66, 73))	('MLAs', 'Chemical', '-', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('carcinomas', 'Disease', (37, 47))	('carcinomas', 'Disease', (252, 262))	('overall', 'MPA', (207, 214))	('better', 'PosReg', (59, 65))	('endometrial adenocarcinomas', 'Disease', (20, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('carcinomas', 'Disease', 'MESH:D009369', (37, 47))	('carcinomas', 'Disease', 'MESH:D009369', (252, 262))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('serous carcinoma', 'Disease', 'MESH:D018297', (125, 141))	('serous carcinoma', 'Disease', (125, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MLAs', 'Var', (49, 53))	('tumors', 'Disease', (114, 120))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (20, 46))
44683	33670088	reported GATA3 positivity in endometrial premalignant and malignant proliferations with an incidence of 8% (5 of 64 cases): one with atypical hyperplasia, one high-grade endometrioid adenocarcinoma, two serous carcinomas and one carcinosarcoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (210, 220))	('GATA3', 'Gene', (9, 14))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (170, 197))	('hyperplasia', 'Disease', (142, 153))	('carcinosarcoma', 'Disease', (229, 243))	('endometrial premalignant', 'Disease', (29, 53))	('serous carcinomas', 'Disease', (203, 220))	('hyperplasia', 'Disease', 'MESH:D006965', (142, 153))	('positivity', 'Var', (15, 25))	('serous carcinomas', 'Disease', 'MESH:D018297', (203, 220))	('carcinosarcoma', 'Disease', 'MESH:D002296', (229, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (170, 197))	('endometrioid adenocarcinoma', 'Disease', (170, 197))
44685	33670088	reported only 1.0% (6 of 585 cases) of endometrial neoplasms with TTF1 expression, including three endometrioid carcinomas, one serous carcinoma, one clear cell carcinoma and one carcinosarcoma.	('carcinosarcoma', 'Disease', (179, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('endometrioid carcinomas', 'Disease', (99, 122))	('serous carcinoma', 'Disease', 'MESH:D018297', (128, 144))	('carcinosarcoma', 'Disease', 'MESH:D002296', (179, 193))	('serous carcinoma', 'Disease', (128, 144))	('neoplasm', 'Phenotype', 'HP:0002664', (51, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('endometrial neoplasms', 'Disease', 'MESH:D016889', (39, 60))	('neoplasms', 'Phenotype', 'HP:0002664', (51, 60))	('endometrial neoplasms', 'Disease', (39, 60))	('clear cell carcinoma', 'Disease', (150, 170))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (99, 122))	('TTF1', 'Gene', (66, 70))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (150, 170))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (99, 122))	('expression', 'Var', (71, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
44687	33670088	These EECs with TTF1 expression are reported to have a worse prognosis.	('EEC', 'Phenotype', 'HP:0012114', (6, 9))	('EEC', 'Chemical', '-', (6, 9))	('TTF1', 'Gene', (16, 20))	('expression', 'Var', (21, 31))
44690	33670088	Serous carcinoma is characterized by p53 mutation and p16 block-staining, which is never seen in MLA.	('Serous carcinoma', 'Disease', 'MESH:D018297', (0, 16))	('Serous carcinoma', 'Disease', (0, 16))	('mutation', 'Var', (41, 49))	('p16', 'Var', (54, 57))	('p53', 'Gene', (37, 40))	('MLA', 'Chemical', '-', (97, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('block-staining', 'NegReg', (58, 72))
44700	33670088	Moreover, p53 wild-type carcinosarcomas often demonstrate microsatellite instability (MSI) (rather representing undifferentiated or dedifferentiated carcinomas), and do not appear to harbor KRAS mutations.	('carcinomas', 'Disease', 'MESH:D009369', (149, 159))	('carcinosarcomas', 'Disease', (24, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('carcinomas', 'Disease', (149, 159))	('p53', 'Var', (10, 13))	('carcinosarcomas', 'Disease', 'MESH:D002296', (24, 39))	('microsatellite instability', 'MPA', (58, 84))
44725	33099834	It has been known for more than 30 years that gene fusions play an important role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('gene fusions', 'Var', (46, 58))
44730	33099834	8  The aberration leads at the molecular level to fusion of two zinc finger genes, JAZF1 (from 7p15) and SUZ12 (previously known as JJAZ1; from 17q21; Figure 1).	('JAZF1', 'Gene', '221895', (83, 88))	('JJAZ1', 'Gene', '23512', (132, 137))	('JJAZ1', 'Gene', (132, 137))	('JAZF1', 'Gene', (83, 88))	('SUZ12', 'Gene', '23512', (105, 110))	('SUZ12', 'Gene', (105, 110))	('fusion', 'Var', (50, 56))
44734	33099834	11  Other partners are EPC1 through a 6;10-rearrangement 11 ; MEAF6 through a t(1;6)(p34;p21) 12 ; BRD8 via t(5;6)(q31;p21) 13 ; EPC2 through a 2;6-rearrangement 14 ; and recently a MBTD1/PHF1 was also reported.	('MEAF6', 'Gene', '64769', (62, 67))	('EPC1', 'Gene', '80314', (23, 27))	('PHF1', 'Gene', '5252', (188, 192))	('EPC1', 'Gene', (23, 27))	('t(5;6)(q31;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (108, 123))	('EPC2', 'Gene', '26122', (129, 133))	('EPC2', 'Gene', (129, 133))	('BRD8', 'Gene', '10902', (99, 103))	('BRD8', 'Gene', (99, 103))	('t(1;6)(p34;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (78, 93))	('t(5;6)(q31;p21) 13', 'Var', (108, 126))	('MBTD1', 'Gene', '54799', (182, 187))	('MEAF6', 'Gene', (62, 67))	('PHF1', 'Gene', (188, 192))	('MBTD1', 'Gene', (182, 187))
44735	33099834	16  showed that tumors bearing PHF1 fusions, independently of which partner gene is involved, typically present sex cord-like differentiation, leading the authors to suggest that rearrangements of this gene preferentially induce such differentiation.	('rearrangements', 'Var', (179, 193))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('sex cord-like differentiation', 'CPA', (112, 141))	('fusions', 'Var', (36, 43))	('PHF1', 'Gene', (31, 35))	('preferentially', 'PosReg', (207, 221))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('PHF1', 'Gene', '5252', (31, 35))	('induce', 'Reg', (222, 228))	('tumors', 'Disease', (16, 22))
44736	33099834	A less frequent chromosomal rearrangement is the t(X;17)(p11;q21) leading to the MBTD1/EZHIP (previously known as CXorf67) fusion.	('t(X;17)(p11;q21', 'Var', (49, 64))	('fusion', 'Var', (123, 129))	('CXorf67', 'Gene', (114, 121))	('MBTD1', 'Gene', '54799', (81, 86))	('MBTD1', 'Gene', (81, 86))	('CXorf67', 'Gene', '340602', (114, 121))	('t(X;17)(p11;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 65))
44754	33099834	41  reported a low frequency of YWHAE and NUTM2A/B rearrangements in epithelioid leiomyosarcoma; admittedly, the immunostaining data of that study were suggestive of an unusual ESS.	('NUTM2A/B', 'Gene', (42, 50))	('leiomyosarcoma', 'Disease', (81, 95))	('rearrangements', 'Var', (51, 65))	('YWHAE', 'Gene', '7531', (32, 37))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (81, 95))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (81, 95))	('NUTM2A/B', 'Gene', '728118;729262', (42, 50))	('YWHAE', 'Gene', (32, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
44756	33099834	42  Despite the fact that no fusion transcript involving the mentioned genes was discovered, the authors suggested that abnormalities of them may contribute to development of uterine angiosarcoma in much the same manner as they do in ESS.	('contribute', 'Reg', (146, 156))	('angiosarcoma', 'Disease', (183, 195))	('uterine angiosarcoma', 'Phenotype', 'HP:0000131', (175, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('angiosarcoma', 'Phenotype', 'HP:0200058', (183, 195))	('abnormalities', 'Var', (120, 133))	('angiosarcoma', 'Disease', 'MESH:D006394', (183, 195))
44771	33099834	52  reported the first HG-ESS with BCOR internal tandem duplication (ITD), the same aberration previously found in clear cell sarcoma of the kidney (CCSK) 58 ,  59  and primitive myxoid mesenchymal tumor of infancy.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (126, 147))	('BCOR', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('BCOR', 'Gene', '54880', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('clear cell sarcoma of the kidney', 'Disease', (115, 147))	('CCSK', 'Chemical', '-', (149, 153))	('tumor', 'Disease', (198, 203))	('clear cell sarcoma of the kidney', 'Disease', 'MESH:D018227', (115, 147))	('internal tandem duplication', 'Var', (40, 67))
44775	33099834	62 ,  63  Truncating mutations or gene deletions occurring in BCOR have also been identified in acute myeloid leukemia, retinoblastoma, diffuse glioma, and medulloblastoma.	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('identified', 'Reg', (82, 92))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (96, 118))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (102, 118))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (96, 118))	('glioma', 'Disease', (144, 150))	('retinoblastoma', 'Disease', 'MESH:D012175', (120, 134))	('medulloblastoma', 'Disease', 'MESH:D008527', (156, 171))	('medulloblastoma', 'Phenotype', 'HP:0002885', (156, 171))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('medulloblastoma', 'Disease', (156, 171))	('BCOR', 'Gene', '54880', (62, 66))	('BCOR', 'Gene', (62, 66))	('Truncating mutations', 'Var', (10, 30))	('retinoblastoma', 'Phenotype', 'HP:0009919', (120, 134))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('retinoblastoma', 'Disease', (120, 134))	('acute myeloid leukemia', 'Disease', (96, 118))	('gene deletions', 'Var', (34, 48))
44776	33099834	64 ,  65 ,  66  The detection of aberrations of this gene already plays a key role in the diagnosis of some malignancies, for example, high-grade neuroepithelial tumor of the central nervous system with BCOR gene alteration.	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (146, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (146, 167))	('BCOR', 'Gene', '54880', (203, 207))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('aberrations', 'Var', (33, 44))	('tumor of the central nervous system', 'Phenotype', 'HP:0100006', (162, 197))	('malignancies', 'Disease', (108, 120))	('neuroepithelial tumor', 'Disease', (146, 167))	('BCOR', 'Gene', (203, 207))
44786	33099834	48  BCOR immunohistochemistry can be used diagnostically to separate all the above-mentioned tumors (with BCOR genetic rearrangement) from their histological mimics.	('genetic rearrangement', 'Var', (111, 132))	('BCOR', 'Gene', '54880', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('BCOR', 'Gene', (106, 110))	('tumors', 'Disease', (93, 99))	('BCOR', 'Gene', (4, 8))	('BCOR', 'Gene', '54880', (106, 110))
44788	33099834	70  who detected rearrangements of YWHAE, BCOR, and PHF1 in a series of tumors previously classified as UUS based on morphologic and immunohistochemical features.	('YWHAE', 'Gene', '7531', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('rearrangements', 'Var', (17, 31))	('BCOR', 'Gene', '54880', (42, 46))	('PHF1', 'Gene', (52, 56))	('detected', 'Reg', (8, 16))	('YWHAE', 'Gene', (35, 40))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('PHF1', 'Gene', '5252', (52, 56))	('BCOR', 'Gene', (42, 46))
44789	33099834	71  identified a YWHAE deletion in a vagina wall metastasis from a monomorphic undifferentiated sarcoma, as the tumor was classified at that time.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('deletion', 'Var', (23, 31))	('undifferentiated sarcoma', 'Disease', (79, 103))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('YWHAE', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('YWHAE', 'Gene', '7531', (17, 22))	('tumor', 'Disease', (112, 117))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (79, 103))
44790	33099834	Also, two tumors with morphologic feature of LG-ESS have had YWHAE rearrangements: a YWHAE/NUTM2A fusion was identified in a tumor confined within the endometrium, 72  whereas deletion of a 3' probe for YWHAE was shown in an LG-ESS and in its recurrence in a case showing progression from LG- to HG-ESS.	('deletion', 'Var', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumors', 'Disease', (10, 16))	('LG-ESS', 'Disease', (225, 231))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('LG-ESS', 'Chemical', '-', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('YWHAE', 'Gene', (61, 66))	('NUTM2A', 'Gene', (91, 97))	('YWHAE', 'Gene', (85, 90))	('YWHAE', 'Gene', (203, 208))	('YWHAE', 'Gene', '7531', (61, 66))	('YWHAE', 'Gene', '7531', (85, 90))	('YWHAE', 'Gene', '7531', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('LG-ESS', 'Chemical', '-', (225, 231))	('NUTM2A', 'Gene', '728118', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', (125, 130))
44793	33099834	50 ,  74 ,  75 ,  76  These tumors harbor gene fusions that are typically associated with LG-ESS.	('LG-ESS', 'Disease', (90, 96))	('gene fusions', 'Var', (42, 54))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('LG-ESS', 'Chemical', '-', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('associated', 'Reg', (74, 84))
44799	33099834	In later years, much effort has gone into the identification of molecular mechanisms behind ESS-specific genetic rearrangements with the goal of unraveling how they contribute to tumorigenesis and, eventually, how this knowledge can lead to novel therapeutic approaches.	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('lead', 'Reg', (233, 237))	('contribute', 'Reg', (165, 175))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('rearrangements', 'Var', (113, 127))	('genetic rearrangements', 'Var', (105, 127))	('tumor', 'Disease', (179, 184))
44802	33099834	78 ,  79  The JAZF1/SUZ12 chimera was first demonstrated to inhibit apoptosis and induce proliferation rates above normal in both benign and malignant uterine tumors, although only in the malignant form was suppression of the wild type/unrearranged SUZ12 allele identified.	('uterine tumors', 'Phenotype', 'HP:0010784', (151, 165))	('malignant uterine tumors', 'Disease', 'MESH:D009369', (141, 165))	('malignant uterine tumors', 'Disease', (141, 165))	('SUZ12', 'Gene', (20, 25))	('inhibit', 'NegReg', (60, 67))	('induce', 'PosReg', (82, 88))	('chimera', 'Var', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('apoptosis', 'CPA', (68, 77))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('SUZ12', 'Gene', '23512', (249, 254))	('uterine tumor', 'Phenotype', 'HP:0010784', (151, 164))	('JAZF1', 'Gene', (14, 19))	('SUZ12', 'Gene', (249, 254))	('proliferation rates', 'CPA', (89, 108))	('SUZ12', 'Gene', '23512', (20, 25))	('JAZF1', 'Gene', '221895', (14, 19))
44804	33099834	80  A similar mechanism was seen for ESS bearing JAZF1/PHF1 fusion with simultaneous silencing of the normal PHF1 allele.	('fusion', 'Var', (60, 66))	('JAZF1', 'Gene', '221895', (49, 54))	('PHF1', 'Gene', (55, 59))	('silencing', 'NegReg', (85, 94))	('PHF1', 'Gene', '5252', (55, 59))	('JAZF1', 'Gene', (49, 54))	('PHF1', 'Gene', (109, 113))	('PHF1', 'Gene', '5252', (109, 113))
44806	33099834	JAZF1/SUZ12 destabilizes the PRC2 components leading to a decrease of methyltransferase activity, especially on H3K27, and therefore activates chromatin and/or genes normally repressed by PRC2.	('methyltransferase', 'Enzyme', (70, 87))	('SUZ12', 'Gene', (6, 11))	('destabilizes', 'NegReg', (12, 24))	('JAZF1', 'Gene', (0, 5))	('H3K27', 'Var', (112, 117))	('activity', 'MPA', (88, 96))	('decrease', 'NegReg', (58, 66))	('chromatin', 'MPA', (143, 152))	('activates', 'PosReg', (133, 142))	('PRC2', 'Gene', (29, 33))	('SUZ12', 'Gene', '23512', (6, 11))	('JAZF1', 'Gene', '221895', (0, 5))
44812	33099834	86  BCOR has a number of functions within normal tissue and its alteration can result in developmental disorders and a variety of hematologic and solid malignancies.	('developmental disorders', 'Disease', 'MESH:D002658', (89, 112))	('BCOR', 'Gene', '54880', (4, 8))	('alteration', 'Var', (64, 74))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('result in', 'Reg', (79, 88))	('BCOR', 'Gene', (4, 8))	('developmental disorders', 'Disease', (89, 112))	('malignancies', 'Disease', (152, 164))
44817	33099834	92  showed MDM2 amplification in an LG-ESS with JAZF1-rearrangement and in a UUS.	('LG-ESS', 'Chemical', '-', (36, 42))	('amplification', 'Var', (16, 29))	('JAZF1', 'Gene', (48, 53))	('MDM2', 'Gene', '4193', (11, 15))	('MDM2', 'Gene', (11, 15))	('JAZF1', 'Gene', '221895', (48, 53))
44819	33099834	The discovery of MDM2 amplification opens up for potential use of targeted therapy in a subset of HG-ESS.	('amplification', 'Var', (22, 35))	('HG-ESS', 'Disease', (98, 104))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))
44820	33099834	57  recently investigated the genomic profile of 40 uterine sarcomas harboring BCOR alterations.	('sarcomas', 'Disease', (60, 68))	('investigated', 'Reg', (13, 25))	('BCOR', 'Gene', '54880', (79, 83))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('alterations', 'Var', (84, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('BCOR', 'Gene', (79, 83))
44821	33099834	The analyzed tumors were found to be stable at the microsatellite level; however, some of them showed homozygous deletion of CDKN2A which codes for an inhibitor of CDK4 and CDKN2B.	('CDKN2B', 'Gene', (173, 179))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('deletion', 'Var', (113, 121))	('CDKN2B', 'Gene', '1030', (173, 179))	('CDK4', 'Gene', (164, 168))	('CDKN2A', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CDK4', 'Gene', '1019', (164, 168))	('CDKN2A', 'Gene', '1029', (125, 131))
44823	33099834	It seems that alteration of CDK4 pathway members contributes to the pathogenesis of BCOR-rearranged tumors, something that may have therapeutic implications.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CDK4', 'Gene', '1019', (28, 32))	('BCOR', 'Gene', (84, 88))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('contributes', 'Reg', (49, 60))	('BCOR', 'Gene', '54880', (84, 88))	('alteration', 'Var', (14, 24))	('CDK4', 'Gene', (28, 32))
44827	33099834	Of all chimeric proteins associated with ESS, YWHAE/NUTM2A/B is the only one that does not undergo epigenetic modification.	('chimeric', 'Var', (7, 15))	('NUTM2A/B', 'Gene', (52, 60))	('YWHAE', 'Gene', (46, 51))	('ESS', 'Disease', (41, 44))	('NUTM2A/B', 'Gene', '728118;729262', (52, 60))	('YWHAE', 'Gene', '7531', (46, 51))
44862	33490290	The miRNA-target network was associated with (TCCGTCC) MIR-184, (TGCACGA) MIR-517, (GTGGTGA) MIR-197, (CCAGGGG) MIR-331, and (CAGCAGG) MIR-370.	('MIR-331', 'Gene', '442903', (112, 119))	('associated', 'Interaction', (29, 39))	('MIR-197', 'Gene', '406974', (93, 100))	('MIR-331', 'Gene', (112, 119))	('MIR-370', 'Gene', (135, 142))	('MIR-184', 'Gene', (55, 62))	('MIR-184', 'Gene', '406960', (55, 62))	('MIR-370', 'Gene', '442915', (135, 142))	('MIR-197', 'Gene', (93, 100))	('MIR-517', 'Var', (74, 81))
44906	33376613	Radiation therapy can cause cervical stenosis, making endometrial examination difficult.	('cause', 'Reg', (22, 27))	('Radiation therapy', 'Var', (0, 17))	('cervical stenosis', 'Disease', 'MESH:D002575', (28, 45))	('cervical stenosis', 'Disease', (28, 45))
45022	32399488	This facilitates good perfusion as not involving the full thickness of the tissue reduces blood perfusion, a disadvantage for wound healing and adds the possibility that shallow driving could lead to tissue laceration and bleeding.	('perfusion', 'MPA', (22, 31))	('lead to', 'Reg', (192, 199))	('bleeding', 'Disease', 'MESH:D006470', (222, 230))	('bleeding', 'Disease', (222, 230))	('shallow driving', 'Var', (170, 185))	('blood perfusion', 'MPA', (90, 105))	('reduces blood perfusion', 'Phenotype', 'HP:0011106', (82, 105))	('tissue laceration', 'CPA', (200, 217))	('reduces', 'NegReg', (82, 89))
45070	32038720	Although these articles established the critical role of lncRNA SOX2-OT expression in some cancers, the prognostic value of SOX2-OT expression in numerous other cancers remained uncharacterized.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('lncRNA', 'Var', (57, 63))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (161, 168))
45087	32038720	This subgroup analysis showed a significantly lower heterogeneity in the above 60 months follow-up group, the tissue group, or the Cholangiocarcinoma group, which suggested that the relationship between high SOX2-OT expression and TNM stage has stronger efficacy in these groups.	('TNM stage', 'CPA', (231, 240))	('SOX2-OT', 'Protein', (208, 215))	('Cholangiocarcinoma', 'Disease', (131, 149))	('high', 'Var', (203, 207))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
45097	32038720	Regarding the clinicopathological characteristics of patients with cancers, our research suggested that high SOX2-OT expression was significantly associated with the invasion of cancers, as reveal by the tumor stage (RR = 1.468, 95% CI: 1.106-1.949), lymphatic metastasis (RR = 1.554, 95% CI: 1.211-1.994), distant metastasis (RR = 3.054, 95% CI: 1.866-4.999), tumor size (RR = 1.264, 95% CI: 1.019-1.566), and depth of tumor invasion (RR = 1.552, 95% CI: 1.274-1.890), but couldn't predict histological differentiation, age, or gender.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('tumor invasion', 'Disease', (420, 434))	('tumor', 'Disease', (361, 366))	('tumor invasion', 'Disease', 'MESH:D009361', (420, 434))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('depth of tumor', 'Disease', 'MESH:D007222', (411, 425))	('depth of tumor', 'Disease', (411, 425))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('tumor', 'Disease', (420, 425))	('lymphatic metastasis', 'CPA', (251, 271))	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('distant metastasis', 'CPA', (307, 325))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('high', 'Var', (104, 108))	('tumor', 'Disease', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('associated', 'Reg', (146, 156))
45101	32038720	Kaplan-Meier analysis initially suggested that SOX2-OT overexpression was associated with a bad OS in adrenocortical cancer (ACC), cervical cancer (CESC), mesothelioma (MESO), and glioma (LGG), and associated with a worse OS in breast cancer (BRCA), kidney renal clear cell carcinoma (KIRC), thymoma (THYM), thyroid cancer (THCA), uterine carcinosarcoma (UCS), and endometrioid cancer (UCEC) according to the TCGA datasets ( Table 7  and  Supplementary Figures 3  and  4 ).	('THCA', 'Disease', (324, 328))	('MESO', 'Disease', (169, 173))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (365, 384))	('carcinosarcoma', 'Disease', (339, 353))	('THYM', 'Disease', (301, 305))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('THCA', 'Phenotype', 'HP:0002890', (324, 328))	('kidney renal clear cell carcinoma', 'Disease', (250, 283))	('thyroid cancer', 'Disease', 'MESH:D013964', (308, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('carcinosarcoma', 'Disease', 'MESH:D002296', (339, 353))	('BRCA', 'Disease', (243, 247))	('thymoma', 'Disease', 'MESH:D013945', (292, 299))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('UCS', 'Phenotype', 'HP:0002891', (355, 358))	('adrenocortical cancer', 'Disease', (102, 123))	('BRCA', 'Disease', 'MESH:D001943', (243, 247))	('THYM', 'Disease', 'MESH:D013945', (301, 305))	('thyroid cancer', 'Phenotype', 'HP:0002890', (308, 322))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('cancer', 'Disease', (117, 123))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (331, 353))	('cancer', 'Disease', (316, 322))	('breast cancer', 'Disease', (228, 241))	('endometrioid cancer', 'Disease', 'MESH:D009369', (365, 384))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (378, 384))	('thymoma', 'Disease', (292, 299))	('thymoma', 'Phenotype', 'HP:0100522', (292, 299))	('KIRC', 'Disease', (285, 289))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('glioma', 'Disease', (180, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (250, 283))	('mesothelioma', 'Disease', (155, 167))	('cancer', 'Disease', (235, 241))	('ACC', 'Disease', (125, 128))	('SOX2-OT', 'Var', (47, 54))	('ACC', 'Disease', 'MESH:D000306', (125, 128))	('MESO', 'Disease', 'MESH:D008654', (169, 173))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('endometrioid cancer', 'Disease', (365, 384))	('BRCA', 'Phenotype', 'HP:0003002', (243, 247))	('KIRC', 'Disease', 'MESH:D002292', (285, 289))	('thyroid cancer', 'Disease', (308, 322))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('THCA', 'Disease', 'MESH:D013964', (324, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (102, 123))
45105	32038720	proposed that SOX2-OT was highly expressed in gastric cancer cells, which promoted the expression of AKT2 by targeting miR-194-5p, thus elevating cell proliferation and metastasis.	('promoted', 'PosReg', (74, 82))	('AKT2', 'Gene', (101, 105))	('gastric cancer', 'Disease', (46, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('expression', 'MPA', (87, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('targeting miR-194-5p', 'Var', (109, 129))	('miR-194-5p', 'Var', (119, 129))	('elevating', 'PosReg', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell proliferation', 'CPA', (146, 164))
45110	32038720	showed that high SOX2-OT expression predicted poor OS and more advanced tumor progression, but failed to predict distant metastasis and lymph node metastasis in Chinese cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Disease', (169, 175))	('high', 'Var', (12, 16))	('tumor', 'Disease', (72, 77))	('expression', 'MPA', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('SOX2-OT', 'Protein', (17, 24))	('poor OS', 'CPA', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
45121	32038720	This research was supported by the National Natural Science Foundation of China (81902498), Natural Science Foundation of Hubei Province of China (2019CFB177), Natural Science Foundation of Hubei Provincial Department of Education (Q20182105), Chen Xiao-ping Foundation for the development of science and technology of Hubei Provincial (CXPJJH11800001-2018333), Natural Science Foundation of Hubei Province of China (2016CFB530) and Faculty Development Foundation of Hubei University of Medicine (2014QDJZR01), and National Students' platform for innovation and entrepreneurship training program (201810929005, 201810929009, 201810929068, and 201813249010).	('201810929068', 'Var', (625, 637))	('201810929009', 'Var', (611, 623))	('201810929005', 'Var', (597, 609))	('201813249010', 'Var', (643, 655))	('2019CFB177', 'Chemical', 'MESH:C045346', (147, 157))
45141	31801560	The laboratory tests showed the serum level of CA125 was 207.5 U/mL (normal < 35.0), CA199 was 59.9 U/mL (normal < 37), and HE4 was 206.9 U/mL (normal < 140.0), although the CEA and AFP levels were normal.	('CA125', 'Gene', '94025', (47, 52))	('AFP', 'Gene', (182, 185))	('CA199', 'Var', (85, 90))	('CA125', 'Gene', (47, 52))	('CEA', 'Gene', (174, 177))	('AFP', 'Gene', '174', (182, 185))	('HE4', 'Gene', (124, 127))	('CEA', 'Gene', '1084', (174, 177))	('HE4', 'Gene', '10406', (124, 127))
45224	31706287	Copy number variation is highly correlated with differential gene expression: a pan-cancer study Cancer is a heterogeneous disease with many genetic variations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('Copy number variation', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))
45225	31706287	Lines of evidence have shown copy number variations (CNVs) of certain genes are involved in development and progression of many cancers through the alterations of their gene expression levels on individual or several cancer types.	('gene expression levels', 'MPA', (169, 191))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('copy number variations', 'Var', (29, 51))	('cancers', 'Disease', (128, 135))	('alterations', 'Reg', (148, 159))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('involved', 'Reg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Disease', (128, 134))
45230	31706287	Genetic structural variation in the human genome can be present in many forms, ranging from single nucleotide polymorphisms (SNPs) to large chromosome aberrance.	('human', 'Species', '9606', (36, 41))	('single nucleotide polymorphisms', 'Var', (92, 123))	('large chromosome', 'Disease', (134, 150))
45233	31706287	It is generally accepted that somatic CNV is highly associated with the development and progression of numerous cancers by impacting gene expression level.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('associated', 'Reg', (52, 62))	('impacting', 'Reg', (123, 132))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('CNV', 'Var', (38, 41))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gene expression level', 'MPA', (133, 154))
45245	31706287	copy number amplification and expression level upregulation ratio against copy number deletion and expression level downregulation, copy number deletion and expression level downregulation ratio against copy number amplification and expression level upregulation more than 50 % on each gene across 9159 tumor samples were applied to identify AUGs and DDGs with a higher rho (> 0.4) and a higher number (> 146.5) of copy number amplification and expression level upregulation than the median level of 30 most popular oncogenes (Additional file 2: Table S4) or a higher rho (> 0.41) and a higher number (> 18.5) of copy number deletion and expression level downregulation than the median level of 10 tumor suppressor genes (Additional file 2: Table S5).	('tumor', 'Phenotype', 'HP:0002664', (698, 703))	('tumor', 'Disease', (698, 703))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('downregulation', 'NegReg', (655, 669))	('tumor', 'Disease', (303, 308))	('upregulation', 'PosReg', (462, 474))	('expression level', 'MPA', (445, 461))	('tumor', 'Disease', 'MESH:D009369', (698, 703))	('expression level', 'MPA', (638, 654))	('AU', 'Disease', 'MESH:C566303', (342, 344))	('copy number deletion', 'Var', (613, 633))
45246	31706287	AUGs and DDGs were sorted by the amount of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation respectively and 31 representative AUGs and 29 representative DDGs matched with KEGG genes were identified from top 100 highly concordant genes.	('downregulation', 'NegReg', (146, 160))	('AU', 'Disease', 'MESH:C566303', (0, 2))	('AU', 'Disease', 'MESH:C566303', (196, 198))	('upregulation', 'PosReg', (90, 102))	('expression', 'MPA', (129, 139))	('copy number deletion', 'Var', (104, 124))
45252	31706287	For all cancer types under study, median Z scores of gene expression with copy number amplified were strikingly higher than those with copy number deleted (Fig.	('cancer', 'Disease', (8, 14))	('higher', 'PosReg', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('copy number amplified', 'Var', (74, 95))	('Z scores', 'MPA', (41, 49))	('gene expression', 'MPA', (53, 68))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
45254	31706287	In addition, the spearman's correlation coefficient (rho) test and linear regression analysis among cell lines and tumors were implemented to uncover the close association between differential gene expression and CNV with rho ranging from 0.075 to 0.53 (mean r = 0.97; Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('differential gene', 'Var', (180, 197))	('CNV', 'Disease', (213, 216))
45255	31706287	Remarkably, for substantial number of genes, their copy numbers exert a positive correlation with the corresponding gene expression level among 1025 cell lines dataset (88.11%; Additional file 1: Figure S3A; Figure S3B) and 9159 tumor samples (94.15%; Fig.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('positive', 'PosReg', (72, 80))	('copy numbers', 'Var', (51, 63))	('gene expression level', 'MPA', (116, 137))
45258	31706287	Concordantly, a recent study by GTEx consortium also associated genetic variants with gene expression levels across 44 human healthy tissues and gene expression levels were found to be affected by local genetic variation for most genes based on eQTL analysis.	('genetic variants', 'Var', (64, 80))	('affected', 'Reg', (185, 193))	('variants', 'Var', (72, 80))	('associated', 'Reg', (53, 63))	('gene expression levels', 'MPA', (86, 108))	('human', 'Species', '9606', (119, 124))
45263	31706287	Intriguingly, the amount of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation, representing our so-called highly concordant genes on CNV and differential gene expression, occupied 15 and 20% of the total variant copy number count on average for cell lines and tumor samples, respectively.	('deletion', 'Var', (101, 109))	('expression', 'MPA', (58, 68))	('downregulation', 'NegReg', (131, 145))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('upregulation', 'PosReg', (75, 87))	('copy number deletion', 'Var', (89, 109))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('expression', 'MPA', (114, 124))	('copy number', 'Var', (28, 39))	('tumor', 'Disease', (328, 333))
45264	31706287	Nevertheless, the mean proportion of copy number amplification and expression level downregulation, copy number deletion and expression level upregulation count only took up 0.7 and 0.5% for both cell lines and tumor samples (Additional file 1: Figure S4A and S4B), which indicated that the copy number amplification barely causes gene expression downregulation and the copy number deletion hardly promotes gene expression upregulation.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('copy number deletion', 'Var', (370, 390))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('downregulation', 'NegReg', (347, 361))	('tumor', 'Disease', (211, 216))	('S4B', 'Chemical', 'MESH:D013455', (260, 263))	('copy number amplification', 'Var', (291, 316))	('gene expression', 'MPA', (331, 346))	('upregulation', 'PosReg', (423, 435))	('gene expression', 'MPA', (407, 422))
45265	31706287	It is obvious that the frequency of copy number amplification and expression level upregulation totally exceeded copy number deletion and expression level downregulation for both cell lines and tumor samples (Fig.	('expression level', 'MPA', (66, 82))	('upregulation', 'PosReg', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('copy number amplification', 'Var', (36, 61))	('expression', 'MPA', (138, 148))	('downregulation', 'NegReg', (155, 169))	('tumor', 'Disease', (194, 199))
45266	31706287	In order to identify highly concordant genes on CNV and differential gene expression, the sum of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation for all genes across 9159 tumor samples in TCGA were counted (Fig.	('tumor', 'Disease', (241, 246))	('copy number deletion', 'Var', (158, 178))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('upregulation', 'PosReg', (144, 156))	('downregulation', 'NegReg', (200, 214))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
45270	31706287	Nine AUGs obtained preponderant count of copy number amplification and expression level upregulation compared to copy number deletion and expression level downregulation across 9159 tumor samples, while the only DDG (STK11) showed an overwhelming degree of copy number deletion and expression level downregulation (73%) against copy number amplification and expression level upregulation, in accordance with previous reports in literature (Table 2).	('expression', 'MPA', (71, 81))	('tumor', 'Disease', (182, 187))	('STK11', 'Gene', (217, 222))	('copy number deletion', 'Var', (257, 277))	('expression', 'MPA', (282, 292))	('upregulation', 'PosReg', (88, 100))	('copy', 'Var', (41, 45))	('expression', 'MPA', (358, 368))	('downregulation', 'NegReg', (155, 169))	('STK11', 'Gene', '6794', (217, 222))	('AU', 'Disease', 'MESH:C566303', (5, 7))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('downregulation', 'NegReg', (299, 313))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
45271	31706287	A&U represents the frequency of a gene with copy number amplified and expression level upregulated across 31 cancer types in TCGA, while D&D represents the frequency of a gene with copy number deleted and expression level downregulated.	('level', 'PosReg', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('and expression', 'MPA', (66, 80))	('cancer', 'Disease', (109, 115))	('expression', 'NegReg', (205, 215))	('with copy number', 'Var', (39, 55))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
45272	31706287	means the gene with copy number amplification and expression level upregulation in tumor, AUG;   means the gene with copy number deletion and expression level downregulation in tumor, DDG.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('expression', 'MPA', (142, 152))	('AU', 'Disease', 'MESH:C566303', (90, 92))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('upregulation', 'PosReg', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('copy number deletion', 'Var', (117, 137))	('downregulation', 'NegReg', (159, 173))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('copy number amplification', 'Var', (20, 45))
45273	31706287	Thus, to identify AUGs and DDGs, the criteria applied in this work is the copy number amplification and expression level upregulation ratio against copy number deletion and expression level downregulation, copy number deletion and expression level downregulation ratio against copy number amplification and expression level upregulation with the cutoff value of 50 %.	('upregulation', 'PosReg', (324, 336))	('upregulation', 'PosReg', (121, 133))	('expression', 'MPA', (173, 183))	('AU', 'Disease', 'MESH:C566303', (18, 20))	('copy number deletion', 'Var', (206, 226))	('expression level', 'MPA', (104, 120))	('copy', 'Var', (148, 152))	('downregulation', 'NegReg', (190, 204))	('downregulation', 'NegReg', (248, 262))
45274	31706287	Further by filtering parameter included a higher rho and a higher number of copy number amplification and expression level upregulation than the median level of 30 most popular oncogenes (Additional file 2: Table S4) or a higher number of copy number deletion and expression level downregulation than the median level of 10 tumor suppressor genes (Additional file 2:Table S5), which ultimately led to 560 AUGs such as DERL1, DVL3, FADD and 365 DDGs (e.g.	('FADD', 'Gene', (431, 435))	('copy number deletion', 'Var', (239, 259))	('FADD', 'Gene', '8772', (431, 435))	('AU', 'Disease', 'MESH:C566303', (405, 407))	('expression', 'MPA', (264, 274))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', (324, 329))	('DVL3', 'Gene', (425, 429))	('downregulation', 'NegReg', (281, 295))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('rho', 'MPA', (49, 52))	('higher', 'PosReg', (42, 48))	('upregulation', 'PosReg', (123, 135))	('DERL1', 'Gene', '79139', (418, 423))	('copy number', 'Var', (76, 87))	('DVL3', 'Gene', '1857', (425, 429))	('DERL1', 'Gene', (418, 423))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
45276	31706287	For representative AUGs and DDGs matched with KEGG pathway-related genes, their aberrant rate of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation in corresponding tumor samples across 31 cancer types were analyzed and shown in Fig.	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('expression', 'MPA', (127, 137))	('copy number deletion', 'Var', (158, 178))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('cancer', 'Disease', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('KEGG', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Disease', (232, 237))	('AU', 'Disease', 'MESH:C566303', (19, 21))	('upregulation', 'PosReg', (144, 156))	('downregulation', 'NegReg', (200, 214))
45279	31706287	Figure 4b shows the distribution of copy number deletion and expression level downregulation rate across 31 cancers of 38 representative DDGs involving in many known tumor suppressor genes such as MTAP, KLHL9, PTEN, SMAD4, RB1, etc.	('SMAD4', 'Gene', '4089', (216, 221))	('RB1', 'Gene', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KLHL9', 'Gene', '55958', (203, 208))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('PTEN', 'Gene', (210, 214))	('downregulation', 'NegReg', (78, 92))	('RB1', 'Gene', '5925', (223, 226))	('PTEN', 'Gene', '5728', (210, 214))	('tumor', 'Disease', (166, 171))	('SMAD4', 'Gene', (216, 221))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('KLHL9', 'Gene', (203, 208))	('MTAP', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MTAP', 'Gene', '4507', (197, 201))	('copy number deletion', 'Var', (36, 56))
45288	31706287	For examples, the copy number amplification and expression level upregulation of FYTTD1 and CTTN would remarkably cause a poor prognosis in tumor patients of ESCA and head and neck squamous cell carcinoma (HNSC) respectively (Fig.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('expression level', 'MPA', (48, 64))	('FYTTD1', 'Gene', '84248', (81, 87))	('CTTN', 'Gene', '2017', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('patients', 'Species', '9606', (146, 154))	('FYTTD1', 'Gene', (81, 87))	('HNSC', 'Disease', (206, 210))	('ESCA', 'Disease', (158, 162))	('copy number amplification', 'Var', (18, 43))	('ESCA', 'Disease', 'MESH:D004938', (158, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (167, 204))	('HNSC', 'Disease', 'MESH:C535575', (206, 210))	('CTTN', 'Gene', (92, 96))	('upregulation', 'PosReg', (65, 77))	('cause', 'Reg', (114, 119))	('tumor', 'Disease', (140, 145))
45289	31706287	5b), while the copy number deletion and expression level downregulation of MTAP was significantly associated with a worse prognosis (Fig.	('copy number deletion', 'Var', (15, 35))	('downregulation', 'NegReg', (57, 71))	('MTAP', 'Gene', (75, 79))	('MTAP', 'Gene', '4507', (75, 79))
45293	31706287	In addition, we overlapped the AUGs and DDGs identified by the ratio of copy number amplification and expression level upregulation versus copy number deletion and expression level downregulation between CCLP and TCGA respectively.	('expression', 'MPA', (102, 112))	('AU', 'Disease', 'MESH:C566303', (31, 33))	('downregulation', 'NegReg', (181, 195))	('upregulation', 'PosReg', (119, 131))	('copy number deletion', 'Var', (139, 159))
45297	31706287	This finding reveals the qualitative relationship between genetic variation and its downstream effect, especially for oncogenes and tumor suppressor genes, which is of a critical importance for prevention, diagnosis and treatment of cancer.	('genetic variation', 'Var', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('oncogenes', 'Gene', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Disease', (132, 137))
45298	31706287	Besides, not only in cell lines but in patients copy number amplification strikingly harbored a higher expressed level compared to copy number deletion.	('higher', 'PosReg', (96, 102))	('patients', 'Species', '9606', (39, 47))	('copy number amplification', 'Var', (48, 73))	('expressed level', 'MPA', (103, 118))
45301	31706287	A recent study by GTEx consortium associated genetic variants with gene expression levels across 44 human healthy tissues and gene expression levels are found to be affected by local genetic variation for most genes based on eQTL analysis.	('variants', 'Var', (53, 61))	('gene expression levels', 'MPA', (67, 89))	('affected', 'Reg', (165, 173))	('human', 'Species', '9606', (100, 105))
45303	31706287	Moreover, it has been widely reported that copy number is remarkably correlated with expression of protein in literature such as FGFR1, HER2, MET, FADD, EGFR.	('correlated', 'Reg', (69, 79))	('FGFR1', 'Gene', (129, 134))	('FADD', 'Gene', (147, 151))	('FADD', 'Gene', '8772', (147, 151))	('FGFR1', 'Gene', '2260', (129, 134))	('copy number', 'Var', (43, 54))	('EGFR', 'Gene', '1956', (153, 157))	('MET', 'Disease', (142, 145))	('HER2', 'Gene', '2064', (136, 140))	('HER2', 'Gene', (136, 140))	('expression of protein', 'MPA', (85, 106))	('EGFR', 'Gene', (153, 157))
45304	31706287	Notably, FGFR1, known as fibroblast growth factor receptor 1, has been discovered that its copy number amplification is strikingly correlated with FGFR1 gene upregulation and FGFR1 protein upregulation in tumor samples.	('protein', 'Protein', (181, 188))	('upregulation', 'PosReg', (158, 170))	('FGFR1', 'Gene', '2260', (9, 14))	('fibroblast growth factor receptor 1', 'Gene', '2260', (25, 60))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('fibroblast growth factor receptor 1', 'Gene', (25, 60))	('FGFR1', 'Gene', (175, 180))	('FGFR1', 'Gene', (147, 152))	('FGFR1', 'Gene', '2260', (147, 152))	('tumor', 'Disease', (205, 210))	('FGFR1', 'Gene', '2260', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('FGFR1', 'Gene', (9, 14))	('copy number amplification', 'Var', (91, 116))	('upregulation', 'PosReg', (189, 201))
45309	31706287	For examples, numerous studies reported that DERL1 overexpression was significantly related to cancer cell proliferation, invasion and poor prognosis, which might be driven by copy number amplification for DERL1 obtained the majority of copy number amplification and expression level upregulation in many cancers (Fig.	('DERL1', 'Gene', (206, 211))	('copy number amplification', 'Var', (237, 262))	('DERL1', 'Gene', '79139', (206, 211))	('related', 'Reg', (84, 91))	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('upregulation', 'PosReg', (284, 296))	('DERL1', 'Gene', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('cancer', 'Disease', (95, 101))	('invasion', 'CPA', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('DERL1', 'Gene', '79139', (45, 50))	('overexpression', 'PosReg', (51, 65))	('expression level', 'MPA', (267, 283))	('copy', 'Var', (176, 180))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Disease', (305, 312))	('cancer', 'Disease', (305, 311))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
45314	31706287	With respect to wnt signaling, lost function of DDGs such as inhibitory SMAD4 and APC would definitely enhance the function of wnt signaling leading to tumorigenesis, while attenuated function of ubiquitin mediated proteolysis facilitate proliferation.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('ubiquitin mediated proteolysis', 'MPA', (196, 226))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('facilitate', 'PosReg', (227, 237))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Disease', (82, 85))	('inhibitory', 'Var', (61, 71))	('enhance', 'PosReg', (103, 110))	('wnt signaling', 'MPA', (127, 140))	('tumor', 'Disease', (152, 157))	('proliferation', 'CPA', (238, 251))	('attenuated', 'NegReg', (173, 183))	('SMAD4', 'Gene', '4089', (72, 77))	('SMAD4', 'Gene', (72, 77))	('function', 'MPA', (115, 123))
45316	31706287	By further integrated analysis of CNV and differential gene expression of FYTTD1 in ESCA patients, we observed that 24.73% patients showed a high level of copy number amplification with a median Z score of 4.15 which means FYTTD1 was strikingly overexpressed (Additional file 1: Figure S6).	('FYTTD1', 'Gene', (74, 80))	('ESCA', 'Disease', 'MESH:D004938', (84, 88))	('FYTTD1', 'Gene', '84248', (74, 80))	('FYTTD1', 'Gene', (223, 229))	('patients', 'Species', '9606', (123, 131))	('overexpressed', 'PosReg', (245, 258))	('FYTTD1', 'Gene', '84248', (223, 229))	('patients', 'Species', '9606', (89, 97))	('copy number', 'Var', (155, 166))	('ESCA', 'Disease', (84, 88))
45321	31706287	In addition, we identified amplification and overexpression of FYTTD1 is highly related with poor prognosis in ESCA, which may be a potential prognostic marker in ESCA.	('ESCA', 'Disease', 'MESH:D004938', (163, 167))	('FYTTD1', 'Gene', (63, 69))	('ESCA', 'Disease', (111, 115))	('ESCA', 'Disease', (163, 167))	('FYTTD1', 'Gene', '84248', (63, 69))	('amplification', 'Var', (27, 40))	('overexpression', 'PosReg', (45, 59))	('ESCA', 'Disease', 'MESH:D004938', (111, 115))
45333	30414738	Among endometrial cancer patients, high grade endometrioid and non-endometrioid histology subsets have significantly worse outcomes.	('endometrial cancer', 'Disease', 'MESH:D016889', (6, 24))	('endometrial cancer', 'Phenotype', 'HP:0012114', (6, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('high grade', 'Var', (35, 45))	('patients', 'Species', '9606', (25, 33))	('endometrial cancer', 'Disease', (6, 24))
45360	30414738	Interestingly, all seven patients who had next generation sequencing of their tumor performed were found to have more than one mutation present, and six of the seven patients had a mutation in TP53.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('TP53', 'Gene', '7157', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation', 'Var', (181, 189))	('TP53', 'Gene', (193, 197))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Disease', (78, 83))	('patients', 'Species', '9606', (166, 174))
45362	30414738	The patient without a TP53 mutation had mutations in PTEN and SMAD4.	('SMAD4', 'Gene', '4089', (62, 67))	('patient', 'Species', '9606', (4, 11))	('mutations', 'Var', (40, 49))	('PTEN', 'Gene', (53, 57))	('TP53', 'Gene', '7157', (22, 26))	('PTEN', 'Gene', '5728', (53, 57))	('SMAD4', 'Gene', (62, 67))	('TP53', 'Gene', (22, 26))
45407	30414738	The authors found that those patients whose tumors had heterologous elements had significantly worse disease-free survival and overall survival.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('worse', 'NegReg', (95, 100))	('patients', 'Species', '9606', (29, 37))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('disease-free survival', 'CPA', (101, 122))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('overall survival', 'CPA', (127, 143))	('heterologous', 'Var', (55, 67))
45429	30414738	If common actionable mutations are identified in this relatively rare cancer type, this might ultimately allow for the use of novel targeted therapies.	('mutations', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('allow', 'Reg', (105, 110))
45511	30550481	Endometrial cancer cumulative incidence at 70 years is consistently high for patients with MLH1 (34%), MSH2 (51%), MSH6 (49%), and PMS2 (24%) germline mutations, and is frequently the first malignancy diagnosed in women with Lynch syndrome.	('MSH2', 'Gene', (103, 107))	('Endometrial cancer', 'Disease', 'MESH:D016889', (0, 18))	('malignancy', 'Disease', (190, 200))	('germline mutations', 'Var', (142, 160))	('women', 'Species', '9606', (214, 219))	('PMS2', 'Gene', (131, 135))	('MSH2', 'Gene', '4436', (103, 107))	('patients', 'Species', '9606', (77, 85))	('MSH6', 'Gene', (115, 119))	('Lynch syndrome', 'Disease', (225, 239))	('Endometrial cancer', 'Disease', (0, 18))	('MLH1', 'Gene', (91, 95))	('MSH6', 'Gene', '2956', (115, 119))	('Endometrial cancer', 'Phenotype', 'HP:0012114', (0, 18))	('MLH1', 'Gene', '4292', (91, 95))	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('high', 'PosReg', (68, 72))	('Lynch syndrome', 'Disease', 'MESH:D003123', (225, 239))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('PMS2', 'Gene', '5395', (131, 135))
45522	30550481	Amputation could potentially interfere in the pathologic assessment of the tumor and the relationship with the upper endocervix, which can be problematic even at the microscopic level.	('interfere', 'NegReg', (29, 38))	('Amputation', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
45551	30550481	Slicing lymph nodes perpendicular to their long axis at 2 mm intervals increases the chance of detecting metastases.	('Slicing', 'Var', (0, 7))	('metastases', 'Disease', (105, 115))	('lymph nodes perpendicular', 'Disease', 'MESH:D000072717', (8, 33))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('lymph nodes perpendicular', 'Disease', (8, 33))
45576	30102398	FACER: comprehensive molecular and functional characterization of epigenetic chromatin regulators Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs).	('CRs', 'Chemical', '-', (193, 196))	('cancer hallmark', 'Disease', (140, 155))	('cancer hallmark', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Epigenetic alterations', 'Var', (98, 120))
45577	30102398	However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers.	('cancer', 'Disease', (146, 152))	('CR', 'Chemical', '-', (45, 47))	('cancers', 'Disease', (146, 153))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Disease', (64, 70))	('deregulation', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
45588	30102398	DNA methylators and histone modifiers can code and decode various modifications on cytosine and histone residues and are usually further divided into readers, writers, and erasers.	('cytosine', 'MPA', (83, 91))	('modifications', 'Var', (66, 79))	('cytosine', 'Chemical', 'MESH:D003596', (83, 91))	('histone', 'Protein', (96, 103))
45591	30102398	Chromatin remodelers are a special type of CRs that can disrupt the contact between nucleosomes and DNA, shuffle nucleosomes around, replace them or remove them from the chromatin, and cause abnormal epigenetic modifications.	('contact', 'Interaction', (68, 75))	('epigenetic modifications', 'MPA', (200, 224))	('cause', 'Reg', (185, 190))	('replace', 'Reg', (133, 140))	('disrupt', 'NegReg', (56, 63))	('CRs', 'Chemical', '-', (43, 46))	('shuffle', 'Var', (105, 112))	('remove', 'NegReg', (149, 155))
45592	30102398	The alteration of epigenetic marks is a prevalent feature in cancer.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('alteration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('epigenetic marks', 'Var', (18, 34))
45594	30102398	For example, it is widely accepted that mutations can perturb CR functions.	('CR functions', 'CPA', (62, 74))	('mutations', 'Var', (40, 49))	('perturb', 'NegReg', (54, 61))	('CR', 'Chemical', '-', (62, 64))
45595	30102398	have found that genetic alteration of DNMT3A (a DNA methylation transferase) can induce genome-wide alterations of DNA methylation and gene expression.	('alterations', 'Reg', (100, 111))	('gene expression', 'MPA', (135, 150))	('genetic alteration', 'Var', (16, 34))	('DNMT3A', 'Gene', (38, 44))	('DNMT3A', 'Gene', '1788', (38, 44))	('DNA methylation', 'MPA', (115, 130))
45596	30102398	Moreover, patients with DNMT3A mutations have poor prognosis compared with those without such mutations.	('DNMT3A', 'Gene', (24, 30))	('mutations', 'Var', (31, 40))	('DNMT3A', 'Gene', '1788', (24, 30))	('patients', 'Species', '9606', (10, 18))
45599	30102398	They found that dysregulation of these CRs results in structural abnormalities in chromatins and epigenetic alterations of numerous cancer-associated genes, which finally lead to increased tumor volume, extracapsular extension, and metastases in prostate cancer patients.	('numerous cancer', 'Disease', 'MESH:D009369', (123, 138))	('structural abnormalities', 'Disease', (54, 78))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('increased', 'PosReg', (179, 188))	('structural abnormalities', 'Disease', 'MESH:C566527', (54, 78))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('metastases in prostate cancer', 'Disease', 'MESH:D009362', (232, 261))	('chromatins', 'Protein', (82, 92))	('metastases in prostate cancer', 'Disease', (232, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('numerous cancer', 'Disease', (123, 138))	('epigenetic alterations', 'Var', (97, 119))	('extracapsular extension', 'CPA', (203, 226))	('dysregulation', 'Var', (16, 29))	('tumor', 'Disease', (189, 194))	('CRs', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('patients', 'Species', '9606', (262, 270))
45600	30102398	These studies demonstrate that CRs hold crucial roles in epigenetics and that various molecular alterations can cause functional perturbation of CRs.	('cause', 'Reg', (112, 117))	('alterations', 'Var', (96, 107))	('CRs', 'Chemical', '-', (145, 148))	('CRs', 'Chemical', '-', (31, 34))
45630	30102398	To evaluate the global regulatory effect of a given CR on the DNA hypermethylation (or hypomethylation) in a specific cancer type, we computed the significance of Pearson correlation (P value) between CR expression and aberrant hypermethylation (or hypomethylation) of tumor samples.	('CR', 'Chemical', '-', (52, 54))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('aberrant', 'Var', (219, 227))	('tumor', 'Disease', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CR', 'Chemical', '-', (201, 203))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
45706	30102398	Mutation frequency and centrality in PPIN were found to be the top two recurrent features (Figure 2I), which were involved in 25 and 29 cancer types, respectively.	('Mutation frequency', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('PPIN', 'Gene', (37, 41))	('cancer', 'Disease', (136, 142))	('involved', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
45717	30102398	Moreover, we found that DNA methylation readers and histone modification writers were the most common functional CRs across all 33 cancer types (Figure 3A).	('cancer', 'Disease', (131, 137))	('DNA methylation readers', 'Var', (24, 47))	('histone modification writers', 'Var', (52, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CRs', 'Chemical', '-', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
45720	30102398	Moreover, histone modification readers and writers as well as chromatin remodelers played important roles across cancer types compared with DNA methylation erasers and histone modification erasers (Figure 3B, bottom).	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('histone', 'Var', (10, 17))	('cancer', 'Disease', (113, 119))	('played', 'Reg', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
45726	30102398	Functional enrichment analysis showed that DNA methylators, histone modifiers and chromatin remodelers were all enriched in at least one cancer hallmark, especially in the hallmark 'genome instability and mutation', highlighting the extent of genome alternations in cancer (Supplementary Figure S8 and Supplementary Table S5).	("mutation'", 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('Supplementary Figure S8', 'Disease', (274, 297))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer hallmark', 'Disease', (137, 152))	('cancer', 'Disease', (137, 143))	('cancer hallmark', 'Disease', 'MESH:D009369', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('Supplementary Figure S8', 'Disease', 'MESH:D017034', (274, 297))
45728	30102398	Functional histone modifiers in almost all cancer types were enriched in the functions 'evading apoptosis', 'genome instability and mutation', 'insensitivity to antigrowth signals', and 'self-sufficiency in growth signals'.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	("'evading", 'Disease', (87, 95))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (192, 213))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	("mutation'", 'Var', (132, 141))
45740	30102398	For example, we found that PHF19, a writer for H3K36me3 as a component of polycomb repressive complex 2 (PRC2), was prioritized as a breast invasive carcinoma (BRCA) related CR in our analyses.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('H3K36me3', 'Var', (47, 55))	('PHF19', 'Gene', '26147', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (160, 164))	('PHF19', 'Gene', (27, 32))	('BRCA', 'Gene', '672', (160, 164))	('BRCA', 'Gene', (160, 164))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (133, 158))	('CR', 'Chemical', '-', (174, 176))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (133, 158))	('breast invasive carcinoma', 'Disease', (133, 158))
45743	30102398	Moreover, the genome-wide H3K36me3 marks showed an obvious increase in cancer.	('H3K36me3 marks', 'Var', (26, 40))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('increase', 'PosReg', (59, 67))
45758	30102398	Among these CRs, 14 were up-regulated in cancer, and 1 was down-regulated (Supplementary Figure S11A).	('up-regulated', 'PosReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CRs', 'Chemical', '-', (12, 15))	('S11A', 'Var', (96, 100))	('down-regulated', 'NegReg', (59, 73))	('S11A', 'SUBSTITUTION', 'None', (96, 100))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
45759	30102398	Interestingly, 11 of these 15 CRs showed consistent deregulation across cancer types compared with the corresponding adjacent normal samples (Supplementary Figure S11B).	('deregulation', 'MPA', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CRs', 'Chemical', '-', (30, 33))	('S11B', 'Var', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('S11B', 'SUBSTITUTION', 'None', (163, 167))	('cancer', 'Disease', (72, 78))
45766	30102398	For cancer-specific CRs, we found that these CRs included 36% of the DNA methylation erasers and 35% of the histone modification erasers.	('CRs', 'Chemical', '-', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('histone modification', 'MPA', (108, 128))	('methylation', 'Var', (73, 84))	('DNA', 'MPA', (69, 72))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('CRs', 'Chemical', '-', (20, 23))
45774	30102398	KMT2C showed a higher mutation frequency in KIRP patients, whereas the aberrant regulation of miRNAs and its regulation of DNA methylation over open sea regions were additional features in KICH patients.	('mutation', 'Var', (22, 30))	('KICH', 'Disease', (189, 193))	('patients', 'Species', '9606', (194, 202))	('DNA methylation', 'MPA', (123, 138))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('KICH', 'Disease', 'None', (189, 193))	('patients', 'Species', '9606', (49, 57))
45780	30102398	We found that common CRs in cancer had higher values for all seven features compared with specific CRs, especially in four functional features (all P < 0.05, Wilcoxon rank-sum test), including mutation frequency, differential expression, degree in PPIN, and regulation of genome hypermethylation (Figure 5C, top, and Supplementary Table S8).	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation frequency', 'Var', (193, 211))	('CRs', 'Chemical', '-', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CRs', 'Chemical', '-', (21, 24))	('PPIN', 'Protein', (248, 252))	('cancer', 'Disease', (28, 34))	('differential expression', 'MPA', (213, 236))
45806	30102398	Patients in subtype 1 of ACC showed the highest mutation frequency of TP53 and CGI methylation, while patients in subtype 3 showed high mutation of KDM6B and the lowest open sea methylation.	('TP53', 'Gene', '7157', (70, 74))	('patients', 'Species', '9606', (102, 110))	('KDM6B', 'Gene', '23135', (148, 153))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (70, 74))	('mutation', 'Var', (48, 56))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('KDM6B', 'Gene', (148, 153))	('methylation', 'Var', (83, 94))	('CGI', 'Protein', (79, 82))
45831	30102398	Analysis of the functional features revealed recurrent multi-omics effects of functional CRs across 33 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('effects', 'Reg', (67, 74))	('CRs', 'Chemical', '-', (89, 92))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('functional', 'Var', (78, 88))
45836	30102398	By comparison between common, specific and mixed CRs as well as DNA methylators, histone modifiers and chromatin remodelers, we found that DNA methylation readers as well as histone modification readers and writers were with more common CRs, suggesting that these three categories of CRs tend to be aberrant across cancer types.	('methylation', 'Var', (143, 154))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('DNA', 'Var', (139, 142))	('cancer', 'Disease', (315, 321))	('CRs', 'Chemical', '-', (284, 287))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('CRs', 'Chemical', '-', (237, 240))	('CRs', 'Chemical', '-', (49, 52))
45837	30102398	We also found that DNA methylation erasers and histone modification erasers tend to be dysregulated in specific cancer type.	('DNA', 'MPA', (19, 22))	('histone modification', 'MPA', (47, 67))	('methylation', 'Var', (23, 34))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
45843	30102398	Moreover, we found that DNA methylators and histone modifiers can induce the development of cancer by regulation of DNA methylation and histone modifications, such as DNMT1, DNMT3A and PHF19.	('PHF19', 'Gene', '26147', (185, 190))	('histone', 'Protein', (136, 143))	('cancer', 'Disease', (92, 98))	('PHF19', 'Gene', (185, 190))	('development of', 'CPA', (77, 91))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('DNMT3A', 'Gene', (174, 180))	('DNMT3A', 'Gene', '1788', (174, 180))	('DNMT1', 'Gene', (167, 172))	('induce', 'PosReg', (66, 72))	('DNA', 'MPA', (116, 119))	('DNMT1', 'Gene', '1786', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('modifications', 'Var', (144, 157))
45862	30200635	Changes in microRNA (miRNA) expression may lead to cancer development and/or contribute to its progression; however, their role in uterine sarcomas is poorly understood.	('progression', 'CPA', (95, 106))	('contribute', 'Reg', (77, 87))	('sarcomas', 'Disease', 'MESH:D012509', (139, 147))	('lead to', 'Reg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Changes', 'Var', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('cancer', 'Disease', (51, 57))	('sarcomas', 'Disease', (139, 147))
45866	30200635	In leiomyosarcoma (LMS), there was an association of lower cancer-specific survival (CSS) with the downregulation of miR-125a-5p and miR-10a-5p, and the upregulation of miR-196a-5p and miR-34c-5p.	('miR-1', 'Gene', '83856', (117, 122))	('upregulation', 'PosReg', (153, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR-1', 'Gene', (133, 138))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (3, 17))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (3, 17))	('miR-1', 'Gene', (117, 122))	('miR-10a', 'Gene', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('downregulation', 'NegReg', (99, 113))	('CSS', 'Chemical', '-', (85, 88))	('miR-1', 'Gene', '83856', (169, 174))	('leiomyosarcoma', 'Disease', (3, 17))	('miR-34c-5p', 'Var', (185, 195))	('miR-1', 'Gene', (169, 174))	('miR-1', 'Gene', '83856', (133, 138))	('miR-10a', 'Gene', '406902', (133, 140))	('cancer', 'Disease', (59, 65))	('lower', 'NegReg', (53, 58))
45868	30200635	In endometrial stromal sarcomas (ESS), the upregulation of miR-373-3p, miR-372-3p, and let-7b-5p, and the down-expression of let-7f-5p, miR-23-3p, and let-7b-5p were associated with lower CSS.	('down-expression', 'NegReg', (106, 121))	('CSS', 'Chemical', '-', (188, 191))	('miR-23-3p', 'Var', (136, 145))	('CSS', 'Disease', (188, 191))	('lower', 'NegReg', (182, 187))	('let-7b', 'Gene', '406884', (151, 157))	('let-7b', 'Gene', (151, 157))	('miR-372-3p', 'Var', (71, 81))	('upregulation', 'PosReg', (43, 55))	('let-7b', 'Gene', '406884', (87, 93))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (3, 31))	('endometrial stromal sarcomas', 'Disease', (3, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('let-7f-5p', 'Var', (125, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('miR-373-3p', 'Var', (59, 69))	('let-7b', 'Gene', (87, 93))
45869	30200635	Only miR-138-5p upregulation was associated with higher survival rates.	('upregulation', 'PosReg', (16, 28))	('miR-138-5p', 'Chemical', '-', (5, 15))	('miR-138-5p', 'Var', (5, 15))	('higher', 'PosReg', (49, 55))	('survival rates', 'CPA', (56, 70))
45870	30200635	miR-335-5p, miR-301a-3p, and miR-210-3p were more highly expressed in patients with tumor metastasis and relapse.	('tumor metastasis', 'Disease', 'MESH:D009362', (84, 100))	('tumor metastasis', 'Disease', (84, 100))	('patients', 'Species', '9606', (70, 78))	('miR-21', 'Gene', '406991', (29, 35))	('relapse', 'CPA', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('miR-335', 'Gene', '442904', (0, 7))	('miR-21', 'Gene', (29, 35))	('miR-335', 'Gene', (0, 7))	('miR-301a-3p', 'Var', (12, 23))
45871	30200635	miR-138-5p, miR-146b-5p, and miR-218-5p expression were associated with higher disease-free survival (DFS) in treated patients.	('miR-218-5p', 'Chemical', '-', (29, 39))	('miR-218-5p', 'Var', (29, 39))	('disease-free survival', 'CPA', (79, 100))	('miR-146b', 'Gene', (12, 20))	('miR-146b', 'Gene', '574447', (12, 20))	('higher', 'PosReg', (72, 78))	('miR-138-5p', 'Chemical', '-', (0, 10))	('patients', 'Species', '9606', (118, 126))	('miR-138-5p', 'Var', (0, 10))
45893	30200635	Shifts in the molecules' expression of miR-301a-3p, miR-29a-3p, miR-29b-3p, and miR-193b-3p and in the tumor suppressor family let-7, miR-7-5p, miR-96-5p, miR-23b-3p, and miR-335-5p were associated to recurrence, metastasis, stages, and high histological degree (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR-1', 'Gene', (80, 85))	('metastasis', 'CPA', (213, 223))	('miR-7-5p', 'Gene', '407045', (134, 142))	('miR-335', 'Gene', (171, 178))	('miR-23b', 'Gene', '407011', (155, 162))	('stages', 'CPA', (225, 231))	('miR-96-5p', 'Var', (144, 153))	('miR-29b-3p', 'Var', (64, 74))	('recurrence', 'CPA', (201, 211))	('miR-301a-3p', 'Var', (39, 50))	('tumor', 'Disease', (103, 108))	('miR-23b', 'Gene', (155, 162))	('miR-7-5p', 'Gene', (134, 142))	('associated', 'Reg', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('miR-29a-3p', 'Var', (52, 62))	('miR-335', 'Gene', '442904', (171, 178))	('miR-1', 'Gene', '83856', (80, 85))
45895	30200635	Significant associations of the downregulation of miR-125a-5p and miR-10a-5 with a lower CSS were observed in LMS, whereas miR-196a-5p and miR-34c-5p upregulation were associated to low CSS (Figure 2).	('miR-1', 'Gene', (66, 71))	('downregulation', 'NegReg', (32, 46))	('miR-1', 'Gene', '83856', (123, 128))	('LMS', 'Disease', (110, 113))	('miR-1', 'Gene', '83856', (66, 71))	('CSS', 'Chemical', '-', (186, 189))	('CSS', 'MPA', (89, 92))	('lower', 'NegReg', (83, 88))	('miR-10a', 'Gene', (66, 73))	('CSS', 'Chemical', '-', (89, 92))	('miR-1', 'Gene', (50, 55))	('upregulation', 'PosReg', (150, 162))	('miR-10a', 'Gene', '406902', (66, 73))	('miR-1', 'Gene', '83856', (50, 55))	('miR-1', 'Gene', (123, 128))	('miR-34c-5p', 'Var', (139, 149))
45898	30200635	The overall survival of ESS patients showed association with six miRNAs' (let-7b-5p, miR-138-5p, miR-373-3p, miR-372-3p, let-7f-5p, and miR-23b-5p) differential gene expression.	('let-7b', 'Gene', '406884', (74, 80))	('let-7b', 'Gene', (74, 80))	('miR-23b', 'Gene', (136, 143))	('miR-373-3p', 'Var', (97, 107))	('let-7f-5p', 'Var', (121, 130))	('miR-138-5p', 'Chemical', '-', (85, 95))	('miR-138-5p', 'Var', (85, 95))	('miR-372-3p', 'Var', (109, 119))	('miR-23b', 'Gene', '407011', (136, 143))	('patients', 'Species', '9606', (28, 36))	('association', 'Interaction', (44, 55))
45900	30200635	In these samples, miR-373-3p and miR-372-3p up-regulation showed correlation with a lower CSS, as well as let-7f-5p and miR-23b-3p downregulation.	('miR-373-3p', 'Var', (18, 28))	('CSS', 'Chemical', '-', (90, 93))	('CSS', 'CPA', (90, 93))	('miR-372-3p', 'Gene', (33, 43))	('let-7f-5p', 'Var', (106, 115))	('miR-23b', 'Gene', (120, 127))	('up-regulation', 'PosReg', (44, 57))	('lower', 'NegReg', (84, 89))	('downregulation', 'NegReg', (131, 145))	('miR-23b', 'Gene', '407011', (120, 127))
45901	30200635	Only miR-138-5p upregulation was associated with higher survival.	('miR-138-5p', 'Var', (5, 15))	('upregulation', 'PosReg', (16, 28))	('higher', 'PosReg', (49, 55))	('miR-138-5p', 'Chemical', '-', (5, 15))
45903	30200635	Three miRNAs (miR-335-5p, miR-301a-3p and miR-210-3p) presented differences of expression when we compared two groups of patients: those who had adjuvant treatment and developed metastasis or tumor recurrence (n = 41) with patients who also had adjuvant treatment but did not develop metastasis or relapse (n = 13) (Figure 5).	('miR-335', 'Gene', (14, 21))	('tumor', 'Disease', (192, 197))	('miR-301a-3p', 'Var', (26, 37))	('differences', 'Reg', (64, 75))	('expression', 'MPA', (79, 89))	('miR-21', 'Gene', (42, 48))	('miR-335', 'Gene', '442904', (14, 21))	('miR-21', 'Gene', '406991', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('metastasis', 'CPA', (178, 188))	('patients', 'Species', '9606', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('patients', 'Species', '9606', (121, 129))
45909	30200635	In the association analysis of the miRNA expression and metastasis and/or relapse in LMS and CS patients, there was a significant differential expression of miR-335-5p (p = 0.015) and miR-301a-3p (p = 0.025) only in LMS.	('metastasis', 'CPA', (56, 66))	('miR-301a-3p', 'Var', (184, 195))	('miR-335', 'Gene', '442904', (157, 164))	('relapse', 'CPA', (74, 81))	('patients', 'Species', '9606', (96, 104))	('miR-335', 'Gene', (157, 164))
45911	30200635	We performed a correlation analysis with all tumor groups that showed a positive association between three miRNAs (miR-138-5p, miR-146-5p and miR-218-5p) with DFS (Table 4); of these, the miR-138-5p displayed a strong correlation with DFS (p < 0.001) (Figure 7).	('miR-1', 'Gene', (127, 132))	('miR-138-5p', 'Chemical', '-', (115, 125))	('miR-1', 'Gene', '83856', (188, 193))	('DFS', 'Disease', (235, 238))	('miR-1', 'Gene', '83856', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('miR-1', 'Gene', (115, 120))	('miR-218-5p', 'Var', (142, 152))	('miR-1', 'Gene', '83856', (115, 120))	('miR-138-5p', 'Chemical', '-', (188, 198))	('miR-1', 'Gene', (188, 193))	('miR-218-5p', 'Chemical', '-', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
45913	30200635	In order to assess the miRNAs' network of genetic interactions and their potential targets, the miR-146b-5p, miR-218-5p and miR-138-5p were selected based on their association with DFS in US and carcinomas patients who had undergone adjuvant treatment (Figure 9, Figure 10 and Figure 11).	('miR-138-5p', 'Chemical', '-', (124, 134))	('carcinomas', 'Disease', (195, 205))	('miR-146b', 'Gene', (96, 104))	('association', 'Interaction', (164, 175))	('miR-138-5p', 'Var', (124, 134))	('miR-146b', 'Gene', '574447', (96, 104))	('miR-218-5p', 'Chemical', '-', (109, 119))	('DFS', 'Disease', (181, 184))	('patients', 'Species', '9606', (206, 214))	('miR-218-5p', 'Var', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinomas', 'Disease', 'MESH:D002277', (195, 205))
45917	30200635	miR-218-5p was directly associated to the CDKN1A gene, and indirectly to the SMO gene.	('miR-218-5p', 'Var', (0, 10))	('associated', 'Reg', (24, 34))	('SMO', 'Gene', '6608', (77, 80))	('miR-218-5p', 'Chemical', '-', (0, 10))	('CDKN1A', 'Gene', (42, 48))	('SMO', 'Gene', (77, 80))	('CDKN1A', 'Gene', '1026', (42, 48))
45918	30200635	Lastly, miR-138-5p was related to the IGF1R gene.	('miR-138-5p', 'Chemical', '-', (8, 18))	('related', 'Reg', (23, 30))	('miR-138-5p', 'Var', (8, 18))	('IGF1R', 'Gene', (38, 43))	('IGF1R', 'Gene', '3480', (38, 43))
45932	30200635	miR-196a-5p, miR-34c-5p, miR-125a-5p, and miR-10a-5p expressions were associated with CSS in LMS women.	('miR-1', 'Gene', '83856', (42, 47))	('miR-10a', 'Gene', '406902', (42, 49))	('miR-1', 'Gene', (25, 30))	('women', 'Species', '9606', (97, 102))	('CSS', 'Chemical', '-', (86, 89))	('miR-1', 'Gene', '83856', (0, 5))	('miR-1', 'Gene', '83856', (25, 30))	('miR-34c-5p', 'Var', (13, 23))	('miR-1', 'Gene', (0, 5))	('associated', 'Reg', (70, 80))	('CSS', 'Disease', (86, 89))	('miR-10a', 'Gene', (42, 49))	('miR-1', 'Gene', (42, 47))
45934	30200635	Differential expressions of let-7b-5p, miR-138-5p, miR-373-3p, miR-372-3p, let-7f-5p, and miR-23b-3p were associated with CSS in HG-ESS.	('miR-372-3p', 'Var', (63, 73))	('associated', 'Reg', (106, 116))	('miR-138-5p', 'Chemical', '-', (39, 49))	('miR-138-5p', 'Var', (39, 49))	('let-7b', 'Gene', '406884', (28, 34))	('let-7f-5p', 'Var', (75, 84))	('miR-23b', 'Gene', '407011', (90, 97))	('let-7b', 'Gene', (28, 34))	('CSS', 'Disease', (122, 125))	('HG-ESS', 'Disease', (129, 135))	('miR-23b', 'Gene', (90, 97))	('CSS', 'Chemical', '-', (122, 125))	('miR-373-3p', 'Var', (51, 61))
45947	30200635	Changes in miR-25 expression have already been associated with lymph node metastasis in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (88, 100))	('associated with', 'Reg', (47, 62))	('miR-25', 'Gene', '407014', (11, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('expression', 'MPA', (18, 28))	('miR-25', 'Gene', (11, 17))	('Changes', 'Var', (0, 7))	('osteosarcoma', 'Phenotype', 'HP:0002669', (88, 100))	('lymph node metastasis', 'CPA', (63, 84))	('osteosarcoma', 'Disease', (88, 100))
45953	30200635	We found that miR-29b-3p and miR-29a-3p regulate SGK1; miR-335-5p, miR-125b-5p and miR-193b-3p regulate SHMT1; miR-130a-3p regulates GJA1; and miR-18a-5p and let-7i-5p regulate THBS1.	('miR-1', 'Gene', '83856', (143, 148))	('SHMT1', 'Gene', '6470', (104, 109))	('miR-1', 'Gene', (111, 116))	('THBS1', 'Gene', (177, 182))	('miR-1', 'Gene', (143, 148))	('GJA1', 'Gene', '2697', (133, 137))	('THBS1', 'Gene', '7057', (177, 182))	('GJA1', 'Gene', (133, 137))	('miR-1', 'Gene', '83856', (83, 88))	('let-7i', 'Gene', (158, 164))	('regulates', 'Reg', (123, 132))	('miR-335', 'Gene', '442904', (55, 62))	('miR-1', 'Gene', '83856', (67, 72))	('SGK1', 'Gene', '6446', (49, 53))	('miR-1', 'Gene', (83, 88))	('miR-29a-3p', 'Var', (29, 39))	('miR-1', 'Gene', (67, 72))	('SGK1', 'Gene', (49, 53))	('regulate', 'Reg', (95, 103))	('SHMT1', 'Gene', (104, 109))	('regulate', 'Reg', (40, 48))	('miR-335', 'Gene', (55, 62))	('miR-29b-3p', 'Var', (14, 24))	('miR-1', 'Gene', '83856', (111, 116))	('let-7i', 'Gene', '406891', (158, 164))
45954	30200635	This analysis indicates that the deregulation of these molecules can be associated with more aggressive tumor phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('associated', 'Reg', (72, 82))	('aggressive tumor', 'Disease', 'MESH:D001523', (93, 109))	('deregulation', 'Var', (33, 45))	('aggressive tumor', 'Disease', (93, 109))
45957	30200635	Our data revealed that the expression profile of three miRNAs miR-146b-5p (p = 0.032) miR-218-5p (p = 0.048) and miR-138-5p (p < 0.001) correlated to DFS in patients that had undergone adjuvant treatment.	('miR-218-5p', 'Var', (86, 96))	('DFS', 'Disease', (150, 153))	('miR-146b', 'Gene', (62, 70))	('miR-146b', 'Gene', '574447', (62, 70))	('expression', 'MPA', (27, 37))	('patients', 'Species', '9606', (157, 165))	('miR-138-5p', 'Chemical', '-', (113, 123))	('miR-218-5p', 'Chemical', '-', (86, 96))	('miR-138-5p', 'Var', (113, 123))	('correlated', 'Reg', (136, 146))
45966	30200635	Although its function is uncertain, the miR-138-5p is an important IGF1R regulator.	('IGF1R', 'Gene', (67, 72))	('miR-138-5p', 'Chemical', '-', (40, 50))	('IGF1R', 'Gene', '3480', (67, 72))	('miR-138-5p', 'Var', (40, 50))
45969	30200635	There is a clue that when correlated with DFS, the expression of miR-146b-5p, miR-218-5p and miR-138-5p may have a role in adjuvant therapy response in US patients.	('miR-138-5p', 'Chemical', '-', (93, 103))	('adjuvant therapy response', 'CPA', (123, 148))	('miR-138-5p', 'Var', (93, 103))	('miR-146b', 'Gene', (65, 73))	('miR-218-5p', 'Chemical', '-', (78, 88))	('role', 'Reg', (115, 119))	('miR-146b', 'Gene', '574447', (65, 73))	('patients', 'Species', '9606', (155, 163))	('miR-218-5p', 'Var', (78, 88))
45982	30200635	We found miR-146b-5p, miR-218-5p and miR-138-5p with higher expression in patients who underwent treatment.	('expression', 'MPA', (60, 70))	('miR-218-5p', 'Chemical', '-', (22, 32))	('higher', 'PosReg', (53, 59))	('miR-138-5p', 'Chemical', '-', (37, 47))	('patients', 'Species', '9606', (74, 82))	('miR-146b', 'Gene', (9, 17))	('miR-138-5p', 'Var', (37, 47))	('miR-218-5p', 'Var', (22, 32))	('miR-146b', 'Gene', '574447', (9, 17))
45983	30200635	Concerning metastasis and recurrence, miR-210-3p was associated with ESS metastasis; miR-127-5p was related to CS relapse; and two members of the miR-29 family (29a-3p and 29b-3p) were associated with aggressive phenotypes in LMS.	('miR-127-5p', 'Gene', '100302123', (85, 95))	('29a-3p', 'Var', (161, 167))	('miR-21', 'Gene', (38, 44))	('associated', 'Reg', (185, 195))	('miR-127-5p', 'Gene', (85, 95))	('associated', 'Reg', (53, 63))	('related', 'Reg', (100, 107))	('miR-21', 'Gene', '406991', (38, 44))	('ESS', 'Disease', (69, 72))	('LMS', 'Disease', (226, 229))
45984	30200635	Besides this, the upregulation of miR-196a-5p, miR-34c-5p, miR-373-3p, miR-372-3p and downregulation of let-7b-5p were strongly associated with a lower CSS.	('upregulation', 'PosReg', (18, 30))	('miR-1', 'Gene', '83856', (34, 39))	('miR-34c-5p', 'Var', (47, 57))	('CSS', 'Chemical', '-', (152, 155))	('let-7b', 'Gene', '406884', (104, 110))	('lower', 'NegReg', (146, 151))	('miR-372-3p', 'Var', (71, 81))	('downregulation', 'NegReg', (86, 100))	('let-7b', 'Gene', (104, 110))	('miR-1', 'Gene', (34, 39))	('miR-373-3p', 'Var', (59, 69))	('CSS', 'Disease', (152, 155))
45993	29618619	Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy.	('interferon', 'Gene', (107, 117))	('CTLA-4', 'Gene', '1493', (236, 242))	('deletion', 'Var', (95, 103))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('CTLA-4', 'Gene', (236, 242))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', '1493', (244, 287))	('interferon', 'Gene', '3439', (107, 117))	('associated with', 'Reg', (201, 216))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', (244, 287))	('defensin', 'Gene', (146, 154))	('resistance to', 'CPA', (217, 230))
45996	29618619	Previous studies estimate that 25% of the cancer genome is affected by arm-level SCNAs and 10% by focal SCNAs with 2% overlap.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('affected', 'Reg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (42, 48))	('SCNAs', 'Var', (81, 86))
45999	29618619	Another study exploring the copy number profiles of 3131 tumor genomes across 26 cancer types identified 158 recurrent focal SCNAs including 76 amplification affecting 1566 genes and 82 deletions affecting 2001 genes.	('amplification affecting', 'Var', (144, 167))	('focal SCNAs', 'Disease', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (57, 62))	('deletions', 'Var', (186, 195))
46005	29618619	Survival analyses of different tumor types indicated that patients with homozygous deletion of interferon or defensin genes exhibit much worse overall or disease-free survival.	('worse', 'NegReg', (137, 142))	('interferon', 'Gene', '3439', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('disease-free survival', 'CPA', (154, 175))	('tumor', 'Disease', (31, 36))	('overall', 'CPA', (143, 150))	('homozygous deletion', 'Var', (72, 91))	('interferon', 'Gene', (95, 105))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('defensin genes', 'Gene', (109, 123))
46006	29618619	RNA-seq gene expression analyses between patients with and without IFN/DEF deletion in 19 cancer types indicate that homozygous deletions of IFN and DEF activate oncogenic and cell cycle pathways but repress immune response pathways.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IFN', 'Gene', '3439', (141, 144))	('repress immune response', 'Phenotype', 'HP:0002721', (200, 223))	('patients', 'Species', '9606', (41, 49))	('DEF', 'Gene', (149, 152))	('immune response pathways', 'Pathway', (208, 232))	('IFN', 'Gene', '3439', (67, 70))	('activate', 'PosReg', (153, 161))	('repress', 'NegReg', (200, 207))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('IFN', 'Gene', (141, 144))	('deletions', 'Var', (128, 137))	('IFN', 'Gene', (67, 70))
46008	29618619	Since a large body of evidence suggest that interferons and defensins play major roles in tumor immunity by recognizing tumor cells and serve as a bridge to spontaneous adaptive T cell response, our findings suggest a common molecular mechanism mediated by the deletion of interferon and defensin genes, through which tumor cells escape immune detection and destruction.	('defensin genes', 'Gene', (288, 302))	('interferon', 'Gene', '3439', (273, 283))	('interferon', 'Gene', '3439', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('interferon', 'Gene', (44, 54))	('interferon', 'Gene', (273, 283))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('deletion', 'Var', (261, 269))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', (120, 125))
46021	29618619	beta = 0.2), the minimum number of required events (K) is calculated as: where Zalpha/2 = 1.96, Zbeta = 0.84, pi1 and pi2 are the proportions to be allocated into two groups and were determined by the HDI/HDD frequencies in each cancer type.	('pi1', 'Var', (110, 113))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Zalpha/2 = 1.96', 'Var', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pi2', 'Var', (118, 121))	('HDD', 'Disease', (205, 208))	('pi2', 'Species', '1214577', (118, 121))	('HDD', 'Disease', 'None', (205, 208))
46053	29618619	Since both interferons and defensins are involved in innate immune response and play important roles in recognizing tumor cells and inducing an anti-tumor immune response, the widespread, homozygous deletion of these genes suggests a common molecular mechanism through which tumor cells escape immune destruction.	('interferon', 'Gene', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('interferon', 'Gene', '3439', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (149, 154))	('deletion', 'Var', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (116, 121))
46078	29618619	We asked the question whether homozygous deletions of interferon genes are passive hitchhiking events due to the nearby CDKN2A deletion, or they play an active role in tumorigenesis and affect the patient survival.	('play', 'Reg', (145, 149))	('affect', 'Reg', (186, 192))	('interferon', 'Gene', '3439', (54, 64))	('tumor', 'Disease', (168, 173))	('CDKN2A', 'Gene', (120, 126))	('interferon', 'Gene', (54, 64))	('deletion', 'Var', (127, 135))	('CDKN2A', 'Gene', '1029', (120, 126))	('patient survival', 'CPA', (197, 213))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patient', 'Species', '9606', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
46080	29618619	We performed the survival analyses on three patient groups: (I) patients only have CDKN2A deletion (CDKN2A-/IFN+); (II) patients have CDKN2A deletion and additional IFN gene deletions (CDKN2A-/IFN-); and (III) patients have neither CDKN2A nor IFN gene deletions (CDKN2A+/IFN+).	('deletion', 'Var', (90, 98))	('IFN', 'Gene', '3439', (271, 274))	('IFN', 'Gene', (243, 246))	('CDKN2A nor IFN', 'Gene', '1029;3439', (232, 246))	('CDKN2A', 'Gene', (83, 89))	('CDKN2A', 'Gene', '1029', (100, 106))	('CDKN2A', 'Gene', (263, 269))	('IFN', 'Gene', (193, 196))	('patient', 'Species', '9606', (64, 71))	('CDKN2A', 'Gene', (232, 238))	('patient', 'Species', '9606', (120, 127))	('CDKN2A-/IFN+);', 'Gene', '1029;3439', (100, 114))	('IFN', 'Gene', (271, 274))	('patients', 'Species', '9606', (210, 218))	('CDKN2A', 'Gene', (185, 191))	('deletion', 'Var', (141, 149))	('CDKN2A', 'Gene', '1029', (83, 89))	('CDKN2A', 'Gene', '1029', (263, 269))	('CDKN2A', 'Gene', (134, 140))	('IFN', 'Gene', '3439', (165, 168))	('CDKN2A', 'Gene', '1029', (232, 238))	('IFN', 'Gene', '3439', (108, 111))	('CDKN2A-/IFN-', 'Gene', (185, 197))	('CDKN2A nor IFN', 'Gene', (232, 246))	('CDKN2A+/IFN+', 'Gene', '3439', (263, 275))	('IFN', 'Gene', '3439', (243, 246))	('CDKN2A', 'Gene', '1029', (185, 191))	('CDKN2A-/IFN+)', 'Gene', (100, 113))	('patient', 'Species', '9606', (44, 51))	('CDKN2A-/IFN-)', 'Gene', '1029;3439', (185, 198))	('patients', 'Species', '9606', (64, 72))	('CDKN2A+/IFN+', 'Gene', (263, 275))	('CDKN2A', 'Gene', '1029', (134, 140))	('IFN', 'Gene', (165, 168))	('patients', 'Species', '9606', (120, 128))	('CDKN2A', 'Gene', (100, 106))	('patient', 'Species', '9606', (210, 217))	('IFN', 'Gene', '3439', (193, 196))	('IFN', 'Gene', (108, 111))
46087	29618619	It could be also due to other confounding factors such as PTEN and RB1 deletions, which tend to be mutually exclusive with HDIs and HDDs (Supplementary Figure 7).	('deletions', 'Var', (71, 80))	('PTEN', 'Gene', '5728', (58, 62))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))	('HDIs and HDDs', 'Disease', 'None', (123, 136))	('PTEN', 'Gene', (58, 62))
46088	29618619	To identify gene expression signatures associated with the deletion of IFN and DEF genes, we performed gene expression analysis on each of the 19 cancer types (or 17 cancer types when COAD and READ are combined as colorectal cancer, LUSC and LUAD are combined as lung cancer) having high frequencies of HDI and HDD.	('cancer', 'Disease', (146, 152))	('lung cancer', 'Disease', (263, 274))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (225, 231))	('COAD', 'Disease', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('IFN', 'Gene', '3439', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('HDD', 'Disease', 'None', (311, 314))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('colorectal cancer', 'Disease', (214, 231))	('HDD', 'Disease', (311, 314))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('IFN', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('deletion', 'Var', (59, 67))	('cancer', 'Disease', (268, 274))	('COAD', 'Disease', 'MESH:D029424', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))
46102	29618619	In a recent report, copy loss of type I interferon genes are found in 6 out of 12 melanoma patients that resist to anti-CTLA-4 treatment, but in none of the 4 responders (P = 0.23, two-tailed Fisher exact test).	('copy loss', 'Var', (20, 29))	('patients', 'Species', '9606', (91, 99))	('interferon', 'Gene', '3439', (40, 50))	('CTLA-4', 'Gene', '1493', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('interferon', 'Gene', (40, 50))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CTLA-4', 'Gene', (120, 126))
46107	29618619	As a comparison, deletions of two tumor suppressor genes CDKN2A (P = 0.63) and PTEN (P = 0.55) are not associated with responders or non-responders (Fig.	('tumor', 'Disease', (34, 39))	('CDKN2A', 'Gene', (57, 63))	('deletions', 'Var', (17, 26))	('CDKN2A', 'Gene', '1029', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PTEN', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PTEN', 'Gene', '5728', (79, 83))
46108	29618619	Taken together, our meta-analyses of two independent melanoma cohorts suggest the deletion of interferon and defensin genes is significantly associated anti-CTLA-4 treatment resistance, and might be a potential prognostic biomarker to predict resistance to other immunotherapies.	('CTLA-4', 'Gene', (157, 163))	('interferon', 'Gene', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('CTLA-4', 'Gene', '1493', (157, 163))	('deletion', 'Var', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('associated', 'Reg', (141, 151))	('interferon', 'Gene', '3439', (94, 104))
46110	29618619	In this study, we analyzed the copy number profiles of 10,759 primary cancer tissues and found the homozygous deletions of type I interferon and defensin genes are pervasive in 19 TCGA cancer types, and the alteration frequency is much higher than those of well-known tumor suppressors PTEN and RB1 in the same cancer type (Supplementary Figure 7).	('interferon', 'Gene', '3439', (130, 140))	('PTEN', 'Gene', '5728', (286, 290))	('cancer', 'Disease', (311, 317))	('defensin', 'Gene', (145, 153))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('RB1', 'Gene', '5925', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('PTEN', 'Gene', (286, 290))	('tumor', 'Disease', (268, 273))	('interferon', 'Gene', (130, 140))	('RB1', 'Gene', (295, 298))	('deletions', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
46111	29618619	More importantly, homozygous deletions of interferon and defensin genes associate with worse overall or disease-free survival, and the resistance to anti-CTLA4 treatment in melanoma patients.	('CTLA4', 'Gene', (154, 159))	('defensin', 'Gene', (57, 65))	('worse', 'NegReg', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('interferon', 'Gene', '3439', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('disease-free survival', 'CPA', (104, 125))	('resistance', 'CPA', (135, 145))	('patients', 'Species', '9606', (182, 190))	('overall', 'CPA', (93, 100))	('interferon', 'Gene', (42, 52))	('CTLA4', 'Gene', '1493', (154, 159))	('homozygous deletions', 'Var', (18, 38))
46112	29618619	Defects in the type I interferon signaling pathway have been proposed as a potential mechanism of cancer escape (insensitivity) to immunotherapy in mice and prostate cancer cell line.	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('interferon', 'Gene', '3439', (22, 32))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('Defects', 'Var', (0, 7))	('interferon', 'Gene', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mice', 'Species', '10090', (148, 152))	('cancer', 'Disease', (98, 104))	('prostate cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
46117	29618619	By analyzing the genomes of 10,759 cancer patients across 31 cancer types, we found interferon and defensin genes are homozygously deleted with high frequencies in 19 cancer types, and the surviving time of patients with these deletions are significantly reduced.	('reduced', 'NegReg', (255, 262))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('interferon', 'Gene', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('surviving time', 'CPA', (189, 203))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('interferon', 'Gene', '3439', (84, 94))	('deletions', 'Var', (227, 236))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (42, 50))	('defensin genes', 'Gene', (99, 113))	('cancer', 'Disease', (35, 41))
46120	29854314	Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer Foretinib (GSK1363089 or XL880), which is an oral multikinase inhibitor developed to primarily target the hepatocyte growth factor (HGF)/Met signaling pathway, has shown anti-tumor effects against some cancers in preclinical and clinical studies.	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('XL880', 'Chemical', 'MESH:C544831', (102, 107))	('cancers', 'Disease', (279, 286))	('p53', 'Gene', '7157', (31, 34))	('factor ', 'Gene', '7422', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('p53', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('GSK1363089', 'Chemical', 'MESH:C544831', (11, 21))	('endometrial cancer', 'Phenotype', 'HP:0012114', (58, 76))	('GSK1363089', 'Chemical', 'MESH:C544831', (88, 98))	('factor ', 'Gene', (201, 208))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('endometrial cancer', 'Disease', (58, 76))	('GSK1363089', 'Var', (11, 21))	('endometrial cancer', 'Disease', 'MESH:D016889', (58, 76))	('Foretinib', 'Chemical', 'MESH:C544831', (77, 86))	('tumor', 'Disease', (252, 257))
46124	29854314	p53 mutations were observed in 37 (10.8%) of 344 endometrial cancer specimens.	('p53', 'Gene', (0, 3))	('endometrial cancer', 'Disease', (49, 67))	('observed', 'Reg', (19, 27))	('endometrial cancer', 'Phenotype', 'HP:0012114', (49, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('endometrial cancer', 'Disease', 'MESH:D016889', (49, 67))	('mutations', 'Var', (4, 13))
46126	29854314	Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib was found to exert greater anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations.	('cancer', 'Disease', (26, 32))	('anti-phosphorylation', 'MPA', (52, 72))	('foretinib', 'Gene', (140, 149))	('endometrial cancer', 'Disease', 'MESH:D016889', (201, 219))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('nde', 'Gene', '54820', (123, 126))	('ter', 'Gene', '9524', (173, 176))	('wild-type', 'Var', (235, 244))	('nde', 'Gene', (123, 126))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('ter', 'Gene', (173, 176))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('endometrial cancer', 'Phenotype', 'HP:0012114', (201, 219))	('endometrial cancer', 'Disease', (201, 219))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('foretinib', 'Chemical', 'MESH:C544831', (140, 149))
46142	29854314	In several epithelial and mesenchymal cancers, the high expression of the Met protein has been reported to be an independent predictor of an adverse outcome, and Met was reported to activate cancer cell dissemination.	('high expression', 'MPA', (51, 66))	('mesenchymal cancers', 'Disease', (26, 45))	('activate', 'PosReg', (182, 190))	('epithelial', 'Disease', (11, 21))	('mesenchymal cancers', 'Disease', 'MESH:C535700', (26, 45))	('cancer', 'Disease', (191, 197))	('nde', 'Gene', '54820', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', (38, 44))	('protein', 'Protein', (78, 85))	('nde', 'Gene', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('nde', 'Gene', '54820', (119, 122))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('Met', 'Gene', (74, 77))	('Met', 'Var', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('nde', 'Gene', (119, 122))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
46160	29854314	It has been well documented that the activation of PI3K signaling increases the translocation of the mouse double minute 2 homolog (MDM2) from the cytoplasm to the nucleus, allowing p53 to be degraded by proteasomes.	('PI3K', 'Var', (51, 55))	('increases', 'PosReg', (66, 75))	('mouse', 'Species', '10090', (101, 106))	('homolog (MDM2', 'Gene', '17246', (123, 136))	('translocation', 'MPA', (80, 93))	('p53', 'Protein', (182, 185))	('degraded', 'MPA', (192, 200))
46169	29854314	Figure 3D shows that the anti-proliferation effect of foretinib was reduced in p53 siRNA-transfected cells.	('foretinib', 'Gene', (54, 63))	('foretinib', 'Chemical', 'MESH:C544831', (54, 63))	('anti-proliferation effect', 'CPA', (25, 50))	('p53', 'Var', (79, 82))	('reduced', 'NegReg', (68, 75))
46172	29854314	As shown in Figure 5A, the HGF siRNA-transfected EC cells showed significant growth inhibition, which occurred in a time-dependent manner, in comparison to the scrambled siRNA-transfected cells.	('growth inhibition', 'CPA', (77, 94))	('HGF siRNA-transfected', 'Var', (27, 48))	('nde', 'Gene', '54820', (125, 128))	('nde', 'Gene', (125, 128))
46173	29854314	Moreover, HGF siRNA transfection induced a significantly greater level of apoptosis in comparison to the scrambled siRNA-transfected cells (Figure 5B and 5C).	('apoptosis', 'MPA', (74, 83))	('HGF siRNA transfection', 'Var', (10, 32))	('transfection', 'Var', (20, 32))	('ter', 'Gene', '9524', (61, 64))	('ter', 'Gene', (61, 64))
46174	29854314	In order to assess whether the p53-dependent apoptosis was induced via the inhibition of autocrine HGF/Met signaling, we examined the expression of p-Akt, p-MDM2, p53 and PUMA in HGF siRNA-transfected EC cells by Western blotting.	('ste', 'Gene', (215, 218))	('ste', 'Gene', '6783', (215, 218))	('nde', 'Gene', (39, 42))	('ter', 'Gene', '9524', (216, 219))	('p-MDM2', 'Var', (155, 161))	('nde', 'Gene', '54820', (39, 42))	('ter', 'Gene', (216, 219))
46176	29854314	These data suggest that autocrine HGF/Met signaling interferes with the p53 activity in EC cells, and that inhibiting autocrine HGF/Met signaling restores the p53 function.	('ter', 'Gene', '9524', (54, 57))	('p53', 'Protein', (72, 75))	('activity', 'MPA', (76, 84))	('inhibiting', 'Var', (107, 117))	('p53 function', 'MPA', (159, 171))	('ter', 'Gene', (54, 57))	('restores', 'PosReg', (146, 154))
46189	29854314	Table 2 shows the association between the malignant potential of the tumor and the p53 status (determined by immunochemical staining).	('ter', 'Gene', '9524', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ter', 'Gene', (97, 100))	('tumor', 'Disease', (69, 74))	('association', 'Interaction', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('p53 status', 'Var', (83, 93))
46191	29854314	Thirty-seven (10.8%) patients were positive for p53 and 307 (89.2%) were negative for p53.	('patients', 'Species', '9606', (21, 29))	('positive', 'Reg', (35, 43))	('p53', 'Var', (48, 51))
46192	29854314	The rate of p53 positivity in the high-grade tumor group (24.0%) was significantly higher than that in the low-grade tumor group (6.0%).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('p53', 'Protein', (12, 15))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('positivity', 'Var', (16, 26))	('higher', 'PosReg', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
46201	29854314	Although the full spectrum of activity is still being uncovered, mutant p53 has been found in various cancers and involvement in the development and progression of cancer has been clarified.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (164, 170))	('found', 'Reg', (85, 90))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
46202	29854314	Mutant p53 has been found in approximately 10-20% of uterine endometrioid carcinomas and >90% of uterine serous or clear cell carcinomas.	('ter', 'Gene', '9524', (54, 57))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (61, 84))	('clear cell carcinomas', 'Disease', (115, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('ter', 'Gene', '9524', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ter', 'Gene', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (115, 136))	('found', 'Reg', (20, 25))	('ter', 'Gene', (98, 101))	('Mutant', 'Var', (0, 6))	('endometrioid carcinomas', 'Disease', (61, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('p53', 'Gene', (7, 10))
46203	29854314	In addition, there is a trend toward a higher frequency of p53 mutations with increasing histopathological grades in uterine endometrioid carcinomas.	('mutations', 'Var', (63, 72))	('p53', 'Gene', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('ter', 'Gene', (118, 121))	('endometrioid carcinomas', 'Disease', (125, 148))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (125, 148))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (125, 147))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (125, 148))	('ter', 'Gene', '9524', (118, 121))
46204	29854314	reported that mutant p53 was found in 43% of Grade 3 uterine endometrioid carcinomas, while it was not detected in Grade 1 endometrioid carcinomas.	('ter', 'Gene', '9524', (54, 57))	('endometrioid carcinomas', 'Disease', (123, 146))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (61, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (123, 146))	('found', 'Reg', (29, 34))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (123, 145))	('mutant', 'Var', (14, 20))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (123, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ter', 'Gene', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('endometrioid carcinomas', 'Disease', (61, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('p53', 'Gene', (21, 24))
46205	29854314	It also reported that p53 mutations are detected in 24-36% of clear cell carcinomas.	('p53', 'Gene', (22, 25))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (62, 83))	('detected', 'Reg', (40, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('mutations', 'Var', (26, 35))	('clear cell carcinomas', 'Disease', (62, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
46206	29854314	Mutations in p53 are not a simple phenomenon because some tumors harbor mutations in p53 that allow the protein to retain its functions.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('protein', 'Protein', (104, 111))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('p53', 'Gene', (85, 88))	('functions', 'MPA', (126, 135))
46213	29854314	This also suggests that foretinib would be effective for treating high-grade endometrial cancer, which causes p53 mutations.	('p53', 'Gene', (110, 113))	('endometrial cancer', 'Disease', 'MESH:D016889', (77, 95))	('mutations', 'Var', (114, 123))	('endometrial cancer', 'Disease', (77, 95))	('foretinib', 'Chemical', 'MESH:C544831', (24, 33))	('endometrial cancer', 'Phenotype', 'HP:0012114', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
46278	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.	('copy number', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated', 'Reg', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cell cycle', 'CPA', (187, 197))	('cancer', 'Disease', (147, 153))	('cell differentiation', 'CPA', (199, 219))
46282	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))
46285	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))	('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))
46293	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))
46302	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))	('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))	('result in', 'Reg', (90, 99))
46307	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))	('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))
46312	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))
46315	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))
46316	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))	('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))	('bladder urothelial carcinoma', 'Disease', (233, 261))	('cancer', 'Disease', (148, 154))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('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))
46319	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))
46350	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))	('MTDH', 'Gene', (116, 120))	('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))	('KRAS', 'Gene', (27, 31))
46375	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))
46376	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))
46377	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))
46378	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))
46379	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))
46388	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))
46391	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))	('MTDH', 'Gene', '92140', (143, 147))	('MTDH', 'Gene', (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))	('gastric', 'Disease', (260, 267))
46403	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))
46404	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))
46406	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))
46408	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))	('effects', 'Reg', (177, 184))	('multiple cancer', 'Disease', 'MESH:D009369', (106, 121))
46427	28088687	Hallmarks of DNA methylation abnormalities in UCS included global hypomethylation, especially in repetitive elements, and hypermethylation of tumor suppressor gene promoters.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('abnormalities', 'Var', (29, 42))	('UCS', 'Phenotype', 'HP:0002891', (46, 49))	('hypermethylation', 'MPA', (122, 138))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('global hypomethylation', 'MPA', (59, 81))
46428	28088687	The carcinoma component of UCS was characterized by hypermethylation of promoters of EMILIN1, NEFM, and CLEC14A, genes that are associated with tumor vascularization.	('tumor', 'Disease', (144, 149))	('NEFM', 'Gene', '4741', (94, 98))	('NEFM', 'Gene', (94, 98))	('EMILIN1', 'Gene', '11117', (85, 92))	('CLEC14A', 'Gene', '161198', (104, 111))	('hypermethylation', 'Var', (52, 68))	('CLEC14A', 'Gene', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('EMILIN1', 'Gene', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('carcinoma component of UCS', 'Disease', (4, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))	('carcinoma component of UCS', 'Disease', 'MESH:C562869', (4, 30))	('UCS', 'Phenotype', 'HP:0002891', (27, 30))
46431	28088687	Human cancers display abnormal DNA methylation patterns including genome-wide hypomethylation and site-specific hypermethylation.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Disease', (6, 13))	('hypomethylation', 'Var', (78, 93))
46433	28088687	Globally, hypomethylation of most genomic transposable elements (TEs) leads to chromosome instability, whereas alterations in methylation levels of other TEs contribute to tumor initiation or progression.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('methylation', 'MPA', (126, 137))	('tumor initiation', 'Disease', 'MESH:D009369', (172, 188))	('hypomethylation', 'Var', (10, 25))	('chromosome instability', 'Phenotype', 'HP:0040012', (79, 101))	('leads to', 'Reg', (70, 78))	('tumor initiation', 'Disease', (172, 188))	('contribute', 'Reg', (158, 168))	('chromosome instability', 'CPA', (79, 101))
46434	28088687	The scope of aberrant methylation of distal enhancers continues to receive attention in many cancers.	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('aberrant methylation', 'Var', (13, 33))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('methylation', 'Var', (22, 33))
46442	28088687	Characteristic mutations in TP53, KRAS, and PIK3CA have been reported in UCS.	('KRAS', 'Gene', '3845', (34, 38))	('PIK3CA', 'Gene', (44, 50))	('TP53', 'Gene', '7157', (28, 32))	('UCS', 'Phenotype', 'HP:0002891', (73, 76))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', (28, 32))	('PIK3CA', 'Gene', '5290', (44, 50))	('UCS', 'Disease', (73, 76))	('KRAS', 'Gene', (34, 38))	('reported', 'Reg', (61, 69))
46471	28088687	In normal endometrium, 80% of the 28M CpGs were methylated (i.e., methylation level >= 0.8), whereas in UCS samples, this ratio fell to 60% to 70% (Supplemental Table 1).	('methylated', 'Var', (48, 58))	('methylation level', 'MPA', (66, 83))	('CpGs', 'Chemical', 'MESH:C015772', (38, 42))	('UCS', 'Phenotype', 'HP:0002891', (104, 107))
46476	28088687	This approach allowed us to discover a total of 7235 recurrent DMRs in at least 2 of the 3 carcinoma components, and 4165 DMRs in the sarcoma components, when compared to normal endometrium.	('DMRs', 'Var', (63, 67))	('DMRs', 'Chemical', '-', (63, 67))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('sarcoma', 'Disease', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('DMRs', 'Chemical', '-', (122, 126))	('carcinoma', 'Disease', (91, 100))
46478	28088687	About 82% of UCS common DMRs were hypermethylated (2490 DMRs), and 18% were hypomethylated (539) (Figure 2C).	('DMRs', 'Chemical', '-', (24, 28))	('UCS', 'Disease', (13, 16))	('DMRs', 'Chemical', '-', (56, 60))	('hypermethylated', 'Var', (34, 49))	('UCS', 'Phenotype', 'HP:0002891', (13, 16))
46491	28088687	Specifically, we found 743 genes with hypermethylated DMRs within 2.5 kb of their transcription start site.	('DMRs', 'Chemical', '-', (54, 58))	('DMRs', 'Var', (54, 58))	('hypermethylated DMRs', 'Var', (38, 58))
46492	28088687	In cancer cells, epigenetic inactivation of tumor-suppressor genes (TSGs) is a key tumorigenic event.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('epigenetic inactivation', 'Var', (17, 40))	('tumor', 'Disease', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
46494	28088687	More specifically, the Wilms' tumor 1 (WT1) gene was one of the TSGs identified as harboring a hypermethylated DMR in its promoter (Figure 3B), and this was validated by TCGA methylation data (Figure 3C).	("Wilms' tumor 1", 'Gene', '7490', (23, 37))	('WT1', 'Gene', (39, 42))	('hypermethylated', 'Var', (95, 110))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (23, 35))	("Wilms' tumor 1", 'Gene', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('WT1', 'Gene', '7490', (39, 42))
46496	28088687	Necdin (NDN) has been reported to be silenced by methylation in urothelial carcinoma.	('NDN', 'Gene', '4692', (8, 11))	('silenced', 'NegReg', (37, 45))	('urothelial carcinoma', 'Disease', (64, 84))	('Necdin', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Necdin', 'Gene', '4692', (0, 6))	('methylation', 'Var', (49, 60))	('NDN', 'Gene', (8, 11))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (64, 84))
46506	28088687	Global hypomethylation of TEs has long been regarded as a hallmark of cancers, with direct implication in cancer genome instability.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Global hypomethylation', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('hallmark of cancers', 'Disease', 'MESH:D009369', (58, 77))	('hallmark of cancers', 'Disease', (58, 77))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('TEs', 'Gene', (26, 29))
46509	28088687	Overall, 15.6% of hypermethylated and 40% of hypomethylated UCS-common DMRs were contributed by TEs (Figure 4B).	('UCS', 'Phenotype', 'HP:0002891', (60, 63))	('UCS-common', 'Disease', (60, 70))	('DMRs', 'Chemical', '-', (71, 75))	('hypermethylated', 'Var', (18, 33))
46510	28088687	For example, LTR12C is an endogenous retroviral element (ERV/LTR) recently reported to produce abnormal transcripts in liver cancer.	('liver cancer', 'Disease', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('LTR12C', 'Var', (13, 19))	('liver cancer', 'Phenotype', 'HP:0002896', (119, 131))	('liver cancer', 'Disease', 'MESH:D006528', (119, 131))
46511	28088687	LTR12C contributed both hypermethylated and hypomethylated DMRs (Figure 4C).	('hypermethylated', 'Var', (24, 39))	('hypomethylated', 'Var', (44, 58))	('DMRs', 'Chemical', '-', (59, 63))	('LTR12C', 'Gene', (0, 6))
46515	28088687	Recurrent hypermethylated protocadherin genes in endometrial cancers occurred within 5q31, spanning three PCDH clusters (PCDHA, PCDHB, and PCDHG; Figure 5A).	('PCDHB', 'Gene', (128, 133))	('PCDHA', 'Gene', (121, 126))	('PCDHA', 'Gene', '56117', (121, 126))	('PCDHB', 'Gene', '56116', (128, 133))	('PCDHG', 'Gene', '56115', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('endometrial cancer', 'Phenotype', 'HP:0012114', (49, 67))	('endometrial cancers', 'Disease', 'MESH:D016889', (49, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('endometrial cancers', 'Disease', (49, 68))	('PCDHG', 'Gene', (139, 144))	('protocadherin genes', 'Gene', (26, 45))	('hypermethylated', 'Var', (10, 25))
46518	28088687	We hypothesized that the presence of DMRs within certain genes might be characteristic of carcinomatous or sarcomatous components of UCS.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('genes', 'Gene', (57, 62))	('carcinomatous or sarcomatous', 'Disease', 'MESH:D055756', (90, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('UCS', 'Phenotype', 'HP:0002891', (133, 136))	('DMRs', 'Chemical', '-', (37, 41))	('carcinomatous or sarcomatous', 'Disease', (90, 118))	('DMRs', 'Var', (37, 41))
46522	28088687	Interestingly, they shared many more hypermethylated DMRs (1582) than hypomethylated DMRs (145).	('DMRs', 'Chemical', '-', (85, 89))	('hypermethylated', 'Var', (37, 52))	('DMRs', 'Chemical', '-', (53, 57))	('1582', 'Var', (59, 63))
46527	28088687	Of 342 genes with CADs located in their promoters, elastic microfibril interface located protein (EMILIN1), neurofilament medium peptide (NEFM), and C-type lectin domain family 14 member A (CLEC14A) showed significant hypermethylation and decreased expression in endometrial carcinoma and carcinomatous components of UCS (Supplementary Figure 2, A and B).	('expression', 'MPA', (249, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('UCS', 'Phenotype', 'HP:0002891', (317, 320))	('EMILIN1', 'Gene', '11117', (98, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('C-type lectin domain family 14 member A', 'Gene', '161198', (149, 188))	('decreased', 'NegReg', (239, 248))	('CLEC14A', 'Gene', '161198', (190, 197))	('endometrial carcinoma and carcinomatous', 'Disease', 'MESH:D016889', (263, 302))	('EMILIN1', 'Gene', (98, 105))	('CLEC14A', 'Gene', (190, 197))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (263, 284))	('hypermethylation', 'Var', (218, 234))	('NEFM', 'Gene', '4741', (138, 142))	('C-type lectin domain family 14 member A', 'Gene', (149, 188))	('NEFM', 'Gene', (138, 142))
46529	28088687	Our DMR analysis revealed a novel connection between epigenetic regulation of miRNAs and the distinction between the sarcomatous and carcinomatous components of UCS.	('sarcomatous', 'Disease', (117, 128))	('carcinomatous', 'Disease', 'MESH:D055756', (133, 146))	('miRNAs', 'Protein', (78, 84))	('carcinomatous', 'Disease', (133, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('epigenetic regulation', 'Var', (53, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('sarcomatous', 'Disease', 'MESH:D018316', (117, 128))	('UCS', 'Phenotype', 'HP:0002891', (161, 164))
46530	28088687	This was highlighted by several DMRs targeting the MIR200 family (MIR200a, MIR200b, MIR200c, MIR141, MIR429) in UCS.	('MIR200', 'Gene', (51, 57))	('MIR429', 'Gene', '554210', (101, 107))	('MIR200a', 'Var', (66, 73))	('MIR200c', 'Gene', (84, 91))	('MIR141', 'Gene', (93, 99))	('MIR429', 'Gene', (101, 107))	('MIR200b', 'Gene', (75, 82))	('DMRs', 'Chemical', '-', (32, 36))	('UCS', 'Phenotype', 'HP:0002891', (112, 115))	('MIR141', 'Gene', '406933', (93, 99))	('MIR200c', 'Gene', '406985', (84, 91))	('MIR200b', 'Gene', '406984', (75, 82))
46537	28088687	Taken together, these results suggest that the methylation pattern of MIR200 family members is an important epigenetic biomarker to distinguish carcinomatous and sarcomatous components of UCS.	('MIR200', 'Gene', (70, 76))	('sarcomatous', 'Disease', 'MESH:D018316', (162, 173))	('carcinomatous', 'Disease', 'MESH:D055756', (144, 157))	('methylation', 'Var', (47, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('sarcomatous', 'Disease', (162, 173))	('carcinomatous', 'Disease', (144, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('UCS', 'Phenotype', 'HP:0002891', (188, 191))
46542	28088687	UCSs with high WT1 and high estrogen receptor beta expression were shown to have decreased survival, supporting a role for WT1 as a biomarker in this tumor type.	('decreased', 'NegReg', (81, 90))	('survival', 'CPA', (91, 99))	('WT1', 'Gene', '7490', (123, 126))	('estrogen receptor beta', 'Gene', '2100', (28, 50))	('WT1', 'Gene', (123, 126))	('high', 'Var', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('UCS', 'Phenotype', 'HP:0002891', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('WT1', 'Gene', '7490', (15, 18))	('tumor', 'Disease', (150, 155))	('estrogen receptor beta', 'Gene', (28, 50))	('WT1', 'Gene', (15, 18))
46546	28088687	Among other candidate genes with a differential methylation pattern between the carcinomatous and sarcomatous components, we noted that EMILIN1 and CLEC4A harbored carcinoma-associated DMRs in their promoters and exhibited decreased expression in carcinoma.	('CLEC4A', 'Gene', '50856', (148, 154))	('expression', 'MPA', (233, 243))	('sarcomatous', 'Disease', 'MESH:D018316', (98, 109))	('carcinomatous', 'Disease', 'MESH:D055756', (80, 93))	('carcinoma', 'Disease', 'MESH:D002277', (164, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('sarcomatous', 'Disease', (98, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Disease', (247, 256))	('decreased', 'NegReg', (223, 232))	('DMRs', 'Chemical', '-', (185, 189))	('CLEC4A', 'Gene', (148, 154))	('carcinoma', 'Disease', (80, 89))	('DMRs', 'Var', (185, 189))	('EMILIN1', 'Gene', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinoma', 'Disease', 'MESH:D002277', (247, 256))	('EMILIN1', 'Gene', '11117', (136, 143))	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('carcinoma', 'Disease', (164, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('carcinomatous', 'Disease', (80, 93))
46551	28088687	We identified component-specific DNA methylation abnormalities of MIR200 in UCS-Ca and in UCS-Sa, as well as in other endometrial tumor types.	('UCS-Sa', 'Disease', (90, 96))	('UCS-Ca', 'Disease', (76, 82))	('endometrial tumor', 'Disease', (118, 135))	('methylation abnormalities', 'Var', (37, 62))	('UCS', 'Phenotype', 'HP:0002891', (76, 79))	('UCS', 'Phenotype', 'HP:0002891', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('endometrial tumor', 'Disease', 'MESH:D016889', (118, 135))	('MIR200', 'Gene', (66, 72))
46553	28088687	Compared to pure carcinomas, UCS cases were found to have an increase in histone H2A/H2B mutations; furthermore, a majority of UCSs showed amplification of chromosome arm 6p, harboring the HIST1H histone gene cluster, and 1q22, harboring the HIST2H gene cluster.	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('carcinomas', 'Disease', (17, 27))	('carcinomas', 'Disease', 'MESH:D002277', (17, 27))	('amplification', 'Var', (139, 152))	('mutations', 'Var', (89, 98))	('UCS', 'Phenotype', 'HP:0002891', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('UCS', 'Phenotype', 'HP:0002891', (127, 130))
46563	28088687	There are recurrent epigenetic differences between the carcinomatous and sarcomatous components, in keeping with the phenotypic differences between them.	('sarcomatous', 'Disease', (73, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('carcinomatous', 'Disease', 'MESH:D055756', (55, 68))	('epigenetic differences', 'Var', (20, 42))	('sarcomatous', 'Disease', 'MESH:D018316', (73, 84))	('carcinomatous', 'Disease', (55, 68))
46564	28088687	The preponderance of hypermethylated DMRs in UCS could suggest a role for hypomethylating agents in clinical practice.	('UCS', 'Phenotype', 'HP:0002891', (45, 48))	('UCS', 'Disease', (45, 48))	('DMRs', 'Chemical', '-', (37, 41))	('DMRs', 'Var', (37, 41))	('hypermethylated DMRs', 'Var', (21, 41))
46590	27775259	Despite insignificant mortality reduction over years 0-14 of 15% (95% confidence interval [CI], -3 to 30; p=0.100) with MMS and 11% (95% CI, -7 to 27; p=0.210) with USS, a prespecified analysis of ovarian cancer death of MMS vs. no screening with exclusion of prevalent cases showed significant decrease of death rates (p=0.021), with an overall average mortality reduction of 20% (95% CI, -2 to 40) and a reduction of 8% (95% CI, -27 to 43) in years 0-7 and 28% (95% CI, -3 to 49) in years 7-14 in favor of MMS, suggesting the long-term effect of an MMS screening program.	('ovarian cancer death', 'Disease', 'MESH:D010051', (197, 217))	('MMS', 'Chemical', '-', (508, 511))	('decrease of death', 'Disease', (295, 312))	('MMS', 'Chemical', '-', (551, 554))	('reduction', 'NegReg', (406, 415))	('decrease of death', 'Disease', 'MESH:D003643', (295, 312))	('ovarian cancer death', 'Disease', (197, 217))	('MMS', 'Chemical', '-', (221, 224))	('reduction', 'NegReg', (32, 41))	('MMS', 'Var', (508, 511))	('ovarian cancer', 'Phenotype', 'HP:0100615', (197, 211))	('MMS', 'Var', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('reduction', 'NegReg', (364, 373))	('MMS', 'Chemical', '-', (120, 123))
46592	27775259	False-positive rate, that resulted in unnecessary surgery for which ovaries had benign pathology or were normal, was 2.3 times higher in the MMS group than in the no screening group.	('MMS', 'Var', (141, 144))	('MMS', 'Chemical', '-', (141, 144))	('higher', 'PosReg', (127, 133))
46596	27775259	First, oral contraceptives reduce the risk of ovarian cancer and are considered safe for BRCA1 and BRCA2 mutations carriers.	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('carriers', 'Reg', (115, 123))	('BRCA1', 'Gene', (89, 94))	('ovarian cancer', 'Disease', (46, 60))	('reduce', 'NegReg', (27, 33))	('BRCA2', 'Gene', (99, 104))	('mutations', 'Var', (105, 114))	('contraceptives reduce the risk of ovarian cancer', 'Phenotype', 'HP:0008209', (12, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('BRCA1', 'Gene', '672', (89, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('BRCA2', 'Gene', '675', (99, 104))
46598	27775259	Although a recently published systematic review concluded that there is a small increased risk of breast cancer in oral pill users (odds ratio [OR], 1.08; 95% CI, 1.00 to 1.17), women with BRCA1 or BRCA2 mutations should consider taking oral pills to reduce their ovarian cancer risk not only because a significant reduction in the risk of ovarian cancer for BRCA1 and BRCA2 mutation carriers (summary relative risk [SRR], 0.50; 95% CI, 0.33 to 0.75), but also because there was no significant association between modern oral contraceptive use and breast cancer risk in these women (SRR, 1.13; 95% CI, 0.88 to 1.45).	('breast cancer', 'Disease', (548, 561))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('BRCA2', 'Gene', '675', (369, 374))	('ovarian cancer', 'Disease', 'MESH:D010051', (264, 278))	('reduction', 'NegReg', (315, 324))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Disease', (340, 354))	('cancer in oral', 'Phenotype', 'HP:0100649', (105, 119))	('BRCA2', 'Gene', (198, 203))	('BRCA1', 'Gene', '672', (359, 364))	('ovarian cancer', 'Phenotype', 'HP:0100615', (340, 354))	('reduce', 'NegReg', (251, 257))	('BRCA1', 'Gene', (359, 364))	('ovarian cancer', 'Disease', (264, 278))	('cancer', 'Phenotype', 'HP:0002664', (555, 561))	('mutation', 'Var', (375, 383))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('mutations', 'Var', (204, 213))	('ovarian cancer', 'Phenotype', 'HP:0100615', (264, 278))	('women', 'Species', '9606', (576, 581))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('BRCA2', 'Gene', '675', (198, 203))	('BRCA1', 'Gene', '672', (189, 194))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('BRCA2', 'Gene', (369, 374))	('breast cancer', 'Disease', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (548, 561))	('BRCA1', 'Gene', (189, 194))	('women', 'Species', '9606', (178, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (340, 354))	('breast cancer', 'Disease', 'MESH:D001943', (548, 561))
46599	27775259	Second, tubal ligation is associated with a reduction in ovarian cancer in both the general population (34%) and high-risk women (57% in BRCA1 mutations carriers).	('BRCA1', 'Gene', '672', (137, 142))	('carriers', 'Reg', (153, 161))	('BRCA1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('reduction in ovarian cancer', 'Disease', 'MESH:D010051', (44, 71))	('women', 'Species', '9606', (123, 128))	('reduction in ovarian cancer', 'Disease', (44, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('mutations', 'Var', (143, 152))
46600	27775259	Third, risk-reducing salpingo-oophorectomy (RRSO), the most proven method so far for the prevention of ovarian cancer in women with BRCA1 or BRCA2 mutation, was shown to have a 70%-85% reduction in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (198, 212))	('reduction in ovarian cancer', 'Disease', (185, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('reduction in ovarian cancer', 'Disease', 'MESH:D010051', (185, 212))	('mutation', 'Var', (147, 155))	('women', 'Species', '9606', (121, 126))	('BRCA2', 'Gene', '675', (141, 146))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BRCA1', 'Gene', '672', (132, 137))	('salpingo-oophorectomy', 'Disease', (21, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (198, 212))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('BRCA1', 'Gene', (132, 137))	('ovarian cancer', 'Disease', (103, 117))	('BRCA2', 'Gene', (141, 146))
46601	27775259	Because the cumulative incidence of ovarian cancer in BRCA1 mutation carrier is low under the age of 40 years but reaches more than 10% by the age of 50 years, all guidelines recommend RRSO be performed between 35 and 40 years.	('ovarian cancer', 'Disease', 'MESH:D010051', (36, 50))	('mutation', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('ovarian cancer', 'Disease', (36, 50))	('BRCA1', 'Gene', '672', (54, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('BRCA1', 'Gene', (54, 59))
46604	27775259	Lastly, by contrast of high-risk women, for average risk women, opportunistic salpingectomy at the time of elective pelvic surgeries including hysterectomy and as an alternative to other sterilization could theoretically reduce the incidence of type 2 ovarian cancer.	('type 2 ovarian cancer', 'Disease', (245, 266))	('hysterectomy', 'Disease', (143, 155))	('reduce', 'NegReg', (221, 227))	('type 2 ovarian cancer', 'Disease', 'MESH:D010051', (245, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('women', 'Species', '9606', (33, 38))	('women', 'Species', '9606', (57, 62))	('opportunistic', 'Var', (64, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (252, 266))
46628	27775259	Although the researchers did not detect recurrent point mutations that were actionable in recurrence samples, they found that at least four common molecular events were associated with acquired resistance: multiple independent reversions of germline BRCA1 or BRCA2 mutations, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1 in about 8% of HGSC relapse samples.	('BRCA1', 'Gene', (250, 255))	('mutations', 'Var', (265, 274))	('BRCA1', 'Gene', (284, 289))	('associated', 'Reg', (378, 388))	('BRCA2', 'Gene', (259, 264))	('loss', 'Var', (276, 280))	('overexpression', 'PosReg', (394, 408))	('promoter fusion', 'Var', (362, 377))	('MDR1', 'Gene', (433, 437))	('BRCA2', 'Gene', '675', (259, 264))	('MDR1', 'Gene', '5243', (433, 437))	('BRCA1', 'Gene', '672', (250, 255))	('BRCA1', 'Gene', '672', (284, 289))
46629	27775259	Gene breakage, which commonly inactivated tumor suppressor genes such as RB1, NF1, RAD51B, and PTEN, was also shown to contribute to acquired chemoresistance.	('acquired chemoresistance', 'CPA', (133, 157))	('RAD51B', 'Gene', '5890', (83, 89))	('tumor', 'Disease', (42, 47))	('RAD51B', 'Gene', (83, 89))	('RB1', 'Gene', (73, 76))	('contribute', 'Reg', (119, 129))	('RB1', 'Gene', '5925', (73, 76))	('NF1', 'Gene', (78, 81))	('Gene breakage', 'Var', (0, 13))	('PTEN', 'Gene', (95, 99))	('NF1', 'Gene', '4763', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('PTEN', 'Gene', '5728', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
46630	27775259	On the other hand, CCNE1 amplification was common in primary resistant and refractory disease.	('common', 'Reg', (43, 49))	('refractory disease', 'Disease', (75, 93))	('primary resistant', 'Disease', (53, 70))	('amplification', 'Var', (25, 38))	('CCNE1', 'Gene', '898', (19, 24))	('CCNE1', 'Gene', (19, 24))
46632	27775259	Another outstanding study of chemoresistance in HGSC identified a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) mutations as a possible predictor of chemosensitivity in ovarian cancer without BRCA1 or BRCA2 mutations.	('ovarian cancer', 'Disease', 'MESH:D010051', (193, 207))	('BRCA1', 'Gene', (216, 221))	('BRCA2', 'Gene', (225, 230))	('ovarian cancer', 'Disease', (193, 207))	('BRCA2', 'Gene', '675', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutations', 'Var', (136, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))	('BRCA1', 'Gene', '672', (216, 221))
46634	27775259	Moreover, ADAMTS mutations were associated with longer OS (HR, 0.54; 95% CI, 0.42 to 0.89; p=0.010) and PFS (HR, 0.42; 95% CI, 0.38 to 0.70; p<0.001).	('OS', 'Chemical', '-', (55, 57))	('longer OS', 'CPA', (48, 57))	('PFS', 'CPA', (104, 107))	('ADAMTS', 'Gene', (10, 16))	('mutations', 'Var', (17, 26))
46635	27775259	The associations remained the same with OS (HR, 0.53; 95% CI 0.32 to 0.87; p=0.010) and PFS (HR, 0.40; 95% CI, 0.25 to 0.62; p<0.001) even after adjustment by BRCA1 or BRCA2 mutation, surgical stage, residual tumor, and patient age.	('BRCA2', 'Gene', '675', (168, 173))	('tumor', 'Disease', (209, 214))	('mutation', 'Var', (174, 182))	('BRCA1', 'Gene', '672', (159, 164))	('patient', 'Species', '9606', (220, 227))	('OS', 'Chemical', '-', (40, 42))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('BRCA1', 'Gene', (159, 164))	('BRCA2', 'Gene', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
46636	27775259	These findings suggested that there were still more events other than ADAMTS or BRCA1/2 mutations that predicted better chemotherapy response because those mutations accounted for only 30% (10% and 20%, respectively) out of 70% of the clinical chemosensitivity rates.	('mutations', 'Var', (88, 97))	('BRCA1/2', 'Gene', (80, 87))	('BRCA1/2', 'Gene', '672;675', (80, 87))
46642	27775259	identified the relationship between ARID1A and EZH2 as the first potential effective target for the treatment of ovarian clear cell carcinoma, of which more than 50% ARID1A is mutated and loses genomic instability, and typically shows low response rate to platinum-based chemotherapy, in particular, in its late stages.	('genomic instability', 'MPA', (194, 213))	('EZH2', 'Gene', (47, 51))	('ovarian clear cell carcinoma', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('mutated', 'Var', (176, 183))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (113, 141))	('platinum', 'Chemical', 'MESH:D010984', (256, 264))	('ARID1A', 'Gene', '8289', (166, 172))	('ARID1A', 'Gene', '8289', (36, 42))	('ARID1A', 'Gene', (166, 172))	('EZH2', 'Gene', '2146', (47, 51))	('ARID1A', 'Gene', (36, 42))	('loses', 'NegReg', (188, 193))
46646	27775259	These findings were published in Nature Medicine for the promise of highly specific small molecule EZH2 inhibitors as a new paradigm for pharmacologically targeting ARID1A mutation in ovarian clear cell carcinoma.	('EZH2', 'Gene', '2146', (99, 103))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (184, 212))	('EZH2', 'Gene', (99, 103))	('ARID1A', 'Gene', '8289', (165, 171))	('ARID1A', 'Gene', (165, 171))	('mutation', 'Var', (172, 180))	('ovarian clear cell carcinoma', 'Disease', (184, 212))	('inhibitors', 'Var', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))
46660	27775259	First, MR. Mirza presented the subgroups for clinical trials in recurrent ovarian cancer in terms of multiple treatment lines, refractory, resistant, platinum-sensitive, asymptomatic CA125 elevation, prior use of antiangiogenic therapy, BRCA mutation, etc.	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BRCA', 'Gene', '672', (237, 241))	('CA125 elevation', 'Phenotype', 'HP:0031030', (183, 198))	('CA125', 'Gene', (183, 188))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('BRCA', 'Gene', (237, 241))	('elevation', 'PosReg', (189, 198))	('ovarian cancer', 'Disease', (74, 88))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (64, 88))	('platinum', 'Chemical', 'MESH:D010984', (150, 158))	('CA125', 'Gene', '94025', (183, 188))	('mutation', 'Var', (242, 250))
46691	27775259	Adverse events related to the injection site such as pain, swelling, and erythema were more common in 9vHPV vaccine group than qHPV vaccine group (90.7% vs. 84.9%) although most of these events were mild to moderate.	('erythema', 'Disease', (73, 81))	('swelling', 'Disease', (59, 67))	('qHPV', 'Chemical', '-', (127, 131))	('9vHPV', 'Chemical', '-', (102, 107))	('pain', 'Phenotype', 'HP:0012531', (53, 57))	('9vHPV vaccine', 'Var', (102, 115))	('pain', 'Disease', 'MESH:D010146', (53, 57))	('pain', 'Disease', (53, 57))	('erythema', 'Phenotype', 'HP:0010783', (73, 81))	('erythema', 'Disease', 'MESH:D004890', (73, 81))
46747	27775259	Clinical benefit rate was significantly higher in trabectedin group than that of dacarbazine group (34% vs. 19%, HR, 2.3; 95% CI, 1.45 to 3.70; p<0.001).	('higher', 'PosReg', (40, 46))	('dacarbazine', 'Chemical', 'MESH:D003606', (81, 92))	('trabectedin', 'Chemical', 'MESH:D000077606', (50, 61))	('trabectedin', 'Var', (50, 61))	('Clinical', 'MPA', (0, 8))
46752	27775259	Lynch syndrome is an autosomal dominant disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2, and EPCAM.	('PMS2', 'Gene', (144, 148))	('caused by', 'Reg', (49, 58))	('autosomal dominant disorder', 'Disease', (21, 48))	('MSH2', 'Gene', '4436', (132, 136))	('MSH6', 'Gene', (138, 142))	('EPCAM', 'Gene', (154, 159))	('germline mutation', 'Var', (61, 78))	('PMS2', 'Gene', '5395', (144, 148))	('MSH6', 'Gene', '2956', (138, 142))	('MLH1', 'Gene', '4292', (126, 130))	('MSH2', 'Gene', (132, 136))	('MLH1', 'Gene', (126, 130))	('Lynch syndrome', 'Disease', (0, 14))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (21, 48))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('EPCAM', 'Gene', '4072', (154, 159))
46755	27775259	reported the associations of endometrial cancer risk with hormonal factors in women with Lynch syndrome were similar to those in the general population, providing directions in counseling women with a MMR gene mutation with regard to hormonal influences on endometrial cancer risk.	('endometrial cancer', 'Disease', (257, 275))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('MMR', 'Gene', (201, 204))	('endometrial cancer', 'Phenotype', 'HP:0012114', (257, 275))	('endometrial cancer', 'Disease', (29, 47))	('women', 'Species', '9606', (78, 83))	('Lynch syndrome', 'Disease', 'MESH:D003123', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('endometrial cancer', 'Disease', 'MESH:D016889', (257, 275))	('mutation', 'Var', (210, 218))	('women', 'Species', '9606', (188, 193))	('Lynch syndrome', 'Disease', (89, 103))	('endometrial cancer', 'Phenotype', 'HP:0012114', (29, 47))	('endometrial cancer', 'Disease', 'MESH:D016889', (29, 47))
46756	27775259	This retrospective cohort study included 1,128 women with a MMR gene mutation from the Colon Cancer Family Registry across the United States, Australia, Canada, and New Zealand between 1997 and 2012.	('Colon Cancer', 'Phenotype', 'HP:0003003', (87, 99))	('Colon Cancer', 'Disease', 'MESH:D015179', (87, 99))	('Colon Cancer', 'Disease', (87, 99))	('women', 'Species', '9606', (47, 52))	('mutation', 'Var', (69, 77))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MMR gene', 'Gene', (60, 68))
46759	27775259	Later age at menarche >=13 years (vs. <13 years; HR per year 0.85; 95% CI, 0.73 to 0.99; p=0.04), multi-parity >=1 live births (vs. nulliparous; HR, 0.21; 95% CI, 0.10 to 0.42; p<0.001), and ever use of hormonal contraceptives >=1 years (vs. <1-year use; HR, 0.39; 95% CI, 0.23 to 0.64; p<0.001) were associated with a lower risk of endometrial cancer.	('multi-parity >=1', 'Var', (98, 114))	('endometrial cancer', 'Phenotype', 'HP:0012114', (333, 351))	('lower', 'NegReg', (319, 324))	('endometrial cancer', 'Disease', 'MESH:D016889', (333, 351))	('Later age at menarche', 'Phenotype', 'HP:0012569', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('endometrial cancer', 'Disease', (333, 351))
46764	27775259	A total of 1,002 tumors were analyzed for MSI, MLH1 methylation, and MMR protein expression, and then classified as normal MMR, defective MMR associated with MLH1 methylation (i.e., a sporadic epigenetic MMR defect), or probable MMR mutation (i.e., defective MMR but no methylation).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('MLH1', 'Gene', '4292', (47, 51))	('MLH1', 'Gene', (47, 51))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('MLH1', 'Gene', '4292', (158, 162))	('MMR', 'Gene', (229, 232))	('MLH1', 'Gene', (158, 162))	('mutation', 'Var', (233, 241))	('associated', 'Reg', (142, 152))	('methylation', 'Var', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
46767	27775259	On the other hand, germline mutation test results for forty-seven DNA samples from probands whose tumor MMR status was probable MMR mutation demonstrated nineteen (40.4%) germline mutations.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('mutation', 'Var', (132, 140))	('MMR', 'Gene', (128, 131))
46770	27775259	Another interesting finding of this study was that some Lynch mutations were found in patients with endometrial cancer diagnosed at age >60 years.	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('found', 'Reg', (77, 82))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (62, 71))	('patients', 'Species', '9606', (86, 94))
46771	27775259	Despite younger age at diagnosis of endometrial cancer of mutations carriers than non-carriers (54.3 years vs. 62.3 years; p<0.01), there were five carriers (0.94%) diagnosed at age >60 years, which represents 24% of Lynch cases presenting with endometrial cancer.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('endometrial cancer', 'Disease', (245, 263))	('endometrial cancer', 'Phenotype', 'HP:0012114', (245, 263))	('endometrial cancer', 'Disease', (36, 54))	('endometrial cancer', 'Phenotype', 'HP:0012114', (36, 54))	('endometrial cancer', 'Disease', 'MESH:D016889', (245, 263))	('endometrial cancer', 'Disease', 'MESH:D016889', (36, 54))
46773	27775259	Nevertheless, the authors concluded that these results from a large cohort of endometrioid endometrial cancer seemed to be enough to indicate that all women with endometrioid endometrial cancer including women diagnosed at age >60 years should undergo Lynch screening that included IHC, MLH1 methylation, and MSI tumor typing.	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (162, 193))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('women', 'Species', '9606', (204, 209))	('MSI tumor', 'Disease', (309, 318))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MLH1', 'Gene', '4292', (287, 291))	('endometrial cancer', 'Phenotype', 'HP:0012114', (175, 193))	('MLH1', 'Gene', (287, 291))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (78, 109))	('endometrioid endometrial cancer', 'Disease', (162, 193))	('methylation', 'Var', (292, 303))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('endometrioid endometrial cancer', 'Disease', (78, 109))	('MSI tumor', 'Disease', 'MESH:D009369', (309, 318))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('women', 'Species', '9606', (151, 156))
46812	27775259	tVEGF-A also revealed a potential predictive value for OS (>Q3 tVEGF-A HR, 0.62 [95% CI, 0.43 to 0.91]; <=Q3 tVEGF-A HR, 1.01 [95% CI, 0.82 to 1.25]; interaction p=0.023) when comparing CPB15+ with CPP group.	('CPB15+', 'Var', (186, 192))	('OS', 'Chemical', '-', (55, 57))	('VEGF', 'Gene', (1, 5))	('VEGF', 'Gene', '7422', (110, 114))	('VEGF', 'Gene', (64, 68))	('VEGF', 'Gene', '7422', (1, 5))	('VEGF', 'Gene', '7422', (64, 68))	('VEGF', 'Gene', (110, 114))
46824	27775259	demonstrated that macrophage-targeted treatment with CSF-1R inhibitors lessen the number of pro-tumor macrophages and allow the vessels in the abdomen to become normal again, easing ascites accumulation without any concern about fatal side effects.	('easing', 'PosReg', (175, 181))	('CSF-1R', 'Gene', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lessen', 'NegReg', (71, 77))	('ascites accumulation', 'Disease', (182, 202))	('inhibitors', 'Var', (60, 70))	('CSF-1R', 'Gene', '1436', (53, 59))	('tumor', 'Disease', (96, 101))	('ascites', 'Phenotype', 'HP:0001541', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('ascites accumulation', 'Disease', 'MESH:D001201', (182, 202))
46828	27775259	However, CSF-1R inhibition by GW2580, a selective CSF-1R inhibitor, was shown to reverse the abnormal vascular features and reduce vascular dysfunction and in this ID8 model as well as human OVCAR3 xenograft model.	('GW2580', 'Var', (30, 36))	('human', 'Species', '9606', (185, 190))	('CSF-1R', 'Gene', '1436', (9, 15))	('reduce', 'NegReg', (124, 130))	('ID8', 'Disease', (164, 167))	('CSF-1R', 'Gene', '1436', (50, 56))	('GW2580', 'Chemical', 'MESH:C506269', (30, 36))	('vascular dysfunction', 'Disease', 'MESH:D002561', (131, 151))	('reverse', 'NegReg', (81, 88))	('abnormal vascular features', 'Phenotype', 'HP:0025015', (93, 119))	('CSF-1R', 'Gene', (9, 15))	('vascular dysfunction', 'Disease', (131, 151))	('CSF-1R', 'Gene', (50, 56))
46834	27775259	While at least 50% of HGSC was reported to have homologous recombination deficiency (HRD), germline BRCA1 and BRCA2 mutations (gBRCAmut) account for up to one third of the patients.	('HGSC', 'Disease', (22, 26))	('BRCA', 'Gene', '672', (110, 114))	('BRCA2', 'Gene', (110, 115))	('BRCA', 'Gene', '672', (100, 104))	('BRCA1', 'Gene', '672', (100, 105))	('BRCA', 'Gene', (110, 114))	('BRCA', 'Gene', (100, 104))	('BRCA', 'Gene', (128, 132))	('deficiency', 'Disease', (73, 83))	('BRCA1', 'Gene', (100, 105))	('BRCA', 'Gene', '672', (128, 132))	('HRD', 'Disease', (85, 88))	('BRCA2', 'Gene', '675', (110, 115))	('mutations', 'Var', (116, 125))	('deficiency', 'Disease', 'MESH:D007153', (73, 83))	('patients', 'Species', '9606', (172, 180))	('HRD', 'Disease', 'None', (85, 88))
46839	27775259	There were only 15 (9%) BRCAwt tumors that had a loss-of-function mutation or homozygous deletion in a HR gene.	('BRCA', 'Gene', '672', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('BRCA', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('loss-of-function', 'NegReg', (49, 65))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutation', 'Var', (66, 74))
46845	27775259	On the basis of synthetic lethality of the combination of genotoxic drugs and Wee1 inhibitor AZD1775 in TP53-deficient cell, the researchers evaluated the efficacy of AZD1775 plus paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in women with TP53-mutant ovarian cancer.	('TP53', 'Gene', '7157', (104, 108))	('carboplatin', 'Chemical', 'MESH:D016190', (195, 206))	('TP53', 'Gene', (268, 272))	('AZD1775', 'Chemical', 'MESH:C549567', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('synthetic', 'Species', '32630', (16, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (280, 294))	('AZD1775', 'Gene', (93, 100))	('TP53', 'Gene', '7157', (268, 272))	('TP53', 'Gene', (104, 108))	('ovarian cancer', 'Disease', (280, 294))	('Wee1', 'Gene', (78, 82))	('carboplatin', 'Chemical', 'MESH:D016190', (236, 247))	('ovarian cancer', 'Phenotype', 'HP:0100615', (280, 294))	('AZD1775', 'Chemical', 'MESH:C549567', (167, 174))	('paclitaxel', 'Chemical', 'MESH:D017239', (180, 190))	('paclitaxel', 'Chemical', 'MESH:D017239', (221, 231))	('women', 'Species', '9606', (257, 262))	('Wee1', 'Gene', '7465', (78, 82))	('AZD1775', 'Var', (167, 174))
46846	27775259	A total of 121 patients with confirmed TP53 mutations were randomly assigned to receive either AZD1775 (225 mg bid) (n=59) or placebo (n=62) for 2.5 days plus paclitaxel (175 mg/m2) and carboplatin (AUC5) intravenously on day1 every three weeks until progression or the completion of six cycles.	('AZD1775', 'Chemical', 'MESH:C549567', (95, 102))	('patients', 'Species', '9606', (15, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (159, 169))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('AZD1775', 'Gene', (95, 102))	('carboplatin', 'Chemical', 'MESH:D016190', (186, 197))	('TP53', 'Gene', (39, 43))
46847	27775259	PFS was significantly longer in AZD1775 group than placebo group (enhanced RECIST: HR, 0.63; 80% CI, 0.45 to 0.89; 95% CI, 0.38 to 1.06; p=0.080; median PFS, 34.14 vs. 31.86 weeks; RECIST: HR, 0.55; 80% CI, 0.39 to 0.79; 95% CI, 0.32 to 0.95; p=0.030; median PFS, 42.86 vs. 34.86 weeks).	('PFS', 'MPA', (0, 3))	('RECIST', 'MPA', (75, 81))	('AZD1775', 'Var', (32, 39))	('enhanced', 'PosReg', (66, 74))	('AZD1775', 'Chemical', 'MESH:C549567', (32, 39))
46849	27775259	The study results suggest that the addition of AZD1775 to paclitaxel and carboplatin could lengthen the PFS compared with paclitaxel and carboplatin alone with acceptable tolerability in women with TP53-mutant ovarian cancer.	('carboplatin', 'Chemical', 'MESH:D016190', (137, 148))	('women', 'Species', '9606', (187, 192))	('AZD1775', 'Chemical', 'MESH:C549567', (47, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('TP53', 'Gene', '7157', (198, 202))	('carboplatin', 'Chemical', 'MESH:D016190', (73, 84))	('PFS', 'MPA', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('paclitaxel', 'Chemical', 'MESH:D017239', (122, 132))	('ovarian cancer', 'Disease', 'MESH:D010051', (210, 224))	('TP53', 'Gene', (198, 202))	('lengthen', 'PosReg', (91, 99))	('paclitaxel', 'Chemical', 'MESH:D017239', (58, 68))	('ovarian cancer', 'Disease', (210, 224))	('AZD1775', 'Var', (47, 54))
46861	27775259	Based on these results, although more severe toxicity profiles were reported in the addition of bevacizumab than chemotherapy alone, the authors concluded that the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life.	('incorporation', 'Var', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('toxicity', 'Disease', 'MESH:D064420', (45, 53))	('toxicity', 'Disease', (45, 53))	('cervical cancer', 'Disease', (224, 239))	('bevacizumab', 'Chemical', 'MESH:D000068258', (181, 192))	('bevacizumab', 'Chemical', 'MESH:D000068258', (96, 107))	('cervical cancer', 'Disease', 'MESH:D002583', (224, 239))
46865	27775259	The HRs of death for bevacizumab were 0.96 (95% CI, 0.51 to 1.83; p=0.909), 0.673 (95% CI, 0.50 to 0.91; p=0.0094), and 0.536 (95% CI, 0.320 to 0.905; p=0.0196) in low-, mid-, and high-risk patients, respectively.	('patients', 'Species', '9606', (190, 198))	('0.536', 'Var', (120, 125))	('bevacizumab', 'Chemical', 'MESH:D000068258', (21, 32))	('0.673', 'Var', (76, 81))
46869	27775259	Given one of the mechanisms underlying resistance to hormonal treatment in endometrial cancer is PI3K pathway activation, targeting mTOR may overcome the resistance, and therefore could improve the poor survival of recurrent or advanced endometrial cancer.	('endometrial cancer', 'Disease', (237, 255))	('mTOR', 'Gene', '2475', (132, 136))	('activation', 'PosReg', (110, 120))	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('mTOR', 'Gene', (132, 136))	('PI3K pathway', 'Pathway', (97, 109))	('targeting', 'Var', (122, 131))	('endometrial cancer', 'Disease', 'MESH:D016889', (237, 255))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('endometrial cancer', 'Phenotype', 'HP:0012114', (237, 255))	('endometrial cancer', 'Disease', (75, 93))	('poor', 'MPA', (198, 202))	('improve', 'PosReg', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))
46875	27775259	Endometrioid histology and CTNNB1 mutations were associated with better response, while serous histology were associated with lack of response.	('Endometrioid', 'Disease', (0, 12))	('CTNNB1', 'Gene', (27, 33))	('mutations', 'Var', (34, 43))	('CTNNB1', 'Gene', '1499', (27, 33))
46905	26980026	We reason that MMMTs with high grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage.	('HB-EGF', 'Gene', '1839', (80, 86))	('carcinomatous component', 'Disease', 'MESH:D055756', (37, 60))	('recurrence/metastasis', 'CPA', (100, 121))	('positivity', 'Var', (65, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('HB-EGF', 'Gene', (80, 86))	('carcinomatous component', 'Disease', (37, 60))	('prone', 'Reg', (91, 96))
46916	26980026	More and more evidence suggests that those tumors are of epithelial origin demonstrating epithelial-mesenchymal transition (EMT).. MMMT carries a poorer prognosis than other high grade endometrial carcinomas, especially for those with early stage diseases.	('endometrial carcinomas', 'Disease', 'MESH:D016889', (185, 207))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (185, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('MMMT', 'Var', (131, 135))	('endometrial carcinomas', 'Disease', (185, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (185, 207))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
46927	26980026	Loss of E-cadherin up-regulates integrin facilitating cell adhesion and spreading in ovarian cancer.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (85, 99))	('integrin', 'Protein', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ovarian cancer', 'Disease', (85, 99))	('spreading', 'CPA', (72, 81))	('up-regulates', 'PosReg', (19, 31))	('cell adhesion', 'CPA', (54, 67))	('Loss', 'Var', (0, 4))
46938	26980026	We hypothesize that MMMTs with high grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage.	('HB-EGF', 'Gene', (85, 91))	('positivity', 'Var', (70, 80))	('HB-EGF', 'Gene', '1839', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('recurrence/metastasis', 'CPA', (105, 126))	('carcinomatous component', 'Disease', 'MESH:D055756', (42, 65))	('carcinomatous component', 'Disease', (42, 65))	('prone', 'Reg', (96, 101))
46974	26980026	Compared to endometrioid carcinoma, serous carcinoma is more frequently associated with heterologous element in MMMT all stages combined (p=0.0227) (suppl Table 1).	('endometrioid carcinoma', 'Disease', (12, 34))	('serous carcinoma', 'Disease', (36, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('associated', 'Reg', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('heterologous element', 'Var', (88, 108))	('serous carcinoma', 'Disease', 'MESH:D018284', (36, 52))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (12, 34))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (12, 34))
46981	26980026	The explanatory analysis of relationship of these three biomarkers across the stages shows correlation coefficients of 0.5289, 0.1079 and 0.0845 for HB-EGF/ integrin- alpha5 (low significance), HB-EGF /EGFR(non-significant) and EGFR/integrin- alpha5 (non-significant) respectively (suppl Table 3).	('HB-EGF', 'Gene', '1839', (149, 155))	('EGFR', 'Gene', (202, 206))	('0.0845', 'Var', (138, 144))	('integrin- alpha5', 'Gene', (233, 249))	('HB-EGF', 'Gene', '1839', (194, 200))	('integrin- alpha5', 'Gene', (157, 173))	('integrin- alpha5', 'Gene', '3678', (157, 173))	('0.1079', 'Var', (127, 133))	('integrin- alpha5', 'Gene', '3678', (233, 249))	('EGFR', 'Gene', '1956', (228, 232))	('HB-EGF', 'Gene', (149, 155))	('HB-EGF', 'Gene', (194, 200))	('EGFR', 'Gene', (228, 232))	('EGFR', 'Gene', '1956', (202, 206))
47012	26980026	The immunohistochemistry used in our study demonstrates the presence of EGFR (phosphorylation or not, mutated or not), and does not directly indicate the function of EGFR.	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('EGFR', 'Gene', (72, 76))	('mutated', 'Var', (102, 109))
47018	26980026	TP53 mutation is identified as a frequent event in MMMT genome in a recent study.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
47208	24100443	There were six patients with less than 6 months of clinical and radiological follow-up: five patients succumbed to disseminated disease following PET/CT, and in one patient a solitary lung metastasis from STUMP/LMS was confirmed by histological analysis.	('patient', 'Species', '9606', (15, 22))	('patients', 'Species', '9606', (15, 23))	('disseminated disease', 'Disease', (115, 135))	('patient', 'Species', '9606', (165, 172))	('LMS', 'Phenotype', 'HP:0100243', (211, 214))	('patient', 'Species', '9606', (93, 100))	('PET/CT', 'Var', (146, 152))	('patients', 'Species', '9606', (93, 101))
47280	24002604	Median operative time was significantly longer in RH and mRH group compared with SH group.	('mRH', 'Chemical', '-', (57, 60))	('mRH', 'Var', (57, 60))	('longer', 'PosReg', (40, 46))
47434	20542546	Mutations of the p53 gene have been found in up to 90% of epithelial tumors that are grade 3 or papillary serous carcinoma but are absent in grade one type I tumors.	('type I tumors', 'Disease', 'MESH:D005776', (151, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('papillary serous carcinoma', 'Disease', 'MESH:D002291', (96, 122))	('type I tumors', 'Disease', (151, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('papillary serous carcinoma', 'Disease', (96, 122))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('found', 'Reg', (36, 41))	('Mutations', 'Var', (0, 9))	('epithelial tumors', 'Disease', (58, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('grade 3', 'Disease', (85, 92))	('p53', 'Gene', (17, 20))	('epithelial tumors', 'Disease', 'MESH:D002277', (58, 75))	('p53', 'Gene', '7157', (17, 20))
47435	20542546	The presence of p53 overexpression and high S phase fraction increases the risk of recurrence seven-fold, and the risk of cancer-related death almost 10-fold when compared to tumors with neither factor.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('high', 'Var', (39, 43))	('cancer', 'Disease', (122, 128))	('p53', 'Gene', (16, 19))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('overexpression', 'PosReg', (20, 34))	('p53', 'Gene', '7157', (16, 19))	('increases', 'PosReg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('recurrence', 'CPA', (83, 93))
47437	20542546	In contrast, PTEN, a tumor suppressor gene on chromosome 10, is often mutated or deleted and is associated with endometrioid histology and a favorable prognosis.	('associated with', 'Reg', (96, 111))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('endometrioid histology', 'Disease', (112, 134))	('tumor suppressor', 'Gene', (21, 37))	('tumor suppressor', 'Gene', '7248', (21, 37))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('deleted', 'Var', (81, 88))
47438	20542546	Other altered oncogene/tumor suppressor gene expression patterns have been demonstrated in endometrial cancer; MDR-1 and ER/PR positivity have been reported to be favorable prognostic factors, while microsatellite instability, HER2/neu receptor positivity, Ki 67, PCNA and EGF-R over-expression have been shown to carry an unfavorable prognosis.	('PCNA', 'Gene', '5111', (264, 268))	('EGF-R', 'Gene', '1956', (273, 278))	('endometrial cancer', 'Disease', 'MESH:D016889', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('positivity', 'Var', (127, 137))	('ER/PR', 'Gene', (121, 126))	('over-expression', 'PosReg', (279, 294))	('tumor suppressor', 'Gene', (23, 39))	('MDR-1', 'Gene', '5243', (111, 116))	('MDR-1', 'Gene', (111, 116))	('endometrial cancer', 'Disease', (91, 109))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('PCNA', 'Gene', (264, 268))	('EGF-R', 'Gene', (273, 278))	('tumor suppressor', 'Gene', '7248', (23, 39))	('HER2/neu receptor positivity, Ki 67', 'Gene', '2064', (227, 262))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('microsatellite instability', 'Var', (199, 225))
47443	20542546	Recent studies have shown that miRNAs are aberrantly expressed in virtually all human cancer types and that specific miRNAs misregulated in each cancer type may act as biomarkers of outcome for that cancer type.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR', 'Gene', '220972', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('miR', 'Gene', (31, 34))	('misregulated', 'Var', (124, 136))	('human', 'Species', '9606', (80, 85))	('miR', 'Gene', '220972', (117, 120))	('cancer', 'Disease', (199, 205))	('miR', 'Gene', (117, 120))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (86, 92))
47602	33182707	Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability Microsatellite instability (MSI) has been detected in multiple types of gynecologic cancers.	('MSI', 'Gene', '5928', (117, 120))	('MSI', 'Gene', (117, 120))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('Microsatellite instability', 'Disease', 'MESH:D053842', (89, 115))	('cancers', 'Disease', (173, 180))	('detected', 'Reg', (131, 139))	('Cancers', 'Disease', (14, 21))	('Microsatellite instability', 'Disease', (89, 115))	('Microsatellite', 'Var', (62, 76))	('Cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Deficient', 'NegReg', (32, 41))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancers', 'Disease', 'MESH:D009369', (14, 21))	('Mismatch', 'MPA', (42, 50))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
47603	33182707	MSI is linked to mutations in mismatch repair (MMR) genes that cause mismatch repair deficit (dMMR) in human cells.	('MSI', 'Gene', '5928', (0, 3))	('linked', 'Reg', (7, 13))	('human', 'Species', '9606', (103, 108))	('cause', 'Reg', (63, 68))	('MMR) genes', 'Gene', (47, 57))	('MSI', 'Gene', (0, 3))	('dMMR', 'Chemical', '-', (94, 98))	('mutations', 'Var', (17, 26))	('mismatch repair deficit', 'Disease', (69, 92))
47607	33182707	In this review, we summarize the MMR defects and MSI observed in gynecological cancers, and new therapeutic strategies to treat these cancers.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('MMR', 'Protein', (33, 36))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('defects', 'Var', (37, 44))	('MSI', 'Gene', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('MSI', 'Gene', '5928', (49, 52))
47608	33182707	Mutations in mismatch repair genes leading to mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) have been implicated in multiple types of gynecologic malignancies.	('MSI', 'Gene', (118, 121))	('mismatch repair genes', 'Gene', (13, 34))	('microsatellite instability', 'MPA', (90, 116))	('malignancies', 'Disease', (177, 189))	('MSI', 'Gene', '5928', (118, 121))	('implicated', 'Reg', (133, 143))	('Mutations', 'Var', (0, 9))	('malignancies', 'Disease', 'MESH:D009369', (177, 189))	('dMMR', 'Chemical', '-', (80, 84))	('leading to', 'Reg', (35, 45))
47612	33182707	However, in 5-10% of cases, MMR protein deficiency is due to a germline mutation in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM.	('MSH6', 'Gene', '2956', (122, 126))	('due', 'Reg', (54, 57))	('MSH2', 'Gene', (116, 120))	('MSH2', 'Gene', '4436', (116, 120))	('MMR protein deficiency', 'Disease', (28, 50))	('PMS2', 'Gene', (128, 132))	('EPCAM', 'Gene', (137, 142))	('MLH1', 'Gene', '4292', (110, 114))	('MLH1', 'Gene', (110, 114))	('PMS2', 'Gene', '5395', (128, 132))	('MMR protein deficiency', 'Disease', 'MESH:C536143', (28, 50))	('mutation', 'Var', (72, 80))	('MSH6', 'Gene', (122, 126))	('EPCAM', 'Gene', '4072', (137, 142))
47613	33182707	These germline mutations, known as Lynch syndrome, are associated with an increased risk of both endometrial and ovarian cancer, in addition to colorectal, gastric, urinary tract, and brain malignancies.	('endometrial and ovarian cancer', 'Disease', 'MESH:D004714', (97, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('Lynch syndrome', 'Disease', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('brain malignancies', 'Phenotype', 'HP:0030692', (184, 202))	('brain malignancies', 'Disease', (184, 202))	('associated', 'Reg', (55, 65))	('Lynch syndrome', 'Disease', 'MESH:D003123', (35, 49))	('germline mutations', 'Var', (6, 24))	('gastric', 'Disease', (156, 163))	('colorectal', 'Disease', (144, 154))	('brain malignancies', 'Disease', 'MESH:D009369', (184, 202))	('urinary tract', 'Disease', (165, 178))
47618	33182707	In this review, we summarize the MMR defects and MSI observed in gynecological cancers, their prognostic value, and advances in therapeutic strategies to treat these cancers.	('cancers', 'Disease', (79, 86))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MMR', 'Gene', (33, 36))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('defects', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('MSI', 'Gene', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('MSI', 'Gene', '5928', (49, 52))
47619	33182707	Mismatch repair (MMR) deficiency leading to microsatellite instability (MSI) and malignancy have been identified in over 20 cancer types, including gynecological cancers.	('MSI', 'Gene', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (124, 130))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('malignancy', 'Disease', (81, 91))	('leading to', 'Reg', (33, 43))	('cancer', 'Disease', (162, 168))	('cancers', 'Disease', (162, 169))	('MSI', 'Gene', '5928', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('microsatellite instability', 'MPA', (44, 70))	('MMR', 'Gene', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('identified', 'Reg', (102, 112))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('deficiency', 'Var', (22, 32))
47625	33182707	When these mutations occur within microsatellite regions causing deletion or expansions of the repetitive DNA sequences, this is referred to as MSI.	('MSI', 'Gene', '5928', (144, 147))	('mutations', 'Var', (11, 20))	('causing', 'Reg', (57, 64))	('MSI', 'Gene', (144, 147))	('deletion', 'Var', (65, 73))	('expansions', 'MPA', (77, 87))
47626	33182707	MSI is the consequence of an impaired MMR due to mutations in the MMR gene.	('mutations', 'Var', (49, 58))	('impaired', 'NegReg', (29, 37))	('MSI', 'Gene', (0, 3))	('MMR', 'MPA', (38, 41))	('MSI', 'Gene', '5928', (0, 3))	('MMR', 'Gene', (66, 69))
47627	33182707	MMR deficiencies can occur through either germline or somatic mutations.	('MMR deficiencies', 'Disease', (0, 16))	('occur', 'Reg', (21, 26))	('germline', 'Var', (42, 50))	('MMR deficiencies', 'Disease', 'MESH:C536928', (0, 16))	('somatic mutations', 'Var', (54, 71))
47628	33182707	A germline mutation of one of the inherited MMR genes (MLH1, MSH2, MSH6, or PMS2) or deletion of the stop codon of the EPCAM gene causes the autosomal dominant condition, Lynch syndrome (also called hereditary nonpolyposis colorectal cancer).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('hereditary nonpolyposis colorectal cancer', 'Disease', (199, 240))	('germline mutation', 'Var', (2, 19))	('EPCAM', 'Gene', (119, 124))	('Lynch syndrome', 'Disease', (171, 185))	('MLH1', 'Gene', '4292', (55, 59))	('deletion of', 'Var', (85, 96))	('autosomal dominant condition', 'Disease', (141, 169))	('PMS2', 'Gene', (76, 80))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (199, 240))	('Lynch syndrome', 'Disease', 'MESH:D003123', (171, 185))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (199, 240))	('MSH2', 'Gene', (61, 65))	('MSH6', 'Gene', (67, 71))	('EPCAM', 'Gene', '4072', (119, 124))	('MSH6', 'Gene', '2956', (67, 71))	('causes', 'Reg', (130, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('MSH2', 'Gene', '4436', (61, 65))	('MLH1', 'Gene', (55, 59))	('PMS2', 'Gene', '5395', (76, 80))
47629	33182707	This includes hypermethylation of the MLH1 promoter, epigenetic inactivation of MSH2, or downregulation of MMR genes by microRNAs.	('hypermethylation', 'Var', (14, 30))	('downregulation', 'NegReg', (89, 103))	('MLH1', 'Gene', '4292', (38, 42))	('MLH1', 'Gene', (38, 42))	('MMR genes', 'Gene', (107, 116))	('epigenetic inactivation', 'Var', (53, 76))	('MSH2', 'Gene', (80, 84))	('MSH2', 'Gene', '4436', (80, 84))
47630	33182707	Sporadic MMR deficiency (dMMR)/MSI is most commonly due to hypermethylation of the MLH1 promoter region.	('MSI', 'Gene', '5928', (31, 34))	('hypermethylation', 'Var', (59, 75))	('Sporadic MMR deficiency', 'Disease', 'MESH:C536928', (0, 23))	('due to', 'Reg', (52, 58))	('dMMR', 'Chemical', '-', (25, 29))	('MLH1', 'Gene', '4292', (83, 87))	('MLH1', 'Gene', (83, 87))	('MSI', 'Gene', (31, 34))	('Sporadic MMR deficiency', 'Disease', (0, 23))
47631	33182707	Cancer development due to dMMR/MSI is triggered by mutations in genes that contain microsatellites and are important for tumor suppression, such as TGFbeta RII, IGFIIR, BAX, hMSH6, and hMSH3 genes.	('mutations', 'Var', (51, 60))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('MSI', 'Gene', (31, 34))	('MSI', 'Gene', '5928', (31, 34))	('microsatellites', 'Var', (83, 98))	('tumor', 'Disease', (121, 126))	('TGFbeta RII', 'Gene', (148, 159))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('hMSH3', 'Gene', '4437', (185, 190))	('triggered', 'Reg', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('hMSH6', 'Gene', (174, 179))	('hMSH3', 'Gene', (185, 190))	('dMMR', 'Chemical', '-', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('TGFbeta RII', 'Gene', '7048', (148, 159))	('Cancer', 'Disease', (0, 6))	('BAX', 'Gene', (169, 172))	('BAX', 'Gene', '581', (169, 172))	('hMSH6', 'Gene', '2956', (174, 179))
47633	33182707	It has been demonstrated that MMR deficient gynecological cancer cells also accumulate mutations in repeat sequences of cell growth, pro-apoptotic, cell regulatory, DNA repair, and oncogenes.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations in repeat sequences', 'Var', (87, 116))	('MMR deficient', 'Disease', 'MESH:C536928', (30, 43))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('MMR deficient', 'Disease', (30, 43))	('cell growth', 'Gene', (120, 131))
47637	33182707	Dinucleotide repeats that are inverted (e.g., (AT)n and (CG)n) are able to form cruciform and hairpin structures.	('Dinucleotide repeats', 'Var', (0, 20))	('Dinucleotide', 'Chemical', 'MESH:D015226', (0, 12))	('form', 'Reg', (75, 79))
47638	33182707	Trinucleotide repeats are observed to adopt hairpin, triplex, or quadruplex structures, depending upon the type of DNA sequence.	('Trinucleotide repeats', 'Var', (0, 21))	('triplex', 'MPA', (53, 60))	('hairpin', 'MPA', (44, 51))	('adopt', 'Reg', (38, 43))	('quadruplex structures', 'CPA', (65, 86))	('Trinucleotide', 'Chemical', '-', (0, 13))
47641	33182707	Trinucleotide alleles are approximately three-fold less abundant than di- and tetranucleotide repeats.	('di- and tetranucleotide', 'Chemical', '-', (70, 93))	('Trinucleotide', 'Var', (0, 13))	('less', 'NegReg', (51, 55))	('Trinucleotide', 'Chemical', '-', (0, 13))
47642	33182707	DNA replication was observed to stall within mono-, di-, tri-, and tetranucleotide microsatellites and the severity was dependent upon the sequence composition of the microsatellites.	('DNA replication', 'CPA', (0, 15))	('tetranucleotide microsatellites', 'Disease', (67, 98))	('tetranucleotide microsatellites', 'Disease', 'MESH:D053842', (67, 98))	('tri-', 'Var', (57, 61))	('mono-', 'Var', (45, 50))
47643	33182707	For instance, Hile and Eckert reported that DNA polymerase kappa was stalled due to triplex DNA formation, which led to interrupted mutations within mononucleotide microsatellites.	('DNA polymerase kappa', 'Gene', '51426', (44, 64))	('mutations', 'Var', (132, 141))	('DNA polymerase kappa', 'Gene', (44, 64))	('mononucleotide', 'Chemical', '-', (149, 163))
47647	33182707	Some tumor suppressors, pro-apoptotic genes, and oncogenes contain microsatellites and MSI at these genomic regions is associated with several types of cancers (Table 1 and Table 2).	('cancers', 'Disease', (152, 159))	('MSI', 'Gene', '5928', (87, 90))	('associated with', 'Reg', (119, 134))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('microsatellites', 'Var', (67, 82))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MSI', 'Gene', (87, 90))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
47648	33182707	For example, mutations in short palindromic sequences were observed in the p53 gene in 21% of patients with ovarian cancer.	('ovarian cancer', 'Disease', (108, 122))	('patients', 'Species', '9606', (94, 102))	('mutations in short palindromic sequences', 'Var', (13, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('observed', 'Reg', (59, 67))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))
47649	33182707	DNA deletions and insertions in the p53 genes were attributable to each of the following mechanisms: Mononucleotide runs, repeats of short tandem sequences, palindromes (inverted repeats of dyad symmetry), and runs of four or more purines or pyrimidines.	('Mononucleotide', 'Chemical', '-', (101, 115))	('Mononucleotide runs', 'Var', (101, 120))	('p53', 'Gene', (36, 39))	('pyrimidines', 'Chemical', 'MESH:D011743', (242, 253))	('purines', 'Chemical', 'MESH:D011687', (231, 238))	('p53', 'Gene', '7157', (36, 39))	('repeats', 'Var', (122, 129))	('runs of', 'Var', (210, 217))	('insertions', 'Var', (18, 28))	('palindromes', 'Var', (157, 168))
47650	33182707	The most common DNA sequence motifs seen at the site of deletions or insertions were runs of two to five consecutive mononucleotides.	('insertions', 'Var', (69, 79))	('deletions', 'Var', (56, 65))	('mononucleotides', 'Chemical', '-', (117, 132))
47653	33182707	Alterations in the DNA sequence at the c-myc gene are reported to be associated with the development of uterine cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Alterations', 'Var', (0, 11))	('associated with', 'Reg', (69, 84))	('c-myc', 'Gene', '4609', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('c-myc', 'Gene', (39, 44))	('cancer', 'Disease', (121, 127))
47655	33182707	In addition, the presence of CAG repeats in the androgen receptor (AR) gene was observed to increase the risk of ovarian cancer in the African American group.	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('AR', 'Gene', '367', (67, 69))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('androgen receptor', 'Gene', '367', (48, 65))	('increase', 'PosReg', (92, 100))	('ovarian cancer', 'Disease', (113, 127))	('presence', 'Var', (17, 25))	('CAG repeats', 'Var', (29, 40))	('androgen receptor', 'Gene', (48, 65))
47656	33182707	Another example is the pro-apoptotic Bax gene that contains a tract of eight consecutive (G)8, and frameshift mutations in the (G)8 mononucleotide repeat are common in endometrial carcinomas with MSI.	('MSI', 'Gene', '5928', (196, 199))	('G', 'Gene', (128, 129))	('Bax', 'Gene', (37, 40))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (168, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('MSI', 'Gene', (196, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (168, 190))	('endometrial carcinomas', 'Disease', (168, 190))	('common', 'Reg', (158, 164))	('Bax', 'Gene', '581', (37, 40))	('mononucleotide', 'Chemical', '-', (132, 146))	('frameshift mutations', 'Var', (99, 119))
47657	33182707	It was suggested that BAX frameshift mutations play a key role in the process of tumor progression.	('frameshift mutations', 'Var', (26, 46))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('BAX', 'Gene', (22, 25))	('tumor', 'Disease', (81, 86))	('BAX', 'Gene', '581', (22, 25))
47658	33182707	TGFbeta RII is reported to harbor a poly(A) tract at codons 125-128 of its open reading frame, which is prone to slippage-related frameshift mutations.	('TGFbeta RII', 'Gene', (0, 11))	('poly(A) tract', 'Var', (36, 49))	('TGFbeta RII', 'Gene', '7048', (0, 11))
47660	33182707	Similarly, a study on endometrial cancer with MSI reported a higher frequency of mutations in the PTEN gene.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('MSI', 'Gene', (46, 49))	('MSI', 'Gene', '5928', (46, 49))	('endometrial cancer', 'Disease', (22, 40))	('PTEN', 'Gene', (98, 102))	('mutations', 'Var', (81, 90))	('PTEN', 'Gene', '5728', (98, 102))	('endometrial cancer', 'Phenotype', 'HP:0012114', (22, 40))	('endometrial cancer', 'Disease', 'MESH:D016889', (22, 40))
47661	33182707	It has been shown that PTEN gene inactivation, mainly due to mutations, plays a pivotal role in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (61, 70))	('PTEN', 'Gene', (23, 27))	('PTEN', 'Gene', '5728', (23, 27))	('inactivation', 'NegReg', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
47662	33182707	studied mononucleotide microsatellites in genes involved in DSB repair and their role in endometrial cancer with MSI.	('mononucleotide', 'Chemical', '-', (8, 22))	('endometrial cancer', 'Disease', 'MESH:D016889', (89, 107))	('endometrial cancer', 'Phenotype', 'HP:0012114', (89, 107))	('MSI', 'Gene', (113, 116))	('MSI', 'Gene', '5928', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mononucleotide microsatellites', 'Var', (8, 38))	('endometrial cancer', 'Disease', (89, 107))
47663	33182707	They found mutations in several DSB repair genes, such as RAD50, MRE11, ATR, BRCA1, CtIP, and MCPH1 suggesting that mutations in multiple genes of the DSB repair pathway are mutated in endometrial cancer with MSI.	('BRCA1', 'Gene', (77, 82))	('mutations', 'Var', (11, 20))	('RAD50', 'Gene', (58, 63))	('ATR', 'Gene', (72, 75))	('RAD50', 'Gene', '10111', (58, 63))	('MCPH1', 'Gene', (94, 99))	('CtIP', 'Gene', '5932', (84, 88))	('MRE11', 'Gene', (65, 70))	('endometrial cancer', 'Phenotype', 'HP:0012114', (185, 203))	('MSI', 'Gene', (209, 212))	('mutations', 'Var', (116, 125))	('CtIP', 'Gene', (84, 88))	('MSI', 'Gene', '5928', (209, 212))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ATR', 'Gene', '545', (72, 75))	('MRE11', 'Gene', '4361', (65, 70))	('endometrial cancer', 'Disease', (185, 203))	('endometrial cancer', 'Disease', 'MESH:D016889', (185, 203))	('MCPH1', 'Gene', '79648', (94, 99))	('BRCA1', 'Gene', '672', (77, 82))	('mutated', 'Var', (174, 181))
47664	33182707	This pathway is conserved from bacteria to humans and targets base substitution mismatches and insertion-deletion mismatches (IDLs).	('base substitution mismatches', 'Var', (62, 90))	('humans', 'Species', '9606', (43, 49))	('insertion-deletion mismatches', 'Var', (95, 124))
47667	33182707	The MutS-alpha is formed by MSH2/MSH6 which recognizes single base mismatches and short insertion-deletion loops, while MutS-beta is formed by MSH2/MSH3 which recognizes IDLs greater than two bases.	('MSH2', 'Gene', (143, 147))	('insertion-deletion loops', 'Var', (88, 112))	('MSH3', 'Gene', '4437', (148, 152))	('MSH2', 'Gene', '4436', (143, 147))	('MSH6', 'Gene', (33, 37))	('MSH2', 'Gene', (28, 32))	('single', 'Var', (55, 61))	('MSH2', 'Gene', '4436', (28, 32))	('MSH3', 'Gene', (148, 152))	('MSH6', 'Gene', '2956', (33, 37))
47672	33182707	Impaired MMR repair due to inherited or spontaneous mutations can give rise to mutations, in particular at microsatellite repeat sequences, causing MSI (Figure 2).	('mutations', 'Var', (52, 61))	('MSI', 'Gene', (148, 151))	('microsatellite', 'Gene', (107, 121))	('MSI', 'Gene', '5928', (148, 151))	('mutations', 'Var', (79, 88))
47674	33182707	Individuals with a germline mutation in the MMR genes have an increased risk of carcinogenesis, for example such as patients with Lynch syndrome.	('germline mutation', 'Var', (19, 36))	('patients', 'Species', '9606', (116, 124))	('Lynch syndrome', 'Disease', (130, 144))	('MMR', 'Gene', (44, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('Lynch syndrome', 'Disease', 'MESH:D003123', (130, 144))	('carcinogenesis', 'Disease', (80, 94))
47675	33182707	The loss of the second allele (loss of heterozygosity (LOH)) due to somatic mutation or epigenetic events further exacerbates the cell dysfunction and leads to tumorigenesis.	('leads to', 'Reg', (151, 159))	('cell dysfunction', 'CPA', (130, 146))	('epigenetic events', 'Var', (88, 105))	('exacerbates', 'PosReg', (114, 125))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))
47676	33182707	However, it was reported that in some instances, MMR genes may exhibit haploinsufficiency within a single allele that is sufficient enough to initiate tumorigenesis depending on mutation and affected MMR gene.	('MMR genes', 'Gene', (49, 58))	('initiate', 'Reg', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('MMR', 'Gene', (200, 203))	('tumor', 'Disease', (151, 156))	('mutation', 'Var', (178, 186))	('haploinsufficiency', 'Disease', (71, 89))	('haploinsufficiency', 'Disease', 'MESH:D058495', (71, 89))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
47677	33182707	Epigenetic alterations such as DNA methylation of the MLH1 is also reported to cause inactivation of MMR system and trigger cancer development.	('trigger', 'PosReg', (116, 123))	('DNA methylation', 'Var', (31, 46))	('cancer', 'Disease', (124, 130))	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('MMR system', 'Pathway', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('inactivation', 'MPA', (85, 97))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
47678	33182707	It was reported that 77% of sporadic endometrial cancers had MSI due to methylated MLH1 promoter.	('endometrial cancers', 'Disease', 'MESH:D016889', (37, 56))	('endometrial cancers', 'Disease', (37, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('methylated', 'Var', (72, 82))	('MLH1', 'Gene', '4292', (83, 87))	('MSI', 'Gene', '5928', (61, 64))	('MSI', 'Gene', (61, 64))	('MLH1', 'Gene', (83, 87))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))
47679	33182707	In addition, mutations in MMR genes are the second highest cause of hereditary ovarian cancer, accounting for 10-15% of hereditary ovarian cancer cases.	('hereditary ovarian cancer', 'Disease', (120, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MMR', 'Gene', (26, 29))	('cause', 'Reg', (59, 64))	('hereditary ovarian cancer', 'Disease', 'MESH:D010051', (68, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('hereditary ovarian cancer', 'Disease', 'MESH:D010051', (120, 145))	('mutations', 'Var', (13, 22))	('hereditary ovarian cancer', 'Disease', (68, 93))
47680	33182707	This includes mutation in the MLH1 or MSH2 gene.	('MLH1', 'Gene', '4292', (30, 34))	('MSH2', 'Gene', (38, 42))	('MSH2', 'Gene', '4436', (38, 42))	('MLH1', 'Gene', (30, 34))	('mutation', 'Var', (14, 22))
47681	33182707	A 2006 study reported that Lynch syndrome patients with MSH6 mutation had a 33% lifetime risk of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('Lynch syndrome', 'Disease', 'MESH:D003123', (27, 41))	('ovarian cancer', 'Disease', (97, 111))	('MSH6', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('MSH6', 'Gene', '2956', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('patients', 'Species', '9606', (42, 50))	('Lynch syndrome', 'Disease', (27, 41))
47682	33182707	A recent study of Lynch syndrome patients, using multigene panel observed that out of the 528 patients with MMR mutations, 11.9% had breast cancer and 27.3% had colorectal cancer, with MSH6 and PMS2 mutations more frequent than MLH1 and MSH2 mutations.	('PMS2', 'Gene', '5395', (194, 198))	('colorectal cancer', 'Disease', (161, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('mutations', 'Var', (112, 121))	('Lynch syndrome', 'Disease', 'MESH:D003123', (18, 32))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('MLH1', 'Gene', (228, 232))	('breast cancer', 'Disease', (133, 146))	('MMR', 'Gene', (108, 111))	('patients', 'Species', '9606', (94, 102))	('MSH2', 'Gene', (237, 241))	('PMS2', 'Gene', (194, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('MLH1', 'Gene', '4292', (228, 232))	('MSH2', 'Gene', '4436', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('MSH6', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('patients', 'Species', '9606', (33, 41))	('Lynch syndrome', 'Disease', (18, 32))	('MSH6', 'Gene', '2956', (185, 189))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))
47685	33182707	It has been observed that mutation in MSH6 and PMS2 increases the risk of breast cancer by 30% and 35%, respectively, irrespective of other personal cancer history.	('MSH6', 'Gene', (38, 42))	('PMS2', 'Gene', '5395', (47, 51))	('breast cancer', 'Disease', (74, 87))	('cancer', 'Disease', (149, 155))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('mutation', 'Var', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('increases', 'PosReg', (52, 61))	('MSH6', 'Gene', '2956', (38, 42))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PMS2', 'Gene', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
47687	33182707	Currently, MSI are mainly detected by PCR of microsatellite regions.	('microsatellite', 'Var', (45, 59))	('MSI', 'Gene', '5928', (11, 14))	('MSI', 'Gene', (11, 14))
47691	33182707	This marker panel, also known as Bethesda panel, consists of two mononucleotide markers (BAT25 and BAT26) and three dinucleotide markers (D2S123, D5S346 and D17S250).	('D2S123', 'Var', (138, 144))	('D5S346', 'Var', (146, 152))	('D17S250', 'Var', (157, 164))	('mononucleotide', 'Chemical', '-', (65, 79))	('BAT25', 'Var', (89, 94))	('BAT26', 'Var', (99, 104))
47697	33182707	They observed that instability of mononucleotide markers was less frequent than dinucleotide markers in ovarian cancer, which was reverse in comparison to colorectal cancer.	('ovarian cancer', 'Disease', (104, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('mononucleotide', 'Chemical', '-', (34, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('instability', 'MPA', (19, 30))	('less', 'NegReg', (61, 65))	('mononucleotide markers', 'Var', (34, 56))	('colorectal cancer', 'Disease', (155, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
47715	33182707	It seems that markers containing mono- and dinucleotide repeats are more frequently used for gynecological cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mono- and dinucleotide', 'Chemical', '-', (33, 55))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('dinucleotide repeats', 'Var', (43, 63))	('mono-', 'Var', (33, 38))
47716	33182707	In addition, target genes with poly(A) and poly(T) repeats are more frequently affected in gynecological cancers (Table 1 and Table 2).	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('affected', 'Reg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('poly(T) repeats', 'Var', (43, 58))	('poly(A', 'Var', (31, 37))
47718	33182707	In addition, recent studies have shown that depending upon cancer type MSI tumors are more prone to exhibit mutations in specific genes (Figure 2).	('cancer type MSI tumors', 'Disease', 'MESH:D009369', (59, 81))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('cancer type MSI tumors', 'Disease', (59, 81))
47721	33182707	A defective MMR system leaves replication defects behind causing MSI.	('MMR system', 'Gene', (12, 22))	('replication defects', 'MPA', (30, 49))	('defective', 'Var', (2, 11))	('causing', 'Reg', (57, 64))	('MSI', 'Gene', '5928', (65, 68))	('MSI', 'Gene', (65, 68))
47724	33182707	Various genes with microsatellites are observed to have mutations as a result of dMMR/MSI and are believed to be the cancer drivers (Figure 2).	('MSI', 'Gene', '5928', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('dMMR', 'Chemical', '-', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('microsatellites', 'Var', (19, 34))	('MSI', 'Gene', (86, 89))	('mutations', 'Reg', (56, 65))
47725	33182707	For example, microsatellites are present in many regulatory genes, tumor suppressor, pro-apoptotic, and oncogenes, which makes these genes vulnerable to mutations (Table 2).	('microsatellites', 'Var', (13, 28))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
47726	33182707	Kawaguchi and colleagues proposed, upon analysis of mutations in 22 patients with sporadic MSI-H endometrial cancer, a novel cascade etiology of carcinogenesis wherein genes affected by MSI could increase in genomic instability and trigger mutagenesis of additional target genes.	('mutations', 'Var', (52, 61))	('genomic instability', 'MPA', (208, 227))	('MSI', 'Gene', (186, 189))	('H endometrial cancer', 'Phenotype', 'HP:0012114', (95, 115))	('mutagenesis', 'MPA', (240, 251))	('MSI-H endometrial cancer', 'Disease', (91, 115))	('increase', 'PosReg', (196, 204))	('MSI', 'Gene', (91, 94))	('MSI', 'Gene', '5928', (91, 94))	('MSI', 'Gene', '5928', (186, 189))	('patients', 'Species', '9606', (68, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (145, 159))	('MSI-H endometrial cancer', 'Disease', 'MESH:D016889', (91, 115))	('endometrial cancer', 'Phenotype', 'HP:0012114', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('carcinogenesis', 'Disease', (145, 159))	('trigger', 'Reg', (232, 239))
47727	33182707	This causes an accumulation of mutations and deficiencies of other cancer-related genes.	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('deficiencies of other cancer', 'Disease', 'MESH:D009369', (45, 73))	('deficiencies of other cancer', 'Disease', (45, 73))	('accumulation', 'PosReg', (15, 27))
47732	33182707	On the other hand, 40% of endometrial cancers patients show mutations in JAKI gene as compared colorectal cancer patients (less than 10%).	('endometrial cancers', 'Disease', 'MESH:D016889', (26, 45))	('patients', 'Species', '9606', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Disease', (95, 112))	('endometrial cancers', 'Disease', (26, 45))	('patients', 'Species', '9606', (113, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('mutations', 'Var', (60, 69))	('endometrial cancer', 'Phenotype', 'HP:0012114', (26, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('JAKI', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
47733	33182707	observed that the RPL22 gene was frequently mutated in MSI endometroid cases (50%) in contrast to TP53 gene, which was mutated in 40% of microsatellite stable (MSS) endometroid tumors.	('MSI', 'Gene', '5928', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('mutated', 'Var', (44, 51))	('RPL22', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('TP53', 'Gene', '7157', (98, 102))	('tumors', 'Disease', (177, 183))	('MSI', 'Gene', (55, 58))	('RPL22', 'Gene', '6146', (18, 23))	('TP53', 'Gene', (98, 102))
47739	33182707	JAK1 mutations are also observed in cervical cancer cases caused by MSI.	('caused', 'Reg', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('observed', 'Reg', (24, 32))	('mutations', 'Var', (5, 14))	('MSI', 'Gene', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('JAK1', 'Gene', (0, 4))	('JAK1', 'Gene', '3716', (0, 4))	('MSI', 'Gene', '5928', (68, 71))	('cancer', 'Disease', (45, 51))
47742	33182707	In summary, carcinogenesis in dMMR/MSI tumors can be explained as a cascade wherein mutations in MMR and subsequent MSI leads to mutagenesis of other regulatory genes, oncogenes, tumor-suppressor genes, and pro-apoptotic genes that can trigger oncogenesis (Figure 2).	('MSI tumors', 'Disease', 'MESH:D009369', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('leads to', 'Reg', (120, 128))	('carcinogenesis', 'Disease', (12, 26))	('dMMR', 'Chemical', '-', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('carcinogenesis', 'Disease', 'MESH:D063646', (12, 26))	('MSI tumors', 'Disease', (35, 45))	('mutations', 'Var', (84, 93))	('MSI', 'Gene', (116, 119))	('tumor', 'Disease', (39, 44))	('MSI', 'Gene', '5928', (116, 119))	('MSI', 'Gene', (35, 38))	('mutagenesis', 'Var', (129, 140))	('MSI', 'Gene', '5928', (35, 38))	('MMR', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (179, 184))
47764	33182707	Among all patients who present with endometrial cancer, the presence of MSI due to a somatic mutation does not appear to affect overall survival with the use of conventional treatment modalities.	('MSI', 'Gene', (72, 75))	('MSI', 'Gene', '5928', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('presence', 'Var', (60, 68))	('endometrial cancer', 'Disease', (36, 54))	('patients', 'Species', '9606', (10, 18))	('endometrial cancer', 'Phenotype', 'HP:0012114', (36, 54))	('endometrial cancer', 'Disease', 'MESH:D016889', (36, 54))
47765	33182707	Yet, there is evidence that survival is improved in early stage tumors with high levels of MSI that are treated with adjuvant radiotherapy.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('MSI', 'Gene', '5928', (91, 94))	('MSI', 'Gene', (91, 94))	('survival', 'CPA', (28, 36))	('improved', 'PosReg', (40, 48))	('high', 'Var', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
47767	33182707	There is a great importance to identify MMR deficient tumors due to germline mutations, rather than somatic mutations alone.	('MMR deficient', 'Disease', 'MESH:C536928', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('germline mutations', 'Var', (68, 86))	('MMR deficient', 'Disease', (40, 53))	('deficient tumors', 'Disease', (44, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('deficient tumors', 'Disease', 'MESH:D009369', (44, 60))
47768	33182707	Patients with a germline mutation of a MMR gene have an increased lifetime risk of several malignancies due to MSI.	('malignancies', 'Disease', (91, 103))	('MSI', 'Gene', '5928', (111, 114))	('MSI', 'Gene', (111, 114))	('germline mutation', 'Var', (16, 33))	('Patients', 'Species', '9606', (0, 8))	('MMR', 'Gene', (39, 42))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))
47770	33182707	There is a cumulative risk for any cancer at age 70 as low as 18% for patients with PMS2 mutations and as high as 72% for both patients with a MLH1 mutation or MSH2 mutation.	('patients', 'Species', '9606', (70, 78))	('MLH1', 'Gene', '4292', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('MLH1', 'Gene', (143, 147))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (89, 98))	('PMS2', 'Gene', (84, 88))	('MSH2', 'Gene', (160, 164))	('MSH2', 'Gene', '4436', (160, 164))	('PMS2', 'Gene', '5395', (84, 88))	('cancer', 'Disease', (35, 41))
47792	33182707	The sequence of events which leads to the presence of these biomarkers in MMR deficiency cancers is caused by the uncorrected mutations that occur when MMR proteins are deficient, which can lead a high tumor mutational burden.	('tumor', 'Disease', (202, 207))	('caused', 'Reg', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('MMR deficiency cancers', 'Disease', 'MESH:C536928', (74, 96))	('MMR deficiency cancers', 'Disease', (74, 96))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('mutations', 'Var', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('deficient', 'NegReg', (169, 178))	('lead', 'Reg', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
47794	33182707	While MMR deficiency can lead to malignancies in many different types of tissue, among gynecologic malignancies that are known to occur due to this mutation, endometrial cancer is the most common and the most likely to be tested for MSI.	('endometrial cancer', 'Disease', 'MESH:D016889', (158, 176))	('MSI', 'Gene', '5928', (233, 236))	('malignancies', 'Disease', (33, 45))	('endometrial cancer', 'Phenotype', 'HP:0012114', (158, 176))	('malignancies', 'Disease', (99, 111))	('malignancies', 'Disease', 'MESH:D009369', (33, 45))	('lead to', 'Reg', (25, 32))	('MMR deficiency', 'Disease', 'MESH:C536928', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('MSI', 'Gene', (233, 236))	('MMR deficiency', 'Disease', (6, 20))	('endometrial cancer', 'Disease', (158, 176))	('mutation', 'Var', (148, 156))	('malignancies', 'Disease', 'MESH:D009369', (99, 111))
47810	33182707	This makes genes containing microsatellites susceptible for genomic instability and has been proposed as an early step in carcinogenesis.	('microsatellites', 'Var', (28, 43))	('carcinogenesis', 'Disease', (122, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))
47811	33182707	In patients with Lynch syndrome inherited genetic and/or epigenetic mechanisms are responsible for the loss of MMR gene expression and MSI.	('MSI', 'Gene', (135, 138))	('expression', 'MPA', (120, 130))	('MSI', 'Gene', '5928', (135, 138))	('epigenetic', 'Var', (57, 67))	('patients', 'Species', '9606', (3, 11))	('MMR gene', 'Gene', (111, 119))	('Lynch syndrome inherited genetic', 'Disease', 'MESH:D030342', (17, 49))	('Lynch syndrome inherited genetic', 'Disease', (17, 49))	('loss', 'NegReg', (103, 107))
47812	33182707	Microsatellites are present in many regulatory, pro-apoptotic, and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Microsatellites', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
47813	33182707	Thus, MSI can lead to genomic instability and mutations for example in genes important for DNA damage repair and regulation of cell growth.	('mutations', 'Var', (46, 55))	('MSI', 'Gene', (6, 9))	('lead to', 'Reg', (14, 21))	('genomic', 'MPA', (22, 29))	('MSI', 'Gene', '5928', (6, 9))
47841	32397158	In addition to obesity, a number of factors have been attributed to an increased likelihood of developing EC, including but not limited to; advancing age, late onset menopause, lower age of menarche, chronic anovulation including polycystic ovarian syndrome, estrogen therapy in the absence of progesterone, tamoxifen therapy, hereditary predisposition (Lynch syndrome), and nulliparity.	('polycystic ovarian syndrome', 'Phenotype', 'HP:0000147', (230, 257))	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('polycystic ovarian syndrome', 'Disease', 'MESH:D011085', (230, 257))	('tamoxifen', 'Chemical', 'MESH:D013629', (308, 317))	('obesity', 'Disease', (15, 22))	('Lynch syndrome', 'Disease', (354, 368))	('EC', 'Phenotype', 'HP:0012114', (106, 108))	('menarche', 'Disease', (190, 198))	('menarche', 'Disease', 'None', (190, 198))	('Lynch syndrome', 'Disease', 'MESH:D003123', (354, 368))	('polycystic ovarian syndrome', 'Disease', (230, 257))	('progesterone', 'Chemical', 'MESH:D011374', (294, 306))	('nulliparity', 'Var', (375, 386))	('onset menopause', 'Phenotype', 'HP:0008209', (160, 175))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))	('estrogen', 'Disease', (259, 267))	('lower age of menarche', 'Phenotype', 'HP:0012569', (177, 198))
47844	32397158	Another showed that variants in CYP19A1 (gene that encodes aromatase/estrogen synthetase) were associated with increasing estradiol levels in post-menopausal women, and risk of EC, in women of European ancestry.	('estrogen synthetase', 'Gene', (69, 88))	('women', 'Species', '9606', (184, 189))	('variants', 'Var', (20, 28))	('CYP19A1', 'Gene', '1588', (32, 39))	('EC', 'Phenotype', 'HP:0012114', (177, 179))	('CYP19A1', 'Gene', (32, 39))	('estrogen synthetase', 'Gene', '1588', (69, 88))	('increasing estradiol levels', 'Phenotype', 'HP:0025134', (111, 138))	('women', 'Species', '9606', (158, 163))	('increasing', 'PosReg', (111, 121))	('estradiol levels', 'MPA', (122, 138))	('estradiol', 'Chemical', 'MESH:D004958', (122, 131))
47845	32397158	SNPs associated with obesity (BMI), but not waist:hip ratio, were also shown to be associated with EC, indicating that obesity is a causal factor for EC.	('EC', 'Phenotype', 'HP:0012114', (150, 152))	('obesity', 'Phenotype', 'HP:0001513', (21, 28))	('obesity', 'Disease', 'MESH:D009765', (119, 126))	('rat', 'Species', '10116', (54, 57))	('SNPs', 'Var', (0, 4))	('obesity', 'Disease', (119, 126))	('obesity', 'Disease', 'MESH:D009765', (21, 28))	('associated', 'Reg', (83, 93))	('obesity', 'Disease', (21, 28))	('obesity', 'Phenotype', 'HP:0001513', (119, 126))	('EC', 'Phenotype', 'HP:0012114', (99, 101))
47872	32397158	However, two small case-control studies showed higher mean HbA1c in EC cases versus controls; and a prospective cohort study in a predominantly Maori population (the Indigenous people of New Zealand) found a four-to-five-fold increase in EC risk with elevated HbA1c (Table 1).	('HbA1c', 'Gene', (260, 265))	('elevated HbA1c', 'Phenotype', 'HP:0040217', (251, 265))	('EC', 'Phenotype', 'HP:0012114', (68, 70))	('HbA1c', 'Gene', (59, 64))	('higher', 'PosReg', (47, 53))	('people', 'Species', '9606', (177, 183))	('EC', 'Phenotype', 'HP:0012114', (238, 240))	('higher mean HbA1c', 'Phenotype', 'HP:0040217', (47, 64))	('elevated', 'Var', (251, 259))
47874	32397158	These include mutations, amplifications, and over-expression of key regulators of glucose metabolism, particularly phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)-Protein kinase B (Akt) family members, which are more common in Type I/endometrioid EC (as reviewed) (Figure 1).	('glucose metabolism', 'Disease', 'MESH:D044882', (82, 100))	('phosphatidylinositol 3-kinase', 'Gene', (159, 188))	('over-expression', 'PosReg', (45, 60))	('PTEN', 'Gene', (149, 153))	('Protein kinase B', 'Gene', '2185', (196, 212))	('phosphatase and tensin homologue', 'Gene', '5728', (115, 147))	('glucose metabolism', 'Disease', (82, 100))	('amplifications', 'Var', (25, 39))	('common', 'Reg', (250, 256))	('Type I/endometrioid EC', 'Disease', (260, 282))	('mutations', 'Var', (14, 23))	('Protein kinase B', 'Gene', (196, 212))	('EC', 'Phenotype', 'HP:0012114', (280, 282))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (159, 188))
47876	32397158	PTEN is a lipid phosphatase that inhibits the PI3K-Akt pathway and loss of PTEN leads to activation of Akt, and other downstream targets, such as Rac1 and CDC42, that play important roles in cell cycle progression, migration and invasion.	('lipid', 'Chemical', 'MESH:D008055', (10, 15))	('Akt', 'Pathway', (103, 106))	('CDC42', 'Gene', '998', (155, 160))	('rat', 'Species', '10116', (218, 221))	('PTEN', 'Gene', (75, 79))	('activation', 'PosReg', (89, 99))	('PI3K-Akt pathway', 'Pathway', (46, 62))	('CDC42', 'Gene', (155, 160))	('inhibits', 'NegReg', (33, 41))	('cell cycle', 'CPA', (191, 201))	('loss', 'Var', (67, 71))	('Rac1', 'Gene', '5879', (146, 150))	('Rac1', 'Gene', (146, 150))
47878	32397158	Other aberrations frequently observed in EC include mutations in V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (Type I EC), over-expression of epidermal growth factor receptor (EGFR) (Type I and II EC), nuclear localization of beta-catenin (mostly Type I EC), loss of liver kinase B1 (LKB1) and tuberous sclerosis 2 (TSC2) (Type I EC), and mutations in TP53 (mostly Type II EC).	('liver kinase B1', 'Gene', '314621', (282, 297))	('epidermal growth factor receptor', 'Gene', '24329', (157, 189))	('beta-catenin', 'Gene', (241, 253))	('sarcoma', 'Disease', (87, 94))	('LKB1', 'Gene', (299, 303))	('loss', 'NegReg', (274, 278))	('LKB1', 'Gene', '314621', (299, 303))	('EC', 'Phenotype', 'HP:0012114', (269, 271))	('TP53', 'Gene', '24842', (367, 371))	('KRAS', 'Gene', '24525', (119, 123))	('epidermal growth factor receptor', 'Gene', (157, 189))	('EC', 'Phenotype', 'HP:0012114', (133, 135))	('EC', 'Phenotype', 'HP:0012114', (212, 214))	('V-Ki-ras2', 'Gene', (65, 74))	('over-expression', 'PosReg', (138, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('EGFR', 'Gene', (191, 195))	('beta-catenin', 'Gene', '84353', (241, 253))	('TP53', 'Gene', (367, 371))	('EGFR', 'Gene', '24329', (191, 195))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (309, 327))	('KRAS', 'Gene', (119, 123))	('EC', 'Phenotype', 'HP:0012114', (345, 347))	('tuberous sclerosis', 'Disease', (309, 327))	('mutations', 'Var', (52, 61))	('rat', 'Species', '10116', (83, 86))	('nuclear localization', 'MPA', (217, 237))	('liver kinase B1', 'Gene', (282, 297))	('mutations', 'Var', (354, 363))	('EC', 'Phenotype', 'HP:0012114', (41, 43))	('rat', 'Species', '10116', (10, 13))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
47879	32397158	Alterations in the expression or activity of these proteins stimulate glucose metabolism by various mechanisms, including through the regulation of glucose transporters (GLUTs) and altering the activity of key glycolytic enzymes (Figure 1).	('glucose', 'Chemical', 'MESH:D005947', (148, 155))	('glycolytic enzymes', 'Enzyme', (210, 228))	('altering', 'Reg', (181, 189))	('stimulate', 'PosReg', (60, 69))	('Alterations', 'Var', (0, 11))	('glucose metabolism', 'Disease', 'MESH:D044882', (70, 88))	('activity', 'MPA', (194, 202))	('activity', 'MPA', (33, 41))	('regulation', 'MPA', (134, 144))	('rat', 'Species', '10116', (4, 7))	('glucose metabolism', 'Disease', (70, 88))	('glucose transporters', 'MPA', (148, 168))	('glucose', 'Chemical', 'MESH:D005947', (70, 77))
47882	32397158	Mutations in POLE have been linked to higher expression of glycolytic enzymes, including phosphoglucose isomerase (PGI), which converts glucose-6-phosphate to fructose-6-phosphate.	('phosphoglucose isomerase', 'Gene', (89, 113))	('PGI', 'Gene', '2821', (115, 118))	('glucose-6-phosphate to fructose-6-phosphate', 'MPA', (136, 179))	('phosphoglucose isomerase', 'Gene', '2821', (89, 113))	('glucose', 'Chemical', 'MESH:D005947', (136, 143))	('expression', 'MPA', (45, 55))	('Mutations', 'Var', (0, 9))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))	('higher', 'PosReg', (38, 44))	('glycolytic', 'Enzyme', (59, 69))	('POLE', 'Gene', (13, 17))	('PGI', 'Gene', (115, 118))	('fructose-6-phosphate', 'Chemical', 'MESH:C027618', (159, 179))
47883	32397158	However, it is unclear how mutations in POLE regulate the expression of glucose metabolizing enzymes, and whether these alterations influence disease progression or response to treatment.	('mutations', 'Var', (27, 36))	('rat', 'Species', '10116', (124, 127))	('expression', 'MPA', (58, 68))	('POLE', 'Gene', (40, 44))	('glucose metabolizing enzymes', 'MPA', (72, 100))	('regulate', 'Reg', (45, 53))	('glucose', 'Chemical', 'MESH:D005947', (72, 79))	('influence', 'Reg', (132, 141))
47884	32397158	Epigenetic alterations may also be responsible for the development of EC, and hyperglycemia is known to impact epigenetics; a phenomenon known as hyperglycemic memory.	('Epigenetic alterations', 'Var', (0, 22))	('hyperglycemia', 'Disease', 'MESH:D006943', (78, 91))	('rat', 'Species', '10116', (15, 18))	('hyperglycemia', 'Disease', (78, 91))	('hyperglycemic memory', 'Disease', 'MESH:D008569', (146, 166))	('EC', 'Phenotype', 'HP:0012114', (70, 72))	('impact', 'Reg', (104, 110))	('hyperglycemia', 'Phenotype', 'HP:0003074', (78, 91))	('hyperglycemic memory', 'Disease', (146, 166))	('responsible', 'Reg', (35, 46))	('epigenetics', 'MPA', (111, 122))
47895	32397158	Functional studies revealed that knockdown of GLUT6 expression in EC cell lines (MFE-296, RL95-2) inhibited glucose uptake (at physiological glucose concentrations of 5 mM), reduced glycolysis, and induced cell death.	('glucose', 'Chemical', 'MESH:D005947', (141, 148))	('glucose', 'Chemical', 'MESH:D005947', (108, 115))	('rat', 'Species', '10116', (156, 159))	('glucose', 'CPA', (108, 115))	('inhibited', 'NegReg', (98, 107))	('death', 'Disease', (211, 216))	('GLUT6', 'Gene', (46, 51))	('knockdown', 'Var', (33, 42))	('induced', 'Reg', (198, 205))	('EC', 'Phenotype', 'HP:0012114', (66, 68))	('glycolysis', 'MPA', (182, 192))	('reduced', 'NegReg', (174, 181))	('GLUT6', 'Gene', '100128062', (46, 51))	('death', 'Disease', 'MESH:D003643', (211, 216))
47908	32397158	High expression of MCT1 is associated with lower recurrence-free survival, cancer-specific survival and overall survival in EC.	('overall survival', 'CPA', (104, 120))	('High', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('MCT1', 'Gene', '6566', (19, 23))	('EC', 'Phenotype', 'HP:0012114', (124, 126))	('recurrence-free survival', 'CPA', (49, 73))	('MCT1', 'Gene', (19, 23))	('lower', 'NegReg', (43, 48))
47920	32397158	Our studies also showed that most EC cell lines (HEC-1A, Ishikawa, MFE-296, MFE-319, AN3CA, RL95-2, but not KLE cells) had higher rates of glycolysis and lipogenesis (derived from glucose), compared with normal endometrial stromal (MAD11) and epithelial (hUE-Ts) cells.	('glycolysis', 'MPA', (139, 149))	('EC', 'Phenotype', 'HP:0012114', (34, 36))	('lipogenesis', 'MPA', (154, 165))	('glucose', 'Chemical', 'MESH:D005947', (180, 187))	('HEC', 'CellLine', 'CVCL:N814', (49, 52))	('higher', 'PosReg', (123, 129))	('rat', 'Species', '10116', (130, 133))	('EC', 'Phenotype', 'HP:0012114', (50, 52))	('MFE-319', 'Var', (76, 83))
47961	32397158	demonstrated that metformin was associated with reversal of atypical endometrial hyperplasia, decreased expression of cell proliferation biomarkers, and a higher overall survival rate among metformin-users compared to non-metformin users and non-diabetic patients.	('rat', 'Species', '10116', (179, 182))	('metformin', 'Chemical', 'MESH:D008687', (222, 231))	('diabetic', 'Disease', (246, 254))	('endometrial hyperplasia', 'Disease', (69, 92))	('metformin', 'Var', (18, 27))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (69, 92))	('patients', 'Species', '9606', (255, 263))	('decreased', 'NegReg', (94, 103))	('expression', 'MPA', (104, 114))	('rat', 'Species', '10116', (130, 133))	('cell proliferation', 'CPA', (118, 136))	('rat', 'Species', '10116', (7, 10))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (69, 92))	('metformin', 'Chemical', 'MESH:D008687', (18, 27))	('higher', 'PosReg', (155, 161))	('metformin', 'Chemical', 'MESH:D008687', (190, 199))	('diabetic', 'Disease', 'MESH:D003920', (246, 254))	('metformin-users', 'Var', (190, 205))
47969	32397158	At these doses, metformin is shown to induce G0/G1 cell cycle arrest, apoptosis, autophagy, increase phosphorylation of AMPK and decreases phosphorylation of ribosomal S6 kinase; a downstream target of mTOR.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('metformin', 'Var', (16, 25))	('phosphorylation', 'MPA', (139, 154))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (51, 68))	('metformin', 'Chemical', 'MESH:D008687', (16, 25))	('induce', 'PosReg', (38, 44))	('arrest', 'Disease', (62, 68))	('phosphorylation', 'CPA', (101, 116))	('AMPK', 'Gene', (120, 124))	('increase', 'PosReg', (92, 100))	('apoptosis', 'CPA', (70, 79))	('mTOR', 'Gene', '2475', (202, 206))	('decreases', 'NegReg', (129, 138))	('autophagy', 'CPA', (81, 90))	('mTOR', 'Gene', (202, 206))	('ribosomal S6', 'MPA', (158, 170))	('AMPK', 'Gene', '5563', (120, 124))
47971	32397158	Additionally, metformin raised the expression of betaKlotho, an essential co-receptor of fibroblast growth factor (FGF) receptor complexes, and inhibited the phosphorylation of the downstream target, ERK1/2, in Ishikawa cells.	('phosphorylation', 'MPA', (158, 173))	('metformin', 'Var', (14, 23))	('betaKlotho', 'Gene', '152831', (49, 59))	('expression', 'MPA', (35, 45))	('inhibited', 'NegReg', (144, 153))	('betaKlotho', 'Gene', (49, 59))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('raised', 'PosReg', (24, 30))
47972	32397158	Interestingly, some studies have reported that metformin may impede tumor progression by reducing TAMs or inducing M1-like polarization of TAMs, while others indicate an anti-inflammatory effect on stromal cells.	('tumor', 'Disease', (68, 73))	('inducing', 'Reg', (106, 114))	('reducing', 'NegReg', (89, 97))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('TAMs', 'MPA', (98, 102))	('impede', 'NegReg', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('TAMs', 'Chemical', '-', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('anti-inflammatory', 'MPA', (170, 187))	('metformin', 'Var', (47, 56))	('M1-like polarization', 'MPA', (115, 135))	('TAMs', 'Chemical', '-', (98, 102))
47976	32397158	However, metformin was only detected at low micromolar concentrations in EC tissues, leading the authors to suggested that the antiproliferative effect of metformin was due to indirect effects, i.e., lowering of blood glucose, insulin, IGF-1, and leptin levels.	('rat', 'Species', '10116', (138, 141))	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('rat', 'Species', '10116', (62, 65))	('leptin', 'Gene', '3952', (247, 253))	('IGF-1', 'Gene', '3479', (236, 241))	('IGF-1', 'Gene', (236, 241))	('EC', 'Phenotype', 'HP:0012114', (73, 75))	('lowering of blood glucose', 'Phenotype', 'HP:0001943', (200, 225))	('leptin', 'Gene', (247, 253))	('glucose', 'Chemical', 'MESH:D005947', (218, 225))	('metformin', 'Var', (155, 164))	('antiproliferative effect', 'CPA', (127, 151))	('blood glucose', 'MPA', (212, 225))	('insulin', 'Gene', (227, 234))	('metformin', 'Chemical', 'MESH:D008687', (155, 164))	('insulin', 'Gene', '3630', (227, 234))	('lowering', 'NegReg', (200, 208))
47982	32397158	Sodium glucose cotransporter 2 (SGLT2) inhibitors are also used for the treatment of T2DM.	('inhibitors', 'Var', (39, 49))	('Sodium glucose cotransporter 2', 'Gene', (0, 30))	('Sodium glucose cotransporter 2', 'Gene', '6524', (0, 30))	('SGLT2', 'Gene', '6524', (32, 37))	('T2DM', 'Disease', (85, 89))	('SGLT2', 'Gene', (32, 37))
47985	32397158	Whether SGLT2 inhibitors will also inhibit tumor growth in preclinical models of EC, or in patients, is yet to be revealed.	('EC', 'Phenotype', 'HP:0012114', (81, 83))	('patients', 'Species', '9606', (91, 99))	('SGLT2', 'Gene', '6524', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('inhibitors', 'Var', (14, 24))	('SGLT2', 'Gene', (8, 13))	('tumor', 'Disease', (43, 48))	('inhibit', 'NegReg', (35, 42))
48022	32366279	Conclusively, our study for the first time curated both genetic and epigenetic variations of ACE2 in human malignancies.	('epigenetic variations', 'Var', (68, 89))	('malignancies', 'Disease', 'MESH:D009369', (107, 119))	('human', 'Species', '9606', (101, 106))	('ACE2', 'Gene', (93, 97))	('malignancies', 'Disease', (107, 119))	('ACE2', 'Gene', '59272', (93, 97))
48028	32366279	In TCGA pan-cancer panel, the most frequent DNA alteration is mutation.	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('mutation', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
48029	32366279	In another pan-cancer panel, the most frequent DNA alteration is amplification.	('cancer', 'Disease', (15, 21))	('amplification', 'Var', (65, 78))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
48030	32366279	Amplifications of ACE2 were observed in NEPC and PRAD patients (Figure S1B).	('NEPC', 'Disease', (40, 44))	('patients', 'Species', '9606', (54, 62))	('ACE2', 'Gene', (18, 22))	('Amplifications', 'Var', (0, 14))	('PRAD', 'Disease', (49, 53))	('observed', 'Reg', (28, 36))	('ACE2', 'Gene', '59272', (18, 22))
48031	32366279	In addition, ACE2 mutations in malignancies were distributed across all exons of ACE2 without hot spot mutation site (Figure S2AC, Table S1).	('ACE2', 'Gene', (13, 17))	('malignancies', 'Disease', 'MESH:D009369', (31, 43))	('ACE2', 'Gene', (81, 85))	('ACE2', 'Gene', '59272', (13, 17))	('malignancies', 'Disease', (31, 43))	('ACE2', 'Gene', '59272', (81, 85))	('mutations', 'Var', (18, 27))
48032	32366279	The most frequent mutation was H195Y/X195_splice (Figure S2B) and X555_splice (Figure S2D).	('H195Y', 'SUBSTITUTION', 'None', (31, 36))	('H195Y', 'Var', (31, 36))	('X555_splice', 'Var', (66, 77))
48050	32366279	Other possibilities, such as histone modifications and glycosylation may give rise in the abnormal expression of ACE2, which requires further explorations.	('abnormal expression', 'MPA', (90, 109))	('ACE2', 'Gene', '59272', (113, 117))	('glycosylation', 'Var', (55, 68))	('give rise', 'Reg', (73, 82))	('ACE2', 'Gene', (113, 117))
48213	32164210	Since both, metastatic invasive lobular carcinoma of the breast and primary endometrial carcinoma demonstrate positivity for ER and PR, immunostaining for hormone receptors is not helpful in distinguishing tumors of metastatic mammary origin from those of primary endometrial origin.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('invasive lobular carcinoma of the breast and primary endometrial carcinoma', 'Disease', 'MESH:D001943', (23, 97))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (32, 49))	('ER', 'Gene', '2099', (125, 127))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('PR', 'Gene', '5241', (132, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('positivity', 'Var', (110, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (76, 97))
48264	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))	(' wid', 'Gene', (89, 93))
48265	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.	('tat', 'Gene', '6898', (256, 259))	('underlies', 'Reg', (219, 228))	('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))	('nal', 'Gene', (166, 169))	('cancer', 'Disease', (296, 302))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
48272	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))
48300	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))
48388	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))
48394	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.	('nes', 'Gene', '10763', (142, 145))	('silencing', 'Var', (23, 32))	('gene expression', 'MPA', (55, 70))	('nes', 'Gene', (142, 145))	('upregulated', 'PosReg', (128, 139))	('down-regulated', 'NegReg', (92, 106))
48419	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))	('induces', 'Reg', (32, 39))
48426	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))	('silencing', 'Var', (199, 208))	('survival', 'CPA', (263, 271))
48427	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))	('silencing', 'Var', (173, 182))	('cancer', 'Disease', (129, 135))	('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))
48431	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))
48450	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))
48475	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).	('driving gene expression', 'MPA', (72, 95))	('tat', 'Gene', '6898', (235, 238))	('TFs', 'Var', (65, 68))	('tat', 'Gene', (235, 238))	('nal', 'Gene', (240, 243))	('nal', 'Gene', '80896', (240, 243))
48621	30897294	For example, Beck et al29 found that the recurrence rate of patients with postoperative progestogen was lower than those with surgery alone in stage I (14.3% vs 38.5%), as well as all stages (33% vs 50%).	('postoperative', 'Var', (74, 87))	('lower', 'NegReg', (104, 109))	('patients', 'Species', '9606', (60, 68))	('recurrence', 'MPA', (41, 51))
48709	30864318	The presence of certain KIR genes can predict response to immunotherapy treatment and survival outcomes in chronic myeloid leukemia and acute myeloid leukemia.	('KIR', 'Gene', '3811', (24, 27))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (107, 131))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (136, 158))	('acute myeloid leukemia', 'Disease', (136, 158))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (107, 131))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (142, 158))	('chronic myeloid leukemia', 'Disease', (107, 131))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (136, 158))	('KIR', 'Gene', (24, 27))	('presence', 'Var', (4, 12))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (115, 131))	('predict', 'Reg', (38, 45))
48751	30864318	For each tumor type, we divided patients into two sets: those that had the median number of inhibitory genes or fewer and those who had greater than the median number of inhibitory genes.	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('inhibitory genes', 'Var', (92, 108))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('fewer', 'NegReg', (112, 117))
48788	30864318	In both of these tumor types, patients with high numbers of inhibitory genes had lower survival rates, suggesting that NK cells were unable to defend against the tumor in these patients.	('high numbers', 'Var', (44, 56))	('inhibitory genes', 'Var', (60, 76))	('lower', 'NegReg', (81, 86))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('patients', 'Species', '9606', (177, 185))	('tumor', 'Disease', (162, 167))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('survival rates', 'CPA', (87, 101))
48791	30864318	Patients with CESC and UCS had better presentation of observed driver mutations to the immune system than other tumors (P=0.0034, Figure 7B), suggesting that the CESC and UCS tumors have immunosuppressive mechanisms at play.	('UCS tumors', 'Disease', 'MESH:D009369', (171, 181))	('tumors', 'Disease', (175, 181))	('CESC', 'Disease', (162, 166))	('mutations', 'Var', (70, 79))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('UCS', 'Phenotype', 'HP:0002891', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('UCS tumors', 'Disease', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('UCS', 'Phenotype', 'HP:0002891', (23, 26))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('CESC', 'Disease', (14, 18))	('tumors', 'Disease', (112, 118))
48792	30864318	One possible mechanism for this immunosuppression is impaired antigen presentation, potentially via mutation or loss of heterozygosity in the HLA region, allowing perpetuation of the tumor despite high affinity of observed drivers for the MHC-I.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('impaired', 'NegReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MHC', 'Gene', (239, 242))	('mutation', 'Var', (100, 108))	('antigen presentation', 'MPA', (62, 82))	('tumor', 'Disease', (183, 188))	('loss', 'Var', (112, 116))	('allowing', 'Reg', (154, 162))	('MHC', 'Gene', '3107', (239, 242))
48854	30086293	In contrast, non-commercial insurance, greater comorbidity, treatment at a community cancer program, higher grade, more advanced size and larger tumor size were all associated with a lower likelihood of a minimally invasive procedure (P<0.05 for all).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('tumor', 'Disease', (145, 150))	('higher grade', 'Var', (101, 113))	('lower', 'NegReg', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
49038	29915801	EWSR1 rearrangement has been recently reported as a characteristic genetic finding of peripheral-type uterine NETs; however, we were unable to perform genetic analysis to test for EWSR1 rearrangement.	('rearrangement', 'Var', (6, 19))	('EWSR1', 'Gene', '2130', (0, 5))	('EWSR1', 'Gene', (180, 185))	('EWSR1', 'Gene', '2130', (180, 185))	('NET', 'Gene', '2004', (110, 113))	('EWSR1', 'Gene', (0, 5))	('NET', 'Gene', (110, 113))
49226	25535730	Comorbidity (yes/no) was captured under the following categories: cardiac, coagulation/thrombosis, diabetes, gastrointestinal, hypertension, integumentary/dermatology, infections, low albumin (<30 g l-1), metabolic/endocrine, neurological, psychiatric, respiratory, smoking, vascular and other neoplasms.	('respiratory', 'Disease', (253, 264))	('low', 'Var', (180, 183))	('psychiatric', 'Disease', 'MESH:D001523', (240, 251))	('integumentary/dermatology', 'Disease', (141, 166))	('infections', 'Disease', 'MESH:D007239', (168, 178))	('neurological', 'Disease', (226, 238))	('infections', 'Disease', (168, 178))	('neoplasms', 'Disease', 'MESH:D009369', (294, 303))	('thrombosis', 'Disease', 'MESH:D013927', (87, 97))	('smoking', 'Disease', (266, 273))	('neoplasms', 'Disease', (294, 303))	('hypertension', 'Disease', 'MESH:D006973', (127, 139))	('thrombosis', 'Disease', (87, 97))	('psychiatric', 'Disease', (240, 251))	('diabetes', 'Disease', 'MESH:D003920', (99, 107))	('<30 g', 'Var', (193, 198))	('hypertension', 'Disease', (127, 139))	('low albumin', 'Phenotype', 'HP:0003073', (180, 191))	('gastrointestinal', 'Disease', (109, 125))	('metabolic/endocrine', 'Disease', (205, 224))	('neoplasms', 'Phenotype', 'HP:0002664', (294, 303))	('cardiac', 'Disease', (66, 73))	('hypertension', 'Phenotype', 'HP:0000822', (127, 139))	('vascular', 'Disease', (275, 283))	('gastrointestinal', 'Disease', 'MESH:D005767', (109, 125))	('diabetes', 'Disease', (99, 107))
49497	23782518	Expression of CD133-1 and CD133-2, which were detected in ovarian carcinomas, was also observed in normal ovaries.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('ovarian carcinomas', 'Disease', (58, 76))	('CD133-2', 'Var', (26, 33))	('CD133-1', 'Gene', (14, 21))	('ovaries', 'Disease', (106, 113))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (58, 76))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (58, 76))	('ovaries', 'Disease', 'MESH:D010051', (106, 113))
49498	23782518	CD133+ ovarian tumor cells were characterized by a higher proliferative potential and clonogenic efficiency than negative cells].	('ovarian tumor', 'Disease', 'MESH:D010051', (7, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CD133+', 'Var', (0, 6))	('proliferative potential', 'CPA', (58, 81))	('ovarian tumor', 'Disease', (7, 20))	('clonogenic efficiency', 'CPA', (86, 107))	('higher', 'PosReg', (51, 57))	('ovarian tumor', 'Phenotype', 'HP:0100615', (7, 20))
49508	23782518	A majority (71%) of 31 ovarian cancer samples analyzed expressed a complex pattern of CD44 splice variants.	('CD44', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ovarian cancer', 'Disease', (23, 37))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('splice variants', 'Var', (91, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))
49510	23782518	CD44+, MYD88+ cells from ascites and solid tumors have been characterized by constitutive nuclear factor kappa beta (NF-kappabeta) activity, cytokine and chemokine production, high capacity for repair, chemoresistance to conventional chemotherapies, resistance to TNF-alpha-mediated apoptosis, capacity to form spheroids in suspension, and the ability to recapitulate in vivo the original tumor.	('original tumor', 'Disease', (380, 394))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('solid tumors', 'Disease', (37, 49))	('CD44+', 'Var', (0, 5))	('MYD88', 'Gene', '4615', (7, 12))	('NF-kappabeta', 'Gene', (117, 129))	('ascites', 'Disease', (25, 32))	('original tumor', 'Disease', 'MESH:D009369', (380, 394))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('TNF-alpha', 'Gene', '7124', (264, 273))	('MYD88', 'Gene', (7, 12))	('NF-kappabeta', 'Gene', '4790', (117, 129))	('solid tumors', 'Disease', 'MESH:D009369', (37, 49))	('TNF-alpha', 'Gene', (264, 273))	('ascites', 'Disease', 'MESH:D001201', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('activity', 'MPA', (131, 139))	('ascites', 'Phenotype', 'HP:0001541', (25, 32))	('cytokine', 'MPA', (141, 149))
49511	23782518	The same research group identified bipotent CD44+ CD34- cells in ovarian cancer and demonstrated that, in addition to being capable of tumor regeneration, these cells also contribute to tumor vascularization by a mechanism that involves inhibitor of kappa-kinase beta (IkappaK-beta).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (186, 191))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (65, 79))	('CD44+ CD34-', 'Var', (44, 55))	('ovarian cancer', 'Disease', (65, 79))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
49519	23782518	Stromal clones expressed MSC markers ITGB1 (CD29), CD44, NT5E (CD73), THY1 (CD90), ENG (CD105), PDGF-Rbeta (CD140B), MCAM (CD146) but not endothelial or hemopoietic markers.	('THY1', 'Gene', (70, 74))	('ITGB1', 'Gene', '3688', (37, 42))	('NT5E', 'Gene', '4907', (57, 61))	('CD73', 'Gene', '4907', (63, 67))	('CD73', 'Gene', (63, 67))	('CD29', 'Gene', '3688', (44, 48))	('CD146', 'Gene', '4162', (123, 128))	('CD140B', 'Gene', '5159', (108, 114))	('CD146', 'Gene', (123, 128))	('CD90', 'Gene', (76, 80))	('NT5E', 'Gene', (57, 61))	('ENG', 'Gene', '2022', (83, 86))	('CD90', 'Gene', '7070', (76, 80))	('CD29', 'Gene', (44, 48))	('PDGF-Rbeta', 'Gene', '5159', (96, 106))	('ITGB1', 'Gene', (37, 42))	('MCAM', 'Gene', (117, 121))	('CD140B', 'Gene', (108, 114))	('ENG', 'Gene', (83, 86))	('PDGF-Rbeta', 'Gene', (96, 106))	('CD105', 'Var', (88, 93))	('THY1', 'Gene', '7070', (70, 74))	('CD44', 'Gene', (51, 55))	('MCAM', 'Gene', '4162', (117, 121))
49523	23782518	CD146+, PDGF-Rbeta+ cells expressed typical MSC surface markers, CD29, CD44, CD73, CD90 and CD105 and were negative for hemopoietic and endothelial markers.	('CD90', 'Gene', '7070', (83, 87))	('CD44', 'Var', (71, 75))	('CD73', 'Gene', (77, 81))	('CD90', 'Gene', (83, 87))	('CD29', 'Gene', '3688', (65, 69))	('PDGF-Rbeta', 'Gene', (8, 18))	('CD105', 'Var', (92, 97))	('CD29', 'Gene', (65, 69))	('CD73', 'Gene', '4907', (77, 81))	('CD146', 'Gene', '4162', (0, 5))	('PDGF-Rbeta', 'Gene', '5159', (8, 18))	('CD146', 'Gene', (0, 5))
49540	23782518	Human and murine myometrial progenitors have been characterized by surface markers and found CD31+, CD34+, CD44+, CD117+, Stro-1+ and Sca-1+.	('CD31', 'Gene', (93, 97))	('CD117+', 'Var', (114, 120))	('Human', 'Species', '9606', (0, 5))	('Sca-1', 'Gene', '110454', (134, 139))	('CD44+', 'Var', (107, 112))	('murine', 'Species', '10090', (10, 16))	('Stro-1+', 'MPA', (122, 129))	('Sca-1', 'Gene', (134, 139))	('CD31', 'Gene', '18613', (93, 97))	('CD34+', 'Var', (100, 105))
49555	23782518	When serially transplanted into NOD/SCID mice, CD133+ cells were capable of initiating tumor formation and recovering the phenotype of the original tumor.	('CD133+', 'Var', (47, 53))	('NOD', 'Gene', '1822', (32, 35))	('SCID', 'Disease', 'MESH:D053632', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mice', 'Species', '10090', (41, 45))	('recovering', 'PosReg', (107, 117))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (87, 92))	('phenotype', 'MPA', (122, 131))	('original tumor', 'Disease', 'MESH:D009369', (139, 153))	('NOD', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('original tumor', 'Disease', (139, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('SCID', 'Disease', (36, 40))
49558	23782518	Clinically, high-level of ALDH1 was correlated with lymphatic invasion, recurrence, and poor prognosis of patients.	('ALDH1', 'Gene', '216', (26, 31))	('correlated', 'Reg', (36, 46))	('ALDH1', 'Gene', (26, 31))	('patients', 'Species', '9606', (106, 114))	('recurrence', 'CPA', (72, 82))	('high-level', 'Var', (12, 22))	('lymphatic invasion', 'CPA', (52, 70))
49577	23782518	Additionally, it was found that exogenous SOX2 could promote both cell proliferation and growth, and enhanced tumor formation in nude mouse.	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('cell proliferation', 'CPA', (66, 84))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('exogenous', 'Var', (32, 41))	('enhanced', 'PosReg', (101, 109))	('mouse', 'Species', '10090', (134, 139))	('growth', 'CPA', (89, 95))	('SOX2', 'Protein', (42, 46))	('promote', 'PosReg', (53, 60))
49582	23782518	They also found that expression of ALDH1 and CD44 were significantly elevated in Twist-over expressing cells, and that beta-catenin and Akt pathways were activated.	('beta-catenin', 'Gene', '1499', (119, 131))	('ALDH1', 'Gene', (35, 40))	('ALDH1', 'Gene', '216', (35, 40))	('expression', 'MPA', (21, 31))	('activated', 'PosReg', (154, 163))	('Akt', 'Gene', '207', (136, 139))	('beta-catenin', 'Gene', (119, 131))	('CD44', 'Gene', (45, 49))	('elevated', 'PosReg', (69, 77))	('Akt', 'Gene', (136, 139))	('Twist-over expressing', 'Var', (81, 102))
49590	23782518	Silencing of E6 inhibited HeLa-SFC sphere formation and cell growth.	('inhibited', 'NegReg', (16, 25))	('HeLa-SFC sphere formation', 'CPA', (26, 51))	('cell growth', 'CPA', (56, 67))	('HeLa', 'CellLine', 'CVCL:0030', (26, 30))	('Silencing', 'Var', (0, 9))
49603	23782518	127822 to AGC), Programa de Apoyo a Proyectos de Investigacion e Innovacion Tecnologica de la Universidad Nacional Autonoma de Mexico (PAPIIT-UNAM; IN226408 to AGC).	('Autonoma de', 'Disease', 'MESH:D005862', (115, 126))	('Autonoma de', 'Disease', (115, 126))	('127822', 'Var', (0, 6))
49605	23782518	127722 to AGC), Programa de Apoyo a Proyectos de Investigacion e Innovacion Tecnologica de la Universidad Nacional Autonoma de Mexico (PAPIIT-UNAM; IN226408 to AGC), and Division de Investigacion Basica del Instituto Nacional de Cancerologia, Secretaria de Salud.	('Secretaria de', 'Disease', 'MESH:D005862', (243, 256))	('de Cancerologia', 'Disease', (226, 241))	('Autonoma de', 'Disease', (115, 126))	('de Cancerologia', 'Disease', 'MESH:D005862', (226, 241))	('Secretaria de', 'Disease', (243, 256))	('Autonoma de', 'Disease', 'MESH:D005862', (115, 126))	('127722', 'Var', (0, 6))
49872	33232359	No cancer-related deaths occurred in the POLE mutant subgroup.	('deaths', 'Disease', 'MESH:D003643', (18, 24))	('deaths', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutant', 'Var', (46, 52))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
49882	33232359	The molecular classification system, identified through The Cancer Genome Atlas (TCGA), categorizes endometrial cancers into four distinct subgroups: polymerase-epsilon (POLE) ultramutated; microsatellite unstable hypermutated; copy-number low; and copy-number high.	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('copy-number high', 'Var', (249, 265))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('copy-number low', 'Var', (228, 243))	('endometrial cancers', 'Disease', 'MESH:D016889', (100, 119))	('endometrial cancers', 'Disease', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('microsatellite unstable hypermutated', 'Var', (190, 226))
49883	33232359	This categorization is based on: overall mutational burden; p53, POLE, and phosphatase and tensin homolog (PTEN) mutations; microsatellite instability; and histology.	('PTEN', 'Gene', (107, 111))	('PTEN', 'Gene', '5728', (107, 111))	('microsatellite instability', 'Var', (124, 150))	('p53', 'Gene', (60, 63))	('mutations', 'Var', (113, 122))	('p53', 'Gene', '7157', (60, 63))	('phosphatase and tensin homolog', 'Gene', '5728', (75, 105))
49884	33232359	Molecular subgroups are associated with different prognoses, so that: POLE ultramutated tumors have an excellent progression-free survival, microsatellite unstable hypermutated and copy-number low tumors an intermediate progression-free survival; and copy-number high tumors a poor progression-free survival.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('microsatellite unstable hypermutated', 'Var', (140, 176))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumors', 'Disease', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumors', 'Disease', (197, 203))
49902	33232359	First, while our p53 and microsatellite instability analyses were solely based on immunohistochemistry, the TransPORTEC classifier uses a combination of TP53 mutational testing and p53 immunohistochemistry to determine p53 status, and primarily the Promega microsatellite instability analysis for determination of microsatellite instability status.	('p53', 'Gene', (181, 184))	('p53', 'Gene', '7157', (181, 184))	('p53', 'Gene', '7157', (219, 222))	('mutational testing', 'Var', (158, 176))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', (153, 157))	('p53', 'Gene', (17, 20))	('p53', 'Gene', (219, 222))	('p53', 'Gene', '7157', (17, 20))
49909	33232359	Aberrant p53 staining was defined as strong and diffuse nuclear staining or completely negative ('null') staining in carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('Aberrant', 'Var', (0, 8))	('carcinoma cells', 'Disease', 'MESH:C538614', (117, 132))	('carcinoma cells', 'Disease', (117, 132))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))	('negative', 'NegReg', (87, 95))
49914	33232359	POLE exonuclease domain mutation (EDM) screening of hot spots in exon 9 (c.857C>G, p.P286R; c.890C>T, p.S297F), exon 13 (c.1231G>C, p.V411L), and exon 14 (c.1366G>C, p.A456P) was performed by direct sequencing.	('c.890C>T', 'Mutation', 'rs587779328', (92, 100))	('p.S297F', 'Mutation', 'p.S297F', (102, 109))	('c.1231G>C', 'Var', (121, 130))	('c.857C>G', 'Mutation', 'rs878854038', (73, 81))	('EDM', 'Disease', 'None', (34, 37))	('c.1366G>C', 'Mutation', 'rs148642064', (155, 164))	('p.P286R', 'Mutation', 'p.P286R', (83, 90))	('c.1366G>C', 'Var', (155, 164))	('EDM', 'Disease', (34, 37))	('c.1231G>C', 'Mutation', 'rs786203757', (121, 130))	('c.890C>T', 'Var', (92, 100))	('p.V411L', 'Mutation', 'rs1196350669', (132, 139))	('p.A456P', 'Mutation', 'rs876658988', (166, 173))	('c.857C>G', 'Var', (73, 81))
49937	33232359	Disease-specific survival was similarly improved for overweight patients (body mass index 25-29.9 kg/m2) and obese patients (body mass index >=30 kg/m2) compared with normal-weight patients (body mass index <25 kg/m2) (Fig 1).	('patients', 'Species', '9606', (115, 123))	('Disease-specific survival', 'CPA', (0, 25))	('overweight', 'Phenotype', 'HP:0025502', (53, 63))	('patients', 'Species', '9606', (64, 72))	('body', 'Var', (74, 78))	('obese', 'Disease', 'MESH:D009765', (109, 114))	('obese', 'Disease', (109, 114))	('patients', 'Species', '9606', (181, 189))	('improved', 'PosReg', (40, 48))
49952	33232359	The presence of uterine risk factors is associated with increased risk for recurrences and poor survival, even in the absence of metastatic nodal disease.	('recurrences', 'CPA', (75, 86))	('poor', 'NegReg', (91, 95))	('nodal disease', 'Disease', 'MESH:D013611', (140, 153))	('presence', 'Var', (4, 12))	('nodal disease', 'Disease', (140, 153))
49967	33232359	Information on the treatment of diabetes was unavailable for our study, which may partly distort the results, as metformin has been shown to improve overall survival and progression-free survival in patients with endometrial cancer.	('metformin', 'Var', (113, 122))	('endometrial cancer', 'Phenotype', 'HP:0012114', (213, 231))	('endometrial cancer', 'Disease', 'MESH:D016889', (213, 231))	('metformin', 'Chemical', 'MESH:D008687', (113, 122))	('overall survival', 'CPA', (149, 165))	('diabetes', 'Disease', (32, 40))	('improve', 'PosReg', (141, 148))	('progression-free survival', 'CPA', (170, 195))	('diabetes', 'Disease', 'MESH:D003920', (32, 40))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('endometrial cancer', 'Disease', (213, 231))
49972	33232359	For example, inactivation of PTEN, whose mutational frequency differs between TCGA subgroups, has been suggested to determine the outcome of endometrial cancer patients in the context of body mass index.	('patients', 'Species', '9606', (160, 168))	('endometrial cancer', 'Disease', (141, 159))	('inactivation', 'Var', (13, 25))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('endometrial cancer', 'Disease', 'MESH:D016889', (141, 159))	('endometrial cancer', 'Phenotype', 'HP:0012114', (141, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('determine', 'Reg', (116, 125))
49998	33232359	The English could be improved in places, for example, in the abstract "For POLE mutant (n = 37) and p53 aberrant (n = 69) subgroups, significant associations between demographic factors and overall mortality, cancer-related mortality and non-cancer related mortality were not observed during a median follow-up time of 81 months (range 1-136)."	('mortality', 'Disease', (257, 266))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('mutant', 'Var', (80, 86))	('mortality', 'Disease', (198, 207))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('mortality', 'Disease', 'MESH:D003643', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('p53', 'Gene', '7157', (100, 103))	('cancer', 'Disease', (209, 215))	('mortality', 'Disease', 'MESH:D003643', (257, 266))	('mortality', 'Disease', (224, 233))	('mortality', 'Disease', 'MESH:D003643', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('p53', 'Gene', (100, 103))
49999	33232359	- this would definitely be better phrased ""For POLE mutant (n = 37) and p53 aberrant (n = 69) subgroups, no significant associations were observed between demographic factors and overall mortality, cancer-related mortality and non-cancer related mortality during a median follow-up time of 81 months (range 1-136)."	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mortality', 'Disease', 'MESH:D003643', (188, 197))	('p53', 'Gene', (73, 76))	('cancer', 'Disease', (232, 238))	('p53', 'Gene', '7157', (73, 76))	('mortality', 'Disease', (214, 223))	('mortality', 'Disease', 'MESH:D003643', (247, 256))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('mortality', 'Disease', (188, 197))	('mortality', 'Disease', (247, 256))	('mutant', 'Var', (53, 59))	('cancer', 'Disease', (199, 205))	('mortality', 'Disease', 'MESH:D003643', (214, 223))
50104	33204876	Body-mass-index and waist-to-hip ratio were positively associated with endometrial cancer in postmenopausal women and women of all ages, respectively, whereas parity was inversely related.	('women', 'Species', '9606', (108, 113))	('endometrial cancer', 'Phenotype', 'HP:0012114', (71, 89))	('women', 'Species', '9606', (118, 123))	('Body-mass-index', 'Var', (0, 15))	('age', 'Gene', '5973', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('endometrial cancer', 'Disease', (71, 89))	('associated with', 'Reg', (55, 70))	('cancer in postmenopausal women', 'Phenotype', 'HP:0008209', (83, 113))	('endometrial cancer', 'Disease', 'MESH:D016889', (71, 89))	('age', 'Gene', (131, 134))
50136	33204876	A higher parity on the other hand is a directly related risk factor to pelvic floor issues, but has been shown to have a protective influence against endometrial cancer.	('pelvic floor issues', 'Disease', (71, 90))	('endometrial cancer', 'Disease', 'MESH:D016889', (150, 168))	('parity', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('endometrial cancer', 'Disease', (150, 168))	('endometrial cancer', 'Phenotype', 'HP:0012114', (150, 168))
50220	28215838	Among 48 cases who received chemotherapy/radiotherapy, local-recurrence risk was lower in WPRT-based therapy than ICBT alone although it did not demonstrate statistical significance (5-year cumulative rates, 3.5% versus 9.1%, P = 0.48).	('WPRT', 'Chemical', '-', (90, 94))	('lower', 'NegReg', (81, 86))	('WPRT-based therapy', 'Var', (90, 108))	('local-recurrence', 'CPA', (55, 71))
50238	28215838	In our analysis of stage IA disease, however, non-chemotherapy treatment had increased risk of both local- and distant-recurrences compared to a chemotherapy-based counterpart.	('non-chemotherapy treatment', 'Var', (46, 72))	('stage IA disease', 'Disease', (19, 35))	('stage IA disease', 'Disease', 'MESH:D058625', (19, 35))
50405	31781441	One possibility is a postrenal obstruction caused by deviation of the ureters.	('postrenal obstruction', 'Disease', (21, 42))	('deviation', 'Var', (53, 62))	('postrenal obstruction', 'Disease', 'MESH:D008173', (21, 42))
50406	31781441	Torsion results in drastic elongation of the broad ligaments; this could obstruct the course of the retroperitoneal ureter at the level of the pelvic side wall.	('retroperitoneal ureter', 'Disease', 'MESH:D012186', (100, 122))	('retroperitoneal ureter', 'Disease', (100, 122))	('elongation', 'CPA', (27, 37))	('Torsion', 'Var', (0, 7))	('obstruct', 'NegReg', (73, 81))
50436	31387281	Although they do not primarily endanger patients  lives, ULM can markedly decrease the quality of life if they become symptomatic.	('quality of life', 'CPA', (87, 102))	('patients', 'Species', '9606', (40, 48))	('decrease', 'NegReg', (74, 82))	('ULM', 'Var', (57, 60))
50488	31387281	(1) Targeted approaches are based on identifying the following mutations/abnormalities in the ctDNA elements: (a) previously accepted abnormal patterns in ctDNAs (e.g., in different cancer type or based on in silico prediction) and (b) the same pattern in the primary tumor and the released ctDNA.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('mutations/abnormalities', 'Var', (63, 86))	('ctDNAs', 'Disease', (155, 161))	('tumor', 'Disease', (268, 273))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
50496	31387281	The origin of the cells was verified by the presence of fusions typical for this tumor.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('fusions', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
50517	31387281	In addition, the let-7 family miRNA family has the HMGA2 gene as a target and HMGA2 abnormal expression, especially from translocations, is considered a typical ULM mark.	('translocations', 'Var', (121, 135))	('HMGA2', 'Gene', (51, 56))	('HMGA2', 'Gene', '8091', (78, 83))	('HMGA2', 'Gene', (78, 83))	('HMGA2', 'Gene', '8091', (51, 56))	('abnormal expression', 'Var', (84, 103))
50524	31387281	In addition, non-sporadic germline mutations of this gene occurred more often in women with both ULM and LMS.	('women', 'Species', '9606', (81, 86))	('germline mutations', 'Var', (26, 44))	('LMS', 'Disease', (105, 108))	('LMS', 'Phenotype', 'HP:0100243', (105, 108))	('ULM', 'Disease', (97, 100))
50525	31387281	Interestingly, malignant uterine LMS also have MED12 gene mutation in almost 70% of tumors, and this can be, therefore, considered a typical mark for these tumors.	('MED12', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutation', 'Var', (58, 66))	('MED12', 'Gene', '9968', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('LMS', 'Phenotype', 'HP:0100243', (33, 36))	('tumors', 'Disease', (156, 162))
50526	31387281	While this common mutation potentially distinguishes the two tumor groups from healthy tissue, unfortunately it cannot be used as a distinguishing factor of these tumors and is, therefore, unsuitable for LB diagnostics.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', (163, 168))	('mutation', 'Var', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
50527	31387281	In contrast to ULM, LMS have quite often mutated TP53 gene.	('LMS', 'Phenotype', 'HP:0100243', (20, 23))	('mutated', 'Var', (41, 48))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('LMS', 'Disease', (20, 23))
50528	31387281	Although mutations in this gene are typical for many cancerous diseases, LB determination of TP53 mutation in women with previous image-diagnosed UMT should always provoke rapid tissue biopsy, subsequent histological examination, and close observation of the patient.	('mutation', 'Var', (98, 106))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancerous diseases', 'Disease', (53, 71))	('UMT', 'Chemical', '-', (146, 149))	('cancerous diseases', 'Disease', 'MESH:D009369', (53, 71))	('patient', 'Species', '9606', (259, 266))	('women', 'Species', '9606', (110, 115))
50535	31387281	However, mutation changes in the TP53, ATRX, and RB1 genes have been detected and analyzed in LB samples in patients with different cancer diseases.	('ATRX', 'Gene', (39, 43))	('cancer diseases', 'Disease', 'MESH:D009369', (132, 147))	('RB1', 'Gene', (49, 52))	('ATRX', 'Gene', '546', (39, 43))	('RB1', 'Gene', '5925', (49, 52))	('TP53', 'Gene', '7157', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', (33, 37))	('patients', 'Species', '9606', (108, 116))	('cancer diseases', 'Disease', (132, 147))	('mutation changes', 'Var', (9, 25))
50537	31387281	The methylation profiles of ULM and sarcoma promoter regions provide further possibilities for tumor differentiation based on LB, because changes in DNA methylation patterns can be identified in ctDNA and have been proposed as potential biomarkers for tumor staging, prognosis, and monitoring of the treatment response.	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('ctDNA', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('sarcoma', 'Disease', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('changes', 'Var', (138, 145))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', (95, 100))
50545	31387281	In addition, women of African origin have hypermethylated DLEC1, KRT1,9 and KLF11 genes in ULM as compared to MM.	('ULM', 'Disease', (91, 94))	('DLEC1', 'Gene', (58, 63))	('DLEC1', 'Gene', '9940', (58, 63))	('KLF11', 'Gene', (76, 81))	('KRT1,9', 'Gene', '3880;3848;3857', (65, 71))	('women', 'Species', '9606', (13, 18))	('KLF11', 'Gene', '8462', (76, 81))	('hypermethylated', 'Var', (42, 57))
50549	31387281	For LMS are typical aberrations altering the cell cycle, whereby promoter region hypermethylation is supposed to induces loss of function of the important cell cycle regulator CDKN2 and hypermethylation also most likely causes the BRCA1 gene s protein reduction in almost 30% of uterine LMS.	('LMS', 'Phenotype', 'HP:0100243', (4, 7))	('protein', 'Protein', (244, 251))	('BRCA1', 'Gene', '672', (231, 236))	('hypermethylation', 'Var', (186, 202))	('reduction', 'NegReg', (252, 261))	('causes', 'Reg', (220, 226))	('loss of function', 'NegReg', (121, 137))	('BRCA1', 'Gene', (231, 236))	('CDKN2', 'Gene', '1029', (176, 181))	('LMS', 'Phenotype', 'HP:0100243', (287, 290))	('CDKN2', 'Gene', (176, 181))	('hypermethylation', 'Var', (81, 97))
50550	31387281	The LMS also have often hypomethylated ESR1 target genes and the polycomb group target genes.	('hypomethylated', 'Var', (24, 38))	('LMS', 'Phenotype', 'HP:0100243', (4, 7))	('ESR1', 'Gene', (39, 43))	('ESR1', 'Gene', '2099', (39, 43))
50561	31387281	These were divided into the following four groups: those with the mutated MED12 gene, those with HMGA2 gene translocations, the group with FH gene biallelic inactivation, and COL4A5-COL4A6 deletions.	('mutated', 'Var', (66, 73))	('MED12', 'Gene', (74, 79))	('COL4A5', 'Gene', '1287', (175, 181))	('MED12', 'Gene', '9968', (74, 79))	('COL4A5', 'Gene', (175, 181))	('deletions', 'Var', (189, 198))	('COL4A6', 'Gene', '1288', (182, 188))	('HMGA2', 'Gene', '8091', (97, 102))	('COL4A6', 'Gene', (182, 188))	('biallelic', 'Var', (147, 156))	('HMGA2', 'Gene', (97, 102))
50566	31387281	However, while it is generally accepted that vitamin D deficiency is strongly associated with ULM occurrence, its abnormal metabolites were not confirmed in these tumors.	('associated', 'Reg', (78, 88))	('abnormal metabolites', 'Phenotype', 'HP:0032180', (114, 134))	('vitamin D', 'Chemical', 'MESH:D014807', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (45, 65))	('vitamin D', 'Gene', (45, 54))	('deficiency', 'Var', (55, 65))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('ULM', 'Disease', (94, 97))
50571	31387281	In addition, FTICR-MSI identified m/z 241.0118 as inositol cyclic phosphate and m/z 160.8417 as carnitine.	('inositol cyclic phosphate', 'Chemical', 'MESH:C010199', (50, 75))	('inositol cyclic phosphate', 'MPA', (50, 75))	('m/z 241.0118', 'Var', (34, 46))	('m/z 160.8417', 'Var', (80, 92))	('carnitine', 'Chemical', 'MESH:D002331', (96, 105))
50572	31387281	In this review, we based the differentiation of UMT on the LB approach because of the diverse action of non-coding RNAs, and mutational and methylation changes and differences in metabolic activity in ULM, other UMT, and MM.	('changes', 'Var', (152, 159))	('mutational', 'Var', (125, 135))	('differences', 'Reg', (164, 175))	('UMT', 'Chemical', '-', (212, 215))	('UMT', 'Chemical', '-', (48, 51))
50590	31387281	The first study of these discrepancies we are aware of was conducted by Osoborne et al.. Woman with metastatic neuroendocrine carcinoma gave birth to a healthy infant, and although both invasive testing during pregnancy and postnatal placental histology revealed no abnormalities, NIPT testing indicated trisomy in chromosomes 13 and 18.	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (111, 135))	('Woman', 'Species', '9606', (89, 94))	('neuroendocrine carcinoma', 'Disease', (111, 135))	('indicated', 'Reg', (294, 303))	('infant', 'Species', '9606', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (111, 135))	('trisomy', 'Var', (304, 311))
50596	31387281	The authors found TP53 and HRAS mutations in both primary tumors and plasma samples.	('primary tumors', 'Disease', 'MESH:D009369', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TP53', 'Gene', '7157', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HRAS', 'Gene', (27, 31))	('found', 'Reg', (12, 17))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (32, 41))	('primary tumors', 'Disease', (50, 64))	('HRAS', 'Gene', '3265', (27, 31))
50597	31387281	However, it is necessary to remember that the percentage of these mutations differs in tissue and plasma samples and the authors do not mention if these leiomyosarcomas arise from uterine tissues or not.	('mutations', 'Var', (66, 75))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (153, 167))	('leiomyosarcomas', 'Disease', (153, 168))	('leiomyosarcomas arise', 'Phenotype', 'HP:0100243', (153, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (153, 168))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (153, 168))
50618	30558398	p53 mutation and increased ERbeta expression might be involved in the etiology of S-uMMMT.	('increased', 'PosReg', (17, 26))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('expression', 'MPA', (34, 44))	('mutation', 'Var', (4, 12))	('increased ERbeta', 'Phenotype', 'HP:0003141', (17, 33))	('S-uMMMT', 'Disease', (82, 89))	('ERbeta', 'Gene', '2100', (27, 33))	('involved', 'Reg', (54, 62))	('ERbeta', 'Gene', (27, 33))
50628	30558398	SERMs or their metabolites may induce a germline or somatic mutation in certain genes, or even epigenetic modifications, resulting in increased oncogenicity and/or invasiveness.	('invasiveness', 'CPA', (164, 176))	('induce', 'Reg', (31, 37))	('ER', 'Gene', '2099', (1, 3))	('increased', 'PosReg', (134, 143))	('germline', 'Var', (40, 48))	('oncogenicity', 'CPA', (144, 156))	('genes', 'Gene', (80, 85))	('epigenetic modifications', 'Var', (95, 119))
50630	30558398	BRCA1 mutation carriers are predisposed to ovarian or uterine papillary serous carcinoma, from which uMMMTs often arise through sarcomatous transformation of high-grade serous carcinomas.	('sarcomatous', 'Disease', 'MESH:D018316', (128, 139))	('BRCA1', 'Gene', (0, 5))	('papillary serous carcinoma', 'Disease', 'MESH:D002291', (62, 88))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (128, 154))	('predisposed', 'Reg', (28, 39))	('papillary serous carcinoma', 'Disease', (62, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('mutation', 'Var', (6, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomatous', 'Disease', (128, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('serous carcinomas', 'Disease', 'MESH:D018284', (169, 186))	('BRCA1', 'Gene', '672', (0, 5))	('serous carcinomas', 'Disease', (169, 186))	('ovarian', 'Disease', (43, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
50664	30558398	In contrast, strong immunoreactivity or complete negativity was present in all 11 patients whose S-uMMMT tissue was available for p53 immunostaining, suggesting that a new p53 mutation had occurred in the uterine tumor.	('tumor', 'Disease', (213, 218))	('patients', 'Species', '9606', (82, 90))	('p53', 'Gene', '7157', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('p53', 'Gene', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('mutation', 'Var', (176, 184))	('uterine tumor', 'Phenotype', 'HP:0010784', (205, 218))	('p53', 'Gene', '7157', (130, 133))	('p53', 'Gene', (172, 175))
50673	30558398	The rate of lymph node metastasis was slightly lower in patients with S-uMMMT compared to those with de novo-uMMMT (23.1% vs 45.9%), but the difference was not statistically significant (p = .174).	('lymph node metastasis', 'CPA', (12, 33))	('patients', 'Species', '9606', (56, 64))	('S-uMMMT', 'Var', (70, 77))	('lower', 'NegReg', (47, 52))
50701	30558398	Tamoxifen-resistant cells with increased expression of CUEDC2 may appear, thereby elevating degradation and turnover of ERalpha and conferring resistance to tamoxifen treatment.	('CUEDC2', 'Gene', (55, 61))	('CUEDC2', 'Gene', '79004', (55, 61))	('ERalpha', 'Gene', '2099', (120, 127))	('increased', 'PosReg', (31, 40))	('ERalpha', 'Gene', (120, 127))	('turnover', 'MPA', (108, 116))	('tamoxifen', 'Chemical', 'MESH:D013629', (157, 166))	('conferring', 'Reg', (132, 142))	('degradation', 'MPA', (92, 103))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('elevating', 'PosReg', (82, 91))	('resistance', 'MPA', (143, 153))	('expression', 'Var', (41, 51))
50706	30558398	In conclusion, the immunohistochemical results in our study suggest that both S-uMMMTs and NS-uMMMTs are related to p53 mutation, and clinicopathologic features were similar in all uMMMTs from different backgrounds.	('S-uMMMTs', 'Disease', (78, 86))	('p53', 'Gene', (116, 119))	('related', 'Reg', (105, 112))	('mutation', 'Var', (120, 128))	('p53', 'Gene', '7157', (116, 119))
50707	30558398	Increased ERbeta expression or ratio of ERbeta to ERalpha in postmenopausal women and binding of ERbeta to mutant p53 might induce carcinogenesis, sarcomatous transformation, epithelial mesenchymal transition, and invasiveness in organ tissues expressing both receptors.	('sarcomatous', 'Disease', (147, 158))	('ERbeta', 'Gene', (97, 103))	('p53', 'Gene', (114, 117))	('ERbeta', 'Gene', '2100', (40, 46))	('ERbeta', 'Gene', (40, 46))	('Increased ERbeta', 'Phenotype', 'HP:0003141', (0, 16))	('ERalpha', 'Gene', '2099', (50, 57))	('carcinogenesis', 'Disease', (131, 145))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (147, 173))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('Increased', 'PosReg', (0, 9))	('invasiveness', 'CPA', (214, 226))	('ERbeta', 'Gene', (10, 16))	('women', 'Species', '9606', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('mutant', 'Var', (107, 113))	('p53', 'Gene', '7157', (114, 117))	('binding', 'Interaction', (86, 93))	('induce', 'PosReg', (124, 130))	('sarcomatous', 'Disease', 'MESH:D018316', (147, 158))	('ERbeta', 'Gene', '2100', (10, 16))	('ERalpha', 'Gene', (50, 57))	('epithelial mesenchymal transition', 'CPA', (175, 208))	('ERbeta', 'Gene', '2100', (97, 103))
50724	28945214	A decade later, different molecular profiles have been described for each category with PTEN gene silencing, DNA mismatch repair genes defects, and KRAS and PIK3CA gene mutations being the major alterations in type I, whereas type II tumors harbor p53 gene mutations, p16 gene inactivation, Her-2/neu overexpression, and loss of heterozygosity on several chromosomes.	('KRAS', 'Gene', (148, 152))	('mutations', 'Var', (257, 266))	('type II tumors', 'Disease', (226, 240))	('p53', 'Gene', '7157', (248, 251))	('p16', 'Gene', '1029', (268, 271))	('Her-2/neu', 'Gene', '2064', (291, 300))	('PIK3CA', 'Gene', (157, 163))	('defects', 'NegReg', (135, 142))	('p53', 'Gene', (248, 251))	('silencing', 'NegReg', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('loss of heterozygosity', 'Var', (321, 343))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('type II tumors', 'Disease', 'MESH:D009369', (226, 240))	('Her-2/neu', 'Gene', (291, 300))	('PTEN', 'Gene', (88, 92))	('PIK3CA', 'Gene', '5290', (157, 163))	('inactivation', 'NegReg', (277, 289))	('overexpression', 'PosReg', (301, 315))	('KRAS', 'Gene', '3845', (148, 152))	('PTEN', 'Gene', '5728', (88, 92))	('p16', 'Gene', (268, 271))	('DNA mismatch repair genes', 'Gene', (109, 134))
50763	28945214	Shorter DFI was significantly associatedwitholderageat diagnosis(>70years), advanced-stage disease, adnexal involvement, and deep MI (P = 0.005, P = 0.001, P = 0.001, and P = 0.003, respectively).	('associatedwitholderageat diagnosis', 'Disease', (30, 64))	('Shorter', 'Var', (0, 7))	('deep MI', 'Disease', (125, 132))	('advanced-stage disease', 'Disease', (76, 98))	('deep MI', 'Disease', 'MESH:D057887', (125, 132))	('adnexal involvement', 'Disease', (100, 119))
50792	28945214	In agreement with these results, our study showed that patients who received radiation therapy had significantly better 5-year OS, whereas patients who received both radiotherapy and chemotherapy or chemotherapy alone had no improvement in their outcomes.	('patients', 'Species', '9606', (139, 147))	('better', 'PosReg', (113, 119))	('5-year OS', 'CPA', (120, 129))	('patients', 'Species', '9606', (55, 63))	('radiation therapy', 'Var', (77, 94))	('OS', 'Chemical', '-', (127, 129))
50820	29622464	After adjusting for sample size per tumor type, we found 23 genes (including ARID1A, ERBB3, BRCA1, FBXW7, KMT2C, PIK3CA, PIK3R1, PPP2R1A, PTEN, and TP53) that were mutated at higher frequencies across the Pan-Gyn tumor types than across the non-Gyn types (FDR < 0.01, Fisher's Exact test) (Figure 1A).	('ARID1A', 'Gene', '8289', (77, 83))	('PIK3CA', 'Gene', '5290', (113, 119))	('TP53', 'Gene', (148, 152))	('KMT2C', 'Gene', '58508', (106, 111))	('KMT2C', 'Gene', (106, 111))	('mutated', 'Var', (164, 171))	('PPP2R1A', 'Gene', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', (36, 41))	('FBXW7', 'Gene', '55294', (99, 104))	('ERBB3', 'Gene', '2065', (85, 90))	('PTEN', 'Gene', (138, 142))	('PIK3R1', 'Gene', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PIK3CA', 'Gene', (113, 119))	('PTEN', 'Gene', '5728', (138, 142))	('Pan', 'Gene', '51816', (205, 208))	('TP53', 'Gene', '7157', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (213, 218))	('ARID1A', 'Gene', (77, 83))	('Pan', 'Gene', (205, 208))	('ERBB3', 'Gene', (85, 90))	('FBXW7', 'Gene', (99, 104))	('PIK3R1', 'Gene', '5295', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('BRCA1', 'Gene', '672', (92, 97))	('PPP2R1A', 'Gene', '5518', (129, 136))	('BRCA1', 'Gene', (92, 97))
50823	29622464	We identified 61 significant regions in the Pan-Gyn tumors, 27 amplifications and 34 deletions, of which 12 amplifications and 6 deletions were not found in the non-Gyn cohort, suggesting relative specificity for Pan-Gyn tumors (Figure 1B, Figure S1A & Table S1).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Pan-Gyn tumors', 'Disease', (44, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('deletions', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('Pan-Gyn tumors', 'Disease', (213, 227))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('Pan-Gyn tumors', 'Disease', 'MESH:C537931', (44, 58))	('Pan-Gyn tumors', 'Disease', 'MESH:C537931', (213, 227))
50824	29622464	Two of the 12 uniquely Pan-Gyn amplifications and one of the six deletions had not previously been reported in single-disease TCGA studies of the same tumor types.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Pan', 'Gene', (23, 26))	('Pan', 'Gene', '51816', (23, 26))	('tumor', 'Disease', (151, 156))	('amplifications', 'Var', (31, 45))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
50830	29622464	MAP2K4 and NF1 were notable tumor suppressor genes with recurring copy number losses specific to Pan-Gyn tumors, whereas PTPRD, RBFOX1, and TP53 were among the tumor suppressors more commonly deleted in non-Gyn samples.	('tumor', 'Disease', (28, 33))	('Pan-Gyn tumors', 'Disease', 'MESH:C537931', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('MAP2K4', 'Gene', '6416', (0, 6))	('MAP2K4', 'Gene', (0, 6))	('TP53', 'Gene', (140, 144))	('RBFOX1', 'Gene', '54715', (128, 134))	('RBFOX1', 'Gene', (128, 134))	('NF1', 'Gene', '4763', (11, 14))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('NF1', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (160, 165))	('Pan-Gyn tumors', 'Disease', (97, 111))	('TP53', 'Gene', '7157', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('losses', 'NegReg', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('copy number', 'Var', (66, 77))
50831	29622464	Significantly recurring deletions were found in known or putative fragile site genes, including LRRN3 (7q31.1) in non-Gyn, ANKS1B (12q23.1) in Pan-Gyn, and RAD51B (14q24) in both cohorts.	('ANKS1B', 'Gene', (123, 129))	('LRRN3', 'Gene', '54674', (96, 101))	('RAD51B', 'Gene', '5890', (156, 162))	('LRRN3', 'Gene', (96, 101))	('RAD51B', 'Gene', (156, 162))	('deletions', 'Var', (24, 33))	('Pan', 'Gene', (143, 146))	('Pan', 'Gene', '51816', (143, 146))	('ANKS1B', 'Gene', '56899', (123, 129))
50834	29622464	We performed bootstrapping-based analyses to investigate whether there were greater numbers of shared mutated or copy-number altered genes among the five Pan-Gyn tumor types vs. random sets of five tumor types.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Pan', 'Gene', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (162, 167))	('copy-number altered', 'Var', (113, 132))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Pan', 'Gene', '51816', (154, 157))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
50836	29622464	We analyzed 2,258 patient samples with mutation data from TCGA for SMGs and operative mutational processes across the Pan-Gyn tumor types.	('mutation', 'Var', (39, 47))	('SMGs', 'Disease', (67, 71))	('Pan', 'Gene', '51816', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patient', 'Species', '9606', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('TCGA', 'Gene', (58, 62))	('Pan', 'Gene', (118, 121))	('tumor', 'Disease', (126, 131))
50839	29622464	Among them, ACVR2A, a member of the TGF-beta superfamily that functions in pathways implicated in both tumor progression and suppression, was the most frequently mutated (in 4.8% of the cohort).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('mutated', 'Var', (162, 169))	('ACVR2A', 'Gene', (12, 18))	('ACVR2A', 'Gene', '92', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
50843	29622464	Mutation signatures have provided insight into mechanisms underlying tumor development and have informed patient therapy.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patient', 'Species', '9606', (105, 112))	('tumor', 'Disease', (69, 74))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
50848	29622464	A smaller correlation was found between S10 and COSMIC signature 3 (r = 0.58), associated with germline and somatic BRCA1 and BRCA2 mutations.	('BRCA1', 'Gene', (116, 121))	('mutations', 'Var', (132, 141))	('BRCA2', 'Gene', (126, 131))	('S10', 'Gene', '3897', (40, 43))	('BRCA1', 'Gene', '672', (116, 121))	('S10', 'Gene', (40, 43))	('BRCA2', 'Gene', '675', (126, 131))
50850	29622464	Cluster C1 was highly enriched with OV samples (and basal BRCA and UCEC to a lesser extent) and contributed strongly to S10, a signature associated with germline and somatic BRCA1 and BRCA2 mutations that correlate with responsiveness to PARP inhibitors and platinum-based therapy.	('BRCA2', 'Gene', (184, 189))	('BRCA', 'Gene', (174, 178))	('BRCA', 'Gene', '672', (174, 178))	('S10', 'Gene', (120, 123))	('BRCA1', 'Gene', (174, 179))	('BRCA', 'Gene', '672', (58, 62))	('mutations', 'Var', (190, 199))	('BRCA', 'Gene', (58, 62))	('BRCA', 'Gene', '672', (184, 188))	('BRCA2', 'Gene', '675', (184, 189))	('platinum', 'Chemical', 'MESH:D010984', (258, 266))	('BRCA', 'Gene', (184, 188))	('PARP', 'Gene', '1302', (238, 242))	('S10', 'Gene', '3897', (120, 123))	('BRCA1', 'Gene', '672', (174, 179))	('PARP', 'Gene', (238, 242))
50851	29622464	C1 also had samples with frequent TP53 mutations and homozygous deletions, supporting the association with an ineffective DNA double-strand break repair COSMIC signature.	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))
50852	29622464	C2, which contained BRCA, OV, and UCEC samples, was associated with transcriptional strand bias for T>C substitutions, whereas C3, which contained BRCA and OV samples, was associated with transcriptional strand bias for T>A mutations.	('BRCA', 'Gene', '672', (20, 24))	('BRCA', 'Gene', (147, 151))	('substitutions', 'Var', (104, 117))	('BRCA', 'Gene', (20, 24))	('associated', 'Reg', (52, 62))	('T>C', 'Gene', (100, 103))	('transcriptional', 'MPA', (68, 83))	('BRCA', 'Gene', '672', (147, 151))
50853	29622464	C5, principally composed of UCEC tumors with high microsatellite instability and mutations in MLH1, MSH2, MSH3, or MSH6, contributed most strongly to signature S6.	('MLH1', 'Gene', (94, 98))	('MSH6', 'Gene', (115, 119))	('MSH3', 'Gene', (106, 110))	('MSH2', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('MSH2', 'Gene', '4436', (100, 104))	('MSH6', 'Gene', '2956', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (81, 90))	('MSH3', 'Gene', '4437', (106, 110))	('MLH1', 'Gene', '4292', (94, 98))	('tumors', 'Disease', (33, 39))
50854	29622464	C9 comprised CESC and BRCA samples and represented the AID/APOBEC signatures S1 and S2, providing further evidence for enrichment of APOBEC mutagenesis in these cancers.	('BRCA', 'Gene', '672', (22, 26))	('AID', 'Gene', (55, 58))	('AID', 'Gene', '57379', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('mutagenesis', 'Var', (140, 151))	('BRCA', 'Gene', (22, 26))
50865	29622464	The left branch with lower degrees of hypermethylation consisted of the majority of OV and UCS, normal and basal-like BRCA, and microsatellite stable UCECs (both endometrioid and serous subtype).	('BRCA', 'Gene', (118, 122))	('microsatellite', 'Var', (128, 142))	('BRCA', 'Gene', '672', (118, 122))
50866	29622464	The hypermethylator (right) cluster included most CESC tumors, the majority of BRCA, and microsatellite unstable UCEC.	('microsatellite unstable', 'Var', (89, 112))	('BRCA', 'Gene', '672', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('BRCA', 'Gene', (79, 83))	('CESC tumors', 'Disease', (50, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('CESC tumors', 'Disease', 'MESH:D009369', (50, 61))
50870	29622464	Hypermethylation and concomitant down-regulation of two genes in the Homologous Repair (HR) pathway, BRCA1 and RAD51C, were observed almost exclusively in OV (12.7% and 3.0%, respectively) and basal-like BRCA cancers (2.8% and 2.6%, respectively).	('RAD51C', 'Gene', (111, 117))	('BRCA cancers', 'Disease', 'MESH:D009369', (204, 216))	('BRCA cancers', 'Disease', (204, 216))	('RAD51C', 'Gene', '5889', (111, 117))	('BRCA1', 'Gene', '672', (101, 106))	('Hypermethylation', 'Var', (0, 16))	('down-regulation', 'NegReg', (33, 48))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('BRCA1', 'Gene', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
50900	29622464	We used cluster assignments from the six major TCGA platforms (mutations, SCNA, DNA methylation, mRNA, miRNA, and protein) to perform integrated clustering across the Pan-Gyn cohort using the CoCA algorithm (Figure S6A).	('mutations', 'Var', (63, 72))	('CoCA', 'Species', '289672', (192, 196))	('Pan', 'Gene', (167, 170))	('Pan', 'Gene', '51816', (167, 170))
50909	29622464	Interestingly, samples with ERBB2 amplification fell into two main clusters; those in clusters C3 (n = 39) and C4 (n = 30) showed high and low immune infiltration levels, respectively (purple and black rectangles in Figure 7A).	('low', 'NegReg', (139, 142))	('ERBB2', 'Gene', '2064', (28, 33))	('ERBB2', 'Gene', (28, 33))	('amplification', 'Var', (34, 47))	('immune infiltration levels', 'MPA', (143, 169))
50919	29622464	ERBB2 mutation and amplification were mutually exclusive, but both sets of tumors might benefit from HER2-targeted therapy.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('HER2', 'Gene', (101, 105))	('benefit', 'Reg', (88, 95))	('ERBB2', 'Gene', '2064', (0, 5))	('HER2', 'Gene', '2064', (101, 105))	('mutation', 'Var', (6, 14))	('ERBB2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
50932	29622464	Immune-high HER2+ tumors showed a trend toward longer survival than their immune-low counterpart, but the difference was not quite statistically significant for the sample size available.	('longer', 'PosReg', (47, 53))	('HER2', 'Gene', (12, 16))	('HER2', 'Gene', '2064', (12, 16))	('Immune-high', 'Var', (0, 11))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('survival', 'CPA', (54, 62))
26790	29622464	This step realigns reads at sites that potentially harbor small insertions or deletions in either the tumor or the matched normal, to decrease the number of false positive single nucleotide variations caused by misaligned reads.	('insertions', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (78, 87))
50948	29622464	Firehose (http://www.broadinstitute.org/cancer/cga/Firehose) takes the BAM files for the tumor and patient-matched normal samples and performs analyses including quality control, local realignment, mutation calling, small insertion and deletion identification, rearrangement detection, coverage calculations and others as described briefly below.	('patient', 'Species', '9606', (99, 106))	('small insertion', 'Var', (216, 231))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('deletion', 'Var', (236, 244))	('mutation calling', 'Var', (198, 214))	('tumor', 'Disease', (89, 94))	('cancer', 'Disease', (40, 46))	('rearrangement', 'Var', (261, 274))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cga', 'Gene', '1113', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cga', 'Gene', (47, 50))
50950	29622464	Sequencing data were processed using two consecutive pipelines:  We identified the mutation and CNV events, which are enriched in gynecologic cancers (BRCA, UCEC, CESC, UCS, and OV) compared to all other cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('BRCA', 'Gene', '672', (151, 155))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('CESC', 'Disease', (163, 167))	('cancers', 'Disease', (142, 149))	('cancers', 'Disease', (204, 211))	('BRCA', 'Gene', (151, 155))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('UCEC', 'Disease', (157, 161))	('mutation', 'Var', (83, 91))	('CNV', 'Gene', (96, 99))	('UCS', 'Disease', (169, 172))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
50973	29622464	For every pyrimidine substitution (C>A, C>G, C>T, T>A, T>C and T>G) we used the 5' and 3' base according to the hg19 human reference genome (http://hgdownload.cse.ucsc.edu/) creating 96 possible mutation contexts as described by Alexandrov et al.	('C>G', 'Var', (40, 43))	('T>C and T>G', 'Var', (55, 66))	('human', 'Species', '9606', (117, 122))	('C>T', 'Var', (45, 48))	('T>A', 'Var', (50, 53))	('T>G', 'Var', (63, 66))	('C>A', 'Var', (35, 38))
50979	29622464	The unsupervised hierarchical clustering, utilizing Ward's objective function and a Euclidean distance metric, was performed on the amplification and deletion lesions predicted by GISTIC2.0 across the gynecologic cancers.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('deletion', 'Var', (150, 158))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancers', 'Disease', (213, 220))
50986	29622464	Unsupervised and dichotomized clustering was performed based on a set of cancer-specific autosomal loci, which were defined as unmethylated in normal tissues and blood cells (mean beta value < 0.2 for each tissue types), but methylated in more than 5% samples of each tumor type included in this analysis (beta value > 0.3).	('methylated', 'Var', (225, 235))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (268, 273))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('autosomal loci', 'Gene', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
51001	29622464	Cluster of Cluster Assignments (CoCA) analysis was performed using the cluster assignments from each of the 6 major platforms (mutations, CNV, DNA methylation, mRNA, miRNA, and protein).	('mRNA', 'MPA', (160, 164))	('mutations', 'Var', (127, 136))	('DNA', 'MPA', (143, 146))	('CoCA', 'Species', '289672', (32, 36))
51003	29622464	Features belonging to the former group were (i) protein expression of ER and PR, BRCA1/BRCA2 mutation status, ERBB2 amplification status, and HPV status.	('BRCA1', 'Gene', (81, 86))	('mutation status', 'Var', (93, 108))	('protein expression', 'MPA', (48, 66))	('BRCA2', 'Gene', '675', (87, 92))	('ER', 'Gene', '2099', (70, 72))	('ER', 'Gene', '2099', (110, 112))	('ERBB2', 'Gene', '2064', (110, 115))	('BRCA1', 'Gene', '672', (81, 86))	('ERBB2', 'Gene', (110, 115))	('BRCA2', 'Gene', (87, 92))
51004	29622464	Features in the latter group were (ii) MSI status, hyper-mutator status (>10 mutations/mbp), SCNA load, AR protein expression, leukocyte infiltration score based on DNA methylation, and mutation status of PTEN, TP53, H-RAS/K-RAS/N-RAS, ERBB2, PIK3CA, and POLE.	('PTEN', 'Gene', '5728', (205, 209))	('TP53', 'Gene', (211, 215))	('mutation', 'Var', (186, 194))	('PIK3CA', 'Gene', (243, 249))	('N-RAS', 'Gene', (229, 234))	('K-RAS', 'Gene', (223, 228))	('MSI', 'Gene', (39, 42))	('MSI', 'Gene', '5928', (39, 42))	('H-RAS', 'Gene', (217, 222))	('mbp', 'Gene', '4155', (87, 90))	('K-RAS', 'Gene', '3845', (223, 228))	('ERBB2', 'Gene', (236, 241))	('TP53', 'Gene', '7157', (211, 215))	('H-RAS', 'Gene', '3265', (217, 222))	('mbp', 'Gene', (87, 90))	('PTEN', 'Gene', (205, 209))	('ERBB2', 'Gene', '2064', (236, 241))	('N-RAS', 'Gene', '4893', (229, 234))	('PIK3CA', 'Gene', '5290', (243, 249))
51005	29622464	We then combined N-RAS, H-RAS, and K-RAS mutations into a single feature (using OR logic), and BRCA1 and BRCA2 mutations into another single feature (again using OR logic), yielding a final tally of 16 features.	('mutations', 'Var', (41, 50))	('mutations', 'Var', (111, 120))	('N-RAS', 'Gene', '4893', (17, 22))	('BRCA1', 'Gene', (95, 100))	('K-RAS', 'Gene', '3845', (35, 40))	('BRCA2', 'Gene', (105, 110))	('H-RAS', 'Gene', '3265', (24, 29))	('K-RAS', 'Gene', (35, 40))	('BRCA2', 'Gene', '675', (105, 110))	('N-RAS', 'Gene', (17, 22))	('BRCA1', 'Gene', '672', (95, 100))	('H-RAS', 'Gene', (24, 29))
51007	29622464	Eleven of those features were discrete (all the mutations, MSI status, hyper-mutator status, ERBB2 amplifications, and HPV status), whereas the remaining 5 features (CNV load, immune score, ER, PR, and AR protein expressions) were continuous.	('ER', 'Gene', '2099', (190, 192))	('mutations', 'Var', (48, 57))	('ER', 'Gene', '2099', (93, 95))	('ERBB2', 'Gene', (93, 98))	('ERBB2', 'Gene', '2064', (93, 98))	('MSI', 'Gene', '5928', (59, 62))	('MSI', 'Gene', (59, 62))
51011	29622464	For both mutations and high-level amplifications, the normalized mutated vs. non-mutated counts in gynecological vs. non-gynecological cancers formed the 2x2 contingency table for each gene.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('mutations', 'Var', (9, 18))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
51014	29622464	The TSG score used the ratio of inactivating mutations (nonsense and frameshift mutations, and variants that affected splice sites) in a specific transcript.	('frameshift mutations', 'Var', (69, 89))	('TSG', 'Gene', (4, 7))	('splice', 'MPA', (118, 124))	('TSG', 'Gene', '57045', (4, 7))
51016	29622464	For the second method, we used the MutSigCV v1.4 (www.broadinstitute.org) to infer significant cancer mutated genes across all PanGyn samples.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('Pan', 'Gene', (127, 130))	('Pan', 'Gene', '51816', (127, 130))	('mutated genes', 'Var', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
51036	28514723	Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (377, 386))	('woman', 'Species', '9606', (198, 203))	('CHEK2:c.1100delC', 'Var', (247, 263))	('CHEK2:c.1100delC', 'DELETION', 'None', (247, 263))	('pelvic genital type leiomyosarcoma', 'Disease', 'MESH:D007890', (298, 332))	('sarcoma', 'Phenotype', 'HP:0100242', (325, 332))	('breast carcinoma', 'Phenotype', 'HP:0003002', (370, 386))	('invasive ductal breast carcinoma', 'Disease', (354, 386))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (318, 332))	('woman', 'Species', '9606', (61, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (151, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (41, 55))	('pelvic genital type leiomyosarcoma', 'Disease', (21, 55))	('LMS', 'Phenotype', 'HP:0100243', (334, 337))	('breast carcinoma', 'Phenotype', 'HP:0003002', (167, 183))	('pelvic genital type leiomyosarcoma', 'Disease', (298, 332))	('genital type leiomyosarcoma', 'Disease', 'MESH:D007890', (305, 332))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (354, 386))	('CHEK2:c.1100delC', 'DELETION', 'None', (83, 99))	('CHEK2:c.1100delC', 'Var', (83, 99))	('genital type leiomyosarcoma', 'Disease', 'MESH:D007890', (28, 55))	('invasive ductal breast carcinoma', 'Disease', (151, 183))	('pelvic genital type leiomyosarcoma', 'Disease', 'MESH:D007890', (21, 55))
51038	28514723	The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk.	('CHEK2:c.1100delC', 'Var', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('increase', 'PosReg', (99, 107))	('CHEK2:c.1100delC', 'DELETION', 'None', (4, 20))
51040	28514723	Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CHEK2', 'Gene', '11200', (90, 95))	('double-strand DNA damage pathway', 'Pathway', (56, 88))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CHEK2', 'Gene', (90, 95))	('variants', 'Var', (152, 160))	('tumor', 'Disease', (163, 168))	('RAD51B', 'Gene', (126, 132))	('RAD51B', 'Gene', '5890', (126, 132))
51042	28514723	This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma.	('invasive ductal breast carcinoma', 'Disease', (148, 180))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (148, 180))	('LMS', 'Phenotype', 'HP:0100243', (28, 31))	('CHEK2:c.1100delC', 'Var', (81, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('patient', 'Species', '9606', (55, 62))	('breast carcinoma', 'Phenotype', 'HP:0003002', (164, 180))	('CHEK2:c.1100delC', 'DELETION', 'None', (81, 97))
51044	28514723	Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis.	('HMGA2', 'Gene', (51, 56))	('play', 'Reg', (76, 80))	('overexpression', 'PosReg', (57, 71))	('RAD51B', 'Gene', (26, 32))	('RAD51B', 'Gene', '5890', (26, 32))	('LMS', 'Disease', (102, 105))	('HMGA2', 'Gene', '8091', (51, 56))	('translocation', 'Var', (33, 46))	('LMS', 'Phenotype', 'HP:0100243', (102, 105))
51046	28514723	Multiple case-control studies have reported an association between the truncating variant CHEK2:c.1100delC (NM_007194.3:c.1100delC, rs555607708, hg19 Chr22:g.29091856AG>A) in the heterozygous state and breast cancer risk in BRCA1/BRCA2-mutation-negative women.	('rs555607708', 'Mutation', 'rs555607708', (132, 143))	('CHEK2:c.1100delC', 'DELETION', 'None', (90, 106))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('BRCA1', 'Gene', '672', (224, 229))	('breast cancer', 'Disease', (202, 215))	('NM_007194.3:c.1100delC', 'Mutation', 'rs555607708', (108, 130))	('CHEK2:c.1100delC', 'Var', (90, 106))	('BRCA2', 'Gene', (230, 235))	('BRCA1', 'Gene', (224, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('women', 'Species', '9606', (254, 259))	('rs555607708', 'Var', (132, 143))	('Chr22:g.29091856AG>A', 'SUBSTITUTION', 'None', (150, 170))	('BRCA2', 'Gene', '675', (230, 235))	('Chr22:g.29091856AG>A', 'Var', (150, 170))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
51047	28514723	The consensus view is that this variant confers an approximately twofold increase in breast cancer risk above that of the general population and is a moderate penetrance allele.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('variant', 'Var', (32, 39))	('increase', 'PosReg', (73, 81))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
51048	28514723	Breast cancers associated with CHEK2:c.1100delC are predominantly estrogen receptor (ER)-positive.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('CHEK2:c.1100delC', 'DELETION', 'None', (31, 47))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('CHEK2:c.1100delC', 'Var', (31, 47))	('estrogen receptor', 'Gene', (66, 83))	('estrogen receptor', 'Gene', '2099', (66, 83))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('Breast cancers', 'Disease', (0, 14))	('ER', 'Gene', '2099', (85, 87))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))
51049	28514723	More recently, CHEK2:c.1100delC has been associated with an increased risk of other cancers (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.15-1.82), among which stomach (HR 5.76, 95% CI 2.12-15.6) and kidney (HR 3.61, 95% CI 1.33-9.79) cancers, as well as sarcomas (HR 3.45, 95% CI 1.09-10.9), displayed the highest increase in risk.	('sarcomas', 'Disease', 'MESH:D012509', (265, 273))	('sarcomas', 'Phenotype', 'HP:0100242', (265, 273))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('sarcomas', 'Disease', (265, 273))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (245, 252))	('cancers', 'Disease', (84, 91))	('stomach', 'Disease', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('kidney', 'Disease', (210, 216))	('CHEK2:c.1100delC', 'DELETION', 'None', (15, 31))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('CHEK2:c.1100delC', 'Var', (15, 31))
51050	28514723	Furthermore, this variant, in its homozygous state, has also been reported in some families with Li-Fraumeni syndrome type 2 (MIM #609265).	('variant', 'Var', (18, 25))	('Li-Fraumeni syndrome type 2', 'Disease', (97, 124))	('Li-Fraumeni syndrome type 2', 'Disease', 'MESH:C563755', (97, 124))	('reported', 'Reg', (66, 74))
51052	28514723	As per the Exome Aggregation Consortium (ExAC) database, the highest minor allele frequency of CHEK2:c.1100delC (NM_007194.3, rs555607708) is in the Finnish population at ~0.008, followed by non-Finn Europeans at 0.002.	('Finn', 'Species', '1754191', (149, 153))	('CHEK2:c.1100delC', 'DELETION', 'None', (95, 111))	('rs555607708', 'Var', (126, 137))	('rs555607708', 'Mutation', 'rs555607708', (126, 137))	('CHEK2:c.1100delC', 'Var', (95, 111))	('Finn', 'Species', '1754191', (195, 199))
51053	28514723	An optimal treatment regime specifically for breast cancer patients carrying the CHEK2:c.1100delC mutation has yet to be elucidated, and it is still unknown why these patients have poorer prognosis when compared with noncarriers or why they are at increased risk of a second metachronous breast cancer.	('breast cancer', 'Disease', (288, 301))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('CHEK2:c.1100delC', 'Var', (81, 97))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('patients', 'Species', '9606', (167, 175))	('breast cancer', 'Disease', (45, 58))	('patients', 'Species', '9606', (59, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (288, 301))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('breast cancer', 'Disease', 'MESH:D001943', (288, 301))	('CHEK2:c.1100delC', 'DELETION', 'None', (81, 97))
51055	28514723	We identified the CHEK2:c.1100delC variant in the LMS tumor sample as well as the blood from a patient with concomitant diagnoses of both pelvic genital type LMS and metastatic invasive ductal breast carcinoma.	('patient', 'Species', '9606', (95, 102))	('invasive ductal breast carcinoma', 'Disease', (177, 209))	('CHEK2:c.1100delC', 'DELETION', 'None', (18, 34))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (177, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('LMS tumor', 'Disease', 'MESH:C535903', (50, 59))	('breast carcinoma', 'Phenotype', 'HP:0003002', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CHEK2:c.1100delC', 'Var', (18, 34))	('pelvic genital type LMS', 'Disease', 'MESH:C535903', (138, 161))	('LMS', 'Phenotype', 'HP:0100243', (50, 53))	('pelvic genital type LMS', 'Disease', (138, 161))	('LMS tumor', 'Disease', (50, 59))	('LMS', 'Phenotype', 'HP:0100243', (158, 161))
51087	28514723	Whole-genome sequencing of a fresh-frozen core biopsy sampling of the LMS (in comparison with whole-genome sequencing of matched peripheral blood) revealed the heterozygous germline CHEK2:c.1100delC truncating variant, present in the germline and retained in the tumor.	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('CHEK2:c.1100delC', 'Var', (182, 198))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('LMS', 'Phenotype', 'HP:0100243', (70, 73))	('tumor', 'Disease', (263, 268))	('CHEK2:c.1100delC', 'DELETION', 'None', (182, 198))
51088	28514723	There was no evidence of a second somatic aberration to the wild-type CHEK2 allele such as loss of heterozygosity (LOH) or a second somatic CHEK2 pathogenic variant.	('CHEK2', 'Gene', (140, 145))	('CHEK2', 'Gene', '11200', (70, 75))	('CHEK2', 'Gene', (70, 75))	('variant', 'Var', (157, 164))	('loss', 'NegReg', (91, 95))	('CHEK2', 'Gene', '11200', (140, 145))
51094	28514723	Of note, a somatic BRCA1 variant of uncertain significance was also identified (p.Gln1327His) and BRCA1 expression appeared comparable to other tumors (Table 1).	('tumors', 'Disease', (144, 150))	('p.Gln1327His', 'Mutation', 'p.Q1327H', (80, 92))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('BRCA1', 'Gene', '672', (19, 24))	('BRCA1', 'Gene', '672', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('BRCA1', 'Gene', (19, 24))	('p.Gln1327His', 'Var', (80, 92))	('BRCA1', 'Gene', (98, 103))
51099	28514723	The second structural variant is a translocation t(12;14)(q14.3;q24.1)(g.65999147;g.68758275) event disrupting RAD51B in intron 7 (NM_133510.3, ENST00000471583) on Chromosome 14 (Fig.	('RAD51B', 'Gene', (111, 117))	('RAD51B', 'Gene', '5890', (111, 117))	('g.65999147', 'Var', (71, 81))	('disrupting', 'NegReg', (100, 110))	('t(12;14)(q14.3;q24.1)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 70))
51106	28514723	Interestingly enough, FH mutations lead to a hereditary cancer predisposition: hereditary leiomyomatosis renal cell carcinoma syndrome.	('mutations', 'Var', (25, 34))	('hereditary cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('hereditary leiomyomatosis renal cell carcinoma syndrome', 'Disease', 'MESH:C535516', (79, 134))	('lead to', 'Reg', (35, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('hereditary cancer', 'Disease', 'MESH:D009369', (45, 62))
51107	28514723	A duplication involving the majority of the Chromosome X long arm leads to ATRX (Xq21.1) and MED12 (Xq13.1) copy gains.	('ATRX', 'Gene', (75, 79))	('MED12', 'Gene', '9968', (93, 98))	('duplication', 'Var', (2, 13))	('ATRX', 'Gene', '546', (75, 79))	('MED12', 'Gene', (93, 98))
51108	28514723	ATRX and MED12 loss-of-function variants have been implicated in leiomyoma and LMS pathophysiology (Discussion and Supplemental Discussion), but no such variants were seen in our sample.	('leiomyoma', 'Disease', (65, 74))	('LMS', 'Phenotype', 'HP:0100243', (79, 82))	('MED12', 'Gene', '9968', (9, 14))	('ATRX', 'Gene', (0, 4))	('leiomyoma', 'Disease', 'MESH:D007889', (65, 74))	('variants', 'Var', (32, 40))	('ATRX', 'Gene', '546', (0, 4))	('MED12', 'Gene', (9, 14))	('loss-of-function', 'NegReg', (15, 31))	('LMS', 'Disease', (79, 82))
51109	28514723	Cancers have specific recurrent mutational signatures (patterns) associated with their underlying somatic molecular pathogenesis and these signatures guide the interpretation of genomic events leading to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutational', 'Var', (32, 42))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('tumor', 'Disease', (204, 209))
51112	28514723	In summary, we describe the findings of genomic profiling in an LMS patient with a germline CHEK2:c.1100delC variant and concomitant diagnosis of metastatic invasive ductal breast carcinoma.	('CHEK2:c.1100delC', 'Var', (92, 108))	('patient', 'Species', '9606', (68, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('breast carcinoma', 'Phenotype', 'HP:0003002', (173, 189))	('invasive ductal breast carcinoma', 'Disease', (157, 189))	('LMS', 'Phenotype', 'HP:0100243', (64, 67))	('CHEK2:c.1100delC', 'DELETION', 'None', (92, 108))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (157, 189))
51113	28514723	Of the known recurrent mutations and large rearrangements observed in leiomyomas and LMSs (Supplemental Discussion), the analysis of our patient's tumor revealed a translocation t(12;14) with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2, a large 16q deletion encompassing FANCA (reported in two cases) (Beck et al.	('disrupting', 'NegReg', (207, 217))	('FANCA', 'Gene', '2175', (303, 308))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('leiomyomas', 'Disease', (70, 80))	('FANCA', 'Gene', (303, 308))	('patient', 'Species', '9606', (137, 144))	('RAD51B', 'Gene', '5890', (218, 224))	('RAD51B', 'Gene', (218, 224))	('mutations', 'Var', (23, 32))	('HMGA2', 'Gene', '8091', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('LMS', 'Phenotype', 'HP:0100243', (85, 88))	('HMGA2', 'Gene', (262, 267))	('leiomyomas', 'Disease', 'MESH:D007889', (70, 80))
51114	28514723	The molecular mechanisms underlying the impact of germline CHEK2 pathogenic variants in relation to tumorigenesis have not been elucidated.	('CHEK2', 'Gene', '11200', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CHEK2', 'Gene', (59, 64))	('tumor', 'Disease', (100, 105))	('variants', 'Var', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
51115	28514723	Somatic CHEK2 point mutations have been identified in osteosarcomas and also rarely in lung and ovarian tumors, but not in other types of sarcomas tested in one study.	('ovarian tumors', 'Phenotype', 'HP:0100615', (96, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('point mutations', 'Var', (14, 29))	('lung and ovarian tumors', 'Disease', 'MESH:D010051', (87, 110))	('identified', 'Reg', (40, 50))	('osteosarcomas', 'Disease', 'MESH:D012516', (54, 67))	('sarcomas', 'Disease', 'MESH:D012509', (59, 67))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcomas', 'Disease', (59, 67))	('sarcomas', 'Disease', (138, 146))	('CHEK2', 'Gene', (8, 13))	('osteosarcomas', 'Disease', (54, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('CHEK2', 'Gene', '11200', (8, 13))	('osteosarcomas', 'Phenotype', 'HP:0002669', (54, 67))
51116	28514723	Despite the involvement of CHEK2 protein in double-strand DNA break (DSB) repair, unlike BRCA1/BRCA2-driven tumors, somatic inactivation of the wild-type allele is uncommon in breast tumors of CHEK2 mutation carriers.	('involvement', 'Reg', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('inactivation', 'Var', (124, 136))	('breast tumors', 'Phenotype', 'HP:0100013', (176, 189))	('tumors', 'Disease', (183, 189))	('CHEK2', 'Gene', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('BRCA2', 'Gene', (95, 100))	('BRCA1', 'Gene', '672', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('CHEK2', 'Gene', (193, 198))	('CHEK2', 'Gene', '11200', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BRCA1', 'Gene', (89, 94))	('mutation', 'Var', (199, 207))	('breast tumors of CHEK2', 'Disease', 'MESH:D001943', (176, 198))	('tumors', 'Disease', (108, 114))	('CHEK2', 'Gene', '11200', (193, 198))	('BRCA2', 'Gene', '675', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('breast tumors of CHEK2', 'Disease', (176, 198))
51119	28514723	Activated CHEK2 then phosphorylates BRCA1 and BRCA2, which in return promotes homology-directed repair, a more accurate DSB repair mechanism when compared with nonhomologous end joining.	('phosphorylates', 'Var', (21, 35))	('BRCA1', 'Gene', (36, 41))	('CHEK2', 'Gene', '11200', (10, 15))	('BRCA2', 'Gene', (46, 51))	('CHEK2', 'Gene', (10, 15))	('promotes', 'PosReg', (69, 77))	('BRCA2', 'Gene', '675', (46, 51))	('BRCA1', 'Gene', '672', (36, 41))	('homology-directed', 'MPA', (78, 95))
51120	28514723	In vivo studies have showed that CHEK2:c.1100delC impairs CHEK2 kinase activity and affects its oligomerization and autophosphorylation.	('affects', 'Reg', (84, 91))	('CHEK2', 'Gene', (58, 63))	('autophosphorylation', 'MPA', (116, 135))	('CHEK2:c.1100delC', 'DELETION', 'None', (33, 49))	('kinase activity', 'MPA', (64, 79))	('CHEK2', 'Gene', '11200', (33, 38))	('oligomerization', 'MPA', (96, 111))	('CHEK2', 'Gene', (33, 38))	('CHEK2:c.1100delC', 'Var', (33, 49))	('CHEK2', 'Gene', '11200', (58, 63))	('impairs', 'NegReg', (50, 57))
51122	28514723	Also, this mutation may affect CHEK2 phosphorylation by ATM, a gene frequently deleted in LMS tumors.	('phosphorylation', 'MPA', (37, 52))	('CHEK2', 'Gene', '11200', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('LMS', 'Phenotype', 'HP:0100243', (90, 93))	('ATM', 'Gene', '472', (56, 59))	('LMS tumors', 'Disease', 'MESH:C535903', (90, 100))	('CHEK2', 'Gene', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('affect', 'Reg', (24, 30))	('mutation', 'Var', (11, 19))	('LMS tumors', 'Disease', (90, 100))	('ATM', 'Gene', (56, 59))
51126	28514723	Mild RAD51B haploinsufficiency was shown to cause a minor increase of sensitivity to DNA-damaging agents in human colon cancer cell lines, whereas more severe RAD51B impairment has been associated with centrosome fragmentation and aneuploidy.	('haploinsufficiency', 'Disease', (12, 30))	('sensitivity to DNA-damaging agents', 'MPA', (70, 104))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Mild', 'Var', (0, 4))	('RAD51B', 'Gene', (159, 165))	('aneuploidy', 'Disease', 'MESH:D000782', (231, 241))	('RAD51B', 'Gene', '5890', (5, 11))	('centrosome fragmentation', 'CPA', (202, 226))	('colon cancer', 'Disease', (114, 126))	('aneuploidy', 'Disease', (231, 241))	('associated', 'Reg', (186, 196))	('increase', 'PosReg', (58, 66))	('RAD51B', 'Gene', '5890', (159, 165))	('impairment', 'NegReg', (166, 176))	('RAD51B', 'Gene', (5, 11))	('human', 'Species', '9606', (108, 113))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('haploinsufficiency', 'Disease', 'MESH:D058495', (12, 30))
51127	28514723	Recurrent translocations involving both RAD51B (14q24.1) and HMGA2 (12q14.3) loci play an important role in the pathogenesis of uterine leiomyoma via impaired cell-cycle checkpoint control and deficient dsDNA repair mechanisms.	('leiomyoma', 'Disease', 'MESH:D007889', (136, 145))	('translocations', 'Var', (10, 24))	('HMGA2', 'Gene', '8091', (61, 66))	('dsDNA repair mechanisms', 'CPA', (203, 226))	('HMGA2', 'Gene', (61, 66))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (128, 145))	('RAD51B', 'Gene', (40, 46))	('cell-cycle checkpoint control', 'CPA', (159, 188))	('RAD51B', 'Gene', '5890', (40, 46))	('impaired', 'NegReg', (150, 158))	('leiomyoma', 'Disease', (136, 145))	('deficient', 'NegReg', (193, 202))
51129	28514723	HMGA2 rearrangements make up a unique subtype of leiomyomas, which also feature overexpression of specific genes: IGF2BP2, PLAG1, IGF2, HMGA2.	('overexpression', 'PosReg', (80, 94))	('IGF2BP2', 'Gene', (114, 121))	('PLAG1', 'Gene', (123, 128))	('rearrangements', 'Var', (6, 20))	('leiomyomas', 'Disease', (49, 59))	('HMGA2', 'Gene', '8091', (136, 141))	('HMGA2', 'Gene', '8091', (0, 5))	('IGF2', 'Gene', '3481', (130, 134))	('IGF2', 'Gene', (114, 118))	('HMGA2', 'Gene', (136, 141))	('HMGA2', 'Gene', (0, 5))	('PLAG1', 'Gene', '5324', (123, 128))	('IGF2BP2', 'Gene', '10644', (114, 121))	('IGF2', 'Gene', (130, 134))	('leiomyomas', 'Disease', 'MESH:D007889', (49, 59))	('IGF2', 'Gene', '3481', (114, 118))
51132	28514723	The acquisition of a TP53 mutation appears to be a frequent and critical difference between leiomyoma and LMS.	('TP53', 'Gene', (21, 25))	('LMS', 'Phenotype', 'HP:0100243', (106, 109))	('mutation', 'Var', (26, 34))	('leiomyoma', 'Disease', (92, 101))	('LMS', 'Disease', (106, 109))	('leiomyoma', 'Disease', 'MESH:D007889', (92, 101))	('TP53', 'Gene', '7157', (21, 25))
51133	28514723	Somatic MED12 alterations are involved in the pathophysiology of both leiomyomas (66%) and LMSs (20%).	('alterations', 'Var', (14, 25))	('leiomyomas', 'Disease', (70, 80))	('MED12', 'Gene', (8, 13))	('involved', 'Reg', (30, 38))	('MED12', 'Gene', '9968', (8, 13))	('LMSs', 'Disease', (91, 95))	('LMS', 'Phenotype', 'HP:0100243', (91, 94))	('leiomyomas', 'Disease', 'MESH:D007889', (70, 80))
51134	28514723	Somatic ATRX mutations are thought to participate in LMS oncogenesis via impaired telomere-maintenance mechanisms.	('impaired', 'NegReg', (73, 81))	('ATRX', 'Gene', '546', (8, 12))	('mutations', 'Var', (13, 22))	('LMS', 'Disease', (53, 56))	('participate', 'Reg', (38, 49))	('ATRX', 'Gene', (8, 12))	('LMS', 'Phenotype', 'HP:0100243', (53, 56))	('telomere-maintenance mechanisms', 'CPA', (82, 113))
51135	28514723	performed whole-exome sequencing in 19 LMSs and found several somatic TP53, MED12, and ATRX mutations, therefore reiterating the central role of these genes in a subset of LMSs.	('MED12', 'Gene', '9968', (76, 81))	('TP53', 'Gene', '7157', (70, 74))	('mutations', 'Var', (92, 101))	('ATRX', 'Gene', (87, 91))	('TP53', 'Gene', (70, 74))	('LMS', 'Phenotype', 'HP:0100243', (39, 42))	('MED12', 'Gene', (76, 81))	('ATRX', 'Gene', '546', (87, 91))	('LMS', 'Phenotype', 'HP:0100243', (172, 175))
51139	28514723	Somatic FH deletion is not an uncommon event in leiomyomas and LMSs, but the exact role of this genomic alteration in smooth muscle tumor malignant progression requires further study.	('muscle tumor', 'Disease', (125, 137))	('LMS', 'Phenotype', 'HP:0100243', (63, 66))	('leiomyomas', 'Disease', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('deletion', 'Var', (11, 19))	('leiomyomas', 'Disease', 'MESH:D007889', (48, 58))	('muscle tumor', 'Disease', 'MESH:D009217', (125, 137))
51141	28514723	Even though CHEK2 mutation carriers display a particularly poor response to neoadjuvant therapy with anthracycline alone (without taxane), there has been no study focusing on platinum or PARP inhibitor response within the CHEK2 mutation carrier breast cancer group.	('PARP', 'Gene', '142', (187, 191))	('anthracycline', 'Chemical', 'MESH:D018943', (101, 114))	('CHEK2', 'Gene', '11200', (222, 227))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('taxane', 'Chemical', 'MESH:C080625', (130, 136))	('CHEK2', 'Gene', (12, 17))	('PARP', 'Gene', (187, 191))	('mutation', 'Var', (18, 26))	('CHEK2', 'Gene', (222, 227))	('platinum', 'Chemical', 'MESH:D010984', (175, 183))	('CHEK2', 'Gene', '11200', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('breast cancer', 'Disease', (245, 258))
51144	28514723	Unlike BRCA1/BRCA2-driven breast cancer cases, CHEK2 mutation carriers more frequently present with HR-positive tumors.	('breast cancer', 'Disease', (26, 39))	('CHEK2', 'Gene', (47, 52))	('BRCA1', 'Gene', '672', (7, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('mutation', 'Var', (53, 61))	('CHEK2', 'Gene', '11200', (47, 52))	('BRCA1', 'Gene', (7, 12))	('present', 'Reg', (87, 94))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('HR-positive tumors', 'Disease', 'MESH:D009369', (100, 118))	('BRCA2', 'Gene', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('HR-positive tumors', 'Disease', (100, 118))	('BRCA2', 'Gene', '675', (13, 18))
51146	28514723	To date, small case-control studies report no significant difference between the response of CHEK2 mutation carriers to hormonal therapy when compared with noncarriers.	('CHEK2', 'Gene', (93, 98))	('CHEK2', 'Gene', '11200', (93, 98))	('mutation', 'Var', (99, 107))
51147	28514723	found a significantly higher incidence of inherited cancer gene mutations in their breast cancer cohort developing treatment-related leukemia, and even though only one case of CHEK2 mutation was identified, this new association carries therapeutic implications for both cancer treatment and monitoring of secondary complications.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('higher', 'PosReg', (22, 28))	('cancer', 'Disease', (270, 276))	('CHEK2', 'Gene', (176, 181))	('inherited cancer', 'Disease', 'MESH:D009386', (42, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('leukemia', 'Disease', (133, 141))	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('inherited cancer', 'Disease', (42, 58))	('CHEK2', 'Gene', '11200', (176, 181))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Disease', (90, 96))
51149	28514723	Theoretically, some aspects of the genomic profiling results in this patient could suggest a platinum agent response and PARP inhibitor response: RAD51B alterations, very high HMGA2 expression, and germline CHEK2 pathogenic mutation.	('HMGA2', 'Gene', (176, 181))	('platinum', 'Chemical', 'MESH:D010984', (93, 101))	('PARP', 'Gene', '142', (121, 125))	('expression', 'MPA', (182, 192))	('alterations', 'Var', (153, 164))	('RAD51B', 'Gene', (146, 152))	('RAD51B', 'Gene', '5890', (146, 152))	('CHEK2', 'Gene', '11200', (207, 212))	('patient', 'Species', '9606', (69, 76))	('HMGA2', 'Gene', '8091', (176, 181))	('PARP', 'Gene', (121, 125))	('CHEK2', 'Gene', (207, 212))
51150	28514723	A recent review of literature by on preclinical RAD51 targeting agents supports the therapeutic role of RAD51 inhibitors (likely combined with PARP inhibitors) to impair homologous recombination DNA repair and therefore induce cancer radiation and chemotherapy sensitization.	('PARP', 'Gene', (143, 147))	('RAD51', 'Gene', (48, 53))	('induce', 'Reg', (220, 226))	('chemotherapy sensitization', 'CPA', (248, 274))	('RAD51', 'Gene', '5888', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('RAD51', 'Gene', (104, 109))	('RAD51', 'Gene', '5888', (104, 109))	('PARP', 'Gene', '142', (143, 147))	('homologous recombination DNA repair', 'MPA', (170, 205))	('impair', 'NegReg', (163, 169))	('cancer radiation', 'Disease', 'MESH:D004194', (227, 243))	('cancer radiation', 'Disease', (227, 243))	('inhibitors', 'Var', (110, 120))
51151	28514723	We would therefore hypothesize that biallelic RAD51B disruption, such as present in our patient, may be a good prognostic factor.	('RAD51B', 'Gene', '5890', (46, 52))	('patient', 'Species', '9606', (88, 95))	('RAD51B', 'Gene', (46, 52))	('biallelic', 'Var', (36, 45))
51152	28514723	Moreover, despite the presence of several mutations in the DSB repair pathway genes and previous exposure to radiation therapy, a well-known dsDNA break inducer, the mutational burden was unremarkable and mutational signature 3, associated with HRD and BRCA1/BRCA2 loss, accounted for <20% (13.4%, 95% CI 6.2%-19.1%) of total somatic single-nucleotide variant burden.	('DSB repair pathway', 'Gene', (59, 77))	('HRD', 'Disease', (245, 248))	('mutational', 'Var', (205, 215))	('BRCA1/BRCA2 loss', 'Disease', 'OMIM:604370', (253, 269))	('HRD', 'Disease', 'None', (245, 248))	('mutations', 'Var', (42, 51))	('BRCA1/BRCA2 loss', 'Disease', (253, 269))
51158	28514723	This is the first report of LMS genomic profiling in a patient with a germline CHEK2:c.1100delC variant and concomitant diagnosis of metastatic invasive ductal breast carcinoma.	('CHEK2:c.1100delC', 'DELETION', 'None', (79, 95))	('LMS', 'Phenotype', 'HP:0100243', (28, 31))	('breast carcinoma', 'Phenotype', 'HP:0003002', (160, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('CHEK2:c.1100delC', 'Var', (79, 95))	('invasive ductal breast carcinoma', 'Disease', (144, 176))	('patient', 'Species', '9606', (55, 62))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (144, 176))
51159	28514723	Our findings suggest that pathogenic germline CHEK2 mutations may increase the risk of several types of malignancies, but that complete tumor genome and transcriptome analysis does not necessarily demonstrate obvious impairment of DSB repair mechanisms.	('mutations', 'Var', (52, 61))	('increase', 'PosReg', (66, 74))	('CHEK2', 'Gene', '11200', (46, 51))	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CHEK2', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('malignancies', 'Disease', (104, 116))	('tumor', 'Disease', (136, 141))
51161	28514723	Our results suggest that translocations with one breakpoint disrupting RAD51B and the second breakpoint upstream of HMGA2 represent a genomic subtype of genital type LMS sharing similarities with leiomyoma.	('leiomyoma', 'Disease', (196, 205))	('HMGA2', 'Gene', '8091', (116, 121))	('disrupting', 'NegReg', (60, 70))	('RAD51B', 'Gene', (71, 77))	('genital type LMS', 'Disease', (153, 169))	('leiomyoma', 'Disease', 'MESH:D007889', (196, 205))	('RAD51B', 'Gene', '5890', (71, 77))	('HMGA2', 'Gene', (116, 121))	('LMS', 'Phenotype', 'HP:0100243', (166, 169))	('translocations', 'Var', (25, 39))
51162	28514723	Both RAD51B alleles were disrupted, as one is involved in the translocation and the second is almost completely removed through a 767,422-bp deletion.	('deletion', 'Var', (141, 149))	('RAD51B', 'Gene', '5890', (5, 11))	('translocation', 'MPA', (62, 75))	('RAD51B', 'Gene', (5, 11))	('involved', 'Reg', (46, 54))
51165	28514723	Future detailed genomic profiling studies are required to inform tailored treatment of such tumors and the optimal management of cancer in patients with a germline CHEK2 mutation remains to be elucidated.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('CHEK2', 'Gene', '11200', (164, 169))	('CHEK2', 'Gene', (164, 169))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('mutation', 'Var', (170, 178))
51170	28514723	The CHEK2:c.1100delC variant was reviewed and validated by Sanger sequencing in the British Columbia Cancer Agency clinical cytogenetics laboratory.	('CHEK2:c.1100delC', 'Var', (4, 20))	('British Columbia Cancer Agency', 'Disease', (84, 114))	('British Columbia Cancer Agency', 'Disease', 'OMIM:176500', (84, 114))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CHEK2:c.1100delC', 'DELETION', 'None', (4, 20))
51171	28514723	The tumor and matched normal samples were analyzed in conjunction to identify LOH and CNVs with CNAseq (v0.0.6) and APOLLOH (v0.1.1), respectively.	('APOLLOH', 'Var', (116, 123))	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
51175	28514723	Small-mutation (SNV, indel) calling takes into consideration the tumor content (42%) and ploidy model (diploid), which corrects for copy-number changes and their effect on variant calling.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Small-mutation', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
51275	28747229	In May 2016, the tumor markers, Ca125, Ca19.9, CEA, and Ca15.3, were all negative.	('Ca15.3', 'CellLine', 'CVCL:0028', (56, 62))	('tumor', 'Disease', (17, 22))	('Ca19.9', 'CellLine', 'CVCL:X558', (39, 45))	('Ca15.3', 'Var', (56, 62))	('CEA', 'Gene', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('CEA', 'Gene', '1084', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
51310	28747229	Non coding RNAs are being linked more frequently to uterine sarcomas and practitioners should bear them in mind when facing an atypical histopathology.	('sarcomas', 'Disease', (60, 68))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (52, 67))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('linked', 'Reg', (26, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('Non coding RNAs', 'Var', (0, 15))
51393	28464838	The most common alteration carried by ESS is the t (7;17) (p15;q21) translocation, which results in JAZF1-SUZ12 gene fusion (also known as JJAZ1).	('JAZF1', 'Gene', '221895', (100, 105))	('SUZ12', 'Gene', (106, 111))	('JJAZ1', 'Gene', '23512', (139, 144))	('results in', 'Reg', (89, 99))	('JJAZ1', 'Gene', (139, 144))	('JAZF1', 'Gene', (100, 105))	('SUZ12', 'Gene', '23512', (106, 111))	('t (7;17) (p15;q21', 'Var', (49, 66))
51482	27921006	A data set comprised of PSW recurrences delineated a cutoff size of GTV = 30 cc, whereas another study including just PA LN recurrences identified a PTV = 17 cc.	('GTV', 'Var', (68, 71))	('PSW', 'Disease', (24, 27))	('PA', 'Chemical', '-', (118, 120))
51495	27921006	Three of these were in the PSW recurrence study by Seo et al., who determined that a D5cc < 30 Gy, V40 < 50 cc, or a GTV < 50 cc drastically decreased the risk of developing a fistula.	('V40 < 50 cc', 'Var', (99, 110))	('D5cc', 'Var', (85, 89))	('fistula', 'Disease', 'MESH:D005402', (176, 183))	('fistula', 'Disease', (176, 183))	('decreased', 'NegReg', (141, 150))	('< 30 Gy', 'Var', (90, 97))
51513	22015044	Overexpression of SNCG seemed to be a predictor biomarker for aggressive tumor behavior and adverse outcome in patients with endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('endometrial cancer', 'Disease', (125, 143))	('aggressive tumor', 'Disease', 'MESH:D001523', (62, 78))	('SNCG', 'Gene', '6623', (18, 22))	('endometrial cancer', 'Phenotype', 'HP:0012114', (125, 143))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SNCG', 'Gene', (18, 22))	('endometrial cancer', 'Disease', 'MESH:D016889', (125, 143))	('Overexpression', 'Var', (0, 14))	('aggressive tumor', 'Disease', (62, 78))	('patients', 'Species', '9606', (111, 119))
51521	22015044	High tumor grade, advanced stage disease, presence of LVI, deep myometrial invasion (outer third) and type II (USC and clear cell subtypes) endometrial adenocarcinoma constitute a high-group risk for recurrence and aggressive outcome in comparison to low-risk group defined by low tumor grade, tumor confined to uterine corpus at presentation, absence of LVI, superficial myometrial invasion (inner third), and type I (EAC and mucinous subtypes) endometrial adenocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('superficial myometrial invasion', 'CPA', (360, 391))	('endometrial adenocarcinoma', 'Disease', (140, 166))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (140, 166))	('tumor', 'Disease', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('low tumor', 'Disease', 'MESH:D009800', (277, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('USC', 'Chemical', '-', (111, 114))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (446, 472))	('tumor confined to uterine', 'Phenotype', 'HP:0010784', (294, 319))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('low tumor', 'Disease', (277, 286))	('endometrial adenocarcinoma', 'Disease', (446, 472))	('High tumor', 'Disease', (0, 10))	('tumor', 'Disease', (294, 299))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (446, 472))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Disease', (5, 10))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (140, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (463, 472))	('High tumor', 'Disease', 'MESH:D009369', (0, 10))	('presence', 'Var', (42, 50))
51583	22015044	showed that knockdown synuclein-gamma in SPEC2 cells resulted in a significant decrease in cell proliferation and an increased sensitivity to paclitaxel-induced apoptosis.	('synuclein-gamma', 'Protein', (22, 37))	('SPEC2', 'Gene', (41, 46))	('increased', 'PosReg', (117, 126))	('paclitaxel', 'Chemical', 'MESH:D017239', (142, 152))	('knockdown', 'Var', (12, 21))	('decrease', 'NegReg', (79, 87))	('SPEC2', 'Gene', '56990', (41, 46))	('sensitivity to paclitaxel-induced apoptosis', 'MPA', (127, 170))	('cell proliferation', 'CPA', (91, 109))
51593	26891131	Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12 Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome.	('ULMSs', 'Phenotype', 'HP:0002891', (124, 129))	('Uterine Leiomyosarcomas', 'Phenotype', 'HP:0002891', (20, 43))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('muscle tumors', 'Disease', 'MESH:D009217', (153, 166))	('Leiomyosarcomas', 'Disease', 'MESH:D007890', (28, 43))	('TP53', 'Gene', (77, 81))	('ATRX', 'Gene', (83, 87))	('ATRX', 'Gene', '546', (83, 87))	('muscle tumors', 'Disease', (153, 166))	('Leiomyosarcomas', 'Disease', (28, 43))	('Mutations', 'Var', (64, 73))	('ULMS', 'Phenotype', 'HP:0002891', (124, 128))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (107, 122))	('TP53', 'Gene', '7157', (77, 81))	('Uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (99, 121))	('leiomyosarcomas', 'Disease', (107, 122))	('Leiomyosarcomas', 'Phenotype', 'HP:0100243', (28, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('Uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (99, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (107, 122))	('MED12', 'Gene', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (107, 121))
51596	26891131	Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs.	('MED12', 'Gene', (37, 42))	('TP53', 'Gene', '7157', (28, 32))	('ATRX', 'Gene', (7, 11))	('TP53', 'Gene', (28, 32))	('MED12', 'Gene', '9968', (37, 42))	('associated', 'Reg', (76, 86))	('alterations', 'Var', (43, 54))	('ATRX', 'Gene', '546', (7, 11))	('ULMSs', 'Disease', (92, 97))	('ULMSs', 'Phenotype', 'HP:0002891', (92, 97))	('ULMS', 'Phenotype', 'HP:0002891', (92, 96))
51597	26891131	All the observed ATRX alterations were either nonsense or frameshift mutations.	('ATRX', 'Gene', (17, 21))	('nonsense', 'Var', (46, 54))	('frameshift mutations', 'Var', (58, 78))	('ATRX', 'Gene', '546', (17, 21))	('alterations', 'Var', (22, 33))
51602	26891131	In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs.	('mutated', 'Var', (83, 90))	('TP53', 'Gene', '7157', (46, 50))	('ULMSs', 'Disease', (94, 99))	('ATRX', 'Gene', (52, 56))	('ULMSs', 'Phenotype', 'HP:0002891', (94, 99))	('MED12', 'Gene', (62, 67))	('TP53', 'Gene', (46, 50))	('ULMS', 'Phenotype', 'HP:0002891', (94, 98))	('ATRX', 'Gene', '546', (52, 56))	('MED12', 'Gene', '9968', (62, 67))
51609	26891131	Here, we performed exome sequencing on 19 tumors, revealing frequent mutations in TP53, ATRX, and MED12.	('TP53', 'Gene', (82, 86))	('mutations', 'Var', (69, 78))	('MED12', 'Gene', (98, 103))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('ATRX', 'Gene', '546', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('MED12', 'Gene', '9968', (98, 103))	('TP53', 'Gene', '7157', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ATRX', 'Gene', (88, 92))
51610	26891131	The discovery of frequent inactivating ATRX mutations provides a potential novel therapeutic target for uterine leiomyosarcomas.	('ATRX', 'Gene', (39, 43))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (112, 127))	('ATRX', 'Gene', '546', (39, 43))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (112, 127))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (112, 126))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (104, 127))	('leiomyosarcomas', 'Disease', (112, 127))	('mutations', 'Var', (44, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))
51619	26891131	Here, we performed exome sequencing on 19 ULMSs to further elucidate the molecular etiology of these tumors, identifying frequent mutations in TP53, alpha thalassemia/mental retardation syndrome X-linked (ATRX), and mediator complex subunit 12 (MED12).	('TP53', 'Gene', (143, 147))	('mediator complex subunit 12', 'Gene', (216, 243))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('ULMSs', 'Phenotype', 'HP:0002891', (42, 47))	('alpha thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (149, 203))	('ATRX', 'Gene', '546', (205, 209))	('MED12', 'Gene', '9968', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mental retardation', 'Phenotype', 'HP:0001249', (167, 185))	('ULMS', 'Phenotype', 'HP:0002891', (42, 46))	('mutations', 'Var', (130, 139))	('TP53', 'Gene', '7157', (143, 147))	('ATRX', 'Gene', (205, 209))	('mediator complex subunit 12', 'Gene', '9968', (216, 243))	('tumors', 'Disease', (101, 107))	('MED12', 'Gene', (245, 250))
51622	26891131	The majority of mutations in each tumor specimen represented single-nucleotide variations (~88%; range 81-95%), while deletions accounted for ~9% (range 4-15%) and insertions ~3% (range 1-7%) (S1 Table).	('tumor', 'Disease', (34, 39))	('insertions', 'Var', (164, 174))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('deletions', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('single-nucleotide variations', 'Var', (61, 89))
51623	26891131	Two tumors, LMS49 and LMS51, harbored more mutations than other ULMSs, but the mutation spectrum followed the common pattern.	('ULMSs', 'Phenotype', 'HP:0002891', (64, 69))	('LMS49', 'CellLine', 'CVCL:0628', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('harbored', 'Reg', (29, 37))	('ULMS', 'Phenotype', 'HP:0002891', (64, 68))
51625	26891131	The majority of these genes (37/43; 86%) were mutated in two tumors, while six genes, TP53, ATRX, MED12, fibrous sheath interacting protein 2 (FSIP2), ATP-binding cassette, sub-family A (ABC1), member 13 (ABCA13), and ankyrin repeat domain 26 (ANKRD26), had mutations in three or more tumors (Fig 1).	('ANKRD26', 'Gene', '22852', (244, 251))	('fibrous sheath interacting protein 2', 'Gene', '401024', (105, 141))	('mutated', 'Var', (46, 53))	('TP53', 'Gene', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('ANKRD26', 'Gene', (244, 251))	('ATRX', 'Gene', (92, 96))	('ATP-binding cassette, sub-family A (ABC1), member 13', 'Gene', '154664', (151, 203))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('MED12', 'Gene', (98, 103))	('ATRX', 'Gene', '546', (92, 96))	('tumors', 'Disease', (285, 291))	('ABCA13', 'Gene', '154664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('fibrous sheath interacting protein 2', 'Gene', (105, 141))	('ABCA13', 'Gene', (205, 211))	('tumors', 'Disease', (61, 67))	('TP53', 'Gene', '7157', (86, 90))	('FSIP2', 'Gene', '401024', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ankyrin repeat domain 26', 'Gene', (218, 242))	('ankyrin repeat domain 26', 'Gene', '22852', (218, 242))	('MED12', 'Gene', '9968', (98, 103))	('mutations', 'Reg', (258, 267))	('FSIP2', 'Gene', (143, 148))
51626	26891131	The most frequently mutated gene was TP53, which was mutated in six tumors (6/19; 32%) (S1 Fig).	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('mutated', 'Var', (53, 60))	('TP53', 'Gene', '7157', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TP53', 'Gene', (37, 41))
51627	26891131	All the observed TP53 mutations have been reported as somatic mutations in the COSMIC-database.	('TP53', 'Gene', '7157', (17, 21))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (17, 21))
51628	26891131	The second most commonly mutated gene was ATRX, which was mutated in five tumors (5/19; 26%) (S1 Fig).	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ATRX', 'Gene', (42, 46))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('ATRX', 'Gene', '546', (42, 46))	('mutated', 'Var', (58, 65))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
51630	26891131	As ATRX mutations have been associated with alternative lengthening of telomeres (ALT), we specifically searched the exome sequencing data for possible mutations in death-domain associated protein (DAXX), as also these mutations have been associated with the ALT phenotype.	('associated', 'Reg', (239, 249))	('associated', 'Reg', (28, 38))	('death-domain associated protein', 'Gene', (165, 196))	('DAXX', 'Gene', '1616', (198, 202))	('mutations', 'Var', (8, 17))	('ATRX', 'Gene', (3, 7))	('ALT', 'Disease', (259, 262))	('ATRX', 'Gene', '546', (3, 7))	('mutations', 'Var', (219, 228))	('DAXX', 'Gene', (198, 202))	('death-domain associated protein', 'Gene', '1616', (165, 196))
51631	26891131	Indeed, one ULMS (LMS61) had a mutation in DAXX.	('DAXX', 'Gene', '1616', (43, 47))	('mutation', 'Var', (31, 39))	('DAXX', 'Gene', (43, 47))	('ULMS', 'Phenotype', 'HP:0002891', (12, 16))
51632	26891131	This mutation was a nonsense mutation (Glu650Stop) most likely leading to a truncated or unstable protein product.	('Glu650Stop', 'Mutation', 'rs587778868', (39, 49))	('truncated', 'MPA', (76, 85))	('leading', 'Reg', (63, 70))	('Glu650Stop', 'Var', (39, 49))
51634	26891131	All these were missense changes affecting amino acids Gly44 (3 mutations) or Leu36 (1 mutation), which have previously been reported as mutational hotspots in uterine leiomyomas.	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (159, 177))	('leiomyomas', 'Disease', 'MESH:D007889', (167, 177))	('Gly44', 'Var', (54, 59))	('Leu36', 'Var', (77, 82))	('Leu36', 'Chemical', '-', (77, 82))	('Gly44', 'Chemical', '-', (54, 59))	('leiomyomas', 'Disease', (167, 177))
51636	26891131	Alterations in FSIP2 (4/19; 21%), ABCA13 (3/19; 16%), and ANKRD26 (3/19; 16%) all represented missense changes that scattered along the gene lengths.	('ABCA13', 'Gene', (34, 40))	('ANKRD26', 'Gene', '22852', (58, 65))	('Alterations', 'Var', (0, 11))	('ANKRD26', 'Gene', (58, 65))	('FSIP2', 'Gene', (15, 20))	('missense changes', 'Var', (94, 110))	('ABCA13', 'Gene', '154664', (34, 40))	('FSIP2', 'Gene', '401024', (15, 20))
51637	26891131	Two tumors had the same Met487Ile substitution in ANKRD26.	('ANKRD26', 'Gene', (50, 57))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('ANKRD26', 'Gene', '22852', (50, 57))	('Met487Ile', 'Mutation', 'rs749894870', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Met487Ile', 'Var', (24, 33))
51638	26891131	One alteration (Gln581Leu) in FSIP2 and all changes in ABCA13 were predicted pathogenic by both Polyphen-2 and SIFT, whereas none of the other variants were predicted damaging by both in silico tools.	('Gln581Leu', 'SUBSTITUTION', 'None', (16, 25))	('changes', 'Reg', (44, 51))	('ABCA13', 'Gene', '154664', (55, 61))	('FSIP2', 'Gene', '401024', (30, 35))	('SIFT', 'Disease', (111, 115))	('Gln581Leu', 'Var', (16, 25))	('SIFT', 'Disease', 'None', (111, 115))	('pathogenic', 'Reg', (77, 87))	('ABCA13', 'Gene', (55, 61))	('FSIP2', 'Gene', (30, 35))
51641	26891131	Aberrant TP53 expression was observed in 33 out of 50 ULMSs (66%) (S3 Table).	('observed', 'Reg', (29, 37))	('Aberrant', 'Var', (0, 8))	('TP53', 'Gene', '7157', (9, 13))	('expression', 'MPA', (14, 24))	('TP53', 'Gene', (9, 13))	('ULMSs', 'Phenotype', 'HP:0002891', (54, 59))	('ULMS', 'Phenotype', 'HP:0002891', (54, 58))
51644	26891131	Telomere-specific fluorescence in situ hybridization (FISH) was carried out to assess the potential effect of ATRX and DAXX mutations on telomere length (Fig 2B and 2D).	('mutations', 'Var', (124, 133))	('ATRX', 'Gene', (110, 114))	('DAXX', 'Gene', '1616', (119, 123))	('ATRX', 'Gene', '546', (110, 114))	('DAXX', 'Gene', (119, 123))
51645	26891131	This included four out of five ATRX mutation-positive tumors (80%) as well as the one DAXX mutation-positive tumor.	('DAXX', 'Gene', '1616', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', (109, 114))	('mutation-positive', 'Var', (36, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ATRX', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('DAXX', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (54, 59))	('ATRX', 'Gene', '546', (31, 35))	('tumors', 'Disease', (54, 60))
51651	26891131	Neither aberrant TP53 or ATRX expression associated with poor survival (P = 0.261, P = 0.127) (Fig 3).	('ATRX', 'Gene', (25, 29))	('ATRX', 'Gene', '546', (25, 29))	('aberrant', 'Var', (8, 16))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
51655	26891131	TP53 was the most commonly mutated gene with 32% of the tumors harboring mutations.	('TP53', 'Gene', '7157', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TP53', 'Gene', (0, 4))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (73, 82))
51656	26891131	Alterations in TP53 have been previously implicated in leiomyosarcomas and suggested to play a role in leiomyosarcoma pathogenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (55, 69))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (103, 117))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (55, 69))	('Alterations', 'Var', (0, 11))	('play', 'Reg', (88, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (55, 70))	('TP53', 'Gene', '7157', (15, 19))	('leiomyosarcoma', 'Disease', (103, 117))	('TP53', 'Gene', (15, 19))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (55, 70))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (103, 117))	('implicated', 'Reg', (41, 51))	('role', 'Reg', (95, 99))	('leiomyosarcomas', 'Disease', (55, 70))	('leiomyosarcoma', 'Disease', (55, 69))
51657	26891131	These mutations are known to alter the protein structure, inhibit its tumor suppressor function, and result in its prolonged half-life.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('half-life', 'MPA', (125, 134))	('inhibit', 'NegReg', (58, 65))	('protein', 'Protein', (39, 46))	('mutations', 'Var', (6, 15))	('alter', 'Reg', (29, 34))
51660	26891131	Loss of ATRX expression has been reported in leiomyosarcomas of various sites and a recent meeting abstract on ULMSs reported genomic alterations of this gene in 32% (8/25) of the studied tumors, supporting our findings.	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('ATRX', 'Gene', '546', (8, 12))	('expression', 'MPA', (13, 23))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('ULMSs', 'Phenotype', 'HP:0002891', (111, 116))	('Loss', 'NegReg', (0, 4))	('genomic alterations', 'Var', (126, 145))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (45, 60))	('ULMS', 'Phenotype', 'HP:0002891', (111, 115))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (45, 60))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('ATRX', 'Gene', (8, 12))	('leiomyosarcomas', 'Disease', (45, 60))
51661	26891131	We successfully analyzed ATRX protein levels in 44 ULMSs and showed that 52% of the tumors, including all reliably analyzed mutation-positive lesions, had clearly reduced expression.	('expression', 'MPA', (171, 181))	('ATRX', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ULMS', 'Phenotype', 'HP:0002891', (51, 55))	('reduced', 'NegReg', (163, 170))	('ULMSs', 'Phenotype', 'HP:0002891', (51, 56))	('mutation-positive', 'Var', (124, 141))	('ATRX', 'Gene', '546', (25, 29))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
51666	26891131	Interestingly, the only ULMS with two ATRX mutations did not show ALT.	('ATRX', 'Gene', '546', (38, 42))	('mutations', 'Var', (43, 52))	('ATRX', 'Gene', (38, 42))	('ULMS', 'Phenotype', 'HP:0002891', (24, 28))
51667	26891131	ATRX is known to functionally cooperate with DAXX and DAXX mutations have been associated with ALT.	('associated', 'Reg', (79, 89))	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', (45, 49))	('ALT', 'Disease', (95, 98))	('DAXX', 'Gene', '1616', (54, 58))	('ATRX', 'Gene', '546', (0, 4))	('mutations', 'Var', (59, 68))	('DAXX', 'Gene', '1616', (45, 49))	('DAXX', 'Gene', (54, 58))
51668	26891131	We therefore scrutinized the exome data for possible DAXX mutations.	('DAXX', 'Gene', '1616', (53, 57))	('DAXX', 'Gene', (53, 57))	('mutations', 'Var', (58, 67))
51669	26891131	Overall, these results show that ALT is very common in ULMS and that in addition to ATRX, also DAXX mutations contribute to the phenotype.	('mutations', 'Var', (100, 109))	('common', 'Reg', (45, 51))	('DAXX', 'Gene', (95, 99))	('ULMS', 'Disease', (55, 59))	('ATRX', 'Gene', '546', (84, 88))	('ULMS', 'Phenotype', 'HP:0002891', (55, 59))	('ALT', 'Disease', (33, 36))	('DAXX', 'Gene', '1616', (95, 99))	('ATRX', 'Gene', (84, 88))	('contribute', 'Reg', (110, 120))
51671	26891131	MED12 was mutated in four ULMSs (21%).	('mutated', 'Var', (10, 17))	('MED12', 'Gene', (0, 5))	('MED12', 'Gene', '9968', (0, 5))	('ULMSs', 'Phenotype', 'HP:0002891', (26, 31))	('ULMS', 'Phenotype', 'HP:0002891', (26, 30))
51672	26891131	All mutations were in exon 2, which is a known mutational hotspot in MED12.	('mutations', 'Var', (4, 13))	('MED12', 'Gene', (69, 74))	('MED12', 'Gene', '9968', (69, 74))
51673	26891131	These mutations were first observed in uterine leiomyomas, and subsequently they have been identified in other tumor types.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('leiomyomas', 'Disease', 'MESH:D007889', (47, 57))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (39, 57))	('tumor', 'Disease', (111, 116))	('observed', 'Reg', (27, 35))	('leiomyomas', 'Disease', (47, 57))	('mutations', 'Var', (6, 15))
51674	26891131	Previous screening studies have reported recurrent MED12 mutations also in ULMS with similar frequencies as observed here.	('ULMS', 'Phenotype', 'HP:0002891', (75, 79))	('mutations', 'Var', (57, 66))	('ULMS', 'Disease', (75, 79))	('MED12', 'Gene', (51, 56))	('MED12', 'Gene', '9968', (51, 56))
51675	26891131	It may be that a subset of ULMSs arises through a leiomyoma precursor, or alternatively MED12 mutations may provide growth advantage to ULMSs.	('ULMS', 'Phenotype', 'HP:0002891', (136, 140))	('MED12', 'Gene', (88, 93))	('mutations', 'Var', (94, 103))	('ULMS', 'Phenotype', 'HP:0002891', (27, 31))	('growth', 'MPA', (116, 122))	('ULMSs', 'Disease', (27, 32))	('leiomyoma', 'Disease', (50, 59))	('ULMSs', 'Phenotype', 'HP:0002891', (27, 32))	('MED12', 'Gene', '9968', (88, 93))	('leiomyoma', 'Disease', 'MESH:D007889', (50, 59))	('ULMSs', 'Phenotype', 'HP:0002891', (136, 141))
51677	26891131	Based on our results, MED12 mutations can co-occur with TP53 and ATRX mutations.	('MED12', 'Gene', (22, 27))	('TP53', 'Gene', '7157', (56, 60))	('ATRX', 'Gene', (65, 69))	('MED12', 'Gene', '9968', (22, 27))	('TP53', 'Gene', (56, 60))	('co-occur', 'Reg', (42, 50))	('ATRX', 'Gene', '546', (65, 69))	('mutations', 'Var', (28, 37))
51678	26891131	FSIP2, ABCA13, and ANKRD26 were mutated in at least three tumors and additional 37 genes had mutations in two tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('ANKRD26', 'Gene', (19, 26))	('mutated', 'Var', (32, 39))	('ABCA13', 'Gene', (7, 13))	('ANKRD26', 'Gene', '22852', (19, 26))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('FSIP2', 'Gene', '401024', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ABCA13', 'Gene', '154664', (7, 13))	('FSIP2', 'Gene', (0, 5))
51679	26891131	Although aberrant expression of both TP53 and ATRX in Stage I ULMSs, the only group of tumors large enough for the analyses, did not associate with poor overall survival, a trend toward poorer survival was seen in the patients.	('ATRX', 'Gene', '546', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ULMSs', 'Disease', (62, 67))	('patients', 'Species', '9606', (218, 226))	('ULMSs', 'Phenotype', 'HP:0002891', (62, 67))	('TP53', 'Gene', '7157', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('ULMS', 'Phenotype', 'HP:0002891', (62, 66))	('tumors', 'Disease', (87, 93))	('TP53', 'Gene', (37, 41))	('aberrant expression', 'Var', (9, 28))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('ATRX', 'Gene', (46, 50))
51681	26891131	In general, TP53 alterations are the most common genetic changes in human cancers and they are particularly associated with an aggressive phenotype.	('human', 'Species', '9606', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('TP53', 'Gene', '7157', (12, 16))	('associated with', 'Reg', (108, 123))	('TP53', 'Gene', (12, 16))	('alterations', 'Var', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
51687	26891131	While MED12 mutations are the most common alterations in benign conventional leiomyomas, TP53 or ATRX mutations have not been observed in these tumors.	('tumors', 'Disease', (144, 150))	('ATRX', 'Gene', '546', (97, 101))	('TP53', 'Gene', '7157', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('TP53', 'Gene', (89, 93))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('mutations', 'Var', (12, 21))	('MED12', 'Gene', (6, 11))	('leiomyomas', 'Disease', 'MESH:D007889', (77, 87))	('ATRX', 'Gene', (97, 101))	('leiomyomas', 'Disease', (77, 87))	('MED12', 'Gene', '9968', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
51688	26891131	Specifically, identification of inactivating ATRX mutations and their association with the ALT phenotype in the substantial proportion of tumors may be translatable into clinical practice should the suggested effect of ATR inhibitors prove effective.	('inactivating', 'Var', (32, 44))	('mutations', 'Var', (50, 59))	('ATRX', 'Gene', (45, 49))	('ALT', 'Disease', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('ATR', 'Gene', (219, 222))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('ATRX', 'Gene', '546', (45, 49))	('ATR', 'Gene', '545', (45, 48))	('ATR', 'Gene', (45, 48))	('ATR', 'Gene', '545', (219, 222))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('association', 'Reg', (70, 81))
51692	26891131	To remove other potential germline variants, the exome data was filtered against data from 2315 Finnish controls (93 individuals from the 1000 Genomes Project, 1941 individuals from The Sequencing Initiative Suomi (SISu) (http://www.sisu.fimm.fi), and 281 in-house control exomes or genomes).	('SISu', 'Disease', 'None', (215, 219))	('SISu', 'Disease', (215, 219))	('variants', 'Var', (35, 43))
51693	26891131	Recently, it has been estimated that about 400 control samples remove germline variation (single-nucleotide variants and indels) from a tumor sample at least as efficiently as the matched normal sample.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('remove', 'NegReg', (63, 69))	('tumor', 'Disease', (136, 141))	('indels', 'Var', (121, 127))
51694	26891131	The functional effects of the variants were predicted by two independent in silico tools: SIFT (http://sift.jcvi.org/) and Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/).	('variants', 'Var', (30, 38))	('SIFT', 'Disease', (90, 94))	('SIFT', 'Disease', 'None', (90, 94))
51695	26891131	All candidate variants in genes mutated in at least three tumors were validated by direct sequencing.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('variants', 'Var', (14, 22))	('tumors', 'Disease', 'MESH:D009369', (58, 64))
51759	25379556	This threshold CA125 level had a sensitivity of 75%, specificity of 76%, positive predictive value of 35% and negative predicative value of 96.25%, and a likelihood ratio of 3.12 for predicting nodal disease.	('CA125 level', 'Var', (15, 26))	('nodal disease', 'Disease', (194, 207))	('nodal disease', 'Disease', 'MESH:D013611', (194, 207))
51760	25379556	Overall, at five-year follow-up, while there were no deaths among the women with preoperative serum CA125 less than 12 U/mL, eleven of the twenty-three deaths (47.82%) in the study occurred in women with a preoperative CA125 more than 28 U/mL.	('death', 'Disease', 'MESH:D003643', (53, 58))	('death', 'Disease', (53, 58))	('deaths', 'Disease', (53, 59))	('deaths', 'Disease', 'MESH:D003643', (152, 158))	('CA125', 'Var', (219, 224))	('deaths', 'Disease', (152, 158))	('deaths', 'Disease', 'MESH:D003643', (53, 59))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (152, 157))
51771	25379556	Alternatively, a CA125 above 28 U/mL may prompt further imaging (to clarify presence or absence of extrapelvic disease) and multidisciplinary discussions as to the best of management plan for the individual (radical surgery/neoadjuvant/adjuvant therapy).	('absence of extrapelvic disease', 'Disease', 'MESH:D004832', (88, 118))	('CA125', 'Var', (17, 22))	('absence of extrapelvic disease', 'Disease', (88, 118))
51952	22685357	The subjects of the current study were 23 patients with LMS associated with non-epithelial malignancy and the prognosis correlated with the presence or absence of expression of GLUT-1 in malignant cells, but not with expression of HK-II.	('LMS', 'Disease', (56, 59))	('epithelial malignancy', 'Phenotype', 'HP:0031492', (80, 101))	('GLUT-1', 'Gene', (177, 183))	('GLUT-1', 'Gene', '6513', (177, 183))	('patients', 'Species', '9606', (42, 50))	('expression', 'MPA', (163, 173))	('malignancy', 'Disease', 'MESH:D009369', (91, 101))	('presence', 'Var', (140, 148))	('HK-II', 'Gene', '3099', (231, 236))	('malignancy', 'Disease', (91, 101))	('absence', 'NegReg', (152, 159))	('HK-II', 'Gene', (231, 236))	('associated', 'Reg', (60, 70))
51988	33718227	Phytochemicals have multi-target effects on tumor; in addition to activating apoptosis, they can also induce autophagy through epigenetic mechanisms.	('induce', 'PosReg', (102, 108))	('apoptosis', 'CPA', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('activating', 'PosReg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('autophagy', 'CPA', (109, 118))	('epigenetic', 'Var', (127, 137))	('tumor', 'Disease', (44, 49))
51992	33718227	Indoleamine-2, 3-dioxygenase-1 (IDO1) is an immune checkpoint and a key rate-limiting enzyme that breaks down tryptophan into kynurenine, which plays an important regulatory effect in tumor immunity.	('breaks down', 'Phenotype', 'HP:0001061', (98, 109))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('IDO1', 'Gene', '3620', (32, 36))	('kynurenine', 'Chemical', 'MESH:D007737', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Indoleamine-2, 3-dioxygenase-1', 'Gene', '3620', (0, 30))	('tryptophan', 'Chemical', 'MESH:D014364', (110, 120))	('tumor', 'Disease', (184, 189))	('IDO1', 'Gene', (32, 36))	('breaks', 'Var', (98, 104))	('tryptophan', 'MPA', (110, 120))
52005	33718227	Pharmacological inhibition of IDO1 with epacadostat or its siRNA-mediated knockdown restored the viability of cells following curdione treatment.	('viability', 'MPA', (97, 106))	('curdione', 'Chemical', 'MESH:C504126', (126, 134))	('IDO1', 'Gene', (30, 34))	('knockdown', 'Var', (74, 83))	('IDO1', 'Gene', '3620', (30, 34))	('epacadostat', 'Chemical', 'MESH:C000613752', (40, 51))	('restored', 'PosReg', (84, 92))
52023	33718227	IDO1-specific siRNA (5'-GGATGTTCATTGCTAAACA-3') was designed and synthesized by RiboBio Co. Ltd. (C10511-05, Beijing, China).	('IDO1', 'Gene', (0, 4))	('C10511-05', 'Var', (98, 107))	('IDO1', 'Gene', '3620', (0, 4))
52039	33718227	The tumor tissue sections were heated in citrate buffer for antigen retrieval and blocked with 10% bovine serum albumin (BSA, C1052, Beyotime, Shanghai, China).	('tumor', 'Disease', (4, 9))	('C1052', 'Var', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('serum albumin', 'Gene', '213', (106, 119))	('serum albumin', 'Gene', (106, 119))	('citrate', 'Chemical', 'MESH:D019343', (41, 48))
52093	33718227	In this study, curdione increased the cell population of the G2/M phase in a concentration-dependent manner, indicating that curdione suppressed the proliferative effect of uLMS cells by inducing cell cycle arrest at G2/M.	('suppressed', 'NegReg', (134, 144))	('uLMS', 'Phenotype', 'HP:0002891', (173, 177))	('curdione', 'Var', (125, 133))	('arrest', 'Disease', 'MESH:D006323', (207, 213))	('inducing', 'Reg', (187, 195))	('proliferative effect', 'CPA', (149, 169))	('curdione', 'Chemical', 'MESH:C504126', (125, 133))	('arrest', 'Disease', (207, 213))	('curdione', 'Chemical', 'MESH:C504126', (15, 23))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (196, 213))
52141	31130286	In particular, mutations of the BRCA1 gene, the most common gene alteration associated with breast cancer, has recently been suggested to be possibly associated with increased risk of uterine cancer with serous histology.	('BRCA1', 'Gene', (32, 37))	('associated', 'Reg', (150, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutations', 'Var', (15, 24))	('uterine cancer', 'Phenotype', 'HP:0010784', (184, 198))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('BRCA1', 'Gene', '672', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
52213	31130286	Additionally, the increasing utilization of genetic testing for BRCA may have played a role in the decreasing risk of postcedent uterine cancer.	('genetic', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('BRCA', 'Gene', '672', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('uterine cancer', 'Phenotype', 'HP:0010784', (129, 143))	('BRCA', 'Gene', (64, 68))
52217	31130286	Currently, whether BRCA mutations increase the risk of uterine cancer remains controversial.	('uterine cancer', 'Phenotype', 'HP:0010784', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('BRCA', 'Gene', '672', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('BRCA', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (63, 69))
52218	31130286	A recent prospective cohort study showed that BRCA1 mutations were associated with a ~20-fold increased risk of serous-type uterine cancer, but the incidence remains low (<1%).	('serous-type uterine cancer', 'Disease', (112, 138))	('mutations', 'Var', (52, 61))	('serous-type uterine cancer', 'Disease', 'MESH:D014594', (112, 138))	('uterine cancer', 'Phenotype', 'HP:0010784', (124, 138))	('BRCA1', 'Gene', '672', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA1', 'Gene', (46, 51))
52219	31130286	Another study showed that the frequency of BRCA mutations in type II uterine cancer was higher than in type I (0.9% versus 0.1%).	('uterine cancer', 'Phenotype', 'HP:0010784', (69, 83))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('higher', 'Reg', (88, 94))	('BRCA', 'Gene', '672', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BRCA', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
52221	31130286	Further study on whether BRCA mutations increase the risk of uterine cancer is warranted.	('BRCA', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('uterine cancer', 'Phenotype', 'HP:0010784', (61, 75))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('BRCA', 'Gene', '672', (25, 29))
52256	32295073	We review inhibitors of ALDH, both general and isoform-specific, which have been used to target CSCs in gynecologic cancers.	('inhibitors', 'Var', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('ALDH', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
52258	32295073	Furthermore, ALDH inhibitors, including 673A and CM037, synergize with chemotherapy to reduce tumor growth.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('673A', 'Chemical', '-', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ALDH', 'Gene', (13, 17))	('tumor', 'Disease', (94, 99))	('673A', 'Var', (40, 44))	('CM037', 'Chemical', '-', (49, 54))	('reduce', 'NegReg', (87, 93))	('CM037', 'Var', (49, 54))
52281	32295073	When combined with cyclophosphamide in ALDH3A1high cell lines, ALDH3A1 inhibitors have been shown to increase sensitivity to the mafosphamide (cyclophosphamide analog).	('ALDH3A1', 'Gene', (63, 70))	('inhibitors', 'Var', (71, 81))	('increase', 'PosReg', (101, 109))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (19, 35))	('sensitivity', 'MPA', (110, 121))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (143, 159))	('mafosphamide', 'Chemical', '-', (129, 141))
52283	32295073	As a consequence of this, ALDHhigh CSCs have a lower baseline ROS level and oxidative damage than the ALDHlow counterparts.	('lower', 'NegReg', (47, 52))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('oxidative damage', 'MPA', (76, 92))	('ROS level', 'MPA', (62, 71))	('ALDHhigh CSCs', 'Var', (26, 39))
52284	32295073	Clinically, high ALDH expression is associated with poor outcomes in several gynecologic malignancies, including ovarian cancer (OC), endometrial, and cervical cancer (CC), as well as other solid tumors including breast, lung adenocarcinoma, rectal, esophageal squamous adenocarcinoma, gastric, colorectal, prostate, and neuroblastoma.	('esophageal squamous adenocarcinoma', 'Phenotype', 'HP:0011459', (250, 284))	('expression', 'Var', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('neuroblastoma', 'Disease', 'MESH:D009447', (321, 334))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (221, 240))	('colorectal', 'Disease', (295, 305))	('rectal', 'Disease', (242, 248))	('esophageal squamous adenocarcinoma', 'Disease', 'MESH:D000077277', (250, 284))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (221, 240))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('cancer', 'Disease', (160, 166))	('endometrial', 'Disease', (134, 145))	('malignancies', 'Disease', (89, 101))	('squamous adenocarcinoma', 'Phenotype', 'HP:0002860', (261, 284))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('prostate', 'Disease', (307, 315))	('colorectal', 'Disease', 'MESH:D015179', (295, 305))	('esophageal squamous adenocarcinoma', 'Disease', (250, 284))	('CC', 'Phenotype', 'HP:0002664', (168, 170))	('tumors', 'Disease', (196, 202))	('OC', 'Phenotype', 'HP:0100615', (129, 131))	('ovarian cancer', 'Disease', (113, 127))	('gastric', 'Disease', (286, 293))	('associated', 'Reg', (36, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('high', 'Var', (12, 16))	('ALDH', 'Protein', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('lung adenocarcinoma', 'Disease', (221, 240))	('neuroblastoma', 'Disease', (321, 334))	('neuroblastoma', 'Phenotype', 'HP:0003006', (321, 334))	('cancer', 'Disease', (121, 127))	('breast', 'Disease', (213, 219))
52329	32295073	In patients with uterine endometrioid carcinosarcoma, high ALDH1 expression predicted poor prognosis, lymphatic invasion, recurrence, and low overall survival.	('carcinosarcoma', 'Disease', 'MESH:D002296', (38, 52))	('uterine endometrioid carcinosarcoma', 'Phenotype', 'HP:0002891', (17, 52))	('poor prognosis', 'CPA', (86, 100))	('high', 'Var', (54, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('recurrence', 'CPA', (122, 132))	('carcinosarcoma', 'Disease', (38, 52))	('overall', 'MPA', (142, 149))	('lymphatic invasion', 'CPA', (102, 120))	('endometrioid carcinosarcoma', 'Phenotype', 'HP:0012114', (25, 52))	('expression', 'MPA', (65, 75))	('patients', 'Species', '9606', (3, 11))	('low', 'NegReg', (138, 141))	('ALDH1', 'Gene', (59, 64))
52332	32295073	Furthermore, when injected into mice subcutaneously, ALDHhigh endometrial cells formed larger tumors more rapidly than the ALDHlow cells, demonstrating that CSCs were able to repopulate the entire endometrial tumor mass.	('endometrial tumor', 'Disease', 'MESH:D016889', (197, 214))	('ALDHhigh', 'Var', (53, 61))	('endometrial tumor', 'Disease', (197, 214))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mice', 'Species', '10090', (32, 36))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
52338	32295073	Expression of ALDH1A1 was 100-fold higher in OC cells selected for taxane-resistance in vitro, and ALDH1A1 knockdown sensitized the resistant cells to chemotherapy.	('knockdown', 'Var', (107, 116))	('ALDH1A1', 'Gene', (14, 21))	('Expression', 'MPA', (0, 10))	('sensitized', 'Reg', (117, 127))	('taxane', 'Chemical', 'MESH:C080625', (67, 73))	('ALDH1A1', 'Gene', (99, 106))	('OC', 'Phenotype', 'HP:0100615', (45, 47))	('higher', 'PosReg', (35, 41))
52342	32295073	Moreover, in tumors harvested during debulking surgeries, ALDHhighCD133+ cells correlated with reduced disease-free and overall survival in OC patients.	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('OC', 'Phenotype', 'HP:0100615', (140, 142))	('patients', 'Species', '9606', (143, 151))	('reduced', 'NegReg', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('ALDHhighCD133+ cells', 'Var', (58, 78))
52352	32295073	Though DSF is primarily an inhibitor for ALDH2, DSF also inhibits ALDH1 isozymes, which are overexpressed in CSCs, providing the rationale for repurposing DSF as an anti-cancer drug.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('ALDH1 isozymes', 'Enzyme', (66, 80))	('DSF', 'Chemical', 'MESH:D004221', (7, 10))	('DSF', 'Var', (48, 51))	('cancer', 'Disease', (170, 176))	('DSF', 'Chemical', 'MESH:D004221', (155, 158))	('ALDH2', 'Gene', '217', (41, 46))	('DSF', 'Chemical', 'MESH:D004221', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ALDH2', 'Gene', (41, 46))	('inhibits', 'NegReg', (57, 65))
52356	32295073	In OC, DSF exhibited cytotoxicity comparable to cisplatin, while having a limited effect on the viability of non-neoplastic cells.	('DSF', 'Var', (7, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('DSF', 'Chemical', 'MESH:D004221', (7, 10))	('cytotoxicity', 'Disease', (21, 33))	('OC', 'Phenotype', 'HP:0100615', (3, 5))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))
52357	32295073	Cell death due to DSF was partly due to programmed cell death, and an additive effect, when combined with chemotherapy, was observed (Table 2).	('DSF', 'Chemical', 'MESH:D004221', (18, 21))	('programmed cell death', 'CPA', (40, 61))	('Cell death', 'CPA', (0, 10))	('DSF', 'Var', (18, 21))
52360	32295073	In another study, DSF induced cell death in OC by promoting a pro-oxidative intracellular environment, causing irreversible damage to the cancer cells within a few hours of treatment via the induction of heat shock proteins.	('cancer', 'Disease', (138, 144))	('DSF', 'Var', (18, 21))	('pro-oxidative intracellular environment', 'MPA', (62, 101))	('shock proteins', 'Disease', (209, 223))	('DSF', 'Chemical', 'MESH:D004221', (18, 21))	('OC', 'Phenotype', 'HP:0100615', (44, 46))	('shock proteins', 'Disease', 'MESH:D012769', (209, 223))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('promoting', 'PosReg', (50, 59))	('shock', 'Phenotype', 'HP:0031273', (209, 214))	('damage', 'MPA', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
52386	32295073	In OC cells, ALDH1A1 inhibition by NCT-501 abrogated CSC expansion induced by the silencing of a tumor suppressor DNA damage-binding protein (DDB2).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('pan', 'Gene', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('pan', 'Gene', '51816', (59, 62))	('OC', 'Phenotype', 'HP:0100615', (3, 5))	('silencing', 'Var', (82, 91))	('NCT-501', 'Gene', (35, 42))	('abrogated', 'NegReg', (43, 52))	('tumor', 'Disease', (97, 102))	('DDB2', 'Gene', '1643', (142, 146))	('DDB2', 'Gene', (142, 146))	('ALDH1A1', 'Gene', (13, 20))	('inhibition', 'NegReg', (21, 31))
52388	32295073	In endometrial CSCs, NCT-501 caused significant inhibition of ALDH activity, reduced spheroid cells, and caused selective cell death in ALDHhigh cells.	('endometrial CSCs', 'Disease', (3, 19))	('ALDH', 'Protein', (62, 66))	('activity', 'MPA', (67, 75))	('reduced', 'NegReg', (77, 84))	('endometrial CSCs', 'Disease', 'MESH:D014591', (3, 19))	('inhibition', 'NegReg', (48, 58))	('NCT-501', 'Var', (21, 28))	('spheroid cells', 'CPA', (85, 99))
52391	32295073	Using this HTS platform, 64,000 compounds were screened and a potent, highly selective, and novel ALDH1A1 inhibitor CM037 (A37) was identified (Table 2).	('CM037', 'Var', (116, 121))	('CM037', 'Chemical', '-', (116, 121))	('ALDH1A1', 'Gene', (98, 105))
52392	32295073	demonstrated that CM037 significantly inhibited tumorsphere formation and CSC viability.	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('inhibited', 'NegReg', (38, 47))	('CSC viability', 'CPA', (74, 87))	('CM037', 'Chemical', '-', (18, 23))	('CM037', 'Var', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
52393	32295073	In a subsequent study by the same group, CM037 treatment promoted DNA damage in OC cells with a corresponding increase in DNA damage response genes.	('increase', 'PosReg', (110, 118))	('promoted', 'PosReg', (57, 65))	('DNA', 'MPA', (122, 125))	('CM037', 'Chemical', '-', (41, 46))	('OC', 'Phenotype', 'HP:0100615', (80, 82))	('DNA damage', 'MPA', (66, 76))	('CM037', 'Var', (41, 46))
52394	32295073	CM037 inhibited ALDH1A1, resulting in the accumulation of intracellular ROS, DNA damage, and apoptosis.	('intracellular ROS', 'MPA', (58, 75))	('CM037', 'Chemical', '-', (0, 5))	('accumulation', 'PosReg', (42, 54))	('ALDH1A1', 'Gene', (16, 23))	('DNA damage', 'MPA', (77, 87))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('inhibited', 'NegReg', (6, 15))	('CM037', 'Var', (0, 5))	('apoptosis', 'CPA', (93, 102))
52395	32295073	demonstrated that CM037 treatment inhibited spheroid formation and preferential death of ALDHhigh cells.	('preferential death', 'CPA', (67, 85))	('inhibited', 'NegReg', (34, 43))	('CM037', 'Chemical', '-', (18, 23))	('spheroid formation', 'CPA', (44, 62))	('CM037', 'Var', (18, 23))
52403	32295073	673A preferentially killed CD133 + CSCs by induction of necroptosis and exhibited synergy with chemotherapy in reducing tumor initiation and promoting tumor eradication in vivo (Table 2).	('673A', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor initiation', 'Disease', (120, 136))	('promoting', 'PosReg', (141, 150))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('necroptosis', 'CPA', (56, 67))	('reducing', 'NegReg', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('673A', 'Chemical', '-', (0, 4))	('tumor initiation', 'Disease', 'MESH:D009369', (120, 136))	('tumor', 'Disease', (120, 125))
52412	32295073	Specifically, aberrant expression of long non-coding RNA (lncRNA) HOX antisense intergenic RNA (HOTAIR) is associated with cancer progression and metastasis in several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('HOTAIR', 'Gene', '100124700', (96, 102))	('metastasis', 'CPA', (146, 156))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('aberrant expression', 'Var', (14, 33))	('cancer', 'Disease', (123, 129))	('associated with', 'Reg', (107, 122))	('cancer', 'Disease', (168, 174))	('HOTAIR', 'Gene', (96, 102))
52418	32295073	siRNA-mediated gene silencing of ALDH1A1 sensitized cisplatin and paclitaxel-resistant OC cell lines to chemotherapy and significantly inhibited tumorigenesis in mice compared to chemotherapy alone.	('paclitaxel', 'Chemical', 'MESH:D017239', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('sensitized', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('OC', 'Phenotype', 'HP:0100615', (87, 89))	('tumor', 'Disease', (145, 150))	('mice', 'Species', '10090', (162, 166))	('ALDH1A1', 'Gene', (33, 40))	('inhibited', 'NegReg', (135, 144))	('cisplatin', 'MPA', (52, 61))	('gene silencing', 'Var', (15, 29))
52419	32295073	Treatment with an ALDH1A1 inhibitor CM037 sensitized OC spheroids to cisplatin treatment.	('OC', 'Phenotype', 'HP:0100615', (53, 55))	('sensitized', 'Reg', (42, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('ALDH1A1', 'Gene', (18, 25))	('OC spheroids', 'CPA', (53, 65))	('CM037', 'Chemical', '-', (36, 41))	('CM037', 'Var', (36, 41))
52420	32295073	ALDH1A family inhibitor 673A synergized with cisplatin treatment, resulting in a 30-fold reduction in cell numbers in chemotherapy-resistant OC cells compared to either therapy alone and was also shown to synergize with cisplatin to inhibit ovarian CSC proliferation.	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('673A', 'Var', (24, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cell numbers in', 'CPA', (102, 117))	('ovarian CSC proliferation', 'Disease', 'MESH:D010049', (241, 266))	('reduction', 'NegReg', (89, 98))	('inhibit', 'NegReg', (233, 240))	('OC', 'Phenotype', 'HP:0100615', (141, 143))	('673A', 'Chemical', '-', (24, 28))	('ovarian CSC proliferation', 'Disease', (241, 266))	('ALDH1A', 'Gene', (0, 6))
52437	31772025	The molecular events underlying UCS are enigmatic, as cancer gene mutations are generally shared among UCS/EC.	('mutations', 'Var', (66, 75))	('UCS/EC', 'Disease', (103, 109))	('UCS', 'Phenotype', 'HP:0002891', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('UCS', 'Phenotype', 'HP:0002891', (32, 35))	('EC', 'Phenotype', 'HP:0012114', (107, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('UCS', 'Disease', (32, 35))
52438	31772025	We take advantage of genetic approaches in mice to show that inactivation of Fbxw7 and Pten results in UCS through spontaneous acquisition of mutations in a third gene (Tp53), arguing for strong biological selection and synergism in UCS.	('inactivation', 'Var', (61, 73))	('Fbxw7', 'Gene', (77, 82))	('mutations', 'Var', (142, 151))	('mice', 'Species', '10090', (43, 47))	('UCS', 'Phenotype', 'HP:0002891', (103, 106))	('results in', 'Reg', (92, 102))	('UCS', 'Disease', (103, 106))	('Tp53', 'Gene', (169, 173))	('Pten', 'Gene', (87, 91))	('Tp53', 'Gene', '22059', (169, 173))	('UCS', 'Phenotype', 'HP:0002891', (233, 236))
52445	31772025	Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas.	('endometrioid adenocarcinomas', 'Disease', (146, 174))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (146, 173))	('precancerous lesions', 'Disease', 'MESH:D011230', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('neoplasia', 'Disease', 'MESH:D009369', (111, 120))	('Pten', 'Gene', (26, 30))	('neoplasia', 'Phenotype', 'HP:0002664', (111, 120))	('precancerous lesions', 'Disease', (60, 80))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (95, 120))	('resulted in', 'Reg', (31, 42))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('Fbxw7', 'Gene', (16, 21))	('Inactivation', 'Var', (0, 12))	('neoplasia', 'Disease', (111, 120))
52447	31772025	Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type.	('carcinosarcoma', 'Disease', 'MESH:D002296', (185, 199))	('mutations', 'Var', (70, 79))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('endometrial cancer', 'Disease', (248, 266))	('acquired', 'Reg', (55, 63))	('carcinosarcoma', 'Disease', (185, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('underpinning uterine', 'Phenotype', 'HP:0000013', (164, 184))	('endometrial cancer', 'Phenotype', 'HP:0012114', (248, 266))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (177, 199))	('endometrial cancer', 'Disease', 'MESH:D016889', (248, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Trp53', 'Gene', (64, 69))
52459	31772025	For example, UCS shares epidemiologic features and patterns of chromosomal instability with high-grade carcinomas, and also shares mutational spectra with ECs, including frequent mutations in loci encoding PI3K pathway components.	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinomas', 'Disease', (103, 113))	('EC', 'Phenotype', 'HP:0012114', (155, 157))	('chromosomal instability', 'Phenotype', 'HP:0040012', (63, 86))	('UCS', 'Phenotype', 'HP:0002891', (13, 16))	('mutations', 'Var', (179, 188))	('PI3K pathway', 'Pathway', (206, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinomas', 'Disease', 'MESH:D009369', (103, 113))
52461	31772025	Systematic genomic characterizations of UCS have identified frequent mutations in some genes, most notably Tp53, but such mutations also frequently occur in serous and high-grade endometrioid cancers and are not specific to UCS.	('mutations', 'Var', (69, 78))	('UCS', 'Phenotype', 'HP:0002891', (224, 227))	('endometrioid cancers', 'Disease', 'MESH:D009369', (179, 199))	('endometrioid cancers', 'Disease', (179, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('Tp53', 'Gene', (107, 111))	('UCS', 'Phenotype', 'HP:0002891', (40, 43))	('occur', 'Reg', (148, 153))	('mutations', 'Var', (122, 131))	('Tp53', 'Gene', '22059', (107, 111))	('serous', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
52465	31772025	Fbxw7 mutations characterize diverse cancers (hematopoietic, colon, stomach, gallbladder/bile duct).	('colon', 'Disease', (61, 66))	('Fbxw7', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('stomach', 'Disease', (68, 75))	('mutations', 'Var', (6, 15))	('characterize', 'Reg', (16, 28))	('hematopoietic', 'Disease', (46, 59))
52466	31772025	In women, carcinomas of the lower female reproductive tract (the Mullerian system), including the uterine cervix and corpus, frequently harbor Fbxw7 mutations.	('carcinomas', 'Disease', 'MESH:D009369', (10, 20))	('mutations', 'Var', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('Fbxw7', 'Gene', (143, 148))	('carcinomas', 'Disease', (10, 20))	('uterine cervix', 'Phenotype', 'HP:0030160', (98, 112))	('harbor', 'Reg', (136, 142))	('women', 'Species', '9606', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
52467	31772025	Indeed, uterine cancers have the highest incidence of Fbxw7 mutations among all human cancers, followed by colon cancer.	('colon cancer', 'Disease', (107, 119))	('cancers', 'Disease', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('uterine cancer', 'Phenotype', 'HP:0010784', (8, 22))	('uterine cancers', 'Phenotype', 'HP:0010784', (8, 23))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Disease', (86, 93))	('mutations', 'Var', (60, 69))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))	('Fbxw7', 'Gene', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
52468	31772025	Concordantly, in diverse nongynecologic mouse models, both the WD40 and truncating mutations have proven potently oncogenic.	('WD40', 'Var', (63, 67))	('mouse', 'Species', '10090', (40, 45))	('oncogenic', 'CPA', (114, 123))	('truncating mutations', 'Var', (72, 92))
52481	31772025	With the original Sprr2f-Cre allele, extensive Cre-mediated recombination was observed in the uterus (endometrial epithelium), kidney (tubular epithelium), and cerebellum (Purkinje cells), as previously reported.	('Sprr2f', 'Gene', '20760', (18, 24))	('Sprr2f', 'Gene', (18, 24))	('Cre-mediated', 'Var', (47, 59))
52486	31772025	Fbxw7 mutations in human EC were first reported in 2002, but their significance and high incidence (~20% of cases) was not fully appreciated until genome sequencing efforts confirmed and extended the initial results.	('Fbxw7', 'Gene', (0, 5))	('human', 'Species', '9606', (19, 24))	('mutations', 'Var', (6, 15))	('EC', 'Phenotype', 'HP:0012114', (25, 27))
52487	31772025	Despite the crucial contribution of Fbxw7 mutation in EC, few studies have focused on the biological basis of its function as an endometrial tumor suppressor in vivo.	('Fbxw7', 'Gene', (36, 41))	('EC', 'Phenotype', 'HP:0012114', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('endometrial tumor', 'Disease', (129, 146))	('mutation', 'Var', (42, 50))	('endometrial tumor', 'Disease', 'MESH:D016889', (129, 146))
52498	31772025	Fbxw7 mice exhibited only small increases in uterine weight, and, while Pten mice showed larger increases, this was due to florid endometrial hyperplasia (a.k.a.	('mice', 'Species', '10090', (77, 81))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (130, 153))	('Fbxw7', 'Var', (0, 5))	('mice', 'Species', '10090', (6, 10))	('uterine', 'MPA', (45, 52))	('increases', 'PosReg', (32, 41))	('endometrial hyperplasia', 'Disease', (130, 153))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (130, 153))
52500	31772025	By 24 wk of age, the difference in uterine weights between Fbxw7/Pten vs. control mice was statistically significant (P < 0.0025, t test), and this difference became even more significant at 36 wk of age (P < 0.0001, t test).	('mice', 'Species', '10090', (82, 86))	('Fbxw7/Pten', 'Var', (59, 69))	('uterine weights', 'CPA', (35, 50))
52501	31772025	Furthermore, 75% of Fbxw7/Pten mice exhibited myometrial invasion by 24 wk, vs. 0% for Pten.	('Fbxw7/Pten', 'Var', (20, 30))	('mice', 'Species', '10090', (31, 35))	('myometrial invasion', 'CPA', (46, 65))
52502	31772025	Per log-rank analysis, survival of Fbxw7/Pten mice was significantly decreased vs. Fbxw7, Pten, or control mice (P < 0.0001 for each of the pairwise comparisons).	('decreased', 'NegReg', (69, 78))	('Fbxw7', 'Var', (83, 88))	('Fbxw7/Pten', 'Var', (35, 45))	('mice', 'Species', '10090', (46, 50))	('mice', 'Species', '10090', (107, 111))	('survival', 'CPA', (23, 31))
52503	31772025	Fbxw7 mice showed slightly but significantly increased survival vs. Pten alone (P = 0.0151; Fig.	('Fbxw7', 'Var', (0, 5))	('mice', 'Species', '10090', (6, 10))	('survival', 'CPA', (55, 63))	('increased', 'PosReg', (45, 54))
52517	31772025	In mTmG;BAC-Sprr2f-Cre females, Cre activity was observed only in endometrial epithelium, with no recombination in endometrial stroma (only endometrial glands turned green).	('endometrial stroma', 'Disease', (115, 133))	('activity', 'MPA', (36, 44))	('Sprr2f', 'Gene', '20760', (12, 18))	('Cre', 'CPA', (32, 35))	('mTmG', 'Var', (3, 7))	('Sprr2f', 'Gene', (12, 18))	('endometrial stroma', 'Disease', 'MESH:D014591', (115, 133))
52521	31772025	All Fbxw7/Pten mice in the survival analysis had metastasis to adjacent organs (ovary, peritoneum), while 58% (15/26) showed distant metastasis.	('Fbxw7/Pten', 'Var', (4, 14))	('metastasis to adjacent organs', 'CPA', (49, 78))	('mice', 'Species', '10090', (15, 19))	('distant metastasis', 'CPA', (125, 143))
52529	31772025	Of the 76 genes, only one:Trp53, the murine homolog of human TP53:was mutated in >=1 tumor (Fig.	('tumor', 'Disease', (85, 90))	('murine', 'Species', '10090', (37, 43))	('human', 'Species', '9606', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Trp53', 'Gene', (26, 31))	('mutated', 'Var', (70, 77))
52530	31772025	All 4 of these tumors harbored mutations leading to amino acid substitutions (A135V, H165R, V170M, R172H) previously documented as recurring cancer drivers in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('A135V', 'Var', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('H165R', 'Mutation', 'rs876659477', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('R172H', 'Mutation', 'p.R172H', (99, 104))	('A135V', 'Mutation', 'p.A135V', (78, 83))	('cancer', 'Disease', (141, 147))	('tumors', 'Disease', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', (165, 171))	('V170M', 'Var', (92, 97))	('V170M', 'Mutation', 'p.V170M', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('H165R', 'Var', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('R172H', 'Var', (99, 104))
52531	31772025	For example, murine R172H corresponds to the human R175H dominant-negative hotspot mutation, and an engineered R172H allele also functions as a genetically dominant oncogene in mice, while murine A135V corresponds to the temperature-sensitive A138V TP53 mutation.	('R175H', 'Mutation', 'rs28934578', (51, 56))	('A135V', 'Var', (196, 201))	('R172H', 'Var', (111, 116))	('A135V', 'Mutation', 'p.A135V', (196, 201))	('human', 'Species', '9606', (45, 50))	('mutation', 'Var', (83, 91))	('R172H', 'Mutation', 'p.R172H', (20, 25))	('murine', 'Species', '10090', (13, 19))	('R172H', 'Var', (20, 25))	('A138V', 'Mutation', 'rs750600586', (243, 248))	('murine', 'Species', '10090', (189, 195))	('mice', 'Species', '10090', (177, 181))	('R172H', 'Mutation', 'p.R172H', (111, 116))
52532	31772025	Only one other mutation was identified among the 76 loci in the 7 cases: KrasG12D in a tumor with no Trp53 mutation but with a "mutant pattern" of p53 overexpression (as detailed later and in Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('KrasG12D', 'Var', (73, 81))	('overexpression', 'PosReg', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
52534	31772025	Intragenic or larger deletions spanning TP53/Trp53 are common cancer-driving events not detectable by exon resequencing, and may account for the observed overexpression/presumptive mutation of p53 protein in the UCS not harboring Trp53 missense mutations.	('UCS', 'Phenotype', 'HP:0002891', (212, 215))	('overexpression/presumptive', 'PosReg', (154, 180))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('deletions', 'Var', (21, 30))	('TP53/Trp53', 'Gene', (40, 50))	('protein', 'Protein', (197, 204))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
52538	31772025	However, the incidence of p53 clonal overexpression by IHC increased over time, reaching 80% in mice euthanized due to illness per tumor burden criteria (Fig.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('p53', 'Var', (26, 29))	('tumor', 'Disease', (131, 136))
52540	31772025	Thus, the incidence of p53 inactivation in these tumors may be >80%.	('inactivation', 'Var', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('p53 inactivation', 'Var', (23, 39))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
52541	31772025	Three of the 4 cases (75%) harboring Tp53 mutations exhibited metastases, vs. 4 of 6 (67%) with either Tp53 mutation or mutant-pattern expression p53 and 22 of 27 (78%) among all mice analyzed as part of the survival curve.	('Tp53', 'Gene', '22059', (37, 41))	('mice', 'Species', '10090', (179, 183))	('exhibited', 'Reg', (52, 61))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('Tp53', 'Gene', (103, 107))	('Tp53', 'Gene', '22059', (103, 107))	('mutant-pattern', 'Var', (120, 134))	('Tp53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('metastases', 'Disease', (62, 72))
52551	31772025	5A), demonstrating that these known Fbxw7 targets likely mediate the actions of Fbxw7 mutations in uterine cancer.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('uterine cancer', 'Phenotype', 'HP:0010784', (99, 113))	('Fbxw7', 'Gene', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
52555	31772025	In addition, several other EMT regulators, including Zeb-1, Twist, beta-catenin, and Snail were also down-regulated following Fbxw7 reexpression (Fig.	('Zeb-1', 'Gene', '21417', (53, 58))	('Fbxw7', 'Gene', (126, 131))	('reexpression', 'Var', (132, 144))	('Twist', 'Gene', (60, 65))	('beta-catenin', 'Gene', '12387', (67, 79))	('Snail', 'Gene', '20613', (85, 90))	('Snail', 'Gene', (85, 90))	('beta-catenin', 'Gene', (67, 79))	('down-regulated', 'NegReg', (101, 115))	('Zeb-1', 'Gene', (53, 58))	('Twist', 'Gene', '22160', (60, 65))
52558	31772025	Treatment with the PI3K inhibitor LY294002 greatly inhibited Gsk3beta(Ser9) phosphorylation, confirming that Gsk3beta is constitutively phosphorylated by Akt in UCS1/2.	('LY294002', 'Var', (34, 42))	('Ser9', 'Chemical', '-', (70, 74))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('UCS', 'Phenotype', 'HP:0002891', (161, 164))	('inhibited', 'NegReg', (51, 60))	('Gsk3beta', 'Protein', (61, 69))
52561	31772025	Gsk3beta phosphorylates c-Myc at T58, and the T58A mutation renders the c-Myc protein insensitive to Gsk3beta recognition and Fbxw7-mediated degradation.	('T58A', 'Mutation', 'c.58T>A', (46, 50))	('T58A', 'Var', (46, 50))	('insensitive', 'NegReg', (86, 97))
52564	31772025	We then assessed the properties of 3D organoids derived from Pten, Fbxw7, or Fbxw7/Pten adult uteri not harboring overt tumors and grown in defined media.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Fbxw7/Pten', 'Var', (77, 87))
52567	31772025	Fbxw7 mutations have been identified across several human EC histotypes, including endometrioid and serous adenocarcinomas, and also in UCS.	('Fbxw7', 'Gene', (0, 5))	('serous adenocarcinomas', 'Disease', (100, 122))	('human', 'Species', '9606', (52, 57))	('EC', 'Phenotype', 'HP:0012114', (58, 60))	('serous adenocarcinomas', 'Disease', 'MESH:D000230', (100, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('identified', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))	('UCS', 'Phenotype', 'HP:0002891', (136, 139))	('endometrioid', 'Disease', (83, 95))
52569	31772025	Tp53 and Fbxw7 mutations were much more likely to coexist in UCS vs. EC.	('Tp53', 'Gene', (0, 4))	('UCS', 'Disease', (61, 64))	('mutations', 'Var', (15, 24))	('Tp53', 'Gene', '22059', (0, 4))	('EC', 'Phenotype', 'HP:0012114', (69, 71))	('Fbxw7', 'Gene', (9, 14))	('UCS', 'Phenotype', 'HP:0002891', (61, 64))
52571	31772025	This supports our finding that Tp53 and Fbxw7 mutations synergize in the formation of UCS.	('synergize', 'Reg', (56, 65))	('mutations', 'Var', (46, 55))	('UCS', 'Phenotype', 'HP:0002891', (86, 89))	('Tp53', 'Gene', (31, 35))	('UCS', 'Disease', (86, 89))	('Tp53', 'Gene', '22059', (31, 35))	('Fbxw7', 'Gene', (40, 45))
52572	31772025	These findings raise the possibility that adenocarcinomas harboring Fbxw7 mutations are more likely to develop into UCS.	('adenocarcinomas', 'Disease', 'MESH:D000230', (42, 57))	('Fbxw7', 'Gene', (68, 73))	('UCS', 'Disease', (116, 119))	('mutations', 'Var', (74, 83))	('adenocarcinomas', 'Disease', (42, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('develop', 'Reg', (103, 110))	('UCS', 'Phenotype', 'HP:0002891', (116, 119))
52578	31772025	While Fbxw7 has been previously documented to undergo recurrent mutations in UCS, and could be surmised to be a tumor suppressor in UCS, prior studies had not pointed to Fbxw7 as a specific driver of the unique clinicopathologic phenotypes associated with UCS.	('UCS', 'Disease', (256, 259))	('UCS', 'Phenotype', 'HP:0002891', (132, 135))	('Fbxw7', 'Gene', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('UCS', 'Phenotype', 'HP:0002891', (77, 80))	('UCS', 'Phenotype', 'HP:0002891', (256, 259))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', (112, 117))
52579	31772025	Here, by taking advantage of defined genetic model systems, we showed that tumorigenesis driven by concurrent Fbxw7 and Pten mutations progresses in a stereotypical manner.	('mutations', 'Var', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Pten', 'Gene', (120, 124))	('stereotypical manner', 'Phenotype', 'HP:0000733', (151, 171))	('Fbxw7', 'Gene', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
52584	31772025	However, one interesting observation was that Trp53 mutations occurred as late events, since IHC showed that Trp53 mutant clones arose within already invasive endometrioid adenocarcinomas.	('mutant', 'Var', (115, 121))	('invasive endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (150, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('invasive endometrioid adenocarcinomas', 'Disease', (150, 187))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (159, 186))	('Trp53', 'Gene', (109, 114))
52585	31772025	For example, mutations in Fgfr2, Kras, Pik3ca, Pik3r1, or Akt1/2/3 lead to constitutive activation of PI3K/Akt signaling, the central pathway misregulated in essentially all ECs.	('activation', 'PosReg', (88, 98))	('Kras', 'Gene', (33, 37))	('PI3K/Akt signaling', 'Pathway', (102, 120))	('Fgfr2', 'Gene', '14183', (26, 31))	('Pik3r1', 'Gene', '18708', (47, 53))	('EC', 'Phenotype', 'HP:0012114', (174, 176))	('Pik3ca', 'Gene', (39, 45))	('Fgfr2', 'Gene', (26, 31))	('Pik3ca', 'Gene', '18706', (39, 45))	('Pik3r1', 'Gene', (47, 53))	('Akt1/2/3', 'Gene', '11651;11652;23797', (58, 66))	('Akt1/2/3', 'Gene', (58, 66))	('mutations', 'Var', (13, 22))
52586	31772025	This study also provides further evidence that Fbxw7 is a strong p53-dependent tumor suppressor in UCS, as in other human cancers.	('Fbxw7', 'Var', (47, 52))	('UCS', 'Disease', (99, 102))	('tumor', 'Disease', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('UCS', 'Phenotype', 'HP:0002891', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('human', 'Species', '9606', (116, 121))
52588	31772025	This genetic interaction is believed to be mediated by factors regulating cell cycle progression and cell growth, including Cyclin E, Notch, c-Jun, c-Myc, and mTOR, all of which are stabilized following Fbxw7 mutation.	('Notch', 'Gene', (134, 139))	('mediated', 'Reg', (43, 51))	('c-Myc', 'MPA', (148, 153))	('c-Jun', 'Gene', (141, 146))	('mTOR', 'Gene', (159, 163))	('Fbxw7', 'Gene', (203, 208))	('mTOR', 'Gene', '56717', (159, 163))	('mutation', 'Var', (209, 217))	('c-Jun', 'Gene', '16476', (141, 146))	('Notch', 'Gene', '4851;18128', (134, 139))
52589	31772025	Kras appears to be another cooperating oncogene, as evidenced by one murine UCS harboring a mutation (present study) and the presence of Kras mutations in primary UCS.	('mutations', 'Var', (142, 151))	('Kras', 'Gene', (137, 141))	('UCS', 'Phenotype', 'HP:0002891', (76, 79))	('UCS', 'Phenotype', 'HP:0002891', (163, 166))	('murine', 'Species', '10090', (69, 75))
52594	31772025	Using an addback system that permitted controlled reexpression of Fbxw7 in murine UCS lines, we demonstrated that Fbxw7 has an important and specific role as a driver of EMT:and one that is distinct from its cooperating drivers in UCS, Pten, and Trp53.	('murine', 'Species', '10090', (75, 81))	('EMT', 'CPA', (170, 173))	('UCS', 'Phenotype', 'HP:0002891', (231, 234))	('UCS', 'Phenotype', 'HP:0002891', (82, 85))	('Fbxw7', 'Var', (114, 119))
52596	31772025	Klf5 has been implicated in EMT, and, more recently, genetic alterations of the Klf5 locus have been proven oncogenic, including focal amplification of Klf5 superenhancers, as well as missense mutations in degron domains that disrupt Klf5-Fbxw7 interactions to stabilize Klf5 protein.	('stabilize', 'PosReg', (261, 270))	('disrupt', 'NegReg', (226, 233))	('interactions', 'Interaction', (245, 257))	('Klf5', 'Gene', '12224', (0, 4))	('Klf5', 'Gene', '12224', (271, 275))	('Klf5', 'Gene', (152, 156))	('Klf5', 'Gene', (80, 84))	('Klf5', 'Gene', '12224', (234, 238))	('Klf5', 'Gene', '12224', (152, 156))	('Klf5', 'Gene', '12224', (80, 84))	('missense mutations', 'Var', (184, 202))	('Klf5', 'Gene', (271, 275))	('Klf5', 'Gene', (234, 238))	('Klf5', 'Gene', (0, 4))
52607	31772025	Fbxw7 mutations are more frequent in UCS, but also occur in usual-type endometrioid adenocarcinomas, raising questions as to the natural progression of such tumors.	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (71, 98))	('Fbxw7', 'Gene', (0, 5))	('UCS', 'Disease', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('endometrioid adenocarcinomas', 'Disease', (71, 99))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('frequent', 'Reg', (25, 33))	('occur', 'Reg', (51, 56))	('UCS', 'Phenotype', 'HP:0002891', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (71, 99))	('mutations', 'Var', (6, 15))
52610	31772025	This is further suggested by the fact that UCSs are more likely to harbor p53 mutations, and our finding that Fbxw7-mutant endometrioid adenocarcinomas are more likely to express L1CAM, a marker of EMT frequently overexpressed in UCS.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (123, 151))	('express', 'Reg', (171, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('Fbxw7-mutant', 'Var', (110, 122))	('L1CAM', 'Protein', (179, 184))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (123, 150))	('mutations', 'Var', (78, 87))	('p53', 'Gene', (74, 77))	('Fbxw7-mutant', 'Gene', (110, 122))	('endometrioid adenocarcinomas', 'Disease', (123, 151))	('UCSs', 'Disease', (43, 47))	('UCS', 'Phenotype', 'HP:0002891', (43, 46))	('UCSs', 'Disease', 'None', (43, 47))	('UCS', 'Phenotype', 'HP:0002891', (230, 233))
52727	28841919	An asymptomatic 61-year-old woman (gravida 0, reaching menopause in her 40s) was referred to our hospital because of elevated levels of CA125 (389 U/mL; normal range < 35 U/mL) and CA19-9 (785 U/mL; normal range < 37 U/mL).	('785 U/mL', 'Var', (189, 197))	('CA125', 'Gene', '94025', (136, 141))	('elevated levels of CA125', 'Phenotype', 'HP:0031030', (117, 141))	('CA125', 'Gene', (136, 141))	('woman', 'Species', '9606', (28, 33))	('reaching menopause', 'Phenotype', 'HP:0008209', (46, 64))	('CA19-9', 'Chemical', 'MESH:C086528', (181, 187))
52746	28841919	Focal but intense expression of CA125 and CA19-9 was observed in the tumor regardless of the histologic pattern (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('CA19-9', 'Chemical', 'MESH:C086528', (42, 48))	('CA125', 'Gene', (32, 37))	('CA19-9', 'Var', (42, 48))	('expression', 'MPA', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CA125', 'Gene', '94025', (32, 37))
52787	28841919	The present patient was referred to our hospital because of elevated serum levels of CA125 and CA19-9.	('serum levels', 'MPA', (69, 81))	('CA125', 'Gene', '94025', (85, 90))	('elevated', 'PosReg', (60, 68))	('CA19-9', 'Var', (95, 101))	('CA125', 'Gene', (85, 90))	('CA19-9', 'Chemical', 'MESH:C086528', (95, 101))	('patient', 'Species', '9606', (12, 19))
52799	30760718	Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('mutations', 'Var', (251, 260))	('Cancer Genome Atlas cohort', 'Disease', 'MESH:D009369', (132, 158))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('Cancer Genome Atlas cohort', 'Disease', (132, 158))	('focal', 'MPA', (207, 212))	('adult cancers', 'Disease', (343, 356))	('adult cancers', 'Disease', 'MESH:C535836', (343, 356))	('HAMP', 'Gene', '57817', (292, 296))	('HAMP', 'Gene', (292, 296))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('HAMP', 'Gene', '57817', (176, 180))	('HAMP', 'Gene', '57817', (118, 122))	('HAMP', 'Gene', (176, 180))	('HAMP', 'Gene', (118, 122))
52801	30760718	For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth.	('genetic depletion', 'Var', (89, 106))	('BRD9', 'Gene', '65980', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('BRD9', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (124, 129))	('BRD9', 'Gene', (50, 54))	('inhibits', 'NegReg', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BRD9', 'Gene', '65980', (110, 114))	('cancer', 'Disease', (72, 78))
52849	30760718	BRD9, BRD4, KAT6A, ATAD2, CLOCK, ASH1L, and BPTF showed high overall G-scores for copy number gain, whereas HDAC4, BRD1, SIRT3, HDAC10, SP100, SP140L, SP110, and PBRM1 had high overall G-scores for copy number loss (overall G-score > 0.9; Fig.	('BRD4', 'Gene', '23476', (6, 10))	('BPTF', 'Gene', (44, 48))	('SP140L', 'Gene', (143, 149))	('SP110', 'Gene', '3431', (151, 156))	('ATAD2', 'Gene', (19, 24))	('SP100', 'Gene', (136, 141))	('KAT6A', 'Gene', '7994', (12, 17))	('HDAC10', 'Gene', '83933', (128, 134))	('SIRT3', 'Gene', (121, 126))	('ASH1L', 'Gene', (33, 38))	('SIRT3', 'Gene', '23410', (121, 126))	('copy number gain', 'Disease', 'MESH:D015430', (82, 98))	('CLOCK', 'Gene', '9575', (26, 31))	('CLOCK', 'Gene', (26, 31))	('BRD1', 'Gene', (115, 119))	('HDAC4', 'Gene', '9759', (108, 113))	('copy number', 'Var', (198, 209))	('ASH1L', 'Gene', '55870', (33, 38))	('copy number gain', 'Disease', (82, 98))	('KAT6A', 'Gene', (12, 17))	('SP110', 'Gene', (151, 156))	('SP100', 'Gene', '6672', (136, 141))	('BRD4', 'Gene', (6, 10))	('SP140L', 'Gene', '93349', (143, 149))	('BRD9', 'Gene', (0, 4))	('PBRM1', 'Gene', '55193', (162, 167))	('ATAD2', 'Gene', '29028', (19, 24))	('BRD1', 'Gene', '23774', (115, 119))	('HDAC10', 'Gene', (128, 134))	('HDAC4', 'Gene', (108, 113))	('BPTF', 'Gene', '2186', (44, 48))	('PBRM1', 'Gene', (162, 167))	('BRD9', 'Gene', '65980', (0, 4))
52851	30760718	3b); in contrast, high-level alterations (GISTIC status = - 2) were markedly less frequent in HAMPs with copy number loss (0.8-9.4%; Fig.	('HAMP', 'Gene', (94, 98))	('HAMP', 'Gene', '57817', (94, 98))	('copy number loss', 'Var', (105, 121))
52855	30760718	The mutation call set was generated via an ensemble calling strategy by the MC3 (Multi-Center Mutation Calling in Multiple Cancers) project, then we integrated five complementary methods to identify the genes with mutations that have significant signs of positive selection during tumor evolution (Fig.	('Multiple Cancers', 'Disease', (114, 130))	('MC3', 'Gene', (76, 79))	('Multiple Cancers', 'Disease', 'MESH:D009369', (114, 130))	('MC3', 'Gene', '4159', (76, 79))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))
52856	30760718	Collectively, across 33 cancer types, we identified 34 HAMPs that have recurrent mutations in at least one cancer type (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('HAMP', 'Gene', '57817', (55, 59))	('HAMP', 'Gene', (55, 59))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
52858	30760718	3b), the recurrent mutations of HAMPs were largely cancer type-specific (Fig.	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (51, 57))	('HAMP', 'Gene', '57817', (32, 36))	('HAMP', 'Gene', (32, 36))
52859	30760718	4b): 17 of 34 (50%) HAMPs with recurrent mutations were only observed in one cancer type and no recurrent mutation of HAMPs was found in more than 7 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('HAMP', 'Gene', '57817', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HAMP', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('HAMP', 'Gene', '57817', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('HAMP', 'Gene', (118, 122))
52861	30760718	UCEC (n = 20), SKCM (n = 8), BLCA (n = 6), cervical squamous cell carcinoma, and endocervical adenocarcinoma (CESC; n = 6), and HNSC (n = 6) had the largest numbers of recurrent mutations in HAMPs, whereas ACC, DLBC, ESCA, KICH, LAML, LGG, mesothelioma (MESO), OV, PAAD, PCPG, READ, SARC, TGCT, THCA, THYM, UCS, and UVM had none (Fig.	('READ', 'Disease', 'None', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('KICH', 'Disease', (223, 227))	('PAAD', 'Phenotype', 'HP:0006725', (265, 269))	('cervical squamous cell carcinoma', 'Disease', (43, 75))	('UCS', 'Phenotype', 'HP:0002891', (307, 310))	('OV', 'Phenotype', 'HP:0012887', (261, 263))	('mesothelioma', 'Disease', (240, 252))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (81, 108))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 75))	('HAMP', 'Gene', '57817', (191, 195))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('ESCA', 'Phenotype', 'HP:0011459', (217, 221))	('READ', 'Disease', (277, 281))	('KICH', 'Disease', 'None', (223, 227))	('HAMP', 'Gene', (191, 195))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('THCA', 'Phenotype', 'HP:0002890', (295, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('mutations', 'Var', (178, 187))	('endocervical adenocarcinoma', 'Disease', (81, 108))
52862	30760718	Among the three types of HAMPs, BRD proteins and HATs had the highest frequencies of recurrent mutations and HDACs had few recurrent events (Fig.	('HAMP', 'Gene', '57817', (25, 29))	('HDAC', 'Gene', (109, 113))	('HAMP', 'Gene', (25, 29))	('HDAC', 'Gene', '9734', (109, 113))	('mutations', 'Var', (95, 104))
52864	30760718	Among eight HAMPs with M-scores > 0.4, EP300, PBRM1, and CREBBP had the largest overall M-scores across the 33 cancer types (Fig.	('CREBBP', 'Gene', (57, 63))	('HAMP', 'Gene', '57817', (12, 16))	('HAMP', 'Gene', (12, 16))	('M-scores', 'MPA', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CREBBP', 'Gene', '1387', (57, 63))	('PBRM1', 'Gene', (46, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('EP300', 'Gene', (39, 44))	('EP300', 'Gene', '2033', (39, 44))	('PBRM1', 'Gene', '55193', (46, 51))	('M-scores > 0.4', 'Var', (23, 37))
52866	30760718	At a pan-cancer level, except for PBRM1, the most common mutation category of HAMPs was missense mutation (53.0-77.5%; Fig.	('cancer', 'Disease', (9, 15))	('HAMP', 'Gene', (78, 82))	('PBRM1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('PBRM1', 'Gene', '55193', (34, 39))	('missense mutation', 'Var', (88, 105))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('HAMP', 'Gene', '57817', (78, 82))
52867	30760718	In contrast, PBRM1 was most commonly affected by truncating mutations (49.1%; Fig.	('truncating mutations', 'Var', (49, 69))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('affected', 'Reg', (37, 45))
52868	30760718	Using the ABSOLUTE algorithm, we also determined the timing of the mutational processes and the clonal statuses of the mutations in HAMPs.	('HAMP', 'Gene', (132, 136))	('mutations', 'Var', (119, 128))	('HAMP', 'Gene', '57817', (132, 136))
52869	30760718	More than 50% of mutations in HAMPs were early genomic events (Fig.	('HAMP', 'Gene', '57817', (30, 34))	('mutations', 'Var', (17, 26))	('HAMP', 'Gene', (30, 34))
52870	30760718	5d and Supplementary Data 15) and more than 65% of mutations in HAMPs were clonal mutations (Fig.	('HAMP', 'Gene', (64, 68))	('mutations', 'Var', (51, 60))	('HAMP', 'Gene', '57817', (64, 68))
52872	30760718	We also analyzed the distributions of the mutations across the gene bodies and found that mutations in HAMPs were widely spatially distributed along the entire coding sequences, not concentrated within a specific local region (Fig.	('HAMP', 'Gene', '57817', (103, 107))	('mutations', 'Var', (90, 99))	('HAMP', 'Gene', (103, 107))
52875	30760718	Notably, we observed that PBRM1 mutations showed a unique pattern in KIRC and cholangiocarcinoma (CHOL).	('CHOL', 'Phenotype', 'HP:0030153', (98, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('mutations', 'Var', (32, 41))	('KIRC', 'Disease', (69, 73))	('cholangiocarcinoma', 'Disease', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
52876	30760718	Compared with other cancer types, KIRC and CHOL showed higher frequencies of PBRM1 mutations (40.1% in KIRC and 19.4% in CHOL vs. an average of 2.3% among other cancer types).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PBRM1', 'Gene', '55193', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('CHOL', 'Phenotype', 'HP:0030153', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (161, 167))	('CHOL', 'Phenotype', 'HP:0030153', (43, 47))
52877	30760718	Importantly, the dominant PBRM1 mutation category and type in KIRC and CHOL were truncating (83.9% and 85.7%, respectively) and homozygous (85.2% and 71.4%, respectively) mutations, which were remarkably higher than the averages in other cancer types (30.3% and 19.4%, respectively).	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('truncating', 'MPA', (81, 91))	('mutation', 'Var', (32, 40))	('CHOL', 'Phenotype', 'HP:0030153', (71, 75))
52878	30760718	Interestingly, we observed that, in both the CREBBP and EP300 genes, the most frequent mutations were located within the catalytic domain, although the mutations were not statistically significant hotspot mutations at the individual gene level based on OncodriveCLUST analysis (Fig.	('CREBBP', 'Gene', '1387', (45, 51))	('EP300', 'Gene', (56, 61))	('EP300', 'Gene', '2033', (56, 61))	('CREBBP', 'Gene', (45, 51))	('mutations', 'Var', (87, 96))
52885	30760718	6a and Supplementary Data 18), which suggests that transcript fusion is a rare genetic alteration compared with SCNAs and mutations in HAMPs in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('adult cancers', 'Disease', 'MESH:C535836', (151, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('adult cancers', 'Disease', (151, 164))	('transcript fusion', 'Var', (51, 68))	('HAMP', 'Gene', '57817', (135, 139))	('HAMP', 'Gene', (135, 139))
52889	30760718	KAT6B-ADK (n = 6), BPTF-PITPNC1 (n = 5), and NCOA3-EYA2 (n = 5) were the most frequent fusions among the common cancer types examined in our study (Fig.	('fusions', 'Var', (87, 94))	('PITPNC1', 'Gene', '26207', (24, 31))	('BPTF', 'Gene', (19, 23))	('cancer', 'Disease', (112, 118))	('PITPNC1', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('NCOA3', 'Gene', '8202', (45, 50))	('EYA2', 'Gene', '2139', (51, 55))	('BPTF', 'Gene', '2186', (19, 23))	('EYA2', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NCOA3', 'Gene', (45, 50))
52893	30760718	Taken together, these results suggest that, although certain HAMP transcript fusions may be actionable for clinical cancer care, transcript fusion is a rare genomic alteration compared with SCNAs and mutations of HAMPs in common cancers.	('HAMP', 'Gene', '57817', (61, 65))	('cancer', 'Disease', (229, 235))	('HAMP', 'Gene', (61, 65))	('transcript fusion', 'Var', (129, 146))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancers', 'Disease', (229, 236))	('HAMP', 'Gene', '57817', (213, 217))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('HAMP', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
52897	30760718	Across the different lineages of cancers, three types of alterations were observed: (1) consistent, putative gain-of-function (such as for KAT6A and CLOCK, which were focally amplified in six and five cancer types, respectively); (2) consistent, putative loss-of-function (such as for PBRM1, which is mutated in four and focally deleted in five cancer types, and for CREBBP, which is mutated in four and focally deleted in two cancer types); and (3) diverse alterations (such as for ATAD2, which is mutated in three and focally amplified in five cancer types, and for BPTF, which is mutated in three and focally amplified in five cancer types).	('gain-of-function', 'PosReg', (109, 125))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('KAT6A', 'Gene', '7994', (139, 144))	('ATAD2', 'Gene', '29028', (483, 488))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('loss-of-function', 'NegReg', (255, 271))	('cancers', 'Disease', (33, 40))	('CREBBP', 'Gene', (367, 373))	('cancer', 'Disease', (546, 552))	('PBRM1', 'Gene', '55193', (285, 290))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (427, 433))	('KAT6A', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (546, 552))	('ATAD2', 'Gene', (483, 488))	('PBRM1', 'Gene', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('BPTF', 'Gene', '2186', (568, 572))	('CREBBP', 'Gene', '1387', (367, 373))	('cancer', 'Disease', (345, 351))	('CLOCK', 'Gene', '9575', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('CLOCK', 'Gene', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (546, 552))	('BPTF', 'Gene', (568, 572))	('deleted', 'Var', (329, 336))
52898	30760718	This suggests that a large fraction of HAMP alterations may be commonly shared by multiple cancer types, whereas others may be tumor-lineage dependent.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HAMP', 'Gene', (39, 43))	('HAMP', 'Gene', '57817', (39, 43))	('multiple cancer', 'Disease', (82, 97))	('tumor', 'Disease', (127, 132))	('alterations', 'Var', (44, 55))	('multiple cancer', 'Disease', 'MESH:D009369', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
52927	30760718	Consistent with the GBA prediction, knocking down BRD9 expression dramatically inhibited cancer cell growth in vitro (Fig.	('BRD9', 'Gene', '65980', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('BRD9', 'Gene', (50, 54))	('expression', 'MPA', (55, 65))	('cancer', 'Disease', (89, 95))	('inhibited', 'NegReg', (79, 88))	('knocking down', 'Var', (36, 49))	('GBA', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
52928	30760718	Finally, we demonstrated that the expression of BRD9 shRNAs significantly suppressed the growth of subcutaneous tumors formed by MDA-MB-231 or OVCAR8 cells in nude mice (Fig.	('subcutaneous tumors', 'Disease', (99, 118))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (129, 139))	('BRD9', 'Gene', (48, 52))	('nude mice', 'Species', '10090', (159, 168))	('OV', 'Phenotype', 'HP:0012887', (143, 145))	('suppressed', 'NegReg', (74, 84))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (99, 118))	('expression', 'Var', (34, 44))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('growth', 'CPA', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('BRD9', 'Gene', '65980', (48, 52))
52929	30760718	Collectively, our results demonstrate that genetic depletion of BDR9 expression significantly represses tumor cell growth in vitro and in vivo, suggesting that small molecular compounds targeting BRD9 may have strong clinical application potentials.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BDR9', 'Gene', (64, 68))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('represses', 'NegReg', (94, 103))	('BRD9', 'Gene', '65980', (196, 200))	('BRD9', 'Gene', (196, 200))	('genetic depletion', 'Var', (43, 60))
52937	30760718	A HAMP with a high score indicates its recurrent alterations are common genomic events across multiple adult cancer types.	('HAMP', 'Gene', '57817', (2, 6))	('alterations', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HAMP', 'Gene', (2, 6))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
52950	30760718	Furthermore, genetic depletion of HDACs in tumor cells leads to cell cycle arrest, apoptosis, and senescence, suggesting that HDACs are required for the survival and growth of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('genetic depletion', 'Var', (13, 30))	('tumor', 'Disease', (176, 181))	('HDAC', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('senescence', 'CPA', (98, 108))	('HDAC', 'Gene', '9734', (34, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('apoptosis', 'CPA', (83, 92))	('tumor', 'Disease', (43, 48))	('HDAC', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('cell cycle arrest', 'CPA', (64, 81))	('HDAC', 'Gene', '9734', (126, 130))
52953	30760718	For example, CREBBP and EP300 were widely mutated across multiple cancer types at relatively low frequencies; most of these mutations were heterozygous missense mutations.	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('EP300', 'Gene', (24, 29))	('EP300', 'Gene', '2033', (24, 29))	('multiple cancer', 'Disease', 'MESH:D009369', (57, 72))	('CREBBP', 'Gene', (13, 19))	('multiple cancer', 'Disease', (57, 72))	('CREBBP', 'Gene', '1387', (13, 19))
52954	30760718	In contrast, PBRM1 showed high-frequency, cancer type-specific mutations in KIRC (40.1%).	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
52960	30760718	Collectively, our comprehensive genomic analysis identified 63 putative cancer-causing HAMPs driven by SCNAs and/or mutations (recurrent score >= 1).	('SCNAs', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (116, 125))	('HAMP', 'Gene', '57817', (87, 91))	('HAMP', 'Gene', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
52963	30760718	For example, the breast and ovarian cancer patients with BRD4 amplifications may be potential candidates for treatment with BET inhibitors that have been successfully developed to the preclinical stage.	('BET', 'Gene', '92737', (124, 127))	('BET', 'Gene', (124, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('patients', 'Species', '9606', (43, 51))	('BRD4', 'Gene', (57, 61))	('amplifications', 'Var', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BRD4', 'Gene', '23476', (57, 61))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (17, 42))
52964	30760718	In addition, eight HAMPs focally lost copy numbers (overall G-score > 0.9) and eight HAMPs showed high frequencies of mutations (overall M-score > 0.4), which indicates that their functions may be reduced and/or deficient due to partial loss of wild-type alleles during cancer development.	('HAMP', 'Gene', (19, 23))	('deficient', 'NegReg', (212, 221))	('copy', 'MPA', (38, 42))	('HAMP', 'Gene', '57817', (85, 89))	('functions', 'MPA', (180, 189))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', (270, 276))	('HAMP', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lost', 'NegReg', (33, 37))	('HAMP', 'Gene', '57817', (19, 23))
52966	30760718	For example, mutations of the BRD-containing protein SMARCA4 in tumor cells results in a unique functional dependence on SMARCA2.	('tumor', 'Disease', (64, 69))	('functional dependence', 'MPA', (96, 117))	('SMARCA4', 'Gene', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (13, 22))	('SMARCA2', 'Gene', (121, 128))	('SMARCA2', 'Gene', '6595', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('results in', 'Reg', (76, 86))	('SMARCA4', 'Gene', '6597', (53, 60))
52968	30760718	Notably, very few homozygous deletions or mutations of HAMPs (except for PBRM1) were observed in cancer, suggesting that HAMPs may be essential for tumor growth, and that complete loss may be lethal.	('deletions', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (148, 153))	('PBRM1', 'Gene', '55193', (73, 78))	('HAMP', 'Gene', '57817', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HAMP', 'Gene', (55, 59))	('HAMP', 'Gene', '57817', (121, 125))	('HAMP', 'Gene', (121, 125))	('PBRM1', 'Gene', (73, 78))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
52982	30760718	Our genomic and functional studies demonstrated that: (1) BRD9 is recurrently and focally amplified in nine cancer types with the highest recurrent score; (2) the expression of BRD9 is significantly increased in cancer specimens compared with that in corresponding normal tissues; (3) computational prediction suggests that BRD9 expression is associated with cell cycle, DNA damage repair, and RNA metabolic pathways in cancer; and (4) genetic depletion of BRD9 by shRNAs reduced cancer cell growth in vitro and in vivo.	('associated', 'Reg', (343, 353))	('genetic depletion', 'Var', (436, 453))	('BRD9', 'Gene', (324, 328))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (480, 486))	('cancer', 'Disease', (420, 426))	('BRD9', 'Gene', '65980', (324, 328))	('BRD9', 'Gene', (457, 461))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('BRD9', 'Gene', '65980', (457, 461))	('BRD9', 'Gene', (58, 62))	('BRD9', 'Gene', (177, 181))	('cancer', 'Disease', (212, 218))	('BRD9', 'Gene', '65980', (58, 62))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (480, 486))	('reduced', 'NegReg', (472, 479))	('BRD9', 'Gene', '65980', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (480, 486))
52988	30760718	Taken together, our functional studies on BRD9 are the proof-of-concept for the HAMP candidates identified in our study and strongly suggest the clinical potential of targeting BRD9 in common adult solid cancers.	('BRD9', 'Gene', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('targeting', 'Var', (167, 176))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRD9', 'Gene', '65980', (177, 181))	('BRD9', 'Gene', (177, 181))	('HAMP', 'Gene', '57817', (80, 84))	('HAMP', 'Gene', (80, 84))	('BRD9', 'Gene', '65980', (42, 46))
52993	30760718	The gene expression data of 2012 cancer cell lines were downloaded through the Expression Atlas (https://www.ebi.ac.uk/gxa/download.html) under the accessions E-MTAB-2770, E-MTAB-3983, and E-MTAB-2706.	('E-MTAB-2770', 'Var', (159, 170))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('MTAB-2706', 'CellLine', 'CVCL:A552', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('E-MTAB-2706', 'Var', (189, 200))
53017	30760718	ABSOLUTE calculated the purity, ploidy, and absolute DNA copy numbers from the segmented copy number alterations and mutation profiles of tumor samples.	('alterations', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (138, 143))
53020	30760718	The cancer cell fraction of each somatic single-nucleotide variant was extracted from the output.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('single-nucleotide variant', 'Var', (41, 66))
53120	30454036	In a univariate analysis of the entire cohort, the following prognostic factors were found to correlate with the mortality rate: LF (HR: 2.7,95% CI: 1.31-5.95, p = 0,006), absence of DF (HR: 0.43,95% CI: 0.18-0.99, p = 0.042), recurrent retroperitoneal sarcoma (HR: 2.81,95% CI 1.33-5.94, p = 0.007), and sarcoma histology (HR: 2.75,95% CI 1.31-5.75, p = 0.007).	('retroperitoneal sarcoma', 'Disease', 'MESH:D012186', (237, 260))	('sarcoma', 'Disease', 'MESH:D012509', (305, 312))	('sarcoma', 'Disease', 'MESH:D012509', (253, 260))	('sarcoma', 'Disease', (305, 312))	('sarcoma', 'Disease', (253, 260))	('absence', 'Var', (172, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('retroperitoneal sarcoma', 'Disease', (237, 260))
53135	30454036	In a multivariate analysis, only the degree of resection statistically significantly influenced LC, such that the patients who underwent R2 resection had a 2.2-fold higher risk of treatment failure (95% CI: 1.2-4.1; p = 0.007).	('patients', 'Species', '9606', (114, 122))	('treatment failure', 'Disease', 'MESH:D016609', (180, 197))	('R2 resection', 'Var', (137, 149))	('treatment failure', 'Disease', (180, 197))
53151	30454036	For example, in a study by Roeder et al., patients with a status of R0 after the resection of locally recurrent rectal cancer were found to have 5 year LC and OS rates that were respectively threefold and fivefold better than those of patients with incomplete resections.	('rectal cancer', 'Disease', 'MESH:D012004', (112, 125))	('rectal cancer', 'Disease', (112, 125))	('patients', 'Species', '9606', (235, 243))	('OS', 'Chemical', '-', (159, 161))	('rectal cancer', 'Phenotype', 'HP:0100743', (112, 125))	('status', 'Var', (58, 64))	('patients', 'Species', '9606', (42, 50))	('better', 'PosReg', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
53178	30454036	For all patients, resections R1 and R2 resection have a decreasing in 5 years survival rate by 7.6% and by 34.7% respectively compared to R0 resection.	('decreasing', 'NegReg', (56, 66))	('R2 resection', 'Var', (36, 48))	('patients', 'Species', '9606', (8, 16))
53187	30454036	Furthermore, R2 resection was associated with a worse 5 year OS rate, compared with R0 or R1 resection (31% vs 13%, p = 0.01).	('R2 resection', 'Var', (13, 25))	('worse', 'NegReg', (48, 53))	('OS', 'Chemical', '-', (61, 63))
53200	30454036	In a study involving 36 patients with recurrent gynecological malignancies conducted by Arias et al., an endometrial histology was found to correlate with better rates of local PFS (p = 0.017) and OS (p = 0.038).	('local PFS', 'CPA', (171, 180))	('endometrial', 'Var', (105, 116))	('OS', 'Chemical', '-', (197, 199))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('better', 'PosReg', (155, 161))	('patients', 'Species', '9606', (24, 32))	('malignancies', 'Disease', (62, 74))
53321	29625048	These integrated subtypes shared mutations, copy-number alterations, pathway commonalities, and micro-environment characteristics that appeared influential in the new molecular taxonomy, beyond any phenotypic contributions from tumor stage or tissue of origin.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('copy-number alterations', 'Var', (44, 67))
53335	29625048	Using aneuploidy (AN), CpG hypermethylation (METH), mRNA (MRNA), miRNA (MIR), and protein (P), the resultant number of groups ranged from 10 to 25 (Figure 1).	('METH', 'Chemical', '-', (45, 49))	('hypermethylation', 'Var', (27, 43))	('miRNA', 'MPA', (65, 70))	('mRNA', 'MPA', (52, 56))	('aneuploidy', 'Var', (6, 16))
53339	29625048	Over one-third of the samples displayed relatively sparse aneuploidy in AN7; these were enriched for THCA, LAML, PRAD, and THYM.	('aneuploidy', 'Var', (58, 68))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('AN7', 'Gene', (72, 75))	('THCA', 'Disease', (101, 105))
53342	29625048	Consistent with previous results, squamous (lung, head and neck, and esophageal) tumors clustered together by aneuploidy patterns, particularly 3p loss and 3q gain (AN3).	('3p loss', 'Var', (144, 151))	('3q gain', 'Var', (156, 163))	('esophageal) tumors clustered', 'Disease', 'MESH:D004938', (69, 97))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
53344	29625048	Despite the exclusion of loci known to be involved in tissue-specific DNA methylation, tumors originating from the same organ often aggregated by cancer-type-specific hypermethylation (Figure 1B; Table S2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('hypermethylation', 'Var', (167, 183))
53348	29625048	Gastrointestinal adenocarcinomas (ESCA, STAD, COAD and READ) were represented in a branch containing METH10 through METH13.	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('Gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (0, 32))	('METH13', 'Chemical', '-', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('COAD', 'Disease', (46, 50))	('STAD', 'Disease', (40, 44))	('METH10', 'Var', (101, 107))	('Gastrointestinal adenocarcinomas', 'Disease', (0, 32))	('METH10', 'Chemical', '-', (101, 107))
53360	29625048	We used clustering of cluster assignments (COCA) algorithm to assess the overlap of platform-specific memberships from each of the five molecular platforms (aneuploidy, mRNA, miRNA, DNA methylation, and RPPA) (Figure 2A).	('COCA', 'Species', '289672', (43, 47))	('miRNA', 'MPA', (175, 180))	('mRNA', 'MPA', (169, 173))	('DNA', 'MPA', (182, 185))	('aneuploidy', 'Var', (157, 167))
53371	29625048	Eight iClusters were dominated by a single tumor type (C24:LAML, C11:LGG [IDH1 mut], C6:OV, C8:UCEC, C12:THCA, C16:PRAD, C26:LIHC, C14:LUAD).	('C26', 'CellLine', 'CVCL:0240', (121, 124))	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('C11', 'Gene', '51728', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('C24:', 'Var', (55, 59))	('IDH1', 'Gene', '3417', (74, 78))	('C12:THCA', 'Var', (101, 109))	('tumor', 'Disease', (43, 48))	('C11', 'Gene', (65, 68))
53372	29625048	Others contained tumors from similar or related cells or tissues: C28:pan-kidney (KIRC, KIRP), C15:SKCM/UVM-melanoma of the skin (SKCM) and eye (UVM), C23:GBM/LGG (IDH1wt), and C5:CNS/ endocrine.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('C15', 'Gene', '51316', (95, 98))	('C23:GBM/LGG', 'Gene', '4691', (151, 162))	('UVM-melanoma of the skin', 'Disease', (104, 128))	('IDH1', 'Gene', (164, 168))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('C15', 'Gene', (95, 98))	('IDH1', 'Gene', '3417', (164, 168))	('C28', 'Var', (66, 69))	('UVM-melanoma of the skin', 'Disease', 'MESH:D008545', (104, 128))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('C23:GBM/LGG', 'Gene', (151, 162))
53376	29625048	C4:pan-GI (CRC) was predominantly COAD and READ with chromosomal instability (CIN) and a distinct aneuploidy profile (Figure 2B).	('CIN', 'Disease', (78, 81))	('COAD', 'Disease', (34, 38))	('pan-GI', 'Var', (3, 9))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('COAD', 'Disease', 'MESH:D029424', (34, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('chromosomal instability', 'Disease', (53, 76))
53377	29625048	The pan-squamous cohort formed three iClusters (C10, C25, and C27).	('C10', 'Gene', '3226', (48, 51))	('C10', 'Gene', (48, 51))	('C25', 'Var', (53, 56))	('C27', 'Var', (62, 65))
53379	29625048	Even though all squamous iClusters were characterized by chromosome 3q amplification, unique features defined C10:pan-SCC (9p deletion) and C25:pan-SCC (Chr11 amp) (Figure 2B).	('amp', 'Chemical', 'MESH:D000249', (71, 74))	('SCC', 'Gene', (118, 121))	('C10', 'Gene', (110, 113))	('SCC', 'Gene', (148, 151))	('C10', 'Gene', '3226', (110, 113))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', '6317', (148, 151))	('amp', 'Chemical', 'MESH:D000249', (159, 162))	('9p deletion', 'Var', (123, 134))
53380	29625048	Among mixed tumor type iClusters, three were defined by copy-number alterations.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('copy-number alterations', 'Var', (56, 79))
53381	29625048	C7:mixed was characterized by chr9 deletion, C2:BRCA (HER2 amp) mainly consisted of ERBB2-amplified tumors (BRCA, BLCA, and STAD), and C13:mixed (Chr8 del) contained highly aneuploid tumors, including a mixture of BRCA-Basal, UCEC (CN-high subtype), UCS, and BLCA.	('BRCA', 'Gene', '672', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BRCA', 'Gene', (48, 52))	('amp', 'Chemical', 'MESH:D000249', (59, 62))	('BRCA', 'Gene', (214, 218))	('amp', 'Chemical', 'MESH:D000249', (90, 93))	('tumors', 'Disease', (183, 189))	('BLCA', 'Disease', (259, 263))	('aneuploid tumors', 'Disease', 'MESH:D000782', (173, 189))	('BRCA', 'Gene', (108, 112))	('UCEC', 'Disease', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HER2', 'Gene', '2064', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('ERBB2', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('C13', 'Gene', (135, 138))	('tumors', 'Disease', (100, 106))	('deletion', 'Var', (35, 43))	('ERBB2', 'Gene', '2064', (84, 89))	('UCS', 'Disease', (250, 253))	('C13', 'Gene', '3229', (135, 138))	('BRCA', 'Gene', '672', (48, 52))	('HER2', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('BRCA', 'Gene', '672', (214, 218))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('aneuploid tumors', 'Disease', (173, 189))
53389	29625048	The silhouette widths ranged from -0.05 to 0.59, with the highest silhouette widths belonging to single-cancer-type-dominant iClusters (C11:LGG [IDH1 mut], C12:THCA, C16:PRAD, and C24:LAML).	('IDH1', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IDH1', 'Gene', '3417', (145, 149))	('C11', 'Gene', '51728', (136, 139))	('C16:PRAD', 'Var', (166, 174))	('C24:LAML', 'Var', (180, 188))	('C11', 'Gene', (136, 139))	('C12:THCA', 'Var', (156, 164))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
53390	29625048	Interestingly, 6 of the 7 pan-organ system iClusters (pan-GI: C1, C4, C18; pan-SCC: C25, C27, and pan-kidney: C28) had similar ranges of silhouette widths to those of single cancer-type dominant iClusters, suggesting that these were as robust as the cancer-type-dominant iClusters.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('SCC', 'Gene', (79, 82))	('C27', 'Var', (89, 92))	('C18', 'Gene', (70, 73))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('C18', 'Gene', '27241', (70, 73))	('SCC', 'Gene', '6317', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
53391	29625048	iClusters driven by a shared specific chromosomal alteration (e.g., C13:mixed [chr8 del]) tended to compose multiple tumor types and appeared to have among the lowest silhouette widths, suggesting substantial molecular heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mixed [chr8 del]', 'Var', (72, 88))	('tumor', 'Disease', (117, 122))	('C13', 'Gene', (68, 71))	('C13', 'Gene', '3229', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
53408	29625048	Melanomas and lung adenocarcinomas have been shown to have relatively high mutation rates, and we observed similar results with C15:SKCM/UVM and C14:LUAD.	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('C15', 'Gene', (128, 131))	('C14:LUAD', 'Var', (145, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (14, 34))	('mutation', 'MPA', (75, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('Melanomas and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('C15', 'Gene', '51316', (128, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
53409	29625048	Mutation frequencies varied widely within the two iClusters with the most diverse tumor compositions: C3:mesenchymal (immune) and C20:mixed (stromal/immune).	('C20', 'Var', (130, 133))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
53416	29625048	Despite having very different cancer type compositions, the pan-squamous iClusters C10:pan-SCC, C25:pan-SCC (chr11 amp), and C27:pan-SCC (HPV) shared many pathway characteristics.	('amp', 'Chemical', 'MESH:D000249', (115, 118))	('SCC', 'Gene', '6317', (133, 136))	('SCC', 'Gene', '6317', (91, 94))	('C10', 'Gene', (83, 86))	('HPV', 'Species', '10566', (138, 141))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SCC', 'Gene', (104, 107))	('C10', 'Gene', '3226', (83, 86))	('C25', 'Var', (96, 99))	('SCC', 'Gene', (91, 94))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('C27', 'Var', (125, 128))
53420	29625048	In addition, C20:mixed (stromal/immune) contained 32% Pan-GI samples and also displayed strong immune-related signaling.	('amp', 'Chemical', 'MESH:D000249', (62, 65))	('C20:mixed', 'Var', (13, 22))	('Pan-GI', 'Protein', (54, 60))
53421	29625048	Beta-catenin/cell-cell adhesion signaling appeared high in C4:pan-GI (CRC), C18:pan-GI (MSI), and C20:mixed (stromal/immune), but not in the smaller C1:STAD (EBV-CIMP).	('SI', 'Disease', 'None', (89, 91))	('C18', 'Gene', (76, 79))	('C4:pan-GI', 'Var', (59, 68))	('Beta-catenin/cell-cell adhesion signaling', 'MPA', (0, 41))	('C20:mixed', 'Var', (98, 107))	('C18', 'Gene', '27241', (76, 79))	('EBV', 'Species', '10376', (158, 161))	('high', 'PosReg', (51, 55))
53439	29625048	Interrogation of individual iClusters for their differentiating PARADIGM pathway features, canonical pathways, and gene programs amenable to drug targeting identified strong immune-related signaling features for both C3:mesenchymal (immune) and C20:mixed (stromal/immune) tumors, suggesting that they may share potential susceptibility to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('C20', 'Var', (245, 248))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('C3', 'Var', (217, 219))	('immune-related signaling', 'MPA', (174, 198))	('AR', 'Gene', '367', (65, 67))
53442	29625048	Compared to the seemingly discohesive groupings of the 17 heterogeneous iClusters, the 11 most homogeneous iClusters (C6:OV, C8:UCEC, C11:LGG [IDH1 mut], C12:THCA, C14:LUAD, C15:SKCM/UVM, C16:PRAD, C19:BRCA [luminal], C21:DLBC, C24:LAML, C26:LIHC) had higher silhouette widths, uniform tumor types, and histopathologies, but showed surprising degrees of spatial discohesion in the TumorMap.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('C21', 'Gene', (218, 221))	('IDH1', 'Gene', (143, 147))	('C11', 'Gene', (134, 137))	('C24:LAML', 'Var', (228, 236))	('higher', 'PosReg', (252, 258))	('Tumor', 'Phenotype', 'HP:0002664', (381, 386))	('C16:PRAD', 'Var', (188, 196))	('C21', 'Gene', '79718', (218, 221))	('C19:BRCA', 'Gene', (198, 206))	('IDH1', 'Gene', '3417', (143, 147))	('tumor', 'Disease', (286, 291))	('C15', 'Gene', '51316', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('C15', 'Gene', (174, 177))	('C26', 'CellLine', 'CVCL:0240', (238, 241))	('silhouette widths', 'CPA', (259, 276))	('C11', 'Gene', '51728', (134, 137))	('C19:BRCA', 'Gene', '672', (198, 206))
53445	29625048	However, exceptions that challenge this concept have also become apparent from such notable examples as the unpredictable clinical responses to a potent BRAF inhibitor across diverse malignancies all expressing the same BRAF mutation.	('BRAF', 'Gene', (153, 157))	('mutation', 'Var', (225, 233))	('BRAF', 'Gene', '673', (220, 224))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('BRAF', 'Gene', (220, 224))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('BRAF', 'Gene', '673', (153, 157))	('malignancies', 'Disease', (183, 195))
53468	29625048	Cervical squamous tumors clustered in high aneuploidy clusters AN1 and AN5.	('squamous tumors', 'Disease', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('squamous tumors', 'Disease', 'MESH:D002294', (9, 24))	('AN1', 'Var', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
53469	29625048	These clusters were also enriched for other Pan-gyn tumors, including ovarian, high-copy number endometrial, and uterine carcinosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('high-copy number', 'Var', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (121, 135))	('ovarian', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (113, 135))	('carcinosarcoma', 'Disease', (121, 135))
53470	29625048	Gynecologic tumors with fewer copy-number alterations including Luminal breast cancers and other endometrial tumors grouped separately in low aneuploidy clusters AN7 and AN8, respectively.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('low aneuploidy clusters', 'Disease', 'MESH:D000782', (138, 161))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('copy-number alterations', 'Var', (30, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('low aneuploidy clusters', 'Disease', (138, 161))	('Gynecologic', 'Disease', (0, 11))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('endometrial tumors', 'Disease', 'MESH:D016889', (97, 115))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('AN7', 'Var', (162, 165))	('endometrial tumors', 'Disease', (97, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
53481	29625048	To minimize the influence of variable tumor purity levels on a clustering result, we dichotomized the data using a beta-value of >= 0.3 to define positive DNA methylation and < 0.3 to specify lack of methylation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('positive DNA methylation', 'Var', (146, 170))
53483	29625048	For clustering analysis of tumors, we selected 3,139 CpG sites that were methylated at a beta-value of >= 0.3 in more than 10% of tumors within any of the 33 cancer types.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('methylated', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
53486	29625048	The heatmap was generated using the original beta-values for the top one-third (n = 1,035) of the most variability methylated CpGs across tumors (Figure 1B).	('CpGs', 'Gene', (126, 130))	('methylated', 'Var', (115, 125))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
53487	29625048	We noted that a fraction of ESCA and STAD was found in METH9 with LUAD and PAAD, a result that may be related to the low tumor cellularity of the cancers in this cluster.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('METH', 'Chemical', '-', (55, 59))	('low tumor', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESCA', 'Disease', (28, 32))	('METH9', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('low tumor', 'Disease', 'MESH:D009800', (117, 126))
53511	29625048	MIR5 contained OV, MIR8 BRCA, MIR12 LGG, MIR13 LIHC, MIR14 THCA, and MIR15 PRAD.	('MIR1', 'Gene', '79187', (69, 73))	('MIR1', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (24, 28))	('MIR12', 'Gene', (30, 35))	('BRCA', 'Gene', (24, 28))	('MIR8', 'Var', (19, 23))	('MIR1', 'Gene', '79187', (53, 57))	('MIR12', 'Gene', '406905', (30, 35))	('MIR1', 'Gene', (53, 57))	('MIR1', 'Gene', '79187', (41, 45))	('MIR1', 'Gene', '79187', (30, 34))	('MIR1', 'Gene', (41, 45))	('MIR1', 'Gene', (30, 34))
53519	29625048	MIR6, the Pan-GI group, was largely COAD and STAD, but also had substantial PAAD, READ and ESCA, with smaller numbers of CHOL and LIHC.	('MIR6', 'Var', (0, 4))	('COAD', 'Disease', (36, 40))	('COAD', 'Disease', 'MESH:D029424', (36, 40))
53729	26715174	Lynch syndrome is currently diagnosed in the presence of one of the following: 1) germline mutation of one of the DNA mismatch repair genes (MLH1, PMS2, MSH2, and MSH6); 2) germline EPCAM mutation; and 3) constitutive epimutation.	('PMS2', 'Gene', (147, 151))	('mutation', 'Var', (91, 99))	('PMS2', 'Gene', '5395', (147, 151))	('diagnosed', 'Reg', (28, 37))	('MSH6', 'Gene', (163, 167))	('EPCAM', 'Gene', (182, 187))	('MSH2', 'Gene', '4436', (153, 157))	('Lynch syndrome', 'Disease', (0, 14))	('MLH1', 'Gene', '4292', (141, 145))	('MLH1', 'Gene', (141, 145))	('MSH2', 'Gene', (153, 157))	('MSH6', 'Gene', '2956', (163, 167))	('EPCAM', 'Gene', '4072', (182, 187))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
53730	26715174	The first scenario, germline mutation of one of the DNA mismatch repair genes is by far the most commonly encountered abnormality among Lynch syndrome patients.	('Lynch syndrome', 'Disease', 'MESH:D003123', (136, 150))	('germline mutation', 'Var', (20, 37))	('Lynch syndrome', 'Disease', (136, 150))	('patients', 'Species', '9606', (151, 159))
53734	26715174	Germline EPCAM mutation leads to down-regulation of MSH2 with similar downstream effect as when the MSH2 gene is mutated, while constitutive epimutation involves widespread methylation of genes throughout the body, including MLH1, the consequence of which is similar to sporadic MLH1 methylation or mutation.	('mutation', 'Var', (15, 23))	('MLH1', 'Gene', (225, 229))	('EPCAM', 'Gene', '4072', (9, 14))	('down-regulation', 'NegReg', (33, 48))	('MSH2', 'Gene', (100, 104))	('methylation', 'MPA', (173, 184))	('MSH2', 'Gene', '4436', (100, 104))	('MSH2', 'Gene', (52, 56))	('MLH1', 'Gene', '4292', (279, 283))	('MSH2', 'Gene', '4436', (52, 56))	('MLH1', 'Gene', (279, 283))	('EPCAM', 'Gene', (9, 14))	('MLH1', 'Gene', '4292', (225, 229))
53737	26715174	Mutation type is associated with the relative risk of developing endometrial carcinoma and extra-gynecologic cancers, the age at which carcinoma develops, and easily detected microsatellite instability.	('endometrial carcinoma', 'Disease', (65, 86))	('carcinoma', 'Disease', 'MESH:D002277', (135, 144))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancers', 'Disease', (109, 116))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (65, 86))	('carcinoma', 'Disease', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('microsatellite instability', 'Var', (175, 201))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (65, 86))	('carcinoma', 'Disease', (77, 86))
53738	26715174	Mutations in one of the DNA mismatch repair genes, MSH6, are more prevalent in Lynch syndrome-associated endometrial carcinoma than in Lynch syndrome-associated colorectal carcinoma, and this accounts for some of the differences them (Table 7).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (105, 126))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (161, 181))	('Lynch syndrome', 'Disease', 'MESH:D003123', (79, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('Lynch syndrome', 'Disease', (135, 149))	('MSH6', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('MSH6', 'Gene', '2956', (51, 55))	('Mutations', 'Var', (0, 9))	('Lynch syndrome', 'Disease', 'MESH:D003123', (135, 149))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (105, 126))	('colorectal carcinoma', 'Disease', (161, 181))	('endometrial carcinoma', 'Disease', (105, 126))	('Lynch syndrome', 'Disease', (79, 93))	('prevalent', 'Reg', (66, 75))
53741	26715174	The average patient with Lynch syndrome-associated endometrial carcinoma is older than someone with Lynch syndrome-associated colorectal carcinoma, more likely to have an MSH6 mutation, less likely to have an MSI-high (MSI-H) tumor, and less likely to have a personal or family history of Lynch syndrome -associated carcinomas.	('endometrial carcinoma', 'Disease', (51, 72))	('MSI-high (MSI-H) tumor', 'Disease', 'MESH:D000848', (209, 231))	('Lynch syndrome', 'Disease', 'MESH:D003123', (25, 39))	('carcinomas', 'Disease', (316, 326))	('colorectal carcinoma', 'Disease', (126, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (126, 146))	('Lynch syndrome', 'Disease', (100, 114))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (51, 72))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('MSH6', 'Gene', (171, 175))	('mutation', 'Var', (176, 184))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (51, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('carcinomas', 'Phenotype', 'HP:0030731', (316, 326))	('carcinomas', 'Disease', 'MESH:D002277', (316, 326))	('Lynch syndrome', 'Disease', (289, 303))	('person', 'Species', '9606', (259, 265))	('MSH6', 'Gene', '2956', (171, 175))	('Lynch syndrome', 'Disease', 'MESH:D003123', (100, 114))	('patient', 'Species', '9606', (12, 19))	('Lynch syndrome', 'Disease', (25, 39))	('Lynch syndrome', 'Disease', 'MESH:D003123', (289, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))
53749	26715174	The most common reason for DNA MMR IHC abnormal/no germline DNA mismatch repair mutation is methylation of the MLH1 promoter, found only in the target organ's cancer.	('cancer', 'Disease', (159, 165))	('MLH1', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MLH1', 'Gene', '4292', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('methylation', 'MPA', (92, 103))	('mutation', 'Var', (80, 88))
53751	26715174	If a cancer cell harbors one allele with a somatic DNA mismatch repair mutation, a second hit needs to occur before damaging the DNA mismatch repair system.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('mutation', 'Var', (71, 79))	('cancer', 'Disease', (5, 11))	('DNA mismatch repair', 'Gene', (51, 70))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
53769	26715174	Most MSI-H colorectal carcinomas that are not associated with Lynch syndrome also have BRAF mutations that can be ascertained with immunohistochemistry or somatic mutation (tumor) testing.	('Lynch syndrome', 'Disease', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('Lynch syndrome', 'Disease', 'MESH:D003123', (62, 76))	('MSI-H colorectal carcinomas', 'Disease', 'MESH:D015179', (5, 32))	('MSI-H colorectal carcinomas', 'Disease', (5, 32))	('mutations', 'Var', (92, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor', 'Disease', (173, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
53787	26715174	Further testing, given this scenario, requires the complicated, expensive, and time consuming MLH1 methylation assay, which is not available at most medical centers, and in some cases, somatic mutation testing.	('MLH1', 'Gene', '4292', (94, 98))	('methylation', 'Var', (99, 110))	('MLH1', 'Gene', (94, 98))
53857	26464434	Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites The epigenetic landscape of cancer includes both focal hypermethylation and broader hypomethylation in a genome-wide manner.	('focal hypermethylation', 'Var', (159, 181))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
53858	26464434	By means of a comprehensive genomic analysis on 6637 tissues of 21 tumor types, we here show that the degrees of overall methylation in CpG island (CGI) and demethylation in intergenic regions, defined as 'backbone', largely vary among different tumors.	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('methylation', 'MPA', (121, 132))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('demethylation', 'Var', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (67, 72))	('vary', 'Reg', (225, 229))	('tumor', 'Disease', (246, 251))	('tumors', 'Disease', (246, 252))
53860	26464434	We found connections between CGI methylation and hypermutability, microsatellite instability, IDH1 mutation, 19p gain and polycomb features, and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains.	('IDH1', 'Gene', (94, 98))	('microsatellite instability', 'MPA', (66, 92))	('NSD1', 'Gene', '64324', (198, 202))	('TP53', 'Gene', '7157', (207, 211))	('backbone', 'MPA', (145, 153))	('IDH1', 'Gene', '3417', (94, 98))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (207, 211))	('gain', 'PosReg', (113, 117))	('NSD1', 'Gene', (198, 202))	('mutations', 'Var', (212, 221))	('chromosomal instability', 'Phenotype', 'HP:0040012', (173, 196))	('loss', 'NegReg', (234, 238))
53861	26464434	These broad epigenetic patterns add a new dimension to our understanding of tumor biology and its clinical implications.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('epigenetic patterns', 'Var', (12, 31))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
53862	26464434	Epigenetic alterations have pivotal roles in development and cancer biology.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
53863	26464434	A canonical observation in many cancers is the de novo methylation of CpG islands (CGIs) in the promoters of tumor-related genes, which is significantly associated with clinical behavior in many tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Disease', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('associated', 'Reg', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('methylation', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (109, 114))
53870	26464434	TF-binding sites behaved differently according to TF contents; the binding sites of embryonic stem cell (ESC)-related TFs including polycomb proteins and CTBP2 were frequently de novo methylated while the binding sites of other differentiation-associated TFs were rather demethylated or unchanged.	('CTBP2', 'Gene', '1488', (154, 159))	('polycomb proteins', 'Protein', (132, 149))	('methylated', 'Var', (184, 194))	('binding', 'Interaction', (67, 74))	('CTBP2', 'Gene', (154, 159))
53889	26464434	After filtering out sex chromosome CpGs and redundant CpGs around SNP and repeat regions, we selected a total of 136 186 CpGs in CGI and averaged their methylation levels for each tumor.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('methylation levels', 'MPA', (152, 170))	('CpGs', 'Var', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))
53890	26464434	Likewise, we selected 49 277 CpGs in backbone, as defined above, and averaged their methylation levels for each tumor.	('CpGs', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('methylation levels', 'MPA', (84, 102))
53895	26464434	Nonetheless, most tumors showed both CGI methylation and backbone demethylation with variable degrees (HC-LB; Figure 1F; Supplementary Figure S2).	('backbone demethylation', 'MPA', (57, 79))	('methylation', 'Var', (41, 52))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', 'MESH:D017034', (103, 144))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', (103, 144))	('CGI', 'MPA', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
53897	26464434	And in most tumors, DNA methylation correlated with mRNA expression, miRNA expression, copy number and pathway clusters suggesting an underlying biological background.	('copy number', 'Var', (87, 98))	('DNA', 'Gene', (20, 23))	('pathway clusters', 'Pathway', (103, 119))	('methylation', 'Var', (24, 35))	('correlated', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mRNA expression', 'MPA', (52, 67))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('miRNA expression', 'MPA', (69, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
53901	26464434	In THCA, histories of lymphocytic thyroiditis significantly correlated with high CGI methylation (P = 6.3 x 10-4).	('CGI', 'Protein', (81, 84))	('thyroiditis', 'Phenotype', 'HP:0100646', (34, 45))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('lymphocytic thyroiditis', 'Disease', (22, 45))	('lymphocytic thyroiditis', 'Phenotype', 'HP:0000872', (22, 45))	('lymphocytic thyroiditis', 'Disease', 'MESH:D013967', (22, 45))	('high', 'Var', (76, 80))
53903	26464434	In COADREAD, CGI methylation was highest in cecum tumors and became modest when moving towards the rectum (P = 1.3 x 10-16; Supplementary Figure S25A).	('highest', 'Reg', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('S25A', 'SUBSTITUTION', 'None', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('S25A', 'Var', (145, 149))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
53904	26464434	In HNSC, CGI methylation was highest in the oral cavity and lower in the caudal direction in the oropharangeal tract (P = 8.9 x 10-5; Supplementary Figure S25B).	('methylation', 'MPA', (13, 24))	('S25B', 'SUBSTITUTION', 'None', (155, 159))	('highest', 'Reg', (29, 36))	('S25B', 'Var', (155, 159))	('CGI', 'MPA', (9, 12))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('lower', 'NegReg', (60, 65))
53910	26464434	In PRAD, Gleason scores tended to be high both in CGI-methylated and backbone-demethylated tumors (P = 6.1 x 10-3 and 3.9 x 10-4, respectively).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CGI-methylated', 'Var', (50, 64))	('high', 'PosReg', (37, 41))	('PRAD', 'Disease', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Gleason', 'MPA', (9, 16))	('backbone-demethylated', 'Var', (69, 90))
53911	26464434	An association of CGI methylation with high mitosis was observed in ACC (P = 4.5 x 10-4).	('association', 'Interaction', (3, 14))	('high mitosis', 'Disease', (39, 51))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('high mitosis', 'Disease', 'MESH:D008228', (39, 51))	('ACC', 'Disease', (68, 71))	('CGI', 'Protein', (18, 21))	('methylation', 'Var', (22, 33))
53914	26464434	MSI-H tumors were very significantly associated with CGI methylation in COADREAD, STAD and UCEC (P = 3.2 x 10-12, 2.4 x 10-7 and 2.0 x 10-22, respectively) (Figure 2B).	('methylation', 'Var', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('associated', 'Reg', (37, 47))	('MSI-H tumors', 'Disease', 'MESH:D009369', (0, 12))	('CGI', 'MPA', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MSI-H tumors', 'Disease', (0, 12))
53915	26464434	In COADREAD, CGI methylation was associated with negative expression of MSH6 and PMS2 proteins (P = 9.3 x 10-3).	('MSH6', 'Gene', (72, 76))	('expression', 'MPA', (58, 68))	('proteins', 'Protein', (86, 94))	('PMS2', 'Gene', '5395', (81, 85))	('methylation', 'Var', (17, 28))	('negative', 'NegReg', (49, 57))	('MSH6', 'Gene', '2956', (72, 76))	('PMS2', 'Gene', (81, 85))
53916	26464434	In BRCA, CGI methylation was significantly associated with positive expression of estrogen and HER2/neu receptors (P = 1.5 x 10-5 and 8.3 x 10-8, respectively) and thus with luminal B subtype (P = 1.3 x 10-9).	('BRCA', 'Gene', (3, 7))	('CGI methylation', 'Var', (9, 24))	('expression', 'MPA', (68, 78))	('methylation', 'Var', (13, 24))	('BRCA', 'Gene', '672', (3, 7))	('positive', 'PosReg', (59, 67))	('estrogen', 'Protein', (82, 90))	('HER2/neu receptors', 'Protein', (95, 113))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
53917	26464434	The number of gene mutations correlated positively with CGI methylation in THCA, KIRC, LAML, LGG, GBM, PRAD, STAD, BRCA, ACC and UCEC (Figure 2A and B).	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('CGI methylation', 'MPA', (56, 71))	('THCA', 'Phenotype', 'HP:0002890', (75, 79))	('BRCA', 'Phenotype', 'HP:0003002', (115, 119))	('BRCA', 'Gene', '672', (115, 119))	('mutations', 'Var', (19, 28))	('BRCA', 'Gene', (115, 119))
53918	26464434	In line with the previous knowledge, IDH1 mutation was associated with high CGI methylation in LGG (P = 2.1 x 10-20), GBM, PRAD and CESC, and IDH2 was so in LAML.	('IDH2', 'Gene', '3418', (142, 146))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('CGI methylation', 'MPA', (76, 91))	('IDH2', 'Gene', (142, 146))
53919	26464434	Mutations in CIC, NOTCH1 and FUBP1 were very significantly associated with high CGI methylation in LGG (P = 5.7 x 10-11, 5.2 x 10-7 and 9.9 x 10-5, respectively), mutation in PIK3CA was so in STAD (P = 7.4 x 10-9), and mutations in PTEN and PIK3R1 were so in UCEC (P = 5.9 x 10-7 and 1.6 x 10-4, respectively).	('PIK3CA', 'Gene', (175, 181))	('NOTCH1', 'Gene', (18, 24))	('UCEC', 'Disease', (259, 263))	('PIK3R1', 'Gene', '5295', (241, 247))	('PIK3R1', 'Gene', (241, 247))	('PIK3CA', 'Gene', '5290', (175, 181))	('associated', 'Reg', (59, 69))	('high CGI methylation', 'MPA', (75, 95))	('Mutations', 'Var', (0, 9))	('FUBP1', 'Gene', '8880', (29, 34))	('PTEN', 'Gene', '5728', (232, 236))	('PTEN', 'Gene', (232, 236))	('mutations', 'Var', (219, 228))	('CIC', 'Gene', (13, 16))	('mutation', 'Var', (163, 171))	('FUBP1', 'Gene', (29, 34))	('NOTCH1', 'Gene', '4851', (18, 24))
53920	26464434	NRAS mutation was frequent in THCA with higher CGI methylation and BRAF was so in THCA with lower backbone methylation (P = 5.9 x 10-3 and 9.9 x 10-7, respectively) but this may be confounded by the difference in methylation according to histological type, as described above, and high frequency of NRAS mutation in follicular and BRAF mutation in papillary types.	('THCA', 'Phenotype', 'HP:0002890', (82, 86))	('BRAF', 'Gene', '673', (331, 335))	('BRAF', 'Gene', '673', (67, 71))	('NRAS', 'Gene', '4893', (299, 303))	('higher', 'PosReg', (40, 46))	('backbone methylation', 'MPA', (98, 118))	('THCA', 'Phenotype', 'HP:0002890', (30, 34))	('BRAF', 'Gene', (67, 71))	('CGI methylation', 'MPA', (47, 62))	('mutation', 'Var', (5, 13))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('BRAF', 'Gene', (331, 335))	('NRAS', 'Gene', (299, 303))
53921	26464434	TP53 mutation was associated with backbone demethylation in STAD and PRAD (P = 5.1 x 10-5 and 4.9 x 10-3, respectively) (Figure 2C), and NSD1 mutation was so in HNSC (P = 3.2 x 10-9) (Supplementary Figure S17B).	('TP53', 'Gene', '7157', (0, 4))	('NSD1', 'Gene', (137, 141))	('backbone demethylation', 'MPA', (34, 56))	('TP53', 'Gene', (0, 4))	('S17B', 'Var', (205, 209))	('S17B', 'SUBSTITUTION', 'None', (205, 209))	('NSD1', 'Gene', '64324', (137, 141))	('HNSC', 'Phenotype', 'HP:0012288', (161, 165))	('mutation', 'Var', (5, 13))
53926	26464434	The most remarkable P value peak was in chromosome 5q showing recurrent correlations between deletion and backbone demethylation in many tumors (Figure 3A and B).	('tumors', 'Disease', (137, 143))	('correlations', 'Reg', (72, 84))	('backbone demethylation', 'MPA', (106, 128))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('deletion', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
53927	26464434	Candidate genes in this region include CHD1, LMNB1, KDM3B, HDAC3 and NSD1, and among them, NSD1 was of particular interest in that mutation in this gene also showed the most significant association with backbone demethylation in HNSC and other tumors (Figure 3C).	('NSD1', 'Gene', (69, 73))	('backbone demethylation', 'MPA', (203, 225))	('mutation', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('HDAC3', 'Gene', (59, 64))	('CHD1', 'Gene', '1105', (39, 43))	('LMNB1', 'Gene', '4001', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('NSD1', 'Gene', '64324', (69, 73))	('NSD1', 'Gene', (91, 95))	('CHD1', 'Gene', (39, 43))	('HNSC', 'Disease', (229, 233))	('tumors', 'Disease', (244, 250))	('KDM3B', 'Gene', '51780', (52, 57))	('LMNB1', 'Gene', (45, 50))	('HDAC3', 'Gene', '8841', (59, 64))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('association', 'Reg', (186, 197))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('NSD1', 'Gene', '64324', (91, 95))	('KDM3B', 'Gene', (52, 57))
53928	26464434	Bi-allelic aberration of NSD1 either by mutation or copy loss showed more demethylation (Figure 3D).	('mutation', 'Var', (40, 48))	('NSD1', 'Gene', (25, 29))	('demethylation', 'MPA', (74, 87))	('copy loss', 'Var', (52, 61))	('NSD1', 'Gene', '64324', (25, 29))
53931	26464434	Among the pathways recurrently associated in several tumors, the bone morphogenic protein (BMP) receptor pathway was significantly suppressed among backbone-demethylated tumors in LGG, PRAD and LIHC and CGI-methylated tumors in LUAD.	('backbone-demethylated', 'Var', (148, 169))	('BMP', 'Gene', '649', (91, 94))	('LIHC', 'Disease', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('CGI-methylated', 'Var', (203, 217))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('LIHC', 'Disease', 'None', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRAD', 'Disease', (185, 189))	('BMP', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('LGG', 'Disease', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('suppressed', 'NegReg', (131, 141))	('LUAD', 'Phenotype', 'HP:0030078', (228, 232))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
53938	26464434	In all tumor types, differentially methylated CpGs were highly enriched in binding sites of polycomb-related SUZ12, EZH2 and CTBP2, and the enrichment rate strongly correlated with the degree of CGI methylation (Supplementary Figure S30).	('EZH2', 'Gene', (116, 120))	('EZH2', 'Gene', '2146', (116, 120))	('tumor', 'Disease', (7, 12))	('SUZ12', 'Gene', (109, 114))	('differentially', 'Var', (20, 34))	('CTBP2', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('CGI methylation', 'MPA', (195, 210))	('CTBP2', 'Gene', '1488', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('binding sites', 'Interaction', (75, 88))	('SUZ12', 'Gene', '23512', (109, 114))	('correlated', 'Reg', (165, 175))
53939	26464434	Demethylated CpGs were often enriched in IKZF1, BATF and ZNF217 binding sites but the enrichment rate usually did not correlate with the degree of backbone demethylation, suggesting a minor role of transcription factors in the genome-wide demethylation (Supplementary Figure S31).	('BATF', 'Gene', (48, 52))	('BATF', 'Gene', '10538', (48, 52))	('IKZF1', 'Gene', '10320', (41, 46))	('ZNF217', 'Gene', (57, 63))	('ZNF217', 'Gene', '7764', (57, 63))	('IKZF1', 'Gene', (41, 46))	('Demethylated', 'Var', (0, 12))
53943	26464434	Intriguingly, CGI-methylated tumors showed better primary responses in STAD and LUAD (P = 7.5 x 10-3 and 1.8 x 10-2, respectively).	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('primary responses', 'CPA', (50, 67))	('LUAD', 'Disease', (80, 84))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('better', 'PosReg', (43, 49))	('STAD', 'Disease', (71, 75))	('CGI-methylated', 'Var', (14, 28))
53950	26464434	As supporting evidence, we could observe correlation of HC-tumors with many CIMP-associated features such as MSI-H and IDH1 mutation.	('HC-tumors', 'Disease', (56, 65))	('CIMP', 'Chemical', '-', (76, 80))	('MSI-H', 'Disease', (109, 114))	('correlation', 'Interaction', (41, 52))	('IDH1', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MSI-H', 'Disease', 'MESH:D000848', (109, 114))	('mutation', 'Var', (124, 132))	('HC-tumors', 'Disease', 'MESH:D009369', (56, 65))	('IDH1', 'Gene', '3417', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
53955	26464434	Polycomb site methylation has now been accepted as a hallmark of cancers, and so the enrichment of polycomb proteins, SUZ12 and EZH2, should be an innate quality.	('hallmark of cancers', 'Disease', (53, 72))	('hallmark of cancers', 'Disease', 'MESH:D009369', (53, 72))	('Polycomb', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EZH2', 'Gene', (128, 132))	('EZH2', 'Gene', '2146', (128, 132))	('SUZ12', 'Gene', '23512', (118, 123))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('SUZ12', 'Gene', (118, 123))
53957	26464434	Global demethylation in repetitive elements has been suggested in many cancers and yet a systematical analysis is lacking.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Global demethylation', 'Var', (0, 20))
53958	26464434	Associations of demethylation with histological grade and stage have been suggested in several tumors, and we could find such an association in an expanded set of tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Associations', 'Interaction', (0, 12))	('demethylation', 'Var', (16, 29))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
53960	26464434	Although it has been experimentally shown that demethylation is linked to mitotic dysfunction and genomic rearrangement and anticipated to cause chromosome instability, it remained uninvestigated in clinical series.	('mitotic dysfunction', 'Disease', (74, 93))	('chromosome instability', 'MPA', (145, 167))	('demethylation', 'Var', (47, 60))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (74, 93))	('linked', 'Reg', (64, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (145, 167))	('genomic rearrangement', 'CPA', (98, 119))	('cause', 'Reg', (139, 144))
53964	26464434	NSD1 is a SET domain histone methyltransferase that primarily dimethylates histone H3K36, implicated in Sotos and Weaver overgrowth syndromes.	('NSD1', 'Gene', (0, 4))	('dimethylates', 'Var', (62, 74))	('overgrowth', 'Phenotype', 'HP:0001548', (121, 131))	('Weaver overgrowth syndromes', 'Disease', 'MESH:C536687', (114, 141))	('histone H3K36', 'Protein', (75, 88))	('Weaver overgrowth syndromes', 'Disease', (114, 141))	('NSD1', 'Gene', '64324', (0, 4))
53969	26464434	TP53 was also among the most significant genes, and this can be understood on the basis that TP53 mutations can directly cause DNA demethylation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('cause', 'Reg', (121, 126))	('DNA demethylation', 'MPA', (127, 144))
53970	26464434	Moreover, TP53 plays critical roles DNA repair and maintaining genomic stability and its mutation may exhibit communal pathways with DNA demethylation leading to chromosome instability.	('chromosome instability', 'MPA', (162, 184))	('TP53', 'Gene', (10, 14))	('mutation', 'Var', (89, 97))	('TP53', 'Gene', '7157', (10, 14))	('genomic', 'MPA', (63, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (162, 184))	('leading to', 'Reg', (151, 161))	('exhibit', 'Reg', (102, 109))
53971	26464434	It is often hypothesized that demethylation in cancer cells can activate proto-oncogenes and thus contribute to tumorigenesis.	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('contribute to', 'Reg', (98, 111))	('cancer', 'Disease', (47, 53))	('demethylation', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('proto-oncogenes', 'Gene', (73, 88))	('activate', 'PosReg', (64, 72))
53972	26464434	As more supporting evidence, we found that many pathways such as BMP receptor, LPA receptor, Ephrin B, PLK1, Aurora A and B, FoxM1, neurotrophic factor and p75NTR pathways tended to be suppressed rather than activated in demethylated tumors.	('Ephrin B', 'Gene', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('LPA', 'Protein', (79, 82))	('neurotrophic factor', 'Gene', '4908', (132, 151))	('demethylated', 'Var', (221, 233))	('BMP', 'Gene', '649', (65, 68))	('Aurora A and B', 'Gene', '6790;9212', (109, 123))	('PLK1', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('activated', 'PosReg', (208, 217))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('neurotrophic factor', 'Gene', (132, 151))	('p75NTR', 'Gene', (156, 162))	('FoxM1', 'Gene', '2305', (125, 130))	('LPA', 'Chemical', 'MESH:C032881', (79, 82))	('BMP', 'Gene', (65, 68))	('PLK1', 'Gene', '5347', (103, 107))	('suppressed', 'NegReg', (185, 195))	('tumors', 'Disease', (234, 240))	('p75NTR', 'Gene', '4804', (156, 162))	('FoxM1', 'Gene', (125, 130))
53974	26464434	We observed that low BMP, especially BMP-7, activity is associated with backbone demethylation and such demethylated tumors show aggressive features like high Gleason score and prostate specific antigen level (Supplementary Figure S10B).	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('S10B', 'Var', (231, 235))	('BMP', 'Gene', '649', (37, 40))	('associated', 'Reg', (56, 66))	('prostate specific antigen', 'Gene', (177, 202))	('low', 'NegReg', (17, 20))	('demethylated', 'Var', (104, 116))	('prostate specific antigen', 'Gene', '354', (177, 202))	('BMP', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BMP-7', 'Gene', '655', (37, 42))	('tumors', 'Disease', (117, 123))	('BMP', 'Gene', (37, 40))	('BMP-7', 'Gene', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('activity', 'MPA', (44, 52))	('backbone demethylation', 'MPA', (72, 94))	('S10B', 'SUBSTITUTION', 'None', (231, 235))	('BMP', 'Gene', '649', (21, 24))
53976	26464434	We also noticed that the demethylated tumors also tended to have worse outcome although the significance varied according to the cutoffs for average backbone methylation (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('demethylated', 'Var', (25, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
53978	26464434	We observed low BMP activity in demethylated LGGs which showed higher histological grade and worse treatment response and survival (Supplementary Figure S9B).	('histological', 'CPA', (70, 82))	('BMP', 'Gene', '649', (16, 19))	('survival', 'CPA', (122, 130))	('treatment response', 'CPA', (99, 117))	('BMP', 'Gene', (16, 19))	('demethylated', 'Var', (32, 44))	('higher', 'PosReg', (63, 69))	('low', 'NegReg', (12, 15))
53985	26464434	We observed that Ephrin pathways are epigenetically suppressed in a set of tumors preferentially by backbone demethylation.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('suppressed', 'NegReg', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Ephrin pathways', 'Pathway', (17, 32))	('tumors', 'Disease', (75, 81))	('backbone demethylation', 'Var', (100, 122))
53987	26464434	We found that PLK1 and Aurora pathways are often suppressed and sometimes activated in backbone-demethylated or CGI-methylated tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CGI-methylated', 'Var', (112, 126))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('activated', 'PosReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('suppressed', 'NegReg', (49, 59))	('backbone-demethylated', 'Var', (87, 108))	('PLK1', 'Gene', (14, 18))	('Aurora pathways', 'Pathway', (23, 38))	('PLK1', 'Gene', '5347', (14, 18))
53989	26464434	Either loss or gain of FoxM function can alter cell fate and promote tumorigenesis, and we observed epigenetic suppression of FoxM1 pathway in a set of tumors.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('loss', 'NegReg', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', (69, 74))	('FoxM function', 'Gene', (23, 36))	('promote', 'PosReg', (61, 68))	('FoxM1', 'Gene', '2305', (126, 131))	('FoxM1', 'Gene', (126, 131))	('tumor', 'Disease', (152, 157))	('alter', 'Reg', (41, 46))	('gain', 'PosReg', (15, 19))	('epigenetic suppression', 'Var', (100, 122))	('cell fate', 'CPA', (47, 56))	('tumors', 'Disease', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
53999	26464434	The slightly-high tumors showed poor survival compared to slightly-low tumors.	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('slightly-high', 'Var', (4, 17))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
54004	26464434	Collectively, we present a pan-cancer model connecting CGI methylation with hypermutability, MSI-H, IDH1 mutation, 19p gain and polycomb proteins and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains (Figure 5).	('MSI-H', 'Disease', 'MESH:D000848', (93, 98))	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', '3417', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (178, 201))	('NSD1', 'Gene', (203, 207))	('MSI-H', 'Disease', (93, 98))	('loss', 'NegReg', (239, 243))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('TP53', 'Gene', '7157', (212, 216))	('IDH1', 'Gene', (100, 104))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (217, 226))	('NSD1', 'Gene', '64324', (203, 207))	('gain', 'PosReg', (119, 123))	('TP53', 'Gene', (212, 216))
54006	26464434	Since many pathways are suppressed in methylated and demethylated tumors, thoughtful usage of new targeted drugs inhibiting such pathways is warranted.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('methylated', 'Var', (38, 48))	('tumors', 'Disease', (66, 72))	('suppressed', 'NegReg', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('pathways', 'Pathway', (11, 19))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('demethylated', 'Var', (53, 65))
54019	26404129	Patient 1 had BRCA1 c.5503C>T (p.Arg1835*), developed breast cancer at 36 years, which was managed with lumpectomy and local radiotherapy, and subsequently developed UC/MMMT at 48 years.	('BRCA1', 'Gene', '672', (14, 19))	('breast cancer', 'Disease', (54, 67))	('p.Arg1835*', 'Mutation', 'rs41293465', (31, 41))	('c.5503C>T (p.Arg1835*', 'Var', (20, 41))	('BRCA1', 'Gene', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('c.5503C>T', 'Mutation', 'rs41293465', (20, 29))	('Patient', 'Species', '9606', (0, 7))	('developed', 'PosReg', (44, 53))
54020	26404129	Patient 2 had BRCA1 c.2560_2561dupGC (p.Gln855fs), developed breast cancer at 34 years, again treated with lumpectomy and local radiotherapy, and was found to have UC/MMMT at 56 years.	('BRCA1', 'Gene', '672', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('developed', 'PosReg', (51, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('BRCA1', 'Gene', (14, 19))	('c.2560_2561dupGC', 'Var', (20, 36))	('c.2560_2561dupGC', 'Mutation', 'rs80357968', (20, 36))	('Patient', 'Species', '9606', (0, 7))	('p.Gln855fs', 'Mutation', 'rs80357968', (38, 48))
54021	26404129	Although BRCA1 mutation carriers are at increased risk of developing endometrial cancers compared to the general population, most of this risk is attributable to tamoxifen use.	('mutation', 'Var', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BRCA1', 'Gene', '672', (9, 14))	('endometrial cancers', 'Disease', (69, 88))	('BRCA1', 'Gene', (9, 14))	('endometrial cancers', 'Disease', 'MESH:D016889', (69, 88))	('tamoxifen', 'Chemical', 'MESH:D013629', (162, 171))
54022	26404129	It has also been suggested that BRCA1 mutations may predispose carriers to uterine papillary serous carcinoma specifically.	('BRCA1', 'Gene', (32, 37))	('papillary serous carcinoma', 'Disease', 'MESH:D002291', (83, 109))	('predispose', 'Reg', (52, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('papillary serous carcinoma', 'Disease', (83, 109))	('BRCA1', 'Gene', '672', (32, 37))	('mutations', 'Var', (38, 47))
54041	26404129	While the risk-reducing role of prophylactic bilateral salpingo-oophorectomy in promoting long-term survival among BRCA1/2 carriers is already established, a similar approach may not be clinically practicable for malignancies as rare as UC/MMMT.	('malignancies', 'Disease', 'MESH:D009369', (213, 225))	('UC/MMMT', 'Disease', (237, 244))	('BRCA1/2', 'Gene', (115, 122))	('promoting', 'PosReg', (80, 89))	('malignancies', 'Disease', (213, 225))	('carriers', 'Var', (123, 131))
54133	24927246	Prior research has observed that low physical activity (PA) negatively impacts QOL in patients with endometrial cancer.	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('low', 'Var', (33, 36))	('QOL', 'MPA', (79, 82))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('negatively', 'NegReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (86, 94))
54149	24927246	For descriptive purposes we calculated categories of BMI, where <25.0, 25.0-29.9, 30.0-34.9, 35.0-39.9, and >=40.0 represent healthy weight, overweight, moderately obese, severely obese, and very severely obese, respectively.	('obese', 'Disease', (180, 185))	('obese', 'Disease', 'MESH:D009765', (205, 210))	('<25.0', 'Var', (64, 69))	('obese', 'Disease', (205, 210))	('obese', 'Disease', 'MESH:D009765', (164, 169))	('obese', 'Disease', 'MESH:D009765', (180, 185))	('obese', 'Disease', (164, 169))	('overweight', 'Phenotype', 'HP:0025502', (141, 151))
54332	33628871	Although SLN mapping demonstrated increased detection of metastasis, and therefore changed decisions regarding adjuvant treatment more often in the SLN group than in the systematic lymphadenectomy group, recurrence-free survival did not differ between the patient cohorts.	('changed', 'Reg', (83, 90))	('SLN', 'Var', (148, 151))	('metastasis', 'CPA', (57, 67))	('increased', 'PosReg', (34, 43))	('patient', 'Species', '9606', (256, 263))
54418	33437754	The newly obtained prediction accuracies caused by a gene were compared to the original prediction accuracy from the model for the cancer type labeled by TCGA data.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gene', 'Var', (53, 57))
54436	33437754	The GCNN model with the PPI+singleton graph included all the 7,091 genes and demonstrated a >5% increase in prediction accuracy compared with the PPI graph with a smaller accuracy variation as shown in Table 2, suggesting that the additional 2,647 genes could be important in determining cancer type.	('GCNN', 'Chemical', '-', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('prediction', 'MPA', (108, 118))	('PPI+singleton', 'Var', (24, 37))	('increase', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
54443	33437754	A total of 68%, 16%, 95.2%, and 72.9%, out of 166 READ samples were classified into COAD cancer type by the co-expression, co-expression+singleton, PPI, and PPI+singleton GCNN model respectively (confusion matrices in Figure 7 and, Figure 8, and further illustrated in Supplement 2, 3, 4, and 5).	('GCNN', 'Chemical', '-', (171, 175))	('D', 'Chemical', 'MESH:D003903', (87, 88))	('PPI+singleton', 'Var', (157, 170))	('COAD cancer', 'Disease', 'MESH:D029424', (84, 95))	('confusion', 'Phenotype', 'HP:0001289', (196, 205))	('D', 'Chemical', 'MESH:D003903', (53, 54))	('COAD cancer', 'Disease', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
54451	33437754	UCS classification performed poorly (misclassification rate of 25%, 25%, 58.9%, and 21.4% for co-expression, co-expression+singleton, PPI model, and PPI+singleton GCNN model, respectively), and most of these misclassified samples were in UCEC as expected.	('PPI+singleton', 'Var', (149, 162))	('co-expression+singleton', 'Var', (109, 132))	('UCEC', 'Disease', (238, 242))	('GCNN', 'Chemical', '-', (163, 167))	('co-expression', 'Var', (94, 107))	('UCS', 'Phenotype', 'HP:0002891', (0, 3))
54533	33322259	The patient was diagnosed with surgical stage IIIA1 according to the latest International Federation of Gynecology and Obstetrics (FIGO) classification, and pT2aN1bMx, according to the TNM classification.	('pT2aN1bMx', 'Var', (157, 166))	('TNM', 'Gene', (185, 188))	('patient', 'Species', '9606', (4, 11))	('TNM', 'Gene', '10178', (185, 188))
54546	33322259	Risk factors are the same as for ovarian carcinomas and sarcomas: obesity, nulliparity, exogenous oestrogen, radiotherapy and long-term Tamoxifen use.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('nulliparity', 'Disease', (75, 86))	('ovarian carcinomas and sarcomas', 'Disease', 'MESH:D010051', (33, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('obesity', 'Phenotype', 'HP:0001513', (66, 73))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (33, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('exogenous', 'Var', (88, 97))	('obesity', 'Disease', 'MESH:D009765', (66, 73))	('radiotherapy', 'Disease', (109, 121))	('Tamoxifen', 'Chemical', 'MESH:D013629', (136, 145))	('obesity', 'Disease', (66, 73))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (33, 51))
54568	33322259	Although the mutation of the p53 gene does not always cause p53 immunostaining, most of the immunostained for p53 tumours have a p53 gene mutation.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumours', 'Disease', (114, 121))	('p53', 'Gene', (110, 113))	('mutation', 'Var', (13, 21))	('p53', 'Gene', '7157', (110, 113))	('p53', 'Gene', (29, 32))	('p53', 'Gene', (60, 63))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('p53', 'Gene', (129, 132))	('mutation', 'Var', (138, 146))	('p53', 'Gene', '7157', (29, 32))	('p53', 'Gene', '7157', (129, 132))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('p53', 'Gene', '7157', (60, 63))
54571	33322259	Other studies, which support carcinosarcoma theory, include clonality studies, genomic analysis, loss of heterozygosity, gene mutations, and expressions.	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('loss of heterozygosity', 'Var', (97, 119))	('carcinosarcoma', 'Disease', 'MESH:D002296', (29, 43))	('carcinosarcoma', 'Disease', (29, 43))
54598	33322259	The authors concluded that median progression free-survival (PFS) was longer in patients treated with carboplatin/paclitaxel, whereas overall survival (OS) was similar for all treatment groups.	('patients', 'Species', '9606', (80, 88))	('carboplatin', 'Chemical', 'MESH:D016190', (102, 113))	('progression', 'MPA', (34, 45))	('paclitaxel', 'Chemical', 'MESH:D017239', (114, 124))	('longer', 'PosReg', (70, 76))	('carboplatin/paclitaxel', 'Var', (102, 124))
54630	33322259	Although some reports showed that descending colon, ischemia or necrosis might occur after high ligation of the IMA (especially for patients with advanced rectal or sigmoid cancer, cerebrovascular disease, and hypertension), in patients without general disease they are less likely to occur.	('descending colon', 'Disease', (34, 50))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('ischemia', 'Disease', 'MESH:D007511', (52, 60))	('necrosis', 'Disease', 'MESH:D009336', (64, 72))	('descending colon', 'Phenotype', 'HP:0012851', (34, 50))	('cancer', 'Disease', (173, 179))	('cerebrovascular disease', 'Disease', 'MESH:D002561', (181, 204))	('patients', 'Species', '9606', (228, 236))	('hypertension', 'Disease', 'MESH:D006973', (210, 222))	('cerebrovascular disease', 'Disease', (181, 204))	('necrosis', 'Disease', (64, 72))	('high ligation', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('hypertension', 'Disease', (210, 222))	('advanced rectal', 'Disease', (146, 161))	('hypertension', 'Phenotype', 'HP:0000822', (210, 222))	('patients', 'Species', '9606', (132, 140))	('ischemia', 'Disease', (52, 60))
54647	33322259	Adhesion between the small bowel and the abdominal aorta leading to obstructive ileus is a possible complication after para-aortic lymph node dissection.	('Adhesion', 'Var', (0, 8))	('para-aortic lymph', 'Disease', 'MESH:D001018', (119, 136))	('ileus', 'Phenotype', 'HP:0002595', (80, 85))	('obstructive ileus', 'Disease', (68, 85))	('para-aortic lymph', 'Disease', (119, 136))
54652	33217970	Each of the four subtypes of uterine cancers, mixed endometrial carcinomas, serous carcinomas, endometroid carcinomas, and carcinosarcomas harbored between 5~20% of ACTG1 gene amplification or overexpression.	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('endometrial carcinomas', 'Disease', (52, 74))	('endometroid carcinomas', 'Disease', 'MESH:D009369', (95, 117))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (52, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('ACTG1', 'Gene', (165, 170))	('amplification', 'Var', (176, 189))	('overexpression', 'PosReg', (193, 207))	('uterine cancer', 'Phenotype', 'HP:0010784', (29, 43))	('carcinosarcomas', 'Disease', 'MESH:D002296', (123, 138))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('serous carcinomas', 'Disease', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (52, 74))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('endometroid carcinomas', 'Disease', (95, 117))	('carcinosarcomas', 'Disease', (123, 138))	('serous carcinomas', 'Disease', 'MESH:D018297', (76, 93))	('uterine cancers', 'Phenotype', 'HP:0010784', (29, 44))
54654	33217970	Functionally, the CRISPR-CAS9 gene deletion of ACTG1 had the most robust and consistent effects in uterine cancer cells relative to 20 other lineages.	('effects', 'Reg', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('uterine cancer', 'Phenotype', 'HP:0010784', (99, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('deletion', 'Var', (35, 43))	('ACTG1', 'Gene', (47, 52))	('cancer', 'Disease', (107, 113))
54658	33217970	While dysregulation of actomyosin genes is associated with diseases including cardiomyopathies, tumor-associated functions of actomyosin genes have been demonstrated in cancer models including colorectal, prostate, breast, ovarian, melanoma, pancreatic, and others.	('cancer', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('pancreatic', 'Disease', 'MESH:D010195', (242, 252))	('cardiomyopathies', 'Disease', (78, 94))	('colorectal', 'Disease', (193, 203))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('myosin', 'Gene', (130, 136))	('prostate', 'Disease', (205, 213))	('myosin', 'Gene', (27, 33))	('pancreatic', 'Disease', (242, 252))	('colorectal', 'Disease', 'MESH:D015179', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cardiomyopathies', 'Phenotype', 'HP:0001638', (78, 94))	('tumor', 'Disease', (96, 101))	('associated', 'Reg', (43, 53))	('breast, ovarian, melanoma', 'Disease', 'MESH:D008545', (215, 240))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('myosin', 'Gene', '79784', (130, 136))	('cardiomyopathies', 'Disease', 'MESH:D009202', (78, 94))	('dysregulation', 'Var', (6, 19))	('myosin', 'Gene', '79784', (27, 33))
54666	33217970	In parallel to these efforts, gene function in cancers can also be broadly evaluated at a genome-scale, based on CRISPR-CAS9 gene deletion screens in over seven hundred cancer cell lines in over twenty cancer lineages.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('deletion screens', 'Var', (130, 146))	('cancer', 'Disease', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Disease', (47, 54))	('cancer', 'Disease', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
54669	33217970	Given the breadth of knowledge regarding their protein structures and mechanistic interactions in the contexts of normal tissue, identifying the recurrent cancer-specific gene alterations provides a foundation towards understanding the essential biology and mechanisms by which they promote cancer malignancy.	('promote', 'PosReg', (283, 290))	('cancer malignancy', 'Disease', (291, 308))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('alterations', 'Var', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer malignancy', 'Disease', 'MESH:D009369', (291, 308))
54675	33217970	MYH6 and MYH7, both on 14q11.2, were expectedly co-amplified and deleted in the same tumor samples (Supplemental Figure S3A) with significant missense and truncation mutations distributed throughout both genes (Supplemental Figure S3B).	('tumor', 'Disease', (85, 90))	('MYH7', 'Gene', (9, 13))	('MYH6', 'Gene', (0, 4))	('truncation mutations', 'Var', (155, 175))	('missense', 'Var', (142, 150))	('MYH7', 'Gene', '4625', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MYH6', 'Gene', '4624', (0, 4))
54676	33217970	The 14q11.2 locus has been previously shown to contain the driver alteration of a prosurvival member of the BCL2 family BCL2L2 gene.	('BCL2L2', 'Gene', (120, 126))	('BCL2', 'Gene', '596', (108, 112))	('BCL2', 'Gene', (120, 124))	('BCL2', 'Gene', (108, 112))	('alteration', 'Var', (66, 76))	('BCL2', 'Gene', '596', (120, 124))	('BCL2L2', 'Gene', '599', (120, 126))
54678	33217970	While skeletal alpha-actin gene, ACTA1, was recurrently amplified or overexpressed, its amplifications and deletions were co-regulated with MDM4 at chromosome 1q42.13 across cancers.	('MDM4', 'Gene', (140, 144))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('ACTA1', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('deletions', 'Var', (107, 116))	('MDM4', 'Gene', '4194', (140, 144))	('ACTA1', 'Gene', '58', (33, 38))
54690	33217970	Overall, we found no consistent relationship between ACTG1 and MYLK2 dysregulation and FGA, indicating that these events were likely not reflective of overall genomic instability.	('MYLK2', 'Gene', '85366', (63, 68))	('MYLK2', 'Gene', (63, 68))	('ACTG1', 'Gene', (53, 58))	('dysregulation', 'Var', (69, 82))	('FGA', 'Gene', '2243', (87, 90))	('FGA', 'Gene', (87, 90))
54691	33217970	Given that ACTG1 and MYLK2 amplifications or overexpression were consistently observed in uterine cancers, we sought to analyze their potential as uterine cancer biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ACTG1', 'Gene', (11, 16))	('uterine cancer', 'Phenotype', 'HP:0010784', (90, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('MYLK2', 'Gene', '85366', (21, 26))	('MYLK2', 'Gene', (21, 26))	('amplifications', 'Var', (27, 41))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('observed', 'Reg', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('uterine cancers', 'Phenotype', 'HP:0010784', (90, 105))	('cancers', 'Disease', (98, 105))	('cancer', 'Disease', (98, 104))	('uterine cancer', 'Phenotype', 'HP:0010784', (147, 161))	('overexpression', 'PosReg', (45, 59))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
54693	33217970	We also examined if nearby genes in the same genomic loci as ACTG1 also predicted poor survival and found that alterations in NPLOC4 (located at 17q25.3) were not associated with poor survival (Supplemental Figure S5).	('poor survival', 'CPA', (82, 95))	('predicted', 'Reg', (72, 81))	('alterations', 'Var', (111, 122))	('NPLOC4', 'Gene', '55666', (126, 132))	('NPLOC4', 'Gene', (126, 132))	('ACTG1', 'Gene', (61, 66))
54696	33217970	ACTG1 gains were enriched in the population of copy number high tumors but reduced in the copy number low tumors (Figure 3B).	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('low tumors', 'Disease', 'MESH:D009800', (102, 112))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('low tumors', 'Disease', (102, 112))	('tumors', 'Disease', (106, 112))	('copy number', 'Var', (47, 58))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('reduced', 'NegReg', (75, 82))	('ACTG1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('gains', 'PosReg', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
54714	33217970	Of tumors within the UCS and UCEC cohorts, we found that UCS and UCEC tumors with ACTG1 gains indeed exhibited lower IFN-gamma signaling and UCS tumors with ACTG1 gains exhibited lower lymphocyte infiltration (IFN-gamma: UCS p-value = 0.081, UCEC p-value = 0.092; Lymphocyte infiltration: UCS p-value = 0.073, UCEC p-value = 0.189) (Figure 5D).	('lower lymphocyte', 'Phenotype', 'HP:0001888', (179, 195))	('lower', 'NegReg', (179, 184))	('UCS', 'Phenotype', 'HP:0002891', (141, 144))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('UCS', 'Phenotype', 'HP:0002891', (221, 224))	('lymphocyte infiltration', 'CPA', (185, 208))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('UCS', 'Phenotype', 'HP:0002891', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('IFN-gamma', 'Gene', '3458', (117, 126))	('IFN-gamma', 'Gene', (117, 126))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('UCS', 'Phenotype', 'HP:0002891', (289, 292))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('lower', 'NegReg', (111, 116))	('gains', 'Var', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('IFN-gamma', 'Gene', '3458', (210, 219))	('IFN-gamma', 'Gene', (210, 219))	('tumors', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('ACTG1', 'Gene', (82, 87))	('UCS', 'Phenotype', 'HP:0002891', (57, 60))
54720	33217970	This frequency of ACTG1 dependency exceeded all the other sarcomeric and cytoskeletal genes in our set, including the recurrently amplified and overexpressed gene MYLK2 (n = 33 and 3, respectively).	('dependency', 'Var', (24, 34))	('MYLK2', 'Gene', (163, 168))	('ACTG1', 'Gene', (18, 23))	('MYLK2', 'Gene', '85366', (163, 168))
54739	33217970	While one may surmise that EMT, as well as PRC2, and cell cycle functions are each critical mechanisms required for the optimal survival of uterine cancer cell lines, it remains unclear if ACTG1 deletion directly impacts these pathways in the ~50% of uterine cancer cell lines that we deemed ACTG1 dependent (Figure 6).	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('impacts', 'Reg', (213, 220))	('deletion', 'Var', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('uterine cancer', 'Phenotype', 'HP:0010784', (140, 154))	('uterine cancer', 'Phenotype', 'HP:0010784', (251, 265))	('ACTG1', 'Gene', (189, 194))	('cancer', 'Disease', (259, 265))
54742	33217970	It is also currently a proposed target in cancers such as B-cell lymphomas (Clinical Trial ID: NCT01897571, NCT02220842), adult sarcomas (NCT03874455) and uterine cancers (NCT03348631).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('NCT03874455', 'Var', (138, 149))	('NCT02220842', 'Var', (108, 119))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (58, 74))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('B-cell lymphomas', 'Disease', (58, 74))	('cancers', 'Disease', (42, 49))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (58, 74))	('lymphomas', 'Phenotype', 'HP:0002665', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('uterine cancer', 'Phenotype', 'HP:0010784', (155, 169))	('cancers', 'Disease', (163, 170))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('uterine cancers', 'Phenotype', 'HP:0010784', (155, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcomas', 'Disease', (128, 136))	('NCT03348631', 'Var', (172, 183))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
54753	33217970	In concordance with this, we found ACTG1 gains in UCEC were associated with multiple immunosuppressive phenotypes including decreases in signaling of IL6, JAK/STAT, Interferon alpha and gamma, and complement (Figure 5), as well as a projected reduction in lymphocyte infiltration by TCIA, suggesting enrichments in EMT could be associated with such immunosuppressive phenotypes.	('IL6', 'Gene', (150, 153))	('lymphocyte', 'CPA', (256, 266))	('signaling', 'MPA', (137, 146))	('TCIA', 'Chemical', '-', (283, 287))	('ACTG1', 'Gene', (35, 40))	('decreases', 'NegReg', (124, 133))	('gains', 'Var', (41, 46))	('reduction', 'NegReg', (243, 252))	('complement', 'MPA', (197, 207))	('JAK/STAT', 'MPA', (155, 163))	('IL6', 'Gene', '3569', (150, 153))
54769	33217970	Negative scores indicate that when the target gene is knocked out, the cancer cell line lost viability.	('lost', 'NegReg', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('knocked out', 'Var', (54, 65))	('viability', 'CPA', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
54771	33217970	We utilized GSEA to interpret gene expression to nominate transcriptional programs that are associated with uterine cancers with ACTG1 gains.	('uterine cancer', 'Phenotype', 'HP:0010784', (108, 122))	('GSEA', 'Chemical', '-', (12, 16))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('ACTG1', 'Gene', (129, 134))	('gains', 'Var', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('uterine cancers', 'Phenotype', 'HP:0010784', (108, 123))
54776	33217970	Genomic alterations of actomyosin genes in Pan-Cancer analysis.	('Cancer', 'Disease', (47, 53))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('Pan', 'Gene', (43, 46))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Pan', 'Gene', '51816', (43, 46))	('myosin', 'Gene', (27, 33))	('myosin', 'Gene', '79784', (27, 33))	('Genomic alterations', 'Var', (0, 19))
54783	33217970	This work was supported by the National Institutes of Health grants: R01HL143830 and R56HL146133 (to D.S.-C.), K08CA237871 (to E.H.S), K00CA212221 (to J.P.R), and American Cancer Society-AstraZeneca (PF-16-142-01-TBE) (to J.H.H.).	('PF-16-142-01', 'CellLine', 'CVCL:0I61', (200, 212))	('R56HL146133', 'CellLine', 'CVCL:2492', (85, 96))	('K00CA212221', 'Var', (135, 146))	('R56HL146133', 'Var', (85, 96))	('R01HL143830', 'Var', (69, 80))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cancer', 'Disease', (172, 178))	('K08CA237871', 'Var', (111, 122))	('R01HL', 'CellLine', 'CVCL:2492', (69, 74))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))
54787	32391256	Cellular experiments in vitro revealed that MELK played an essential role in ULMS cells' chemoresistance and that a high expression of MELK could lead to doxorubicin resistance.	('ULMS', 'Phenotype', 'HP:0002891', (77, 81))	('MELK', 'Gene', '9833', (135, 139))	('MELK', 'Gene', (135, 139))	('MELK', 'Gene', (44, 48))	('doxorubicin resistance', 'MPA', (154, 176))	('MELK', 'Gene', '9833', (44, 48))	('doxorubicin', 'Chemical', 'MESH:D004317', (154, 165))	('high expression', 'Var', (116, 131))	('chemoresistance', 'CPA', (89, 104))	('ULM', 'Phenotype', 'HP:0000131', (77, 80))	('lead to', 'Reg', (146, 153))
54792	32391256	OTSSP167, a MELK inhibitor, may increase ULMS sensitivity to doxorubicin.	('MELK', 'Gene', (12, 16))	('ULM', 'Phenotype', 'HP:0000131', (41, 44))	('MELK', 'Gene', '9833', (12, 16))	('increase', 'PosReg', (32, 40))	('ULMS', 'Phenotype', 'HP:0002891', (41, 45))	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('sensitivity to doxorubicin', 'MPA', (46, 72))	('OTSSP167', 'Chemical', 'MESH:C585656', (0, 8))	('OTSSP167', 'Var', (0, 8))	('ULMS', 'Disease', (41, 45))
54805	32391256	In addition, high MELK expression level is related to poor prognosis in breast cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('MELK', 'Gene', (18, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('MELK', 'Gene', '9833', (18, 22))	('patients', 'Species', '9606', (86, 94))
54828	32391256	The primer sequence used for miR-34a was TGGCAGTGTCTTAGCTGGTTGT.	('miR-34a', 'Gene', '407040', (29, 36))	('miR-34a', 'Gene', (29, 36))	('TGGCAGTGTCTTAGCTGGTTGT', 'Var', (41, 63))
54842	32391256	Then, the HEK293T cells were used to produce lentivirus by transfecting pMD2.G, psPAX2, and constructive vectors.	('HEK293T', 'CellLine', 'CVCL:0063', (10, 17))	('transfecting', 'Var', (59, 71))	('psPAX2', 'Gene', (80, 86))
54864	32391256	The antibodies used include the following: MELK (SIGMA: HPA017214), P53 (Cell Signaling Technology: 48818), phospho-JAK2 (Y1007 + Y1008) (Abcam: ab32101), phosphor-STAT3 (Y705) (Abcam: b76315), STAT3 (Cell Signaling Technology: 30835), IL6 (Proteintech: 21865), IL6R (Proteintech: 23457), BCL2 (Proteintech: 12789), and GAPDH (Cell Signaling Technology: 2118).	('BCL2', 'Gene', '596', (289, 293))	('GAPDH', 'Gene', '2597', (320, 325))	('MELK', 'Gene', (43, 47))	('IL6', 'Gene', '3569', (262, 265))	('BCL2', 'Gene', (289, 293))	('GAPDH', 'Gene', (320, 325))	('IL6R', 'Gene', (262, 266))	('IL6', 'Gene', '3569', (236, 239))	('STAT3', 'Gene', (164, 169))	('JAK2', 'Gene', '3717', (116, 120))	('MELK', 'Gene', '9833', (43, 47))	('P53', 'Gene', (68, 71))	('STAT3', 'Gene', (194, 199))	('IL6', 'Gene', (262, 265))	('STAT3', 'Gene', '6774', (164, 169))	('Y705', 'Var', (171, 175))	('IL6R', 'Gene', '3570', (262, 266))	('IL6', 'Gene', (236, 239))	('STAT3', 'Gene', '6774', (194, 199))	('Y1007 + Y1008', 'Var', (122, 135))	('P53', 'Gene', '7157', (68, 71))	('JAK2', 'Gene', (116, 120))
54874	32391256	Moreover, in the proliferation assay, the relative viability of the ULMS cells with MELK overexpression was significantly higher than that of the negative control cells, especially in the last 2 days (Figure 2B).	('ULM', 'Phenotype', 'HP:0000131', (68, 71))	('MELK', 'Gene', '9833', (84, 88))	('proliferation assay', 'CPA', (17, 36))	('MELK', 'Gene', (84, 88))	('higher', 'PosReg', (122, 128))	('overexpression', 'Var', (89, 103))	('ULMS', 'Phenotype', 'HP:0002891', (68, 72))
54875	32391256	Analogously, MELK expression remarkably increased colony formation in ULMS cell lines (P < 0.05; Figure 2D), and conversely MELK suppression decreased colony formation (P < 0.05; Figure 2E).	('suppression decreased', 'NegReg', (129, 150))	('colony formation', 'CPA', (50, 66))	('MELK', 'Gene', (13, 17))	('MELK', 'Gene', '9833', (13, 17))	('ULMS', 'Phenotype', 'HP:0002891', (70, 74))	('colony formation', 'CPA', (151, 167))	('ULM', 'Phenotype', 'HP:0000131', (70, 73))	('increased', 'PosReg', (40, 49))	('MELK', 'Gene', (124, 128))	('MELK', 'Gene', '9833', (124, 128))	('expression', 'Var', (18, 28))
54881	32391256	Moreover, the miRNA profiling heatmap showed that miR-19a-3p, miR-34a-5p, miR-449a, miR-33a-5p, and miR-29b-3p were suppressed in MELK-overexpressing cells both with and without doxorubicin treatment (Figure 3B).	('suppressed', 'NegReg', (116, 126))	('miR-449a', 'Gene', '554213', (74, 82))	('miR-29b-3p', 'Var', (100, 110))	('miR-33a', 'Gene', '407039', (84, 91))	('MELK', 'Gene', (130, 134))	('MELK', 'Gene', '9833', (130, 134))	('doxorubicin', 'Chemical', 'MESH:D004317', (178, 189))	('miR-19a-3p', 'Gene', (50, 60))	('miR-33a', 'Gene', (84, 91))	('miR-449a', 'Gene', (74, 82))	('miR-34a', 'Gene', '407040', (62, 69))	('miR-34a', 'Gene', (62, 69))
54886	32391256	Western blot showed that MELK overexpression promoted higher levels of phosphor-JAK2 (Y1007 + Y1008) and phosphor-STAT3 (Y705) (i.e., increased p-JAK2 and the ratio of p-STAT3:STAT3).	('Y705', 'Var', (121, 125))	('JAK2', 'Gene', (80, 84))	('higher', 'PosReg', (54, 60))	('STAT3', 'Gene', (176, 181))	('STAT3', 'Gene', '6774', (114, 119))	('STAT3', 'Gene', '6774', (170, 175))	('STAT3', 'Gene', (114, 119))	('STAT3', 'Gene', (170, 175))	('MELK', 'Gene', '9833', (25, 29))	('Y1007 + Y1008', 'Var', (86, 99))	('JAK2', 'Gene', '3717', (146, 150))	('MELK', 'Gene', (25, 29))	('JAK2', 'Gene', '3717', (80, 84))	('increased', 'PosReg', (134, 143))	('JAK2', 'Gene', (146, 150))	('STAT3', 'Gene', '6774', (176, 181))
54887	32391256	Conversely, MELK inhibition reduced JAK2 and STAT3 phosphorylation (i.e., decreased p-JAK2 and the ratio of p-STAT3:STAT3).	('STAT3', 'Gene', '6774', (110, 115))	('reduced', 'NegReg', (28, 35))	('MELK', 'Gene', (12, 16))	('JAK2', 'Gene', (36, 40))	('STAT3', 'Gene', (45, 50))	('MELK', 'Gene', '9833', (12, 16))	('STAT3', 'Gene', (110, 115))	('STAT3', 'Gene', '6774', (45, 50))	('inhibition', 'Var', (17, 27))	('STAT3', 'Gene', '6774', (116, 121))	('ratio of', 'MPA', (99, 107))	('decreased', 'NegReg', (74, 83))	('STAT3', 'Gene', (116, 121))	('JAK2', 'Gene', '3717', (86, 90))	('JAK2', 'Gene', '3717', (36, 40))	('JAK2', 'Gene', (86, 90))
54905	32391256	Furthermore, we measured the expression of phospho-JAK2 (Y1007 + Y1008) and phospho-STAT3 (Y705) in macrophages treated with the respective conditioned media of stably transfected ULMS cells overexpressing MELK, those suppressing MELK, and corresponding NC cells.	('STAT3', 'Gene', '6774', (84, 89))	('suppressing', 'NegReg', (218, 229))	('overexpressing', 'PosReg', (191, 205))	('STAT3', 'Gene', (84, 89))	('JAK2', 'Gene', '3717', (51, 55))	('MELK', 'Gene', (230, 234))	('ULMS', 'Phenotype', 'HP:0002891', (180, 184))	('MELK', 'Gene', (206, 210))	('JAK2', 'Gene', (51, 55))	('MELK', 'Gene', '9833', (230, 234))	('MELK', 'Gene', '9833', (206, 210))	('Y705', 'Var', (91, 95))	('Y1007 + Y1008', 'Var', (57, 70))	('ULM', 'Phenotype', 'HP:0000131', (180, 183))
54909	32391256	The ELISA assessment of IL-6 concentrations revealed that the IL-6 was meaningfully higher in the cultured medium of M2 macrophages treated with IL-4 than in the cultured medium of untreated macrophages (P < 0.01; Figure 4I).	('IL-4', 'Gene', (145, 149))	('IL-4', 'Gene', '3565', (145, 149))	('treated', 'Var', (132, 139))	('IL-6', 'Gene', '3569', (24, 28))	('IL-6', 'Gene', '3569', (62, 66))	('IL-6', 'Gene', (24, 28))	('IL-6', 'Gene', (62, 66))	('higher', 'PosReg', (84, 90))
54918	32391256	Our experiment in vivo (Figure 5A) affirmed that both doxorubicin alone and the combination of doxorubicin and OTSSP167 could significantly suppress tumor growth, whereas the combination treatment produced the lowest tumor weight (mean tumor weight of the three subgroups: 0.4897 +- 0.03658, 0.2900 +- 0.02153, and 0.1618 +- 0.01732; P < 0.01) and tumor size (mean tumor size of the three subgroups: 1.200 +- 0.05701, 0.9100 +- 0.05788, and 0.6800 +- 0.04062; P < 0.01; Figures 5B,C).	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor weight', 'Disease', 'MESH:D015431', (217, 229))	('OTSSP167', 'Var', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor weight', 'Disease', (217, 229))	('0.6800 +- 0.04062', 'Var', (441, 458))	('tumor', 'Disease', (217, 222))	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('0.4897 +- 0.03658', 'Var', (273, 290))	('doxorubicin', 'Var', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('0.1618 +- 0.01732', 'Var', (315, 332))	('doxorubicin', 'Chemical', 'MESH:D004317', (54, 65))	('tumor', 'Disease', (365, 370))	('lowest', 'NegReg', (210, 216))	('OTSSP167', 'Chemical', 'MESH:C585656', (111, 119))	('doxorubicin', 'Var', (54, 65))	('tumor weight', 'Disease', 'MESH:D015431', (236, 248))	('0.9100 +- 0.05788', 'Var', (418, 435))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('tumor weight', 'Disease', (236, 248))	('0.2900 +- 0.02153', 'Var', (292, 309))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (348, 353))	('suppress', 'NegReg', (140, 148))	('tumor', 'Disease', (236, 241))
54921	32391256	Choi and Ku reported that with the treatment of 5-fluorouracil or radiation, the level of MELK expression in rectal cancer cell lines was significantly increased, and their data also suggested that MELK participated in cell cycle, which indicated that MELK potentially acted to mitigate chemotherapy and radiation.	('MELK', 'Gene', '9833', (90, 94))	('cell cycle', 'CPA', (219, 229))	('MELK', 'Gene', '9833', (198, 202))	('level', 'MPA', (81, 86))	('MELK', 'Gene', (198, 202))	('increased', 'PosReg', (152, 161))	('cancer', 'Disease', (116, 122))	('MELK', 'Gene', (252, 256))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('participated', 'Reg', (203, 215))	('MELK', 'Gene', '9833', (252, 256))	('rectal cancer', 'Phenotype', 'HP:0100743', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('5-fluorouracil', 'Var', (48, 62))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (48, 62))	('MELK', 'Gene', (90, 94))	('expression', 'MPA', (95, 105))
54926	32391256	Seong and Ha demonstrated that MELK could regulate the stability of p53 by phosphorylating Ser15 in its N-terminal transactivation region, thereby promoting p53-dependent cell cycle arrest and apoptosis.	('p53', 'Gene', '7157', (157, 160))	('promoting', 'PosReg', (147, 156))	('apoptosis', 'CPA', (193, 202))	('arrest', 'Disease', (182, 188))	('MELK', 'Gene', (31, 35))	('stability', 'MPA', (55, 64))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (171, 188))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('MELK', 'Gene', '9833', (31, 35))	('arrest', 'Disease', 'MESH:D006323', (182, 188))	('p53', 'Gene', (157, 160))	('Ser15', 'Chemical', '-', (91, 96))	('phosphorylating', 'Var', (75, 90))
54942	32391256	In addition, in p53 mutated colorectal cancer cells, a conservative STAT3 binding site directly repressed miR-34a, which was suggested as a p53-independent expression of miR-34a in IL-6-induced epithelial-mesenchymal transition and invasion.	('IL-6', 'Gene', (181, 185))	('p53', 'Gene', '7157', (16, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('rectal cancer', 'Phenotype', 'HP:0100743', (32, 45))	('p53', 'Gene', (16, 19))	('miR-34a', 'Gene', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('miR-34a', 'Gene', (106, 113))	('mutated', 'Var', (20, 27))	('miR-34a', 'Gene', '407040', (170, 177))	('invasion', 'CPA', (232, 240))	('miR-34a', 'Gene', '407040', (106, 113))	('p53', 'Gene', '7157', (140, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('STAT3', 'Gene', (68, 73))	('colorectal cancer', 'Disease', (28, 45))	('STAT3', 'Gene', '6774', (68, 73))	('IL-6', 'Gene', '3569', (181, 185))	('p53', 'Gene', (140, 143))
54944	32391256	In the current study, MELK overexpression was shown to induce increased p-JAK2 and p-STAT3 and then to decrease miRNA-34a expression, as seen in decreased miRNA-34a in the exosomes of ULMS cells with MELK overexpression.	('MELK', 'Gene', (200, 204))	('increased', 'PosReg', (62, 71))	('JAK2', 'Gene', '3717', (74, 78))	('expression', 'MPA', (122, 132))	('MELK', 'Gene', '9833', (200, 204))	('overexpression', 'Var', (27, 41))	('miRNA-34a', 'Gene', (112, 121))	('miRNA-34a', 'Gene', '407040', (112, 121))	('JAK2', 'Gene', (74, 78))	('MELK', 'Gene', '9833', (22, 26))	('MELK', 'Gene', (22, 26))	('STAT3', 'Gene', '6774', (85, 90))	('miRNA-34a', 'Gene', '407040', (155, 164))	('STAT3', 'Gene', (85, 90))	('ULMS', 'Phenotype', 'HP:0002891', (184, 188))	('decrease', 'NegReg', (103, 111))	('ULM', 'Phenotype', 'HP:0000131', (184, 187))	('miRNA-34a', 'Gene', (155, 164))
54973	32391256	The accession number is SRR11249953, SRR11249952, SRR11249951, SRR11249950, SRR11249949, SRR11249948, SRR11249947, SRR11249946.	('SRR11249946', 'Chemical', '-', (115, 126))	('SRR11249951', 'Var', (50, 61))	('SRR11249946', 'Var', (115, 126))	('SRR11249950', 'Var', (63, 74))	('SRR11249950', 'Chemical', '-', (63, 74))	('SRR11249948', 'Chemical', '-', (89, 100))	('SRR11249949', 'Chemical', '-', (76, 87))	('SRR11249953', 'Var', (24, 35))	('SRR11249949', 'Var', (76, 87))	('SRR11249952', 'Chemical', '-', (37, 48))	('SRR11249953', 'Chemical', '-', (24, 35))	('SRR11249951', 'Chemical', '-', (50, 61))	('SRR11249948', 'Var', (89, 100))	('SRR11249947', 'Chemical', '-', (102, 113))	('SRR11249952', 'Var', (37, 48))	('SRR11249947', 'Var', (102, 113))
54976	31754644	Metabolic gene alterations impact the clinical aggressiveness and drug responses of 32 human cancers Malignant cells reconfigure their metabolism to support oncogenic processes such as accelerated growth and proliferation.	('cancers', 'Disease', (93, 100))	('Metabolic gene', 'Gene', (0, 14))	('metabolism', 'MPA', (135, 145))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('accelerated growth', 'CPA', (185, 203))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('alterations', 'Var', (15, 26))	('aggressiveness', 'Phenotype', 'HP:0000718', (47, 61))	('proliferation', 'CPA', (208, 221))	('drug responses', 'CPA', (66, 80))	('impact', 'Reg', (27, 33))	('aggressiveness', 'Disease', 'MESH:D001523', (47, 61))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('aggressiveness', 'Disease', (47, 61))
54978	31754644	We find that mutations and copy number variations of metabolic genes are pervasive across all human cancers.	('metabolic genes', 'Gene', (53, 68))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (94, 99))	('mutations', 'Var', (13, 22))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('copy number variations', 'Var', (27, 49))	('cancers', 'Disease', (100, 107))
54979	31754644	Based on the frequencies of metabolic gene alterations, we further find that there are two distinct cancer supertypes that tend to be associated with different clinical outcomes.	('metabolic gene', 'Gene', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (43, 54))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
54985	31754644	Although many of the metabolic processes occurring in cancer cells are similar to those occurring in healthy proliferating cells, a series of genetic and epigenetic modifications in cancer cells can result in the aberrant regulation of these processes.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('regulation', 'MPA', (222, 232))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('genetic', 'Var', (142, 149))	('cancer', 'Disease', (182, 188))	('aberrant', 'Reg', (213, 221))	('result in', 'Reg', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('epigenetic modifications', 'Var', (154, 178))
54986	31754644	These alterations include diverse driver mutations and gene copy number alterations, which can impart a substantial degree of metabolic heterogeneity to different tumours of the same cancer type.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (183, 189))	('tumours', 'Disease', (163, 170))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gene copy number alterations', 'Var', (55, 83))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('tumours', 'Disease', 'MESH:D009369', (163, 170))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
54988	31754644	These and other studies have also yielded a growing appreciation of how the aberrant metabolic changes in cancer cells influence the anticancer drug responses of different tumours.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('metabolic changes', 'CPA', (85, 102))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('influence', 'Reg', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('aberrant', 'Var', (76, 84))	('tumours', 'Phenotype', 'HP:0002664', (172, 179))	('tumours', 'Disease', 'MESH:D009369', (172, 179))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (137, 143))	('tumours', 'Disease', (172, 179))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
54995	31754644	Valuable in this regard, are large-scale drug response screening projects such as the Genomics of Drug Sensitivity in Cancer (GDSC;) and the Cancer Cell Line Encyclopedia which provide transcriptome and epigenetic profiles for over one thousand human cancer cell lines together with their dose-response profiles to hundreds of anticancer drugs.	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (98, 114))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('human', 'Species', '9606', (245, 250))	('epigenetic', 'Var', (203, 213))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Disease', (251, 257))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))
55006	31754644	For instance, mutations of PIK3CA reprogramme metabolism and are associated with poorer survival outcomes in several cancers, including those of the colon, rectum, breast and lungs.	('rectum', 'Disease', (156, 162))	('lungs', 'Disease', (175, 180))	('breast', 'Disease', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PIK3CA', 'Gene', (27, 33))	('associated', 'Reg', (65, 75))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('reprogramme', 'Reg', (34, 45))	('PIK3CA', 'Gene', '5290', (27, 33))	('colon', 'Disease', (149, 154))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('mutations', 'Var', (14, 23))	('poorer', 'NegReg', (81, 87))	('cancers', 'Disease', (117, 124))
55012	31754644	We clustered the 32 human cancers based on the frequencies of gene alterations of metabolic pathways.	('human', 'Species', '9606', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gene alterations', 'Var', (62, 78))	('metabolic pathways', 'Pathway', (82, 100))
55023	31754644	We found that alterations to genes involved in second-tier pathways were more frequent in the HM cancers than in the LM cancers (Fig.	('alterations', 'Var', (14, 25))	('genes', 'Gene', (29, 34))	('HM cancers', 'Disease', (94, 104))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('HM cancers', 'Disease', 'MESH:D009369', (94, 104))	('frequent', 'Reg', (78, 86))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('second-tier', 'Pathway', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('LM cancer', 'Phenotype', 'HP:0002665', (117, 126))
55031	31754644	We anticipate that studying alterations of selenoamino acid metabolism could yield targets for the development of new therapeutics and predictive biomarkers that would aid the treatment of various cancers.	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('selenoamino acid', 'Chemical', 'MESH:D000596', (43, 59))	('alterations', 'Var', (28, 39))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (197, 204))	('selenoamino acid metabolism', 'MPA', (43, 70))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
55035	31754644	Since the changes in phospholipid metabolism can affect the proliferation of cancer cells and their responses to drugs, it is plausible that at least some of the observed alterations in genes involved in phospholipid metabolism may have biological and clinical relevance.	('responses to drugs', 'MPA', (100, 118))	('affect', 'Reg', (49, 55))	('proliferation', 'CPA', (60, 73))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('phospholipid metabolism', 'MPA', (21, 44))	('changes', 'Var', (10, 17))
55040	31754644	We discovered that 78% of all tumours harbour alteration in these genes (Fig.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('alteration', 'Var', (46, 56))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
55043	31754644	Collectively these results reiterate that alterations within genes involved in particular aspects of lipid, carbohydrate and amino acid metabolism are found in many different cancers.	('carbohydrate', 'Chemical', 'MESH:D002241', (108, 120))	('alterations', 'Var', (42, 53))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('found', 'Reg', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
55070	31754644	Among these, afatinib, CP724714 and gefitinib target the EGFR signalling pathway, whereas TAK-715 targets JNK and p38 signalling, and vinorelbine inhibits mitosis by destabilising microtubules (Supplementary file 2).	('destabilising', 'NegReg', (166, 179))	('target', 'Reg', (46, 52))	('p38', 'Gene', (114, 117))	('afatinib', 'Chemical', 'MESH:C522924', (13, 21))	('vinorelbine', 'Chemical', 'MESH:C030852', (134, 145))	('microtubules', 'MPA', (180, 192))	('inhibits', 'NegReg', (146, 154))	('CP724714', 'Chemical', 'MESH:C521104', (23, 31))	('EGFR', 'Gene', '1956', (57, 61))	('mitosis', 'CPA', (155, 162))	('gefitinib', 'Chemical', 'MESH:C419708', (36, 45))	('p38', 'Gene', '1432', (114, 117))	('EGFR', 'Gene', (57, 61))	('JNK', 'MPA', (106, 109))	('CP724714', 'Var', (23, 31))
55078	31754644	Since the frequencies of alterations to genes involved in metabolic pathways are likely to influence the responses of patients to anticancer drugs, we identified GDSC cancer cell lines displaying similar gene alterations to those found in individual primary tumours to test whether this might be the case (see methods section).	('alterations', 'Var', (25, 36))	('primary tumours', 'Disease', (250, 265))	('primary tumours', 'Disease', 'MESH:D009369', (250, 265))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('influence', 'Reg', (91, 100))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumours', 'Phenotype', 'HP:0002664', (258, 265))	('responses', 'MPA', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('patients', 'Species', '9606', (118, 126))
55082	31754644	Also, cell lines of lung adenocarcinoma with alterations in genes involved in the biological oxidation pathways are more resistant to 52 anticancer drugs than are those without alterations to these genes (Fig.	('alterations', 'Var', (45, 56))	('lung adenocarcinoma', 'Disease', (20, 39))	('resistant', 'CPA', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (20, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (20, 39))	('cancer', 'Disease', (141, 147))
55083	31754644	Altogether, we found 2186 instances where alterations to genes involved in a specific metabolic pathway are associated with the efficacy of anticancer drugs in the cancer cell lines (Supplementary file 2).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('alterations', 'Var', (42, 53))	('genes', 'Gene', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', (164, 170))	('associated', 'Reg', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('efficacy', 'MPA', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
55086	31754644	Given that we had found that tumours displaying different numbers of alterations to metabolic genes exhibit different clinical and survival outcomes, we decided to examine this in more detail for particular cancer types.	('alterations', 'Var', (69, 80))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('metabolic genes', 'Gene', (84, 99))	('particular cancer', 'Disease', (196, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('particular cancer', 'Disease', 'MESH:D009369', (196, 213))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
55087	31754644	Using data of primary cancers from the TCGA, for patients' tumours with or without alterations in genes involved in abacavir metabolism, we found that the durations of the disease-free progression periods were significantly lower for oesophageal adenocarcinoma patients with alterations to these genes (log rank p = 0.004; Fig.	('abacavir', 'Chemical', 'MESH:C106538', (116, 124))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('oesophageal adenocarcinoma', 'Disease', (234, 260))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('lower', 'NegReg', (224, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (261, 269))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (234, 260))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumours', 'Disease', (59, 66))	('alterations', 'Var', (275, 286))
55088	31754644	Conversely, disease-free progression periods were higher for uterine corpus endometrial carcinoma patients with alterations to genes involved in abacavir metabolism (log rank p = 0.041; Fig.	('higher', 'PosReg', (50, 56))	('disease-free progression periods', 'CPA', (12, 44))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (76, 97))	('patients', 'Species', '9606', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('endometrial carcinoma', 'Disease', (76, 97))	('abacavir', 'Chemical', 'MESH:C106538', (145, 153))	('alterations', 'Var', (112, 123))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (76, 97))
55089	31754644	This then indicates that, even within each cancer type, the numbers of alterations found in metabolic genes involved in particular pathways can, in addition to influencing anticancer drug responses, detectably impact patient survival.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patient survival', 'CPA', (217, 233))	('cancer', 'Disease', (43, 49))	('metabolic genes', 'Gene', (92, 107))	('patient', 'Species', '9606', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('alterations', 'Var', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('impact', 'Reg', (210, 216))	('influencing', 'Reg', (160, 171))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
55090	31754644	We examined the relationships between the numbers of alterations within the metabolic genes of primary tumours and cell lines of 32 different human cancer types and both clinical outcomes and likely drug responses.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('primary tumours', 'Disease', (95, 110))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('alterations', 'Var', (53, 64))	('human', 'Species', '9606', (142, 147))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('metabolic genes', 'Gene', (76, 91))	('primary tumours', 'Disease', 'MESH:D009369', (95, 110))
55095	31754644	Just as others have shown that alterations of genes involved in signalling pathways can have clinical implications, we show here that individuals with HM tumours tend to have worse clinical outcomes than those afflicted with LM tumours.	('LM tumours', 'Disease', (225, 235))	('worse', 'NegReg', (175, 180))	('alterations', 'Var', (31, 42))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('HM tumours', 'Disease', 'MESH:D009369', (151, 161))	('HM tumours', 'Disease', (151, 161))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('LM tumours', 'Disease', 'MESH:D009369', (225, 235))	('tumours', 'Phenotype', 'HP:0002664', (228, 235))
55097	31754644	Our analyses indicate that alterations of genes involved in the central metabolic pathways and the regulators of these pathways are pervasive across all human cancers (Fig.	('cancers', 'Disease', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('alterations', 'Var', (27, 38))
55099	31754644	In various cancers, MYC and HIF1A alterations dysregulate multiple metabolic enzymes including, hexokinase, isocitrate dehydrogenase, pyruvate dehydrogenase kinase and lactate dehydrogenase.	('MYC', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HIF1A', 'Gene', '3091', (28, 33))	('isocitrate dehydrogenase', 'Enzyme', (108, 132))	('alterations', 'Var', (34, 45))	('pyruvate', 'Chemical', 'MESH:D011773', (134, 142))	('MYC', 'Gene', '4609', (20, 23))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('pyruvate dehydrogenase kinase', 'Enzyme', (134, 163))	('hexokinase', 'Gene', (96, 106))	('lactate dehydrogenase', 'Enzyme', (168, 189))	('HIF1A', 'Gene', (28, 33))	('isocitrate', 'Chemical', 'MESH:D007523', (108, 118))	('dysregulate', 'Reg', (46, 57))	('metabolic enzymes', 'Enzyme', (67, 84))	('hexokinase', 'Gene', '3098', (96, 106))	('lactate', 'Chemical', 'MESH:D019344', (168, 175))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))
55113	31754644	Taking a step back, we are reminded that among tumours that are derived from any particular tissue, there exist distinct tumour subtypes that differ from one another both in the gene alterations they display, and in the actual metabolic perturbations that these gene alterations cause.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('gene alterations', 'MPA', (178, 194))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumour', 'Disease', (47, 53))	('alterations', 'Var', (267, 278))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumours', 'Disease', (47, 54))	('tumour', 'Disease', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
55116	31754644	This then supports the assertion that for any given cancer patient, the overall landscape of metabolic gene alterations could be used to identify generally applicable anticancer drug classes, following which alterations to specific metabolic genes could be used to eliminate the remaining drug choices that have the highest chances of failure.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('alterations', 'Var', (108, 119))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('patient', 'Species', '9606', (59, 66))	('cancer', 'Disease', (171, 177))	('alterations', 'Var', (208, 219))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
55117	31754644	Our results have revealed that within each of the 32 cancer types, there exist subtypes that have alterations in genes that are involved in metabolic pathways that are less commonly associated with cancers (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', (198, 204))	('genes', 'Gene', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('alterations', 'Var', (98, 109))
55118	31754644	Interestingly, we found that for different cancer types, alterations of genes involved in a particular metabolic pathway may not produce similar clinical outcomes.	('alterations', 'Var', (57, 68))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
55119	31754644	For example, we found that for patients with alterations to genes involved in abacavir metabolism, those afflicted with oesophageal adenocarcinoma present with worse outcomes whereas those afflicted with uterine corpora endometrial carcinoma present with better outcomes (Fig.	('alterations', 'Var', (45, 56))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (220, 241))	('oesophageal adenocarcinoma', 'Disease', (120, 146))	('endometrial carcinoma', 'Disease', (220, 241))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (220, 241))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (120, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('patients', 'Species', '9606', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('abacavir', 'Chemical', 'MESH:C106538', (78, 86))
55122	31754644	Altogether, we have shown both that metabolic gene alterations which potentially dysregulate metabolic pathways are a pervasive phenomenon across all 32 of the investigated human cancer types, and that numbers of metabolic gene alterations are linked to treatment outcomes.	('dysregulate', 'Reg', (81, 92))	('alterations', 'Var', (51, 62))	('metabolic pathways', 'Pathway', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('linked', 'Reg', (244, 250))	('alterations', 'Var', (228, 239))	('human', 'Species', '9606', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('metabolic gene', 'Gene', (36, 50))	('cancer', 'Disease', (179, 185))
55123	31754644	Further, our analysis of the drug response profiles of well-characterised cancer cell lines suggests that alterations of genes of various metabolic pathways may also be predictive of drug responses.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('drug', 'Disease', (183, 187))	('cancer', 'Disease', (74, 80))	('alterations', 'Var', (106, 117))	('genes', 'Gene', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
55129	31754644	For each of the 32 human cancers, we calculated the overall percentage of samples with mutations and/or copy number alterations in genes that belong to each of the sixteen first-tier metabolic pathway as defined in the Reactome pathway database (see the spreadsheet, "Metabolic Pathways - First Tier", of Supplementary file 2).	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('copy number alterations', 'Var', (104, 127))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('genes', 'Gene', (131, 136))	('cancers', 'Disease', (25, 32))	('human', 'Species', '9606', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('mutations', 'Var', (87, 96))
55135	31754644	Again, we used the approach for determining the extent of gene alterations (as described above) to calculate the fraction of tumours with alterations to genes involved in second-tier metabolic pathways across each cancer type (Fig.	('tumours', 'Disease', 'MESH:D009369', (125, 132))	('cancer', 'Disease', (214, 220))	('tumours', 'Disease', (125, 132))	('alterations', 'Var', (138, 149))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
55136	31754644	Also, using the same approach, we calculated the fraction of tumours with alterations in the genes that encode enzymes of the central metabolic pathway and their regulators (Fig.	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('tumours', 'Disease', (61, 68))	('alterations', 'Var', (74, 85))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
55235	30758678	In endometrial and cervical cancer, DWI, and DCE improve staging accuracy and tumor delineation.	('tumor delineation', 'Disease', 'MESH:D009369', (78, 95))	('tumor delineation', 'Disease', (78, 95))	('DCE', 'Gene', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('improve', 'PosReg', (49, 56))	('DWI', 'Var', (36, 39))	('DCE', 'Gene', '1718', (45, 48))	('endometrial and cervical cancer', 'Disease', 'MESH:D016889', (3, 34))	('staging accuracy', 'CPA', (57, 73))
55278	30758678	Eligibility criteria for vaginal radical trachelectomy (VRT) and abdominal radical trachelectomy (ART) include tumor size (<= 2 cm for VRT, <= 4 cm for ART), and tumor distance from the internal cervical os (> 1 cm for VRT, > 0.5 cm for ART).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('vaginal radical trachelectomy', 'Disease', (25, 54))	('tumor', 'Disease', (162, 167))	('<=', 'Var', (123, 125))	('tumor', 'Disease', (111, 116))	('abdominal radical trachelectomy', 'Disease', (65, 96))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
55318	30758678	In a recent meta-analysis of 15 studies including 849 patients, T2WI plus DWI showed superior specificity (0.947) compared to DCE imaging (0.86; p = 0.0035).	('patients', 'Species', '9606', (54, 62))	('specificity', 'MPA', (94, 105))	('DCE', 'Gene', '1718', (126, 129))	('T2WI', 'Var', (64, 68))	('DCE', 'Gene', (126, 129))
55328	30758678	In T2WI, an EC tumor appears as a diffuse or well-delineated soft tissue mass within the endometrial cavity, which shows heterogeneous intermediate SI relative to the hyperintense normal endometrium and hypointense myometrium.	('T2WI', 'Var', (3, 7))	('EC tumor', 'Disease', 'MESH:D009369', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EC tumor', 'Disease', (12, 20))	('soft tissue mass', 'Phenotype', 'HP:0031459', (61, 77))	('EC', 'Phenotype', 'HP:0012114', (12, 14))	('SI', 'Disease', 'None', (148, 150))
55340	30758678	On T2WI, uterine serosa invasion appears as an area of intermediate-to-high SI disrupting the normal smooth contour of the outer myometrium.	('SI', 'Disease', 'None', (76, 78))	('T2WI', 'Var', (3, 7))	('uterine serosa invasion', 'CPA', (9, 32))	('disrupting', 'NegReg', (79, 89))
55342	30758678	On T2WI, cervical stroma invasion is seen as a disruption of the normal low SI of the cervical stroma by the intermediate SI of the tumor.	('T2WI', 'Var', (3, 7))	('SI of the tumor', 'Disease', 'MESH:D009369', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('SI of the cervical stroma', 'Disease', (76, 101))	('SI of the cervical stroma', 'Disease', 'MESH:D002575', (76, 101))	('SI of the tumor', 'Disease', (122, 137))	('cervical stroma invasion', 'CPA', (9, 33))
55499	30053901	Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Disease', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('protein/phosphoprotein', 'MPA', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (142, 157))
55503	30053901	Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively.	('alterations', 'Var', (76, 87))	('tumors', 'Disease', (98, 104))	('ESR1', 'Gene', '2099', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mTOR', 'Gene', (191, 195))	('AKT', 'Gene', '207', (229, 232))	('mTOR', 'Gene', '2475', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESR1', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('BRAF', 'Gene', (224, 228))	('AKT', 'Gene', (229, 232))	('BRAF', 'Gene', '673', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
55504	30053901	We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool.	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
55506	30053901	Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.	('oncology', 'Phenotype', 'HP:0002664', (167, 175))	('alterations', 'Var', (82, 93))	('patients', 'Species', '9606', (179, 187))	('multi-omics', 'Var', (70, 81))
55513	30053901	The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and other large-scale sequencing data sets represent an opportunity to identify "druggable" variants, i.e., variants that render a cancer type susceptible to a drug.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('render', 'Reg', (212, 218))	('variants', 'Var', (182, 190))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('variants', 'Var', (198, 206))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))
55516	30053901	We identified tumors with drug-associated mutations and found considerable opportunity for repurposing of drugs across cancer types.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (119, 125))	('drug-associated', 'Reg', (26, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
55517	30053901	We used a structure-based computational tool to identify putative druggable mutations based on proximity to known druggable mutations and experimentally validated a subset of putative druggable mutations in BRAF.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('mutations', 'Var', (76, 85))	('mutations', 'Var', (194, 203))
55525	30053901	Tumor type is included for each variant/drug entry because, with infrequent exception, a variant's effect on a tumor's response to a given drug has only been rigorously studied in one or only a few cancer type(s).	('response to a given drug', 'MPA', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('variant', 'Var', (89, 96))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
55526	30053901	For a variant/drug entry based on preclinical data, tumor type was either inferred from the xenograft or cell line, or left unspecified.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variant/drug', 'Var', (6, 18))	('tumor', 'Disease', (52, 57))	('unspecified', 'Species', '32644', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
55527	30053901	Copy number amplifications (CNA) and losses (CNL), high expression outliers in oncogenes, low expression outliers in tumor suppressors, and fusions that may lead to druggability are also included.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('druggability', 'MPA', (165, 177))	('losses', 'NegReg', (37, 43))	('tumor', 'Disease', (117, 122))	('lead to', 'Reg', (157, 164))	('Copy number amplifications', 'Var', (0, 26))	('oncogenes', 'Gene', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
55528	30053901	Effect describes whether a variant correlates with increased sensitivity of a tumor to a drug or increased resistance of a tumor to a drug.	('increased', 'PosReg', (97, 106))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('sensitivity', 'MPA', (61, 72))	('tumor', 'Disease', (78, 83))	('variant', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('resistance', 'MPA', (107, 117))
55529	30053901	A given drug entry in DEPO could be associated with multiple drug families to allow for the possibility of combining therapies (e.g., dabrafenib [B-Raf inhibitor] and trametinib [MEK inhibitor] for BRAF V600E/K-mutant melanoma) and multi-targeted tyrosine kinase inhibitors (e.g., afatinib as a dual HER2 and EGFR inhibitor).	('EGFR', 'Gene', '1956', (309, 313))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('MEK', 'Gene', '5609', (179, 182))	('dabrafenib', 'Chemical', 'MESH:C561627', (134, 144))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('B-Raf', 'Gene', '673', (146, 151))	('V600E', 'Var', (203, 208))	('HER2', 'Gene', '2064', (300, 304))	('MEK', 'Gene', (179, 182))	('EGFR', 'Gene', (309, 313))	('tyrosine kinase', 'Gene', (247, 262))	('tyrosine kinase', 'Gene', '7294', (247, 262))	('afatinib', 'Chemical', 'MESH:D000077716', (281, 289))	('trametinib', 'Chemical', 'MESH:C560077', (167, 177))	('V600E', 'SUBSTITUTION', 'None', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('B-Raf', 'Gene', (146, 151))	('HER2', 'Gene', (300, 304))
55533	30053901	Variant calls were obtained from the TCGA Genome Data Analysis Centers (GDAC), Data Coordinating Center (DCC), and previously published TCGA marker papers until the end of 2014 (https://cancergenome.nih.gov/publications).	('Variant', 'Var', (0, 7))	('GDAC', 'Chemical', '-', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DCC', 'Chemical', '-', (105, 108))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
55534	30053901	Variant calls were excluded if metastases or recurrent samples were present for samples that already had a primary tumor in the mutation annotation file (MAF).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('metastases', 'Disease', (31, 41))	('Variant', 'Var', (0, 7))
55537	30053901	We identified tumors in our pan-cancer cohort that harbored one or more drug-associated SNP or indel.	('indel', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('SNP', 'Var', (88, 91))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
55538	30053901	Iterating through a mutation annotation format (MAF) file containing all variants in our pan-cancer cohort, we performed two actions for each entry in the MAF.	('cancer', 'Disease', (93, 99))	('variants', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
55539	30053901	First, we queried a hash table containing all druggable, unambiguous mutations in DEPO (e.g., BRAF V600E) and a separate hash table containing all druggable, ambiguous, single-residue mutations in DEPO (e.g., BRAF V600).	('single-residue', 'Var', (169, 183))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('DEPO', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (94, 98))	('DEPO', 'Gene', (82, 86))
55540	30053901	Second, we queried several classes of mutations that occur in a specific exon or segment of a gene (EGFR exon 19 in-frame deletion).	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))
55542	30053901	In some cases, DEPO contains multiple entries per gene/mutation pair to reflect possible druggability of a gene/mutation pair in more than one tumor type, or that it may confer an effect (e.g., sensitivity or resistance) that depends on tumor type or other therapeutic context.	('tumor', 'Disease', (237, 242))	('resistance', 'CPA', (209, 219))	('tumor', 'Disease', (143, 148))	('druggability', 'MPA', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('gene/mutation', 'Var', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sensitivity', 'MPA', (194, 205))
55543	30053901	For example, when visualizing "drug repurposing" across tumor types, a given mutation could be associated with > 1 "cancer-type-specific" tumor type, if a given gene/mutation pair had druggability information in DEPO in multiple tumor types at the same level of evidence.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (138, 143))	('mutation', 'Var', (77, 85))	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
55547	30053901	When considering potential druggable events in the cancer-type-non-specific setting, the drug with the highest level of evidence found across all tumor types was used for a specific variant (Additional file 2: Table S3).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (182, 189))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
55549	30053901	If any sensitive interaction for a variant was found regardless of the tumor type and level, it was considered a "druggable" event for these analyses.	('variant', 'Var', (35, 42))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
55550	30053901	HotSpot3D was used to spatially cluster "known" drug-associated mutations in DEPO with putative druggable mutations in our pan-cancer cohort.	('DEPO', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (127, 133))
55564	30053901	The distribution of LN(IC50) values of cell lines with DEPO mutations (both sensitive and resistant) for both the cancer-type-specific and non-specific settings were compared to a background distribution using the Mann-Whitney U test.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DEPO', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (114, 120))
55571	30053901	Constructions expressing BRAF variants were generated from a plasmid expressing a wild-type BRAF (Addgene, #40775) with an N-terminal Flag tag using Q5 site-directed mutagenesis (New England BioLabs).	('variants', 'Var', (30, 38))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
55572	30053901	Cells were transiently transfected with wild-type or mutant BRAF constructs using Lipofectamine 2000 reagent (Life Technologies) in six-well plates.	('BRAF', 'Gene', (60, 64))	('Lipofectamine 2000 reagent', 'Chemical', '-', (82, 108))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (53, 59))
55579	30053901	For each tumor, we mapped its "druggable" variants against one or more drugs, which were then mapped to one or more drug classes (Additional file 2: Table S8).	('tumor', 'Disease', (9, 14))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))
55580	30053901	For each variant, we used the drug that had the highest level of evidence in DEPO regardless of cancer type (Additional file 2: Table S3).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('variant', 'Var', (9, 16))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
55581	30053901	For the purposes of visualization, we only considered ten FDA-approved drug classes (Additional file 2: Table S9) mapping to the largest number of variants across our pan-cancer cohort (Additional file 2: Table S10).	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('variants', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
55587	30053901	Further, a substantial number (~ 25%) of sensitive variant/drug interactions are approved by the FDA for a particular cancer type or are based on late-stage clinical studies.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('particular cancer type', 'Disease', (107, 129))	('particular cancer type', 'Disease', 'MESH:D009369', (107, 129))	('variant/drug', 'Var', (51, 63))
55588	30053901	Several genes account for a large proportion of variant/drug interactions (e.g., EGFR, KIT, ERBB2, BRCA1, PDGFRA), reflecting interest in therapeutically exploiting a relatively limited number of cancer driver genes (Fig.	('ERBB2', 'Gene', '2064', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('KIT', 'Gene', (87, 90))	('PDGFRA', 'Gene', '5156', (106, 112))	('ERBB2', 'Gene', (92, 97))	('BRCA1', 'Gene', (99, 104))	('variant/drug', 'Var', (48, 60))	('EGFR', 'Gene', '1956', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('BRCA', 'Phenotype', 'HP:0003002', (99, 103))	('BRCA1', 'Gene', '672', (99, 104))	('PDGFRA', 'Gene', (106, 112))	('EGFR', 'Gene', (81, 85))
55590	30053901	Our analysis reveals 2364 mutations across 2114 tumors that are associated with sensitivity to one or more drugs (mean = 1.12/tumor) (Additional file 2: Table S2).	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('sensitivity', 'MPA', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (126, 131))
55591	30053901	The low fraction of drug-associated mutations likely reflects the large number of passengers in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (36, 45))
55592	30053901	Thirty-two percent of tumors had at least one drug-associated mutation, a percentage that is consistent with the 28% of screened patients that could be matched with a targeted therapy or trial.	('patients', 'Species', '9606', (129, 137))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
55594	30053901	2), that is, tumors with mutations associated with a known drug response in the cancer type with the highest level of evidence.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (80, 86))
55595	30053901	Only 3.3% of the samples contain a druggable mutation known to be FDA approved; however, if we consider less mature evidence: clinical trials, preclinical, and case reports, we could potentially increase the percentage of tumors with drug-associated mutations to 8.2, 8.5, and 10.5%, respectively.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('drug-associated', 'Reg', (234, 249))	('mutations', 'Var', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('increase', 'PosReg', (195, 203))
55596	30053901	Here, skin cutaneous melanoma (SKCM) is the cancer type with the largest fraction of drug-associated mutations (78%).	('mutations', 'Var', (101, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('skin cutaneous melanoma', 'Disease', (6, 29))	('CM', 'Disease', 'MESH:D009202', (33, 35))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
55597	30053901	SKCM with a BRAF V600E/K mutation (40% of patients) can be treated with BRAF and MEK inhibitors based on FDA approval.	('BRAF', 'Gene', (72, 76))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('V600E', 'SUBSTITUTION', 'None', (17, 22))	('CM', 'Disease', 'MESH:D009202', (2, 4))	('patients', 'Species', '9606', (42, 50))	('MEK', 'Gene', (81, 84))	('BRAF', 'Gene', '673', (72, 76))	('MEK', 'Gene', '5609', (81, 84))
55598	30053901	The NRAS Q61 mutations found in 12% of SKCM patients are more challenging to treat, as is any RAS-mutant cancer due to activation of multiple signaling pathways.	('patients', 'Species', '9606', (44, 52))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CM', 'Disease', 'MESH:D009202', (41, 43))	('activation', 'PosReg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRAS', 'Gene', (4, 8))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (4, 8))
55600	30053901	In colon and rectal carcinoma (COADREAD), glioblastoma multiforme (GBM), and lung adenocarcinoma (LUAD), 21, 14, and 40% of their respective tumors contain a drug-associated mutation in a cancer-type-specific setting.	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('colon and rectal carcinoma', 'Disease', 'MESH:D012004', (3, 29))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (13, 29))	('mutation', 'Var', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('glioblastoma multiforme', 'Disease', (42, 65))	('cancer', 'Disease', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung adenocarcinoma', 'Disease', (77, 96))	('contain', 'Reg', (148, 155))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('drug-associated', 'Reg', (158, 173))
55601	30053901	In COADREAD, drug-associated variants PIK3CA E542K, E545K, and H1047R are present in 2.1, 5.2, and 1.8% of tumors, respectively, and are associated with sensitivity to PI3K/AKT/mTOR pathway inhibitors in early-stage trials and aspirin in observational studies.	('H1047R', 'Mutation', 'rs121913279', (63, 69))	('AKT', 'Gene', (173, 176))	('sensitivity', 'MPA', (153, 164))	('associated with', 'Reg', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mTOR', 'Gene', (177, 181))	('E542K', 'Mutation', 'rs121913273', (45, 50))	('E545K', 'Mutation', 'rs104886003', (52, 57))	('aspirin', 'Chemical', 'MESH:D001241', (227, 234))	('PIK3CA', 'Gene', '5290', (38, 44))	('E542K', 'Var', (45, 50))	('AKT', 'Gene', '207', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('mTOR', 'Gene', '2475', (177, 181))	('E545K', 'Var', (52, 57))	('PIK3CA', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('H1047R', 'Var', (63, 69))
55603	30053901	In GBM, the EGFR extracellular mutations (A289V, G598V, and R108K) and IDH1 mutation R132H are present in 10 and 4.5% of tumors, respectively, and are associated with drug response based on preclinical data.	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('A289V', 'Mutation', 'rs149840192', (42, 47))	('associated', 'Reg', (151, 161))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('IDH1', 'Gene', (71, 75))	('G598V', 'Var', (49, 54))	('R108K', 'Mutation', 'rs1057519828', (60, 65))	('EGFR', 'Gene', '1956', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('IDH1', 'Gene', '3417', (71, 75))	('G598V', 'Mutation', 'rs139236063', (49, 54))	('R132H', 'Var', (85, 90))	('EGFR', 'Gene', (12, 16))	('A289V', 'Var', (42, 47))	('R108K', 'Var', (60, 65))
55604	30053901	In non-small cell lung cancer, EGFR inhibitors (e.g., erlotinib) are FDA approved for tumors with activating EGFR mutations, which are present at 10 and 1% in our LUAD and lung squamous cell carcinoma (LUSC) cohorts, respectively.	('mutations', 'Var', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'Gene', '1956', (109, 113))	('non-small cell lung cancer', 'Disease', (3, 29))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', '1956', (31, 35))	('tumors', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('EGFR', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('activating', 'PosReg', (98, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('EGFR', 'Gene', (31, 35))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))
55605	30053901	Despite the promise of targeted therapy, only 10.5% of this pan-cancer cohort contains potential drug-associated mutations in a cancer-type-specific setting.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('drug-associated', 'Reg', (97, 112))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (128, 134))
55606	30053901	With drug repurposing across cancer types, in which a drug used primarily in cancer type A with mutation X is repurposed for cancer type B with mutation X, we find that an additional 5.4% of patients may be treated with a FDA-approved drug-variant interaction (Figs.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
55608	30053901	In this cancer-type-non-specific setting, cancer types in which at least 40% of tumors have drug-associated mutations include low-grade glioma (LGG, 76%), thyroid carcinoma (THCA, 70%), and colorectal adenocarcinoma (COADREAD, 42%).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('THCA', 'Phenotype', 'HP:0002890', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (80, 86))	('colorectal adenocarcinoma', 'Disease', (190, 215))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (155, 172))	('cancer', 'Disease', (8, 14))	('thyroid carcinoma', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('glioma', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (190, 215))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('mutations', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (42, 48))
55609	30053901	A small number of drug-associated mutations occur at high frequency in these cancer types.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
55612	30053901	However, BRAF V600E also occurs at a lower frequency in HNSC, KIRP, LGG, and GBM, indicating significant repurposing potential for BRAF inhibitors (Fig.	('HNSC', 'Phenotype', 'HP:0012288', (56, 60))	('BRAF', 'Gene', (131, 135))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (9, 13))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', '673', (9, 13))
55613	30053901	However, COADREAD has been difficult to treat due to a large presence of KRAS and BRAF mutations; EGFR inhibition as monotherapy is used for COADREAD, but only in tumors with wild-type KRAS.	('EGFR', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (185, 189))	('KRAS', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (82, 86))	('KRAS', 'Gene', '3845', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (82, 86))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (185, 189))
55617	30053901	COADREAD or other cancer types having RAS mutations, such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (AML), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC), could benefit from further exploration of combinatorial therapies targeting downstream targets of KRAS (Fig.	('corpus endometrial carcinoma', 'Disease', (207, 235))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (207, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('acute myeloid leukemia', 'Disease', (134, 156))	('cancer', 'Disease', (18, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (61, 125))	('RAS', 'Gene', (38, 41))	('AML', 'Disease', 'MESH:D015470', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('AML', 'Disease', (158, 161))	('stomach adenocarcinoma', 'Disease', (164, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('AML', 'Phenotype', 'HP:0004808', (158, 161))	('KRAS', 'Gene', '3845', (342, 346))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KRAS', 'Gene', (342, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('mutations', 'Var', (42, 51))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (214, 235))
55620	30053901	Together, cancer-type-specific and non-specific mutational analyses identified potential therapeutic targets in 2114 tumors (32%), some of which will be considered druggable only with further clinical development and FDA approval.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (10, 16))
55621	30053901	We applied a structure-based clustering tool, HotSpot3D, to the pan-cancer dataset to reveal putative functional mutations (Additional file 2: Table S13).	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
55622	30053901	HotSpot3D's utility in predicting functional mutations is supported by experimental evidence using cell lines expressing one of several EGFR-mutant proteins.	('EGFR', 'Gene', '1956', (136, 140))	('mutations', 'Var', (45, 54))	('proteins', 'Protein', (148, 156))	('EGFR', 'Gene', (136, 140))
55623	30053901	Among all genes in our analysis, EGFR contains the highest number of putative sensitive mutations, with 36 mutations that clustered with 19 mutations in DEPO from seven different clusters (Fig.	('mutations', 'Var', (107, 116))	('DEPO', 'Gene', (153, 157))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))
55625	30053901	This procedure yielded four different clusters with a "resistant" mutation in AKT1, MAP2K1, and RAC1; these four clusters contained 14 putative resistant mutations clustering with four known resistant mutations (Additional file 2: Table S13).	('AKT1', 'Gene', (78, 82))	('contained', 'Reg', (122, 131))	('MAP2K1', 'Gene', (84, 90))	('RAC1', 'Gene', '5879', (96, 100))	('AKT1', 'Gene', '207', (78, 82))	('mutation', 'Var', (66, 74))	('RAC1', 'Gene', (96, 100))	('MAP2K1', 'Gene', '5604', (84, 90))
55626	30053901	RAC1 yielded the largest cluster, with RAC1 P29S mediating resistance to BRAF inhibitors in BRAF-mutant SKCM.	('BRAF', 'Gene', '673', (73, 77))	('P29S', 'Mutation', 'rs1057519874', (44, 48))	('resistance to', 'MPA', (59, 72))	('BRAF', 'Gene', '673', (92, 96))	('CM', 'Disease', 'MESH:D009202', (106, 108))	('RAC1', 'Gene', '5879', (39, 43))	('BRAF', 'Gene', (92, 96))	('RAC1', 'Gene', (39, 43))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (44, 48))	('BRAF', 'Gene', (73, 77))	('RAC1', 'Gene', (0, 4))	('mediating', 'Reg', (49, 58))
55627	30053901	Other mutations in this cluster that may affect binding affinity of BRAF inhibitors (or that may mediate resistance to BRAF inhibitors) are C18Y, E31D, A159V, P29L/T, and P34S.	('P29L', 'SUBSTITUTION', 'None', (159, 163))	('C18Y', 'SUBSTITUTION', 'None', (140, 144))	('BRAF', 'Gene', '673', (68, 72))	('E31D', 'Var', (146, 150))	('BRAF', 'Gene', '673', (119, 123))	('A159V', 'Mutation', 'p.A159V', (152, 157))	('BRAF', 'Gene', (68, 72))	('binding', 'Interaction', (48, 55))	('BRAF', 'Gene', (119, 123))	('P34S', 'Var', (171, 175))	('C18Y', 'Var', (140, 144))	('P34S', 'Mutation', 'p.P34S', (171, 175))	('E31D', 'Mutation', 'p.E31D', (146, 150))	('P29L', 'Var', (159, 163))	('affect', 'Reg', (41, 47))	('A159V', 'Var', (152, 157))
55628	30053901	For example, KIT has multiple clusters with known mutations; one of which has three known mutations (E490D, Y494C, S476G) in the same cluster, which are FDA approved as sensitive to combined therapy of imatinib, sunitinib, and regorafenib (KIT and angiogenesis inhibitor).	('E490D', 'Mutation', 'p.E490D', (101, 106))	('S476G', 'Var', (115, 120))	('regorafenib', 'Chemical', 'MESH:C559147', (227, 238))	('E490D', 'Var', (101, 106))	('Y494C', 'Var', (108, 113))	('sunitinib', 'Chemical', 'MESH:D000077210', (212, 221))	('Y494C', 'Mutation', 'p.Y494C', (108, 113))	('S476G', 'Mutation', 'p.S476G', (115, 120))	('imatinib', 'Chemical', 'MESH:D000068877', (202, 210))
55629	30053901	In addition, this cluster contains two other unique mutations (D439H, I438L) not in DEPO that, based on our analysis using HotSpot3D, could also affect binding affinity and potentially tumor sensitivity to KIT combined with angiogenesis inhibitors (Additional file 2: Table S13).	('tumor', 'Disease', (185, 190))	('I438L', 'Var', (70, 75))	('D439H', 'Mutation', 'p.D439H', (63, 68))	('affect', 'Reg', (145, 151))	('binding affinity', 'Interaction', (152, 168))	('I438L', 'Mutation', 'p.I438L', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('D439H', 'Var', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
55630	30053901	To do this, we assessed the activity and drug sensitivity of a set of six BRAF mutations (F635I, G596D, K601E, W604L, L613F, G596R) in close spatial proximity to the well-studied V600E pathogenic mutation (Fig.	('L613F', 'Mutation', 'p.L613F', (118, 123))	('G596D', 'Mutation', 'rs397507483', (97, 102))	('K601E', 'Mutation', 'rs121913364', (104, 109))	('W604L', 'Mutation', 'p.W604L', (111, 116))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('F635I', 'Mutation', 'p.F635I', (90, 95))	('L613F', 'Var', (118, 123))	('K601E', 'Var', (104, 109))	('G596R', 'Mutation', 'rs121913361', (125, 130))	('G596D', 'Var', (97, 102))	('G596R', 'Var', (125, 130))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('F635I', 'Var', (90, 95))	('drug sensitivity', 'Phenotype', 'HP:0020174', (41, 57))	('W604L', 'Var', (111, 116))
55632	30053901	Therefore, we transfected BRAF mutations, along with wild-type BRAF and BRAF V600E, into HEK293T cells in the presence or absence of BRAF inhibitor dabrafenib, and used phosphorylation changes in MEK1/2 as an indicator of BRAF activity.	('MEK1/2', 'Gene', '5604;5605', (196, 202))	('mutations', 'Var', (31, 40))	('MEK1/2', 'Gene', (196, 202))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (26, 30))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('BRAF', 'Gene', '673', (222, 226))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (26, 30))	('HEK293T', 'CellLine', 'CVCL:0063', (89, 96))	('BRAF', 'Gene', (222, 226))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', '673', (63, 67))	('phosphorylation', 'MPA', (169, 184))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (72, 76))
55633	30053901	The undetectable level of endogenous BRAF in HEK293T cells eliminates potential ambiguity in interpreting the effects of transfected BRAF mutations.	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', (133, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('mutations', 'Var', (138, 147))
55634	30053901	As expected, BRAF V600E caused drastically increased phosphorylation in MEK1/2 that is reduced by dabrafenib (Fig.	('V600E', 'Var', (18, 23))	('MEK1/2', 'Gene', '5604;5605', (72, 78))	('MEK1/2', 'Gene', (72, 78))	('BRAF', 'Gene', '673', (13, 17))	('dabrafenib', 'Chemical', 'MESH:C561627', (98, 108))	('BRAF', 'Gene', (13, 17))	('increased', 'PosReg', (43, 52))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('phosphorylation', 'MPA', (53, 68))
55635	30053901	Three (G596D, K601E, and W604L) out of six other transfected BRAF mutations also showed higher levels of MEK1/2 phosphorylation and sensitivity to dabrafenib than wild-type BRAF, suggesting that a high percentage of mutations identified by Hotspot3D in close spatial proximity to V600E are activated and similarly sensitive to dabrafenib.	('mutations', 'Var', (66, 75))	('K601E', 'Var', (14, 19))	('dabrafenib', 'Chemical', 'MESH:C561627', (327, 337))	('W604L', 'Var', (25, 30))	('G596D', 'Mutation', 'rs397507483', (7, 12))	('BRAF', 'Gene', '673', (173, 177))	('V600E', 'Mutation', 'rs113488022', (280, 285))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (61, 65))	('MEK1/2', 'Gene', '5604;5605', (105, 111))	('MEK1/2', 'Gene', (105, 111))	('higher', 'PosReg', (88, 94))	('W604L', 'Mutation', 'p.W604L', (25, 30))	('G596D', 'Var', (7, 12))	('sensitivity', 'MPA', (132, 143))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('V600E', 'Var', (280, 285))	('K601E', 'Mutation', 'rs121913364', (14, 19))
55636	30053901	Notably, BRAF G596R-transfected cells appeared to have a much lower level of MEK1/2 phosphorylation when compared to those transfected with wild-type BRAF, supporting prior findings that G596R results in BRAF loss of function.	('loss of function', 'NegReg', (209, 225))	('BRAF', 'Gene', (204, 208))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))	('G596R', 'Mutation', 'rs121913361', (14, 19))	('BRAF', 'Gene', (150, 154))	('lower', 'NegReg', (62, 67))	('BRAF', 'Gene', '673', (150, 154))	('G596R', 'Mutation', 'rs121913361', (187, 192))	('G596R', 'Var', (187, 192))	('MEK1/2', 'Gene', '5604;5605', (77, 83))	('MEK1/2', 'Gene', (77, 83))	('G596R-transfected', 'Var', (14, 31))	('BRAF', 'Gene', '673', (204, 208))
55638	30053901	For example, in the case of breast cancer, elevated mRNA expression and copy number amplification of ESR1 correlate with elevated protein expression of ER, as well as with sensitivity to hormonal therapy with tamoxifen.	('ESR1', 'Gene', '2099', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('copy number amplification', 'Var', (72, 97))	('elevated', 'PosReg', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (209, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('ESR1', 'Gene', (101, 105))	('breast cancer', 'Disease', (28, 41))	('protein expression', 'MPA', (130, 148))	('mRNA expression', 'MPA', (52, 67))	('elevated', 'PosReg', (121, 129))
55644	30053901	Interestingly, tumors with "druggable" gene fusions tend to express elevated levels of the corresponding druggable gene (Additional file 2: Table S15, Additional file 3: Figure S1), suggesting that fusions may be one of several drivers of gene and protein expression.	('levels of', 'MPA', (77, 86))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fusions', 'Var', (44, 51))	('elevated', 'PosReg', (68, 76))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
55656	30053901	Similarly, 26 and 52% of BRCA and UCEC, respectively, show elevated activity at ESR1's p.S118 phosphosite.	('BRCA', 'Gene', (25, 29))	('ESR1', 'Gene', '2099', (80, 84))	('p.S118', 'Var', (87, 93))	('S118 phosphosite', 'Chemical', '-', (89, 105))	('activity', 'MPA', (68, 76))	('elevated', 'PosReg', (59, 67))	('ESR1', 'Gene', (80, 84))	('BRCA', 'Phenotype', 'HP:0003002', (25, 29))	('BRCA', 'Gene', '672', (25, 29))
55659	30053901	EGFR phosphosites p.Y1068 and p.Y1173 are active in GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LUAD, and LUSC.	('p.Y1068', 'Var', (18, 25))	('EGFR', 'Gene', (0, 4))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('GBM', 'Disease', (52, 55))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HNSC', 'Phenotype', 'HP:0012288', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('phosphosite', 'Chemical', '-', (5, 16))	('p.Y1173', 'Var', (30, 37))	('EGFR', 'Gene', '1956', (0, 4))
55669	30053901	RAC1 P29S co-occurs with mutations in BRAF and MEK1 in four SKCM tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('mutations', 'Var', (25, 34))	('MEK1', 'Gene', '5604', (47, 51))	('BRAF', 'Gene', '673', (38, 42))	('MEK1', 'Gene', (47, 51))	('SKCM tumors', 'Disease', 'MESH:D009369', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SKCM tumors', 'Disease', (60, 71))	('BRAF', 'Gene', (38, 42))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (5, 9))	('RAC1', 'Gene', (0, 4))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
55670	30053901	RAC1 P29S renders SKCM resistant to BRAF/MEK inhibition; testing for RAC1 P29S may identify patients with BRAF V600E SKCM unlikely to benefit from BRAF/MEK inhibitor.	('CM', 'Disease', 'MESH:D009202', (20, 22))	('V600E', 'Var', (111, 116))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('patients', 'Species', '9606', (92, 100))	('RAC1', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (36, 40))	('P29S', 'Mutation', 'rs1057519874', (74, 78))	('BRAF', 'Gene', (36, 40))	('MEK', 'Gene', '5609', (41, 44))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('RAC1', 'Gene', '5879', (0, 4))	('MEK', 'Gene', '5609', (152, 155))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('RAC1', 'Gene', (69, 73))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('MEK', 'Gene', (41, 44))	('BRAF', 'Gene', '673', (106, 110))	('MEK', 'Gene', (152, 155))	('BRAF', 'Gene', (106, 110))	('RAC1', 'Gene', '5879', (69, 73))
55672	30053901	AKT1 E17K co-occurs with BRAF V600E in five tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('E17K', 'SUBSTITUTION', 'None', (5, 9))	('AKT1', 'Gene', '207', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('AKT1', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRAF', 'Gene', (25, 29))	('E17K', 'Var', (5, 9))
55674	30053901	Transcriptomic and proteomic expression profiling reveals 48 additional tumors with BRAF V600E/K and elevated AKT (AKT1/2/3) expression at the mRNA or protein/phosphoprotein levels; these may also benefit from BRAF/AKT inhibition (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('elevated', 'PosReg', (101, 109))	('AKT', 'Gene', '207', (115, 118))	('AKT1/2/3', 'Gene', (115, 123))	('AKT', 'Gene', (110, 113))	('tumors', 'Disease', (72, 78))	('V600E', 'SUBSTITUTION', 'None', (89, 94))	('AKT', 'Gene', '207', (215, 218))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('AKT', 'Gene', '207', (110, 113))	('AKT1/2/3', 'Gene', '207;208;10000', (115, 123))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('AKT', 'Gene', (115, 118))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('AKT', 'Gene', (215, 218))	('V600E', 'Var', (89, 94))
55677	30053901	Additionally, 105 tumors contain activating PIK3CA mutations co-occurring with elevated mRNA or protein expression of ESR1 or PGR.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PGR', 'Gene', '5241', (126, 129))	('ESR1', 'Gene', '2099', (118, 122))	('PIK3CA', 'Gene', '5290', (44, 50))	('mRNA or protein expression', 'MPA', (88, 114))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('activating', 'PosReg', (33, 43))	('elevated', 'PosReg', (79, 87))	('ESR1', 'Gene', (118, 122))	('PGR', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
55683	30053901	Overall, the mean LN(IC50) for cell lines that contain a sensitive mutation from DEPO was significantly lower than background LN(IC50) in both the cancer-type-specific and non-specific setting (Mann-Whitney U test, P = 1.1e-96 and P = 1.3e-109, respectively) (Fig.	('DEPO', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutation', 'Var', (67, 75))	('lower', 'NegReg', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
55685	30053901	In both the cancer-type-specific and non-specific settings, 19 variant/drug combinations had significantly lower mean LN(IC50) than background LN(IC50) for the corresponding drug.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('variant/drug', 'Var', (63, 75))	('cancer', 'Disease', (12, 18))	('lower', 'NegReg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('combinations', 'Var', (76, 88))
55687	30053901	For example, cell lines with BRAF V600E were associated with sensitivity to BRAF inhibitors PLX4720 (1), PLX4720 (2), and dabrafenib in both the cancer-type-specific (SKCM) and non-specific settings (BRCA, COADREAD, GBM, LGG, LIHC, and THCA) (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('LIHC', 'Disease', 'None', (226, 230))	('THCA', 'Phenotype', 'HP:0002890', (236, 240))	('BRCA', 'Phenotype', 'HP:0003002', (200, 204))	('PLX4720', 'Var', (105, 112))	('CM', 'Disease', 'MESH:D009202', (169, 171))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('BRCA', 'Gene', '672', (200, 204))	('sensitivity', 'MPA', (61, 72))	('V600E', 'Var', (34, 39))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('dabrafenib', 'Chemical', 'MESH:C561627', (122, 132))	('LIHC', 'Disease', (226, 230))	('BRCA', 'Gene', (200, 204))	('PLX4720', 'Gene', (92, 99))
55688	30053901	Two out of six mutations (PIK3CA H1047R and KRAS G12C) was associated with sensitivity in either the cancer-type-specific or the non-specific setting.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('H1047R', 'Var', (33, 39))	('G12C', 'Mutation', 'rs121913530', (49, 53))	('cancer', 'Disease', (101, 107))	('PIK3CA', 'Gene', '5290', (26, 32))	('sensitivity', 'Disease', (75, 86))	('associated', 'Reg', (59, 69))	('H1047R', 'Mutation', 'rs121913279', (33, 39))	('KRAS', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('KRAS', 'Gene', '3845', (44, 48))	('PIK3CA', 'Gene', (26, 32))
55703	30053901	First, with DEPO, our analysis of druggability in a given tumor is exclusively based on mutation/drug interactions rather than gene/drug interactions, with variants including both predefined mutations (e.g., BRAF V600E) and categories of mutations (e.g., EGFR exon 19 deletions).	('EGFR', 'Gene', '1956', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (255, 259))	('BRAF', 'Gene', '673', (208, 212))	('BRAF', 'Gene', (208, 212))	('deletions', 'Var', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('V600E', 'Mutation', 'rs113488022', (213, 218))
55706	30053901	Third, it uses an analytic tool to create a set of putative druggable mutations, of which a subset occurring in BRAF were tested and validated in vitro.	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))
55710	30053901	Realistically, only a fraction of the 48% of tumors with potential drug-associated omics alterations will be clinically druggable because the mere presence of a shared genetic biomarker (mutation, mRNA/protein expression outlier) does not guarantee clinical efficacy across cancer types, nor does it guarantee acceptable clinical toxicity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('toxicity', 'Disease', 'MESH:D064420', (330, 338))	('toxicity', 'Disease', (330, 338))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alterations', 'Var', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
55711	30053901	Further, we recognize that our computational survey of the landscape of potential drug-associated omics alterations may include some controversial drug/biomarker relationships (e.g., PI3K inhibitors in PIK3CA-mutant cancers), some of which have either failed clinical trials and/or are still being actively developed in clinical trials.	('alterations', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
55714	30053901	Second, our analysis does not account for clonal heterogeneity, which is not unreasonable given that therapies targeting genomic alterations with high variant allele frequencies can induce substantial tumor regression.	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('variant', 'Var', (151, 158))
55724	30053901	ACC Adrenocortical carcinoma AML/LAML Acute myeloid leukemia BLCA Bladder urothelial carcinoma BRCA Breast adenocarcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CNA Copy number amplification CNL Copy number loss CNV Copy number variation COADREAD Colon and rectal carcinoma CPTAC Clinical Proteomic Tumor Analysis Consortium DCC Data Coordinating Center DEPO Database of Evidence for Precision Oncology FBS Fetal bovine serum FDA Food and Drug Administration FFPE Formalin-fixed, paraffin-embedded GBM Glioblastoma multiforme GDAC Genome Data Analysis Centers GDSC Genomics of Drug Sensitivity in Cancer HNSC Head and neck squamous cell carcinoma IQR Interquartile range KICH Kidney chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LGG Low-grade glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma MAF Mutation annotation file NGS Next-generation sequencing NSCLC Non-small cell lung cancer OV Ovarian serous carcinoma PNNL Pacific Northwest National Laboratory PRAD Prostate adenocarcinoma RBN Replicates-based normalization RPPA Reverse phase protein array SKCM Skin cutaneous melanoma SNP Single nucleotide polymorphism STAD Stomach adenocarcinoma STR Short tandem repeat TCGA The Cancer Genome Atlas TCPA The Cancer Protein Atlas THCA Thyroid carcinoma TKI Tyrosine kinase inhibitor UCEC Uterine corpus endometrial carcinoma UCS Uterine carcinosarcoma VCF Variant call format LD designed and supervised the research.	('adenocarcinoma', 'Disease', (1262, 1276))	('Kidney renal clear cell carcinoma', 'Disease', (731, 764))	('carcinosarcoma', 'Disease', (1467, 1481))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (1310, 1329))	('adenocarcinoma', 'Disease', (1102, 1116))	('RBN', 'Chemical', '-', (1117, 1120))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (777, 807))	('cancer', 'Phenotype', 'HP:0002664', (1010, 1016))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('DCC', 'Chemical', '-', (356, 359))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('carcinoma', 'Disease', (1445, 1454))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (38, 60))	('squamous cell carcinoma', 'Disease', (900, 923))	('CM', 'Disease', 'MESH:D009202', (1187, 1189))	('carcinoma', 'Disease', 'MESH:D002277', (798, 807))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1262, 1276))	('Cancer', 'Disease', 'MESH:D009369', (1339, 1345))	('glioma', 'Phenotype', 'HP:0009733', (822, 828))	('bovine', 'Species', '9913', (444, 450))	('Cancer', 'Phenotype', 'HP:0002664', (1310, 1316))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (44, 60))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (1426, 1454))	('VCF', 'Gene', '6899', (1482, 1485))	('PNNL', 'Chemical', '-', (1045, 1049))	('Breast adenocarcinoma', 'Disease', 'MESH:D000230', (100, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1195, 1213))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (1365, 1382))	('adenocarcinoma', 'Disease', (177, 191))	('Kidney renal papillary cell carcinoma', 'Disease', (770, 807))	('Non-small cell lung cancer', 'Disease', (990, 1016))	('carcinoma', 'Disease', (85, 94))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (288, 304))	('Skin cutaneous melanoma', 'Disease', (1190, 1213))	('Ovarian serous carcinoma', 'Disease', (1020, 1044))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (770, 807))	('urothelial carcinoma', 'Disease', (74, 94))	('FBS', 'Disease', (434, 437))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('VCF', 'Gene', (1482, 1485))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (990, 1016))	('Uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (1459, 1481))	('NSCLC', 'Disease', 'MESH:D002289', (984, 989))	('Cancer Protein Atlas', 'Disease', 'MESH:D009369', (1339, 1359))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1433, 1454))	('Cancer', 'Disease', (1339, 1345))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('Cancer Genome Atlas', 'Disease', (1310, 1329))	('Ovarian serous carcinoma', 'Disease', 'MESH:D010051', (1020, 1044))	('THCA', 'Phenotype', 'HP:0002890', (1360, 1364))	('UCEC Uterine corpus', 'Phenotype', 'HP:0000139', (1413, 1432))	('adenocarcinoma', 'Disease', (107, 121))	('squamous cell carcinoma', 'Disease', (136, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1102, 1116))	('paraffin', 'Chemical', 'MESH:D010232', (511, 519))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (990, 1016))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (608, 624))	('corpus endometrial carcinoma', 'Disease', (1426, 1454))	('KICH', 'Chemical', '-', (702, 706))	('Tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Kidney chromophobe', 'Disease', 'MESH:D000238', (707, 725))	('Cancer', 'Disease', (628, 634))	('adenocarcinoma', 'Disease', (875, 889))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (649, 677))	('carcinoma', 'Disease', 'MESH:D002277', (755, 764))	('Kidney chromophobe', 'Disease', (707, 725))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1093, 1116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (900, 923))	('Liver hepatocellular carcinoma', 'Disease', (834, 864))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (834, 864))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('adenocarcinoma', 'Disease', 'MESH:D000230', (875, 889))	('Cancer', 'Disease', 'MESH:D009369', (628, 634))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (654, 677))	('Cancer', 'Phenotype', 'HP:0002664', (1339, 1345))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (164, 191))	('LUSC', 'Phenotype', 'HP:0030359', (890, 894))	('LIHC', 'Disease', (829, 833))	('Formalin', 'Chemical', 'MESH:D005557', (495, 503))	('adenocarcinoma', 'Disease', 'MESH:D000230', (177, 191))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (900, 923))	('carcinosarcoma', 'Disease', 'MESH:D002296', (1467, 1481))	('glioma', 'Disease', 'MESH:D005910', (822, 828))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (654, 677))	('carcinoma', 'Disease', 'MESH:D002277', (1267, 1276))	('NSCLC', 'Disease', (984, 989))	('carcinoma', 'Disease', (755, 764))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (994, 1016))	('Cancer', 'Phenotype', 'HP:0002664', (628, 634))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Tyrosine kinase', 'Gene', '7294', (1387, 1402))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (1254, 1276))	('NSCLC', 'Phenotype', 'HP:0030358', (984, 989))	('melanoma', 'Phenotype', 'HP:0002861', (1205, 1213))	('Breast adenocarcinoma', 'Phenotype', 'HP:0003002', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (914, 923))	('carcinoma', 'Disease', (150, 159))	('carcinoma', 'Disease', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (668, 677))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (731, 764))	('carcinoma', 'Disease', 'MESH:D002277', (295, 304))	('HNSC', 'Phenotype', 'HP:0012288', (635, 639))	('Glioblastoma multiforme', 'Disease', (533, 556))	('Variant', 'Var', (1486, 1493))	('Cancer', 'Disease', (1310, 1316))	('Stomach adenocarcinoma', 'Disease', (1254, 1276))	('GDAC', 'Chemical', '-', (557, 561))	('lung cancer', 'Phenotype', 'HP:0100526', (1005, 1016))	('carcinoma', 'Disease', (1267, 1276))	('carcinoma', 'Disease', (1035, 1044))	('LGG Low', 'Phenotype', 'HP:0004315', (808, 815))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('Breast adenocarcinoma', 'Disease', (100, 121))	('carcinoma', 'Disease', (1107, 1116))	('AML', 'Disease', (29, 32))	('carcinoma', 'Disease', 'MESH:D002277', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1190, 1213))	('FBS', 'Disease', 'MESH:D005198', (434, 437))	('Cancer', 'Disease', 'MESH:D009369', (1310, 1316))	('carcinoma', 'Disease', (914, 923))	('glioma', 'Disease', (822, 828))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (533, 556))	('carcinoma', 'Disease', (668, 677))	('carcinoma', 'Disease', (112, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('LUAD', 'Phenotype', 'HP:0030078', (865, 869))	('Acute myeloid leukemia', 'Disease', (38, 60))	('AML', 'Disease', (34, 37))	('carcinoma', 'Disease', (295, 304))	('BRCA', 'Gene', (95, 99))	('LIHC', 'Disease', 'None', (829, 833))	('carcinoma', 'Disease', 'MESH:D002277', (1035, 1044))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (38, 60))	('carcinoma', 'Disease', 'MESH:D002277', (19, 28))	('carcinoma', 'Disease', 'MESH:D002277', (1107, 1116))	('carcinoma', 'Disease', (880, 889))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('carcinoma', 'Disease', (855, 864))	('endocervical adenocarcinoma', 'Disease', (164, 191))	('Tyrosine kinase', 'Gene', (1387, 1402))	('carcinoma', 'Disease', (182, 191))	('neck squamous cell carcinoma', 'Disease', (649, 677))	('Cancer Protein Atlas', 'Disease', (1339, 1359))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (870, 889))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', 'MESH:D002277', (1445, 1454))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('Oncology', 'Phenotype', 'HP:0002664', (425, 433))	('UCS', 'Phenotype', 'HP:0002891', (1455, 1458))	('BLCA', 'Chemical', '-', (61, 65))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('Glioblastoma', 'Phenotype', 'HP:0012174', (533, 545))	('Prostate adenocarcinoma', 'Disease', (1093, 1116))	('carcinoma', 'Disease', 'MESH:D002277', (880, 889))	('TCPA', 'Chemical', '-', (1330, 1334))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (840, 864))	('carcinoma', 'Disease', (798, 807))	('carcinoma', 'Disease', 'MESH:D002277', (855, 864))	('carcinoma', 'Disease', (19, 28))	('BRCA', 'Gene', '672', (95, 99))
55732	29455465	Adjusting for stage, race, and adjuvant therapy, PFS and OS were reduced in patients with high IGF2 (H-score >= median) in the EC and EN compartments.	('patients', 'Species', '9606', (76, 84))	('reduced', 'NegReg', (65, 72))	('IGF2', 'Gene', '3481', (95, 99))	('high IGF2', 'Phenotype', 'HP:0030269', (90, 99))	('PFS', 'CPA', (49, 52))	('high', 'Var', (90, 94))	('IGF2', 'Gene', (95, 99))
55734	29455465	In a race-stratified multivariable analysis, high IGF2 in the epithelial compartments more than doubled the risk of death in black women; HR = 2.43 (95% CI: 1.18-5.01, P = 0.02) for high IGF2 in the EC; and HR = 2.34 (95% CI: 1.25-4.39, P = 0.008) for high IGF2 in the EN.	('women', 'Species', '9606', (131, 136))	('death', 'Disease', 'MESH:D003643', (116, 121))	('high IGF2', 'Phenotype', 'HP:0030269', (182, 191))	('death', 'Disease', (116, 121))	('high IGF2', 'Phenotype', 'HP:0030269', (45, 54))	('IGF2', 'Gene', (187, 191))	('IGF2', 'Gene', (50, 54))	('IGF2', 'Gene', '3481', (257, 261))	('high', 'Var', (45, 49))	('high IGF2', 'Phenotype', 'HP:0030269', (252, 261))	('IGF2', 'Gene', '3481', (187, 191))	('IGF2', 'Gene', (257, 261))	('IGF2', 'Gene', '3481', (50, 54))
55735	29455465	In conclusion, high tumor IGF2 expression is an independent risk factor for reduced PFS and OS in UCS.	('high', 'Var', (15, 19))	('IGF2', 'Gene', '3481', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('PFS', 'Disease', (84, 87))	('reduced', 'NegReg', (76, 83))	('expression', 'MPA', (31, 41))	('CS', 'Chemical', 'MESH:D002586', (99, 101))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IGF2', 'Gene', (26, 30))	('UCS', 'Phenotype', 'HP:0002891', (98, 101))	('tumor', 'Disease', (20, 25))
55740	29455465	Mutations in chromatin remodeling genes and histones are implicated in the tumorigenesis of carcinosarcoma, characterized by sarcomatous transformation of carcinoma cells via epithelial mesenchymal transition (EMT) 2, 3, 4, 5.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinosarcoma', 'Disease', (92, 106))	('sarcomatous transformation of carcinoma', 'Disease', (125, 164))	('implicated', 'Reg', (57, 67))	('chromatin remodeling genes', 'Gene', (13, 39))	('sarcomatous transformation of carcinoma', 'Disease', 'MESH:D018316', (125, 164))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Mutations', 'Var', (0, 9))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (125, 151))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('carcinosarcoma', 'Disease', 'MESH:D002296', (92, 106))	('tumor', 'Disease', (75, 80))
55752	29455465	Reactivation of fetal IGF2 promoters and IGF2 overexpression is associated with worse prognosis in epithelial ovarian cancer and other cancers 17, 18, 19.	('IGF2', 'Gene', (41, 45))	('overexpression', 'PosReg', (46, 60))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('IGF2', 'Gene', '3481', (22, 26))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (99, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Reactivation', 'Var', (0, 12))	('IGF2', 'Gene', '3481', (41, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('epithelial ovarian cancer', 'Disease', (99, 124))	('IGF2', 'Gene', (22, 26))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (99, 124))
55753	29455465	Dysregulation of the IGF signaling pathway is linked to EMT, a major driver of metastasis and drug resistance and a defining feature of UCS 15.	('metastasis', 'Disease', (79, 89))	('IGF signaling pathway', 'Pathway', (21, 42))	('Dysregulation', 'Var', (0, 13))	('drug resistance', 'Phenotype', 'HP:0020174', (94, 109))	('linked', 'Reg', (46, 52))	('CS', 'Chemical', 'MESH:D002586', (137, 139))	('metastasis', 'Disease', 'MESH:D009362', (79, 89))	('EMT', 'Disease', (56, 59))	('UCS', 'Phenotype', 'HP:0002891', (136, 139))
55766	29455465	Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and low- versus high IGF2 expression was compared using the log rank test.	('high IGF2', 'Phenotype', 'HP:0030269', (110, 119))	('IGF2', 'Gene', (115, 119))	('IGF2', 'Gene', '3481', (115, 119))	('low-', 'Var', (98, 102))
55774	29455465	As the H-scores were not normally distributed, the median values rather than the mean values were selected as the optimal cutoff for defining high- versus low IGF2 expression.	('IGF2', 'Gene', '3481', (159, 163))	('IGF2', 'Gene', (159, 163))	('expression', 'MPA', (164, 174))	('high-', 'Var', (142, 147))	('low', 'NegReg', (155, 158))
55778	29455465	Patients with high-CS epithelial IGF2 expression had reduced PFS compared with patients with low epithelial IGF2 expression (Log rank test P = 0.036 and P = 0.002 for epithelial nuclear and cytoplasmic compartments, respectively).	('PFS', 'MPA', (61, 64))	('IGF2', 'Gene', '3481', (33, 37))	('IGF2', 'Gene', (108, 112))	('high-CS', 'Var', (14, 21))	('IGF2', 'Gene', (33, 37))	('CS', 'Chemical', 'MESH:D002586', (19, 21))	('reduced', 'NegReg', (53, 60))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (79, 87))	('IGF2', 'Gene', '3481', (108, 112))
55781	29455465	In univariable regression, black race, higher stage, high epithelial nuclear and cytoplasmic IGF2 expression were associated with an increased hazard of disease progression.	('disease', 'Disease', (153, 160))	('IGF2', 'Gene', (93, 97))	('high epithelial', 'Var', (53, 68))	('IGF2', 'Gene', '3481', (93, 97))	('expression', 'MPA', (98, 108))
55782	29455465	In the multivariable model, after controlling for race, stage and adjuvant therapy (specifically chemotherapy), high IGF2 expression in both the epithelial nuclear and cytoplasmic compartments was associated with roughly twice the hazard of progression compared with low IGF2 expression (Epithelial nuclear HR = 1.80, 95% CI: 1.08-2.99, P = 0.02 and epithelial cytoplasmic HR = 2.07, 95% CI: 1.19-3.60, P = 0.01).	('IGF2', 'Gene', (117, 121))	('high', 'Var', (112, 116))	('IGF2', 'Gene', '3481', (271, 275))	('IGF2', 'Gene', '3481', (117, 121))	('high IGF2', 'Phenotype', 'HP:0030269', (112, 121))	('IGF2', 'Gene', (271, 275))
55786	29455465	Similar to PFS, OS was significantly lower in women with high-CS epithelial IGF2 expression (Log rank test P = 0.03 and P = 0.005 for epithelial nuclear and cytoplasmic compartments, respectively).	('high-CS', 'Var', (57, 64))	('IGF2', 'Gene', (76, 80))	('CS', 'Chemical', 'MESH:D002586', (62, 64))	('lower', 'NegReg', (37, 42))	('IGF2', 'Gene', '3481', (76, 80))	('expression', 'MPA', (81, 91))	('women', 'Species', '9606', (46, 51))
55791	29455465	In the multivariable model, after controlling for race, stage and adjuvant therapy, high IGF2 expression in both the epithelial nuclear and cytoplasmic compartments was associated with roughly twice the risk of death compared with low IGF2 expression (Epithelial nuclear HR = 1.86, 95% CI: 1.10-3.15, P = 0.02 and epithelial cytoplasmic HR = 1.98, 95% CI: 1.11-3.54, P = 0.02).	('IGF2', 'Gene', '3481', (235, 239))	('high', 'Var', (84, 88))	('death', 'Disease', (211, 216))	('IGF2', 'Gene', (235, 239))	('IGF2', 'Gene', '3481', (89, 93))	('high IGF2', 'Phenotype', 'HP:0030269', (84, 93))	('IGF2', 'Gene', (89, 93))	('death', 'Disease', 'MESH:D003643', (211, 216))
55793	29455465	After stratifying patients by FIGO stage, high epithelial cytoplasmic expression of IGF2 in early-stage UCS (stage I/II) was associated with an increased risk of disease progression (HR = 2.18, 95% CI: 1.05-4.54, P = 0.04) and death (HR = 3.41, 95% CI: 1.47-7.90, P < 0.01) after adjusting for race and adjuvant therapy (Table 3).	('UCS', 'Phenotype', 'HP:0002891', (104, 107))	('IGF2', 'Gene', '3481', (84, 88))	('disease progression', 'CPA', (162, 181))	('CS', 'Chemical', 'MESH:D002586', (105, 107))	('IGF2', 'Gene', (84, 88))	('death', 'Disease', 'MESH:D003643', (227, 232))	('death', 'Disease', (227, 232))	('associated with', 'Reg', (125, 140))	('patients', 'Species', '9606', (18, 26))	('high epithelial cytoplasmic expression', 'Var', (42, 80))
55794	29455465	Additionally, in women with early-stage disease, black race was an independent poor prognostic factor for progression of disease (HR.2.83, 95% CI: 1.21-6.64, P = 0.02) and death (HR = 2.80, 95% CI: 1.06-7.39; P = 0.04).	('progression', 'Disease', (106, 117))	('death', 'Disease', 'MESH:D003643', (172, 177))	('black race', 'Var', (49, 59))	('death', 'Disease', (172, 177))	('women', 'Species', '9606', (17, 22))
55797	29455465	After stratification of patients by race, high IGF2 in the EC or the EN compartments was independently associated with worse survival in black women with UCS.	('worse', 'NegReg', (119, 124))	('UCS', 'Disease', (154, 157))	('high IGF2', 'Phenotype', 'HP:0030269', (42, 51))	('IGF2', 'Gene', '3481', (47, 51))	('IGF2', 'Gene', (47, 51))	('UCS', 'Phenotype', 'HP:0002891', (154, 157))	('patients', 'Species', '9606', (24, 32))	('high', 'Var', (42, 46))	('women', 'Species', '9606', (143, 148))	('CS', 'Chemical', 'MESH:D002586', (155, 157))
55801	29455465	We also found that black women had higher tumor epithelial IGF2 expression compared to white women, and that high IGF2 was independently associated with worse survival in black women.	('women', 'Species', '9606', (25, 30))	('expression', 'MPA', (64, 74))	('high', 'Var', (109, 113))	('tumor', 'Disease', (42, 47))	('women', 'Species', '9606', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('IGF2', 'Gene', (114, 118))	('IGF2', 'Gene', '3481', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('high IGF2', 'Phenotype', 'HP:0030269', (109, 118))	('women', 'Species', '9606', (93, 98))	('higher', 'PosReg', (35, 41))	('IGF2', 'Gene', (59, 63))	('IGF2', 'Gene', '3481', (114, 118))
55816	29455465	A recent analysis of The Cancer Genome Atlas (TCGA) breast cancer cohort estimated that inherited germline variants account for 44% of racial differences in breast cancer subtype distribution 24.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('variants', 'Var', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('Cancer Genome Atlas', 'Disease', (25, 44))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (25, 44))
55820	29455465	It has been reported that metabolic variables such as insulin resistance preferentially cluster with genetic ancestry 26.	('insulin', 'Gene', (54, 61))	('insulin', 'Gene', '3630', (54, 61))	('genetic ancestry 26', 'Var', (101, 120))	('insulin resistance', 'Phenotype', 'HP:0000855', (54, 72))	('cluster', 'Reg', (88, 95))
55823	29455465	For example, increasing poverty and nonwhite race is associated with elevated C-reactive protein (CRP) levels 30.	('nonwhite race', 'Var', (36, 49))	('elevated C-reactive protein', 'Phenotype', 'HP:0011227', (69, 96))	('C-reactive protein', 'Gene', (78, 96))	('CRP', 'Gene', (98, 101))	('C-reactive protein', 'Gene', '1401', (78, 96))	('CRP', 'Gene', '1401', (98, 101))	('elevated', 'PosReg', (69, 77))
55826	29455465	IGF2 is one of a relatively small number of imprinted genes in mammals, by which epigenetic silencing results in monoallelic expression specific to parental origin 10.	('epigenetic silencing', 'Var', (81, 101))	('monoallelic expression', 'MPA', (113, 135))	('IGF2', 'Gene', '3481', (0, 4))	('results in', 'Reg', (102, 112))	('IGF2', 'Gene', (0, 4))
55829	29455465	Several important IGF2 regulatory mechanisms have been identified, many of which overlap with functions during fetal development, including altered transcription factor expression, epigenetic changes such as altered DNA methylation, as well as changes in post-transcriptional and post-translational modulators of IGF2 expression 10.	('IGF2', 'Gene', (313, 317))	('IGF2', 'Gene', (18, 22))	('DNA', 'MPA', (216, 219))	('changes', 'Reg', (244, 251))	('IGF2', 'Gene', '3481', (313, 317))	('altered', 'Var', (208, 215))	('IGF2', 'Gene', '3481', (18, 22))
55830	29455465	Epigenetic events, particularly DNA methylation changes, are triggered by environmental factors and are key drivers of cancer development and progression 34.	('DNA', 'MPA', (32, 35))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
55831	29455465	Differences in methylation status have been previously linked to racial disparity in breast, prostate, colorectal, and endometrial cancers 35.	('prostate', 'Disease', (93, 101))	('methylation', 'Var', (15, 26))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('endometrial cancer', 'Phenotype', 'HP:0012114', (119, 137))	('endometrial cancers', 'Disease', 'MESH:D016889', (119, 138))	('linked', 'Reg', (55, 61))	('endometrial cancers', 'Disease', (119, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('colorectal', 'Disease', 'MESH:D015179', (103, 113))	('breast', 'Disease', (85, 91))	('colorectal', 'Disease', (103, 113))
55847	29416878	In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio >= 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio >=1.5 but <2.2).	('carcinosarcoma', 'Disease', 'MESH:D002296', (174, 188))	('carcinosarcoma', 'Disease', 'MESH:D002296', (38, 52))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('GPC5', 'Gene', '2262', (347, 351))	('rhabdomyosarcoma', 'Disease', (194, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('adenosarcoma', 'Disease', (237, 249))	('adenosarcoma', 'Disease', 'MESH:D018195', (237, 249))	('carcinosarcomas', 'Disease', 'MESH:D002296', (38, 53))	('sarcomas', 'Disease', (72, 80))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (217, 231))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (217, 231))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (194, 210))	('sarcomas', 'Disease', (45, 53))	('amplification', 'Var', (82, 95))	('GPC5', 'Gene', '2262', (105, 109))	('carcinosarcomas', 'Disease', (38, 53))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (272, 291))	('GPC5', 'Gene', '2262', (99, 103))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (194, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('GPC5', 'Gene', (347, 351))	('leiomyosarcoma', 'Disease', (217, 231))	('endometrial sarcoma', 'Disease', (272, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('carcinosarcoma', 'Disease', (174, 188))	('carcinosarcoma', 'Disease', (38, 52))	('GPC5', 'Gene', (105, 109))	('GPC5', 'Gene', (99, 103))
55856	29416878	The more widely accepted 'combination' and 'conversion' models imply monoclonality; according to the former, malignant transformation of a bipotential progenitor cell results in a tumour with a 'combination' of phenotypes, while in the latter scenario, tumour progression in a pre-existing endometrial carcinoma causes 'conversion' to sarcomatous differentiation.	("'combination", 'MPA', (194, 206))	('tumour', 'Disease', (180, 186))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (290, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('tumour', 'Disease', (253, 259))	('results in', 'Reg', (167, 177))	('sarcomatous', 'Disease', 'MESH:D018316', (335, 346))	("'conversion", 'Disease', (319, 330))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (290, 311))	('malignant', 'Var', (109, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('sarcomatous', 'Disease', (335, 346))	('endometrial carcinoma', 'Disease', (290, 311))
55859	29416878	In contrast, a similar approach used to study another mixed uterine tumour, namely, de-differentiated endometrial carcinoma, identified additional mutations in the undifferentiated component relative to the low-grade endometrioid carcinoma component 3.	('endometrioid carcinoma component', 'Disease', 'MESH:D016889', (217, 249))	('endometrial carcinoma', 'Disease', (102, 123))	('mutations', 'Var', (147, 156))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (217, 239))	('uterine tumour', 'Phenotype', 'HP:0010784', (60, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (102, 123))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('endometrioid carcinoma component', 'Disease', (217, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (102, 123))
55860	29416878	Given that the majority of uterine carcinosarcomas contain a serous carcinoma component and that the genomic landscape of serous carcinoma is dominated by frequent copy number gains and losses 4, 5, we hypothesized that an unbiased approach interrogating genome-wide copy number alterations (CNAs) may yield further insight into the underlying molecular basis of sarcomatous differentiation.	('carcinosarcomas', 'Disease', 'MESH:D002296', (35, 50))	('carcinosarcomas', 'Disease', (35, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('serous carcinoma component', 'Disease', 'MESH:D018284', (61, 87))	('sarcomatous', 'Disease', 'MESH:D018316', (363, 374))	('serous carcinoma component', 'Disease', (61, 87))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (27, 49))	('serous carcinoma', 'Disease', (122, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('copy number alterations', 'Var', (267, 290))	('serous carcinoma', 'Disease', 'MESH:D018284', (61, 77))	('serous carcinoma', 'Disease', 'MESH:D018284', (122, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (363, 370))	('sarcomatous', 'Disease', (363, 374))
55861	29416878	In this study, using a molecular inversion probe microarray profiling strategy to assess genomic CNAs and allelic imbalances, we provide evidence supporting the conversion theory of histogenesis and identify candidate genetic alterations that may be responsible for sarcomatous transformation of endometrial carcinoma.	('responsible', 'Reg', (250, 261))	('sarcomatous transformation of endometrial carcinoma', 'Disease', 'MESH:D016889', (266, 317))	('genetic alterations', 'Var', (218, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (296, 317))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('imbalances', 'Phenotype', 'HP:0002172', (114, 124))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (266, 292))
55871	29416878	The GPC5 BAC was labeled with red (02N34-050; Abbott Molecular) dUTPs using a nick translation kit (07J00-001; Abbott Molecular) according to the manufacturer's instructions.	('02N34-050', 'Var', (35, 44))	('dUTPs', 'Chemical', 'MESH:C027078', (64, 69))	('GPC5', 'Gene', '2262', (4, 8))	('GPC5', 'Gene', (4, 8))
55881	29416878	The average score was taken from repeated scoring of whole tissue sections and from replicate cores on the tissue microarray and used to classify GPC5 copy number status.	('copy number', 'Var', (151, 162))	('GPC5', 'Gene', (146, 150))	('GPC5', 'Gene', '2262', (146, 150))
55882	29416878	The cut-off values for scoring HER2 FISH in breast carcinoma, as per the 2007 ASCO/CAP Guidelines 7, were used for classification: GPC5/CEP13 ratio >= 2.2 for high-copy gain, and >= 1.5 but < 2.2 for low-copy gain.	('breast carcinoma', 'Disease', 'MESH:D001943', (44, 60))	('breast carcinoma', 'Disease', (44, 60))	('high-copy', 'Var', (159, 168))	('>= 1.5', 'Var', (179, 185))	('breast carcinoma', 'Phenotype', 'HP:0003002', (44, 60))	('gain', 'PosReg', (169, 173))	('GPC5', 'Gene', '2262', (131, 135))	('GPC5', 'Gene', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
55890	29416878	Copy number profiles of the epithelial component from each case were consistent with the subtype-associated profiles reported in The Cancer Genome Atlas endometrial carcinoma study: high frequency of CNAs in serous and low frequency in endometrioid 8 (Figure 1A,B).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (153, 174))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Cancer Genome Atlas endometrial carcinoma', 'Disease', (133, 174))	('CNAs', 'Var', (200, 204))	('Cancer Genome Atlas endometrial carcinoma', 'Disease', 'MESH:D016889', (133, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))
55896	29416878	To identify potential genetic drivers of sarcomatous transformation, matched pair analysis was used to identify recurrent CNAs remaining in the sarcoma component copy number profile after subtracting out the copy number profile of the corresponding carcinoma component.	('sarcomatous transformation', 'Disease', 'MESH:D018316', (41, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('carcinoma component', 'Disease', (249, 268))	('sarcomatous transformation', 'Disease', (41, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('sarcoma component copy number', 'Disease', (144, 173))	('sarcoma component copy number', 'Disease', 'MESH:D012509', (144, 173))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (41, 67))	('carcinoma component', 'Disease', 'MESH:C562869', (249, 268))	('CNAs remaining', 'Var', (122, 136))
55899	29416878	Adapting the conservative cut-off values established for scoring HER2 FISH in breast carcinoma, as per the 2007 ASCO/CAP Guidelines 7 (GPC5/CEP13 ratio >= 2.2 for high-copy gain, and >= 1.5 but < 2.2 for low-copy gain), amplification of GPC5 was detected exclusively in the sarcoma component in five cases (Cases #1,2, 3, 6, and 9; Table 2 and Figure 3D,F).	('breast carcinoma', 'Disease', 'MESH:D001943', (78, 94))	('breast carcinoma', 'Disease', (78, 94))	('sarcoma component', 'Disease', (274, 291))	('GPC5', 'Gene', '2262', (237, 241))	('GPC5', 'Gene', (237, 241))	('GPC5', 'Gene', '2262', (135, 139))	('breast carcinoma', 'Phenotype', 'HP:0003002', (78, 94))	('GPC5', 'Gene', (135, 139))	('detected', 'Reg', (246, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('sarcoma component', 'Disease', 'MESH:D012509', (274, 291))	('amplification', 'Var', (220, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))
55900	29416878	In addition, one case harboured high-copy amplification throughout the tumour (Case #5).	('high-copy amplification', 'Var', (32, 55))	('tumour', 'Disease', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
55903	29416878	In an independent cohort comprised of 97 uterine mixed/mesenchymal tumours represented on a tissue microarray, the frequency of GPC5 amplification was 15 [11 (11.3%) high-gain, 4 (2.8%) low-gain; Table 3].	('mesenchymal tumours', 'Disease', (55, 74))	('GPC5', 'Gene', '2262', (128, 132))	('mesenchymal tumours', 'Disease', 'MESH:D008637', (55, 74))	('amplification', 'Var', (133, 146))	('GPC5', 'Gene', (128, 132))	('high-gain', 'Var', (166, 175))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
55919	29416878	In the first in-depth interrogation of the mutational landscape of gynecologic carcinosarcomas by whole exomic sequencing, Jones et al confirmed the presence of carcinoma-associated mutations in TP53 and components of the PI3K pathway, and identified novel genetic modifications in chromatin remodelling genes 11.	('carcinosarcomas', 'Disease', (79, 94))	('TP53', 'Gene', (195, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('PI3K pathway', 'Pathway', (222, 234))	('genetic modifications', 'Var', (257, 278))	('mutations', 'Var', (182, 191))	('carcinoma', 'Disease', 'MESH:D002277', (161, 170))	('carcinosarcomas', 'Disease', 'MESH:D002296', (79, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Disease', (161, 170))
55920	29416878	It should be noted that 4 of 22 cases were mismatch repair- and ARID1A-deficient, raising concern that they may in fact represent de-differentiated endometrial carcinomas 12, rather than carcinosarcoma sensu stricto.	('carcinosarcoma sensu', 'Disease', 'MESH:D002296', (187, 207))	('endometrial carcinomas', 'Disease', (148, 170))	('ARID1A-deficient', 'Disease', 'MESH:D007153', (64, 80))	('carcinosarcoma sensu', 'Disease', (187, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('mismatch repair-', 'Var', (43, 59))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (148, 170))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (148, 170))	('ARID1A-deficient', 'Disease', (64, 80))
55922	29416878	These conclusions were confirmed in a subsequent whole-exome analysis of uterine and ovarian carcinosarcomas, in which novel missense mutations in genes coding for histone proteins, H2A and H2B, were identified in 21% of cases 13.	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('ovarian carcinosarcomas', 'Disease', (85, 108))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (85, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('H2A', 'Gene', (182, 185))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (85, 108))	('H2B', 'Gene', (190, 193))	('missense mutations', 'Var', (125, 143))	('uterine', 'Disease', (73, 80))
55925	29416878	After divergence into separate cell lineages at a variable time-point during tumour progression, mutations continue to accumulate independently in these subclonal populations.	('mutations', 'Var', (97, 106))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (77, 83))
55939	29416878	gains in GPC5, and histone gene mutations) causing a permanent switch in lineage commitment does not fit with the transient EMT model.	('histone gene', 'Gene', (19, 31))	('transient EMT', 'Phenotype', 'HP:0002326', (114, 127))	('mutations', 'Var', (32, 41))	('GPC5', 'Gene', '2262', (9, 13))	('GPC5', 'Gene', (9, 13))	('lineage commitment', 'CPA', (73, 91))	('gains', 'PosReg', (0, 5))
55961	29214032	Type 1 carcinomas (estrogen dependent) have high rates of K-ras and PTEN loss or mutation, as well as defects in mismatch repair genes, which lead to microsatellite instability (MSI).	('MSI', 'Disease', 'None', (178, 181))	('PTEN loss', 'Disease', (68, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (7, 17))	('MSI', 'Disease', (178, 181))	('mutation', 'Var', (81, 89))	('Type 1 carcinomas', 'Disease', (0, 17))	('PTEN loss', 'Disease', 'MESH:D006223', (68, 77))	('defects', 'NegReg', (102, 109))	('Type 1 carcinomas', 'Disease', 'MESH:C538557', (0, 17))	('microsatellite instability', 'MPA', (150, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('K-ras', 'Gene', (58, 63))	('lead to', 'Reg', (142, 149))	('K-ras', 'Gene', '3845', (58, 63))	('mismatch repair genes', 'Gene', (113, 134))
55963	29214032	Type 2 cancers have p53 mutations, may have overexpression of human epidermal growth factor receptor 2 (HER-2/neu), and show aneuploidy.	('p53', 'Gene', (20, 23))	('epidermal growth factor receptor 2', 'Gene', (68, 102))	('p53', 'Gene', '7157', (20, 23))	('epidermal growth factor receptor 2', 'Gene', '2064', (68, 102))	('aneuploidy', 'Disease', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('human', 'Species', '9606', (62, 67))	('overexpression', 'PosReg', (44, 58))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('HER-2/neu', 'Gene', (104, 113))	('Type 2 cancers', 'Disease', 'MESH:D009369', (0, 14))	('aneuploidy', 'Disease', 'MESH:D000782', (125, 135))	('HER-2/neu', 'Gene', '2064', (104, 113))	('mutations', 'Var', (24, 33))	('Type 2 cancers', 'Disease', (0, 14))
55964	29214032	It should be noted that there are limitations to this dualistic classification of ECs, as there is heterogeneity and often overlap of the underlying genetics; for example, many high-grade endometrioid cancers can harbor p53 mutations and behave like other type 2 cancers.	('p53', 'Gene', (220, 223))	('p53', 'Gene', '7157', (220, 223))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('endometrioid cancers', 'Disease', (188, 208))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('cancers', 'Disease', (263, 270))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutations', 'Var', (224, 233))	('endometrioid cancers', 'Disease', 'MESH:D016889', (188, 208))
55969	29214032	These data revealed that EC can be classified into four molecularly phenotypically different groups: 1) DNA polymerase epsilon catalytic subunit (POLE) ultramutated (very high mutation rate, hot spot mutations in POLE, endometrioid histology, frequently grade 3 [>50%], associated with a good prognosis, comprises 1% of cases of recurrent disease, and characterized by mutations in PTEN [94%], PIK3CA [71%], PIK3R1 [65%], FBXW7 [82%], ARID1A [76%], KRAS [53%], and ARID5B [47%]); 2) MSI hypermutated (high mutation rate, microsatellite unstable, frequently with MLH-1 promoter hypermethylation, endometrioid histology, comprises approximately 25% of cases of recurrent disease, and characterized by mutations in PTEN [88%], RPL22 [33%], KRAS [35%], PIK3CA [54%], PIK3R1 [40%], and ARID1A [37%]); 3) copy-number low (lower mutation rate, microsatellite stable (MSS), endometrioid histology, grade 1/2 tumors, and characterized by mutations in PTEN [77%], CTNNB1 [52%], PIK3CA [53%], PIK3R1 [33%], and ARID1A [42%]); and 4) copy-number high serous-like (lowest mutation rate, serous, comprises approximately 25% of grade 3 endometrioid cases, poorest prognosis, and characterized by mutations in TP53 [92%], PPP2R1A [22%], PIK3CA [47%], and chromosomal instability).	('PIK3CA', 'Gene', '5290', (749, 755))	('MSS', 'Disease', 'MESH:D013132', (860, 863))	('PTEN', 'Gene', (942, 946))	('PIK3R1', 'Gene', (982, 988))	('PTEN', 'Gene', (712, 716))	('MSI', 'Disease', (483, 486))	('ARID5B', 'Gene', '84159', (465, 471))	('chromosomal instability', 'Phenotype', 'HP:0040012', (1239, 1262))	('PIK3CA', 'Gene', (394, 400))	('RPL22', 'Gene', (724, 729))	('KRAS', 'Gene', (449, 453))	('MLH-1', 'Gene', (562, 567))	('FBXW7', 'Gene', (422, 427))	('tumors', 'Disease', 'MESH:D009369', (900, 906))	('ARID1A', 'Gene', (781, 787))	('TP53', 'Gene', (1194, 1198))	('PIK3R1', 'Gene', '5295', (763, 769))	('CTNNB1', 'Gene', '1499', (954, 960))	('PIK3R1', 'Gene', (408, 414))	('PTEN', 'Gene', '5728', (942, 946))	('ARID5B', 'Gene', (465, 471))	('PTEN', 'Gene', '5728', (712, 716))	('PIK3CA', 'Gene', '5290', (1221, 1227))	('ARID1A', 'Gene', '8289', (781, 787))	('PIK3CA', 'Gene', '5290', (968, 974))	('PPP2R1A', 'Gene', '5518', (1206, 1213))	('PIK3CA', 'Gene', (749, 755))	('mutations', 'Var', (1181, 1190))	('ARID1A', 'Gene', (1000, 1006))	('PIK3R1', 'Gene', '5295', (982, 988))	('CTNNB1', 'Gene', (954, 960))	('MLH-1', 'Gene', '4292', (562, 567))	('FBXW7', 'Gene', '55294', (422, 427))	('PTEN', 'Gene', (382, 386))	('tumors', 'Phenotype', 'HP:0002664', (900, 906))	('PPP2R1A', 'Gene', (1206, 1213))	('PIK3CA', 'Gene', '5290', (394, 400))	('PIK3R1', 'Gene', (763, 769))	('TP53', 'Gene', '7157', (1194, 1198))	('ARID1A', 'Gene', '8289', (1000, 1006))	('KRAS', 'Gene', '3845', (737, 741))	('ARID1A', 'Gene', (435, 441))	('MSS', 'Disease', (860, 863))	('tumor', 'Phenotype', 'HP:0002664', (900, 905))	('PIK3CA', 'Gene', (1221, 1227))	('PIK3CA', 'Gene', (968, 974))	('PIK3R1', 'Gene', '5295', (408, 414))	('PTEN', 'Gene', '5728', (382, 386))	('tumors', 'Disease', (900, 906))	('KRAS', 'Gene', '3845', (449, 453))	('MSI', 'Disease', 'None', (483, 486))	('KRAS', 'Gene', (737, 741))	('RPL22', 'Gene', '6146', (724, 729))	('ARID1A', 'Gene', '8289', (435, 441))
55972	29214032	A TCGA analysis of 57 primary uterine carcinosarcoma tumor samples revealed extensive copy-number alterations and highly recurrent somatic mutations.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (30, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('copy-number alterations', 'Var', (86, 109))	('carcinosarcoma tumor', 'Disease', (38, 58))	('carcinosarcoma tumor', 'Disease', 'MESH:D002296', (38, 58))
55973	29214032	Similar to endometrioid and serous endometrial carcinomas, mutations in TP53 (91%), PIK3CA (35%), PPP2R1A (28%), FBXW7 (28%), PTEN (19%), FBXW7, and KRAS (12%) were identified.	('PPP2R1A', 'Gene', '5518', (98, 105))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (35, 57))	('KRAS', 'Gene', (149, 153))	('FBXW7', 'Gene', (113, 118))	('FBXW7', 'Gene', '55294', (138, 143))	('PPP2R1A', 'Gene', (98, 105))	('PTEN', 'Gene', '5728', (126, 130))	('TP53', 'Gene', '7157', (72, 76))	('serous endometrial carcinomas', 'Disease', (28, 57))	('serous endometrial carcinomas', 'Phenotype', 'HP:0012887', (28, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('serous endometrial carcinomas', 'Disease', 'MESH:D016889', (28, 57))	('FBXW7', 'Gene', '55294', (113, 118))	('PIK3CA', 'Gene', '5290', (84, 90))	('FBXW7', 'Gene', (138, 143))	('mutations', 'Var', (59, 68))	('KRAS', 'Gene', '3845', (149, 153))	('TP53', 'Gene', (72, 76))	('PIK3CA', 'Gene', (84, 90))	('PTEN', 'Gene', (126, 130))
55975	29214032	Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified; 62% of tumors had one or more potentially clinically relevant mutations in the PI3K/AKT/mTOR pathway, and approximately 23% of cases had alterations in cell-cycle genes.	('mutations', 'Var', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('AKT', 'Gene', '207', (194, 197))	('cell-cycle genes', 'Gene', (262, 278))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('mTOR', 'Gene', '2475', (198, 202))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('AKT', 'Gene', (194, 197))	('mTOR', 'Gene', (198, 202))	('alterations', 'Reg', (247, 258))
55977	29214032	Lynch syndrome, an autosomal dominant inherited cancer susceptibility syndrome, is caused by a germline mutation in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and accounts for 2-5% of endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (210, 220))	('MSH2', 'Gene', (151, 155))	('MMR', 'Gene', (133, 136))	('R', 'Chemical', '-', (135, 136))	('MSH6', 'Gene', (157, 161))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (198, 220))	('PMS2', 'Gene', '5395', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('autosomal dominant inherited cancer', 'Disease', (19, 54))	('MSH6', 'Gene', '2956', (157, 161))	('MSH2', 'Gene', '4436', (151, 155))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (198, 220))	('mutation', 'Var', (104, 112))	('autosomal dominant inherited cancer', 'Disease', 'MESH:D009386', (19, 54))	('Lynch syndrome', 'Disease', (0, 14))	('PMS2', 'Gene', (167, 171))	('MLH1', 'Gene', (145, 149))	('endometrial carcinomas', 'Disease', (198, 220))	('MLH1', 'Gene', '4292', (145, 149))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('caused by', 'Reg', (83, 92))
55989	29214032	Currently, there are a myriad of studies evaluating the impact of calorie restriction and exercise in promoting weight loss in obese patients with EC (NCT02665962, NCT02665962), as well as the impact of ketogenic diet in overweight or obese patients with newly diagnosed EC (NCT03285152).	('obese', 'Disease', 'MESH:D009765', (235, 240))	('overweight', 'Phenotype', 'HP:0025502', (221, 231))	('weight loss', 'Disease', (112, 123))	('weight loss', 'Phenotype', 'HP:0001824', (112, 123))	('patients', 'Species', '9606', (133, 141))	('obese', 'Disease', (235, 240))	('obese', 'Disease', 'MESH:D009765', (127, 132))	('CT', 'Chemical', 'MESH:D002251', (165, 167))	('weight loss', 'Disease', 'MESH:D015431', (112, 123))	('NCT02665962', 'Var', (164, 175))	('NCT02665962', 'Var', (151, 162))	('obese', 'Disease', (127, 132))	('CT', 'Chemical', 'MESH:D002251', (152, 154))	('patients', 'Species', '9606', (241, 249))	('CT', 'Chemical', 'MESH:D002251', (276, 278))
55995	29214032	Class IA PI3Ks are most associated with promoting carcinogenesis.	('PI3Ks', 'Var', (9, 14))	('carcinogenesis', 'Disease', (50, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (50, 64))
56005	29214032	Components of the mTOR pathway are often mutated, amplified, or aberrantly expressed in ECs, further supporting the link between obesity and this disease.	('mTOR', 'Gene', (18, 22))	('mTOR', 'Gene', '2475', (18, 22))	('ECs', 'Disease', (88, 91))	('obesity', 'Disease', 'MESH:D009765', (129, 136))	('obesity', 'Disease', (129, 136))	('aberrantly', 'Var', (64, 74))	('obesity', 'Phenotype', 'HP:0001513', (129, 136))
56073	29214032	Ongoing trials of ado-trastuzumab emtansine and afatinib (irreversible EGFR, HER2, and HER4 inhibitor) for patients with EC and HER2-amplified or mutant cancers are accruing (NCT02675829, NCT02491099).	('HER2', 'Gene', (128, 132))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('HER2', 'Gene', '2064', (128, 132))	('afatinib', 'Chemical', 'MESH:D000077716', (48, 56))	('HER2', 'Gene', (77, 81))	('HER4', 'Gene', (87, 91))	('HER2', 'Gene', '2064', (77, 81))	('CT', 'Chemical', 'MESH:D002251', (189, 191))	('mutant', 'Var', (146, 152))	('CT', 'Chemical', 'MESH:D002251', (176, 178))	('HER4', 'Gene', '2066', (87, 91))	('EGFR', 'Gene', '1956', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('ado-trastuzumab emtansine', 'Chemical', 'MESH:C550911', (18, 43))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (107, 115))
56078	29214032	These studies may have been strengthened by limiting eligibility to patients with alterations in this pathway, although it is also possible that a single or multiple target biomarkers may be insufficient to predict for response due to the inherent complexity of this pathway.	('patients', 'Species', '9606', (68, 76))	('insufficient', 'Disease', (191, 203))	('alterations', 'Var', (82, 93))	('insufficient', 'Disease', 'MESH:D000309', (191, 203))
56090	29214032	A phase 2, two-stage, two-arm PIK3CA mutation stratified trial of MK-2206, an allosteric inhibitor of AKT, of previously treated endometrial cancer also revealed limited single-agent activity in both mutant (1 partial response) and wild-type (1 partial response) EC populations, although activity was detected in serous histology tumors with exploratory analysis, revealing that all patients with a 6-month PFS had serous EC.	('MK-2206', 'Chemical', 'MESH:C548887', (66, 73))	('PIK3CA', 'Gene', (30, 36))	('endometrial cancer', 'Phenotype', 'HP:0012114', (129, 147))	('patients', 'Species', '9606', (383, 391))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('endometrial cancer', 'Disease', 'MESH:D016889', (129, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', (330, 336))	('PIK3CA', 'Gene', '5290', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (330, 336))	('mutant', 'Var', (200, 206))	('serous EC', 'Disease', (415, 424))	('tumors', 'Disease', 'MESH:D009369', (330, 336))	('AKT', 'Gene', '207', (102, 105))	('endometrial cancer', 'Disease', (129, 147))	('AKT', 'Gene', (102, 105))
56095	29214032	A phase 2 trial of LY3023414, a PI3K/mTOR inhibitor (NCT02549989), in EC with PI3K pathway activation without concurrent resistance mutations is ongoing.	('CT', 'Chemical', 'MESH:D002251', (54, 56))	('LY3023414', 'Var', (19, 28))	('LY3023414', 'Chemical', 'MESH:C000621566', (19, 28))	('PI3K pathway', 'Pathway', (78, 90))	('mTOR', 'Gene', (37, 41))	('mTOR', 'Gene', '2475', (37, 41))
56096	29214032	HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma.	('PIK3CA', 'Gene', '5290', (32, 38))	('mutations', 'Var', (46, 55))	('serous carcinoma', 'Disease', (78, 94))	('PIK3CA', 'Gene', (32, 38))	('serous carcinoma', 'Disease', 'MESH:D018284', (78, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HER2/neu', 'Gene', '2064', (0, 8))	('common', 'Reg', (60, 66))	('HER2/neu', 'Gene', (0, 8))
56101	29214032	Currently, there are numerous metformin chemoprevention studies, as well as studies of metformin combinations with standard chemotherapy (NCT02065687) and with hormonal and mTOR agents (NCT01797523).	('CT', 'Chemical', 'MESH:D002251', (139, 141))	('NCT02065687', 'Var', (138, 149))	('metformin', 'Chemical', 'MESH:D008687', (30, 39))	('mTOR', 'Gene', '2475', (173, 177))	('combinations', 'Interaction', (97, 109))	('mTOR', 'Gene', (173, 177))	('metformin', 'Chemical', 'MESH:D008687', (87, 96))	('metformin', 'Gene', (87, 96))	('CT', 'Chemical', 'MESH:D002251', (187, 189))
56102	29214032	Preclinical studies have shown that inhibition of the PI3K/akt/mTOR pathway may sensitize EC cell lines to PARP inhibitors, and that loss of PTEN function may predict sensitivity to PARP due to a synthetic lethality process.	('sensitize', 'Reg', (80, 89))	('sensitivity', 'MPA', (167, 178))	('mTOR', 'Gene', (63, 67))	('PTEN', 'Gene', (141, 145))	('PARP', 'Gene', '142', (107, 111))	('PTEN', 'Gene', '5728', (141, 145))	('predict', 'Reg', (159, 166))	('inhibition', 'NegReg', (36, 46))	('akt', 'Gene', (59, 62))	('akt', 'Gene', '207', (59, 62))	('PARP', 'Gene', (182, 186))	('function', 'MPA', (146, 154))	('PARP', 'Gene', (107, 111))	('loss', 'Var', (133, 137))	('mTOR', 'Gene', '2475', (63, 67))	('PARP', 'Gene', '142', (182, 186))
56104	29214032	In addition, a phase I study is exploring the role of the PARP inhibitor olaparib in combination with the mTORC1/2 inhibitor AZD2014 or the AKT inhibitor AZD5363 for gynecological cancers, including advanced ECs (NCT02208375).	('PARP', 'Gene', '142', (58, 62))	('AKT', 'Gene', (140, 143))	('mTORC1', 'Gene', '382056', (106, 112))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('olaparib', 'Chemical', 'MESH:C531550', (73, 81))	('AZD2014', 'Chemical', 'MESH:C585537', (125, 132))	('AZD5363', 'Chemical', 'MESH:C575618', (154, 161))	('mTORC1', 'Gene', (106, 112))	('PARP', 'Gene', (58, 62))	('AZD5363', 'Var', (154, 161))	('AKT', 'Gene', '207', (140, 143))	('advanced ECs', 'Disease', (199, 211))	('CT', 'Chemical', 'MESH:D002251', (214, 216))
56118	29214032	Multiple monotherapy trials (NCT02628067, NCT02912572, NCT02899793, NCT02630823), combination immunotherapy trials (NCT03015129 NCT02982486), and immunotherapy trials in combination with paclitaxel and carboplatin (NCT02549209) are planned or ongoing.	('CT', 'Chemical', 'MESH:D002251', (129, 131))	('CT', 'Chemical', 'MESH:D002251', (43, 45))	('NCT02628067', 'Var', (29, 40))	('CT', 'Chemical', 'MESH:D002251', (30, 32))	('NCT02912572', 'Var', (42, 53))	('CT', 'Chemical', 'MESH:D002251', (69, 71))	('NCT02630823', 'Var', (68, 79))	('paclitaxel', 'Chemical', 'MESH:D017239', (187, 197))	('CT', 'Chemical', 'MESH:D002251', (117, 119))	('CT', 'Chemical', 'MESH:D002251', (56, 58))	('CT', 'Chemical', 'MESH:D002251', (216, 218))	('carboplatin', 'Chemical', 'MESH:D016190', (202, 213))	('NCT03015129 NCT02982486', 'Var', (116, 139))	('NCT02899793', 'Var', (55, 66))
56205	27367496	Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations The link between BRCA mutations and uterine cancer is unclear.	('mutations', 'Var', (97, 106))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('BRCA', 'Gene', '672', (124, 128))	('women', 'Species', '9606', (81, 86))	('BRCA', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('BRCA', 'Gene', '672', (92, 96))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Uterine cancer', 'Phenotype', 'HP:0010784', (0, 14))	('uterine cancer', 'Phenotype', 'HP:0010784', (143, 157))	('BRCA', 'Gene', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
56206	27367496	Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial.	('BRCA', 'Gene', (102, 106))	('mutations', 'Var', (107, 116))	('women', 'Species', '9606', (91, 96))	('BRCA', 'Gene', '672', (118, 122))	('BRCA', 'Gene', (118, 122))	('BRCA', 'Gene', '672', (102, 106))	('women', 'Species', '9606', (124, 129))
56208	27367496	This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy.	('BRCA1', 'Gene', (81, 86))	('BRCA2', 'Gene', (90, 95))	('mutation', 'Var', (96, 104))	('BRCA2', 'Gene', '675', (90, 95))	('BRCA1', 'Gene', '672', (81, 86))	('women', 'Species', '9606', (56, 61))
56220	27367496	In 2002, Kauff et al and Rebbeck et al published the first 2 studies demonstrating that risk-reducing salpingo-oophorectomy (RRSO) decreased the risk for breast and ovarian or fallopian tube cancer in women with mutations in the BRCA1 (OMIM 113705) (BRCA1+ women) or BRCA2 (OMIM 600185) (BRCA2+ women) gene.	('fallopian tube cancer', 'Phenotype', 'HP:0030394', (176, 197))	('BRCA1', 'Gene', (250, 255))	('BRCA2', 'Gene', (267, 272))	('women', 'Species', '9606', (201, 206))	('decreased', 'NegReg', (131, 140))	('breast and ovarian or fallopian tube cancer', 'Disease', 'MESH:D005185', (154, 197))	('BRCA1', 'Gene', '672', (229, 234))	('women', 'Species', '9606', (295, 300))	('BRCA2', 'Gene', (288, 293))	('BRCA1', 'Gene', '672', (250, 255))	('BRCA2', 'Gene', '675', (267, 272))	('mutations', 'Var', (212, 221))	('women', 'Species', '9606', (257, 262))	('BRCA1', 'Gene', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('BRCA2', 'Gene', '675', (288, 293))
56221	27367496	Subsequent studies have confirmed that RRSO not only reduces the risk for ovarian or fallopian tube cancer by 80% to 90% and the risk for breast cancer by 40% to 70% but also reduces disease-specific and overall mortality.	('reduces', 'NegReg', (175, 182))	('RRSO', 'Var', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('reduces', 'NegReg', (53, 60))	('fallopian tube cancer', 'Phenotype', 'HP:0030394', (85, 106))	('ovarian or fallopian tube cancer', 'Disease', 'MESH:D005185', (74, 106))	('ovarian or fallopian tube cancer', 'Disease', (74, 106))
56239	27367496	Similarly, endometrial carcinomas with mixed histologic features were also classified as serous/serous-like if a serous component was present, because the Cancer Genome Atlas Research Network recently demonstrated that most of these cases cluster in the copy-number high (serous-like) group.	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (11, 33))	('copy-number', 'Var', (254, 265))	('Cancer', 'Phenotype', 'HP:0002664', (155, 161))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (11, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (11, 32))	('Cancer', 'Disease', (155, 161))	('Cancer', 'Disease', 'MESH:D009369', (155, 161))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('endometrial carcinomas', 'Disease', (11, 33))
56250	27367496	Of 1083 women who met the final eligibility criteria, 627 (57.9%) were BRCA1+, 453 (41.8%) were BRCA2+, and 3 (0.3%) had mutations in both genes.	('BRCA1', 'Gene', (71, 76))	('mutations', 'Var', (121, 130))	('women', 'Species', '9606', (8, 13))	('BRCA2', 'Gene', '675', (96, 101))	('BRCA1', 'Gene', '672', (71, 76))	('BRCA2', 'Gene', (96, 101))
56276	27367496	The lack of BRCA1 protein expression in all 3 available BRCA1-associated serous/serous-like specimens and the loss of the wild-type BRCA1 allele in 2 of 3 available tumors support the biologic plausibility that the loss of BRCA1 function was important in the tumorigenesis of the serous/serous-like cancers seen in our cohort.	('lack', 'NegReg', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('protein', 'Protein', (18, 25))	('BRCA1', 'Gene', '672', (132, 137))	('all 3', 'Gene', (40, 45))	('BRCA1', 'Gene', '672', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('BRCA1', 'Gene', (132, 137))	('cancers', 'Disease', 'MESH:D009369', (299, 306))	('all 3', 'Gene', '5079', (40, 45))	('BRCA1', 'Gene', (12, 17))	('expression', 'MPA', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('BRCA1', 'Gene', '672', (223, 228))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA1', 'Gene', (223, 228))	('tumors', 'Disease', (165, 171))	('BRCA1', 'Gene', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('tumor', 'Disease', (165, 170))	('cancers', 'Disease', (299, 306))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('loss', 'Var', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', (259, 264))
56282	27367496	Several studies have also evaluated the potential association between serous endometrial carcinoma and BRCA mutations.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (77, 98))	('BRCA', 'Gene', '672', (103, 107))	('mutations', 'Var', (108, 117))	('BRCA', 'Gene', (103, 107))	('serous endometrial carcinoma', 'Disease', 'MESH:D016889', (70, 98))	('serous endometrial carcinoma', 'Disease', (70, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))
56284	27367496	However, only selective founder and protein-truncating mutations in exon 11 of BRCA1 and exons 10 and 11 of BRCA2 were examined.	('BRCA2', 'Gene', (108, 113))	('protein-truncating', 'Var', (36, 54))	('BRCA1', 'Gene', '672', (79, 84))	('BRCA2', 'Gene', '675', (108, 113))	('BRCA1', 'Gene', (79, 84))
56285	27367496	In 2001, Levine et al similarly did not find any founder BRCA mutations in 21 serous/serous-like endometrial carcinomas from individuals of Jewish heritage.	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (97, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (97, 119))	('BRCA', 'Gene', '672', (57, 61))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (97, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('endometrial carcinomas', 'Disease', (97, 119))	('BRCA', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
56286	27367496	However, 2 independent Israeli studies since reported that 4 of 31 (12.9%) and 7 of 59 (11.9%) consecutive Jewish patients with serous endometrial carcinoma, respectively, carried a BRCA1 mutation.	('BRCA1', 'Gene', '672', (182, 187))	('mutation', 'Var', (188, 196))	('BRCA1', 'Gene', (182, 187))	('serous endometrial carcinoma', 'Disease', 'MESH:D016889', (128, 156))	('serous endometrial carcinoma', 'Disease', (128, 156))	('patients', 'Species', '9606', (114, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (135, 156))
56287	27367496	Also, a recent multi-institutional study identified nonfounder BRCA1 mutations in 3 of 151 unselected patients (2.0%) with serous endometrial carcinoma.	('mutations', 'Var', (69, 78))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (130, 151))	('serous endometrial carcinoma', 'Disease', (123, 151))	('BRCA1', 'Gene', (63, 68))	('patients', 'Species', '9606', (102, 110))	('serous endometrial carcinoma', 'Disease', 'MESH:D016889', (123, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('BRCA1', 'Gene', '672', (63, 68))
56288	27367496	When all 5 studies to date are pooled, 3 of 207 serous/serous-like carcinomas in admixed US and Canadian patients (1.4%) and 11 of 111 serous/serous-like carcinomas in US and Israeli Jews (9.9%) had a detectable BRCA1 mutation (eTable 4 in the Supplement).	('BRCA1', 'Gene', (212, 217))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (218, 226))	('serous/serous-like', 'Disease', (48, 66))	('carcinomas', 'Disease', 'MESH:D002277', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinomas', 'Disease', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('BRCA1', 'Gene', '672', (212, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('carcinomas', 'Disease', (154, 164))	('carcinomas', 'Disease', 'MESH:D002277', (154, 164))
56289	27367496	In the only other prospective study analyzing the risk for uterine cancer after RRSO in BRCA mutation carriers with complete histologic information available, 2 endometrioid carcinomas developed during 6 years of follow-up in 315 BRCA+ women.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (161, 183))	('BRCA', 'Gene', (230, 234))	('BRCA', 'Gene', '672', (230, 234))	('endometrioid carcinomas', 'Disease', (161, 184))	('cancer', 'Disease', (67, 73))	('uterine cancer', 'Phenotype', 'HP:0010784', (59, 73))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (161, 184))	('women', 'Species', '9606', (236, 241))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (161, 184))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA', 'Gene', '672', (88, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('mutation', 'Var', (93, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('BRCA', 'Gene', (88, 92))
56294	27367496	In 2 cases, we also demonstrated that loss of the wild-type BRCA1 allele was the likely cause.	('loss', 'Var', (38, 42))	('BRCA1', 'Gene', (60, 65))	('BRCA1', 'Gene', '672', (60, 65))
56304	27367496	The cause of this association is unclear, but as none of these studies have examined BRCA mutation status, the association may be explained in part by BRCA1 mutations.	('BRCA', 'Gene', '672', (151, 155))	('BRCA', 'Gene', (85, 89))	('BRCA', 'Gene', (151, 155))	('BRCA1', 'Gene', '672', (151, 156))	('mutations', 'Var', (157, 166))	('BRCA1', 'Gene', (151, 156))	('BRCA', 'Gene', '672', (85, 89))
56308	27367496	Given this, we have estimated the penetrance of serous/serous-like cancer through age 70 years in women with BRCA1 mutations using 2 approaches.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('BRCA1', 'Gene', (109, 114))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (67, 73))	('women', 'Species', '9606', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1', 'Gene', '672', (109, 114))
56403	28741605	Some studies have reported low rates of TP53 mutations, and low-level amplification of MDM2 and other genes on chromosome band 12q14-15.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('MDM2', 'Gene', '4193', (87, 91))	('amplification', 'MPA', (70, 83))	('MDM2', 'Gene', (87, 91))
56404	28741605	Recently described alterations in adenosarcoma include MYBL1 amplification and ATRX mutation, each of which has been detected in 50% of adenosarcomas with sarcomatous overgrowth.	('detected', 'Reg', (117, 125))	('amplification', 'Var', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('sarcomatous overgrowth', 'Disease', (155, 177))	('adenosarcomas', 'Disease', 'MESH:D018195', (136, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('adenosarcoma', 'Disease', (34, 46))	('adenosarcoma', 'Disease', 'MESH:D018195', (34, 46))	('MYBL1', 'Gene', (55, 60))	('MYBL1', 'Gene', '4603', (55, 60))	('overgrowth', 'Phenotype', 'HP:0001548', (167, 177))	('sarcomatous overgrowth', 'Disease', 'MESH:D018316', (155, 177))	('adenosarcoma', 'Disease', (136, 148))	('adenosarcoma', 'Disease', 'MESH:D018195', (136, 148))	('ATRX', 'Gene', (79, 83))	('adenosarcomas', 'Disease', (136, 149))	('ATRX', 'Gene', '546', (79, 83))	('mutation', 'Var', (84, 92))
56487	28178664	Here we found that more than half of subtype I patients are likely to be at stage I and possesses the characteristics of less tumor invasion and low tumor weight (Table 1).	('less', 'NegReg', (121, 125))	('low tumor', 'Disease', 'MESH:D009800', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('subtype', 'Var', (37, 44))	('patients', 'Species', '9606', (47, 55))	('low tumor', 'Disease', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
56499	28178664	Inhibition of SYK activity by SYK-specific inhibitors such as PRT060318 and fostamatinib disodium provides great clinical outcome to certain cancer patients with abnormal SYK activities, indicating that subtype I patients may be benefited from SYK-specific kinase inhibitors.	('patients', 'Species', '9606', (148, 156))	('activity', 'MPA', (18, 26))	('PRT060318', 'Var', (62, 71))	('PRT060318', 'Chemical', 'MESH:C569036', (62, 71))	('Inhibition', 'NegReg', (0, 10))	('SYK', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('SYK', 'Gene', (171, 174))	('SYK', 'Gene', '6850', (30, 33))	('fostamatinib disodium', 'Chemical', '-', (76, 97))	('SYK', 'Gene', '6850', (171, 174))	('SYK', 'Gene', (244, 247))	('SYK', 'Gene', (14, 17))	('patients', 'Species', '9606', (213, 221))	('SYK', 'Gene', '6850', (244, 247))	('SYK', 'Gene', '6850', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
56504	28178664	Cancer patients with high CCNE1 expression levels have shown increased sensitivity to CDK2 inhibitors SNS-032.	('CCNE1', 'Gene', '898', (26, 31))	('CCNE1', 'Gene', (26, 31))	('CDK2', 'Gene', (86, 90))	('high', 'Var', (21, 25))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('sensitivity to', 'MPA', (71, 85))	('increased', 'PosReg', (61, 70))	('SNS-032', 'Chemical', 'MESH:C484864', (102, 109))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('expression', 'MPA', (32, 42))	('patients', 'Species', '9606', (7, 15))	('CDK2', 'Gene', '1017', (86, 90))
56505	28178664	Therefore, inhibitors targeting cell-cycle proteins may potentially provide better therapeutic effects to subtype II patients.	('cell-cycle', 'Protein', (32, 42))	('patients', 'Species', '9606', (117, 125))	('inhibitors', 'Var', (11, 21))
56519	27843957	It has been suggested that possession of HER2 lead to cell proliferation and also apoptosis suppression.	('cell proliferation', 'CPA', (54, 72))	('apoptosis suppression', 'CPA', (82, 103))	('possession', 'Var', (27, 37))	('HER2', 'Gene', (41, 45))	('HER2', 'Gene', '2064', (41, 45))
56572	27843957	In recent study, several mutations in the extracellular and tyrosine kinases domains of HER2, was reported in urothelial bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (25, 34))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (110, 136))	('bladder cancers', 'Phenotype', 'HP:0009725', (121, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('HER2', 'Gene', (88, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('HER2', 'Gene', '2064', (88, 92))	('urothelial bladder cancers', 'Disease', (110, 136))	('reported', 'Reg', (98, 106))
56573	27843957	HER2 amplifications were detected in 9% of bladder cancer specimens.	('amplifications', 'Var', (5, 19))	('bladder cancer', 'Disease', 'MESH:D001749', (43, 57))	('bladder cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('bladder cancer', 'Phenotype', 'HP:0009725', (43, 57))	('detected', 'Reg', (25, 33))
56575	27843957	Furthermore, identifying of HER2 mutations and the role of this pathway in bladder carcinogenesis is desirable.	('HER2', 'Gene', '2064', (28, 32))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (75, 97))	('mutations', 'Var', (33, 42))	('bladder carcinogenesis', 'Disease', (75, 97))	('HER2', 'Gene', (28, 32))
56600	27843957	They found that near 33% of uterine serous carcinoma were positive for HER2 gene amplification and protein overexpression.	('serous carcinoma', 'Disease', (36, 52))	('HER2', 'Gene', (71, 75))	('positive', 'Reg', (58, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('HER2', 'Gene', '2064', (71, 75))	('amplification', 'Var', (81, 94))	('serous carcinoma', 'Disease', 'MESH:D018284', (36, 52))	('overexpression', 'PosReg', (107, 121))	('protein', 'Protein', (99, 106))
56617	27843957	The use of T-DM1 in other malignances with HER2 overexpression and gene-amplification except than breast cancer is of key interest.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('HER2', 'Gene', (43, 47))	('DM1', 'Gene', (13, 16))	('HER2', 'Gene', '2064', (43, 47))	('gene-amplification', 'Var', (67, 85))	('DM1', 'Gene', '1760', (13, 16))	('overexpression', 'PosReg', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
56722	24594074	This resulted in classification of endometrial cancers into four categories: POLE ultra mutated, microsatellite instability hyper mutated, copy-number low, and copy-number high.	('microsatellite instability hyper', 'Disease', 'MESH:D053842', (97, 129))	('copy-number high', 'Var', (160, 176))	('resulted in', 'Reg', (5, 16))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('copy-number low', 'Var', (139, 154))	('endometrial cancers', 'Disease', 'MESH:D016889', (35, 54))	('endometrial cancer', 'Phenotype', 'HP:0012114', (35, 53))	('endometrial cancers', 'Disease', (35, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('microsatellite instability hyper', 'Disease', (97, 129))
56724	24594074	Identification of mutation(s) that drive tumorigenesis coupled with the identification of signaling pathway cross-talks confer the greatest potential for a successful targeted approach to treatment.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutation', 'Var', (18, 26))
56727	24594074	Clinical evidence suggests that angiogenesis plays a role in endometrial cancer Pazopanib, a small molecule inhibitor of VEGFR, has limited activity in the management of carcinosarcoma of the uterus Mutational Profiles and Chromosomal amplifications may profile potential driver of disease	('carcinosarcoma of the uterus', 'Phenotype', 'HP:0010784', (170, 198))	('carcinosarcoma of the uterus', 'Disease', (170, 198))	('endometrial cancer', 'Disease', 'MESH:D016889', (61, 79))	('Chromosomal amplifications', 'Var', (223, 249))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('VEGFR', 'Gene', '3791', (121, 126))	('endometrial cancer', 'Disease', (61, 79))	('VEGFR', 'Gene', (121, 126))	('Pazopanib', 'Chemical', 'MESH:C516667', (80, 89))	('carcinosarcoma of the uterus', 'Disease', 'MESH:D002296', (170, 198))	('endometrial cancer', 'Phenotype', 'HP:0012114', (61, 79))
56802	25276325	The RCN conducted a small review of symptom palliation that found that low dose RT was associated with excellent short term pain relief, but that symptoms typically recurred at a later date, reflecting the systemic nature of this disease.	('low dose', 'Var', (71, 79))	('pain', 'Disease', (124, 128))	('pain', 'Phenotype', 'HP:0012531', (124, 128))	('pain', 'Disease', 'MESH:D010146', (124, 128))
56832	23251510	The 5-year survival rates of women with low grade endometrial stromal sarcoma, endometrial stromal sarcoma, leiomyosarcoma (LMS), and adenosarcoma were 97.5%, 73.5%, 60.1%, and 77.2%, respectively (p<0.0001, log rank test).	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (50, 77))	('women', 'Species', '9606', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('adenosarcoma', 'Disease', (134, 146))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (108, 122))	('adenosarcoma', 'Disease', 'MESH:D018195', (134, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('endometrial stromal sarcoma', 'Disease', (79, 106))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (79, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('endometrial stromal sarcoma', 'Disease', (50, 77))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (108, 122))	('low grade', 'Var', (40, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('leiomyosarcoma', 'Disease', (108, 122))
56871	23251510	Women diagnosed with a primary cancer of the uterus (ICD-O3 C54.0-C54.3, C54.8-C54.9, C55.9) with valid histological codes from 8000-8991, between 1979 and 2008 were eligible for this study.	('Women', 'Species', '9606', (0, 5))	('C55.9', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('cancer of the uterus', 'Phenotype', 'HP:0010784', (31, 51))	('C54.8-C54.9', 'Var', (73, 84))
57008	22362447	The homozygous deficient mice for LMP2 show tissue- and substrate-dependent abnormalities in the biological functions of the proteasome, and impaired functioning of the proteasome in the splenocytes or hepatic cells.	('impaired', 'NegReg', (141, 149))	('deficient', 'Var', (15, 24))	('abnormalities', 'Reg', (76, 89))	('mice', 'Species', '10090', (25, 29))	('biological functions of the proteasome', 'MPA', (97, 135))	('LMP2', 'Gene', (34, 38))	('functioning', 'MPA', (150, 161))
57021	22362447	All lymph nodes were negative for LMS metastases, and IHC analyses showed positivity for Ki-67 and negativity for LMP2.	('positivity', 'Var', (74, 84))	('Ki-67', 'Gene', (89, 94))	('LMS', 'Phenotype', 'HP:0100243', (34, 37))	('LMS metastases', 'Disease', (34, 48))	('Ki-67', 'Gene', '17345', (89, 94))	('LMS metastases', 'Disease', 'MESH:D009362', (34, 48))	('negativity', 'NegReg', (99, 109))	('LMP2', 'Gene', (114, 118))
57031	22362447	Thus, a lowered level of IRF1 resulting from a deficiency in LMP2 might seem to be a risk factor for uterine LMS in mice.	('uterine LMS', 'Disease', (101, 112))	('mice', 'Species', '10090', (116, 120))	('LMP2', 'Gene', (61, 65))	('IRF1', 'Gene', (25, 29))	('IRF1', 'Gene', '16362', (25, 29))	('LMS', 'Phenotype', 'HP:0100243', (109, 112))	('lowered', 'NegReg', (8, 15))	('level', 'MPA', (16, 21))	('deficiency', 'Var', (47, 57))
39766	22362447	If the TP53 gene is damaged, tumor suppression is severely reduced.	('damaged', 'Var', (20, 27))	('reduced', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('TP53 gene', 'Gene', (7, 16))
57034	22362447	People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, more than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutation', 'Var', (160, 168))	('human', 'Species', '9606', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (86, 92))	('People', 'Species', '9606', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('deletion', 'Var', (172, 180))	('TP53', 'Gene', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
57036	22362447	Uterine LMS incidence and death rates were similar in LMP2-/- TP53-/- mice and closely matched control LMP2-/-TP53+/+ mice.	('death', 'Disease', 'MESH:D003643', (26, 31))	('death', 'Disease', (26, 31))	('LMS', 'Phenotype', 'HP:0100243', (8, 11))	('LMP2-/- TP53-/-', 'Var', (54, 69))	('mice', 'Species', '10090', (70, 74))	('mice', 'Species', '10090', (118, 122))	('Uterine LMS incidence', 'CPA', (0, 21))
57037	22362447	The correlation of defective TP53 function with uterine LMS tumorigenesis is unclearly understood.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('uterine LMS', 'Disease', (48, 59))	('LMS', 'Phenotype', 'HP:0100243', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('defective', 'Var', (19, 28))	('tumor', 'Disease', (60, 65))	('TP53', 'Protein', (29, 33))
57044	22362447	Since no spontaneous development of uterine LMS is observed in IRF1-, calponin h1-deficient mice or heterozygous Rb mice, the lack of LMP2 may be largely associated with the expression of other known or unknown cell-cycle regulatory factors or oncogenic factors (Figure 1).	('mice', 'Species', '10090', (116, 120))	('Rb', 'Phenotype', 'HP:0009919', (113, 115))	('LMP2', 'Gene', (134, 138))	('lack', 'Var', (126, 130))	('IRF1', 'Gene', (63, 67))	('IRF1', 'Gene', '16362', (63, 67))	('LMS', 'Phenotype', 'HP:0100243', (44, 47))	('associated', 'Reg', (154, 164))	('mice', 'Species', '10090', (92, 96))
57175	33552546	Overall, 87% of patients received chemotherapy, 34% received targeted therapy and 16% received radiotherapy, and there were no significant differences between the DM and non-DM groups.	('DM', 'Phenotype', 'HP:0000819', (174, 176))	('DM', 'Disease', 'MESH:D009223', (174, 176))	('patients', 'Species', '9606', (16, 24))	('DM', 'Phenotype', 'HP:0000819', (163, 165))	('DM', 'Disease', 'MESH:D009223', (163, 165))	('chemotherapy', 'CPA', (34, 46))	('targeted', 'Var', (61, 69))
57237	32881280	BMI body mass index BRCA breast cancer susceptibility gene CAP College of American Pathologists CI confidence interval CLIA Clinical Laboratory Improvement Amendments ctDNA circulating tumor DNA Del deletion HR hazard ratio ID identification number In/del insertion/deletion MAF mutation allele frequency NR not reached OS overall survival PREDICT Profile-Related Evidence Determining Individualized Cancer Therapy SE standard error SNV single nucleotide variant UCSD University of California San Diego VUS variants of unknown significance In 2019, approximately 109 000 women were diagnosed with gynecologic cancer, and approximately 33 100 women died from their disease [1].	('UCSD', 'Chemical', '-', (463, 467))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('died', 'Disease', (648, 652))	('women', 'Species', '9606', (571, 576))	('tumor', 'Disease', (185, 190))	('BRCA', 'Gene', '672', (20, 24))	('Cancer', 'Phenotype', 'HP:0002664', (400, 406))	('cancer', 'Disease', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('women', 'Species', '9606', (642, 647))	('Cancer', 'Disease', (400, 406))	('single nucleotide variant', 'Var', (437, 462))	('cancer', 'Disease', (609, 615))	('BRCA', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (609, 615))	('died', 'Disease', 'MESH:D003643', (648, 652))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('variants', 'Var', (507, 515))	('Cancer', 'Disease', 'MESH:D009369', (400, 406))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('SE', 'Disease', 'None', (415, 417))	('cancer', 'Disease', 'MESH:D009369', (609, 615))
57243	32881280	Molecular signatures have recently predicted therapeutic response in patients with gynecologic malignancies.	('malignancies', 'Disease', (95, 107))	('predicted', 'Reg', (35, 44))	('Molecular', 'Var', (0, 9))	('patients', 'Species', '9606', (69, 77))	('therapeutic', 'Disease', (45, 56))	('malignancies', 'Disease', 'MESH:D009369', (95, 107))
57244	32881280	Breast cancer susceptibility gene (BRCA) 1/2 mutated and homologous recombination-deficient epithelial ovarian cancers have demonstrated dramatic responses to PARP inhibitors, HER2-positive uterine serous cancers benefit from the incorporation of trastuzumab, and mismatch repair deficient or microsatellite unstable high tumors benefit from immune checkpoint inhibition with guidelines recommending MSI testing in ovarian, cervical, and vulvar cancers [4, 5, 6].	('ovarian', 'Disease', 'MESH:D010049', (415, 422))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('HER2', 'Gene', '2064', (176, 180))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('microsatellite unstable high tumors', 'Disease', 'MESH:D053842', (293, 328))	('mutated', 'Var', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (445, 452))	('ovarian', 'Disease', 'MESH:D010049', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('serous cancers', 'Disease', (198, 212))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('HER2', 'Gene', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('ovarian', 'Disease', (415, 422))	('vulvar cancers', 'Disease', (438, 452))	('PARP', 'Gene', '1302', (159, 163))	('deficient epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (82, 118))	('vulvar cancer', 'Phenotype', 'HP:0030416', (438, 451))	('vulvar cancers', 'Disease', 'MESH:D014846', (438, 452))	('deficient epithelial ovarian cancers', 'Disease', (82, 118))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('microsatellite unstable high tumors', 'Disease', (293, 328))	('ovarian cancers', 'Phenotype', 'HP:0100615', (103, 118))	('trastuzumab', 'Chemical', 'MESH:D000068878', (247, 258))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('ovarian', 'Disease', (103, 110))	('serous cancers', 'Disease', 'MESH:D009369', (198, 212))	('BRCA) 1/2', 'Gene', '672;675', (35, 44))	('Breast cancer', 'Disease', (0, 13))	('PARP', 'Gene', (159, 163))
57262	32881280	Frequency and type [single nucleotide variant (SNV), amplification, or deletion, which included frameshift mutations, deletions, and insertion/deletions] of genetic alterations were then reported in the cohort of all gynecologic cancer patients and in the ovarian, uterine, and cervical/vaginal/vulvar cancer cohorts.	('vulvar cancer', 'Phenotype', 'HP:0030416', (295, 308))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('patients', 'Species', '9606', (236, 244))	('vulvar cancer', 'Disease', 'MESH:D014846', (295, 308))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('ovarian', 'Disease', 'MESH:D010049', (256, 263))	('ovarian', 'Disease', (256, 263))	('deletions', 'Var', (118, 127))	('cancer', 'Disease', (302, 308))	('vulvar cancer', 'Disease', (295, 308))
57270	32881280	Univariate analysis was performed to calculate hazard ratios (HR) for age, BMI, site of primary tumor, TP53 alteration, PIK3CA alteration, median maximum ctDNA mutation allele frequency (MAF), number of characterized alterations, and number of lines of chemotherapy prior to first ctDNA collection; in general, cohorts were divided at the median of each value.	('TP53', 'Gene', '7157', (103, 107))	('PIK3CA', 'Gene', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TP53', 'Gene', (103, 107))	('tumor', 'Disease', (96, 101))	('PIK3CA', 'Gene', '5290', (120, 126))	('alteration', 'Var', (127, 137))	('ctDNA', 'Gene', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('alteration', 'Var', (108, 118))
57280	32881280	Amplifications were more common in the ovarian cancer cohort when compared to uterine or cervical cancer cohorts (Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('common', 'Reg', (25, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('ovarian cancer', 'Disease', (39, 53))	('cancer', 'Disease', (47, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Amplifications', 'Var', (0, 14))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
57299	32881280	TP53 alterations were seen in over 50% of patients, and PIK3CA alterations were seen in nearly 25% of patients.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (102, 110))	('PIK3CA', 'Gene', (56, 62))	('alterations', 'Var', (5, 16))	('patients', 'Species', '9606', (42, 50))	('PIK3CA', 'Gene', '5290', (56, 62))
57300	32881280	These numbers are similar to a recent publication of 2579 'pan-gynecologic cancer' patients (1087 breast cancers, 579 ovarian cancers, 548 endometrial cancers, 308 cervical cancers, and 57 uterine carcinosarcomas) in The Cancer Genome Atlas; they reported TP53 and PIK3CA alteration rates of 44% and 32%, respectively [14].	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (105, 111))	('TP53', 'Gene', '7157', (256, 260))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancers', 'Disease', 'MESH:D001943', (98, 112))	('ovarian cancers', 'Disease', (118, 133))	('breast cancers', 'Disease', (98, 112))	('Cancer', 'Disease', 'MESH:D009369', (221, 227))	('ovarian cancers', 'Disease', 'MESH:D010051', (118, 133))	('carcinosarcomas', 'Disease', 'MESH:D002296', (197, 212))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (126, 132))	('PIK3CA', 'Gene', (265, 271))	('alteration', 'Var', (272, 282))	('breast cancers', 'Phenotype', 'HP:0003002', (98, 112))	('cancer', 'Disease', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('patients', 'Species', '9606', (83, 91))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('carcinosarcomas', 'Disease', (197, 212))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('TP53', 'Gene', (256, 260))	('ovarian cancers', 'Phenotype', 'HP:0100615', (118, 133))	('Cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cervical cancers', 'Disease', (164, 180))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cervical cancers', 'Disease', 'MESH:D002583', (164, 180))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('endometrial cancers', 'Disease', 'MESH:D016889', (139, 158))	('PIK3CA', 'Gene', '5290', (265, 271))	('endometrial cancers', 'Disease', (139, 158))	('Cancer', 'Disease', (221, 227))
57321	32881280	Thirty-four percent (N = 17) of ovarian cancer patients had BRCA alterations detected on germline or somatic tissue or ctDNA testing, while only 4% (N = 2) had BRCA alterations detected on ctDNA (Table 1).	('alterations', 'Var', (65, 76))	('ovarian cancer', 'Disease', (32, 46))	('patients', 'Species', '9606', (47, 55))	('BRCA', 'Gene', '672', (160, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('BRCA', 'Gene', (160, 164))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))	('BRCA', 'Gene', '672', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BRCA', 'Gene', (60, 64))
57339	33178590	A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs).	('MET', 'Gene', '79811', (122, 125))	('mutations', 'Var', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (46, 52))	('MET', 'Gene', (122, 125))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('copy number variants', 'Var', (162, 182))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
57341	33178590	Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis.	('MET', 'Gene', '79811', (140, 143))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('MET', 'Gene', (140, 143))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('amplification', 'Var', (123, 136))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))
57346	33178590	This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.	('MET', 'Gene', '79811', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('abnormal', 'Var', (76, 84))	('MET', 'Gene', (220, 223))	('alterations', 'Var', (97, 108))	('cancer', 'Disease', (172, 178))	('MET', 'Gene', '79811', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (72, 75))	('associations', 'Interaction', (150, 162))
57349	33178590	It is frequently activated in human tumors by various mechanisms, such as mutations, amplification, and overexpression, thus leading to malignant transformation and metastasis.	('leading to', 'Reg', (125, 135))	('metastasis', 'CPA', (165, 175))	('malignant transformation', 'CPA', (136, 160))	('human', 'Species', '9606', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('overexpression', 'Var', (104, 118))	('mutations', 'Var', (74, 83))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
57352	33178590	Moreover, in esophageal carcinoma (ESCA) and kidney renal papillary cell carcinoma (KIRP), gene amplification with consequent protein overexpression and constitutive kinase activation of MET has been reported.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('protein', 'Protein', (126, 133))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('overexpression', 'PosReg', (134, 148))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (52, 82))	('MET', 'Gene', '79811', (187, 190))	('ESCA', 'Phenotype', 'HP:0011459', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('MET', 'Gene', (187, 190))	('kidney renal papillary cell carcinoma', 'Disease', (45, 82))	('gene amplification', 'Var', (91, 109))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (45, 82))	('esophageal carcinoma', 'Disease', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
57355	33178590	Especially in lung cancer, inhibition of MET receptor activity has shown promising results and has become a standard therapy for patients.	('patients', 'Species', '9606', (129, 137))	('MET', 'Gene', (41, 44))	('lung cancer', 'Disease', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('inhibition', 'Var', (27, 37))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))	('activity', 'MPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('MET', 'Gene', '79811', (41, 44))
57369	33178590	Especially, in single- and cross-cancer queries, OQL algorithm can be utilized to accurately identify copy number alterations, mutations, mRNA, and protein expression profiles.	('mRNA', 'MPA', (138, 142))	('copy number alterations', 'Var', (102, 125))	('cross-cancer', 'Disease', (27, 39))	('cross-cancer', 'Disease', 'MESH:D009369', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (127, 136))
57387	33178590	MET mutations were observed most commonly in UCEC (12.3%), SKCM (10.5%), KIRP (8.8%), bladder urothelial carcinoma (BLCA, 4.4%), COADREAD (4.4%), and LUAD (4.2%).	('KIRP', 'Disease', (73, 77))	('MET', 'Gene', '79811', (0, 3))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('observed', 'Reg', (19, 27))	('COADREAD', 'Disease', (129, 137))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mutations', 'Var', (4, 13))	('SKCM', 'Disease', (59, 63))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
57393	33178590	The most common domains were the other domain (91 samples), Sema domain (83 samples), Pkinase-Tyr domain (69 samples), TIG domain (563-654 aa, 18 samples), TIG domain (742-815 aa, 17 samples), TIG domain (657-728 aa, 12 samples), and PSI domain (7 samples).	('Tyr', 'Chemical', 'MESH:D014443', (94, 97))	('657-728 aa', 'Var', (205, 215))	('Sema', 'Gene', (60, 64))	('Sema', 'Gene', '7869', (60, 64))	('TIG', 'Disease', (119, 122))
57395	33178590	Mutations in KIRP were primarily located in the Pkinase-Tyr domain, approximately three times more than the mutations located in the other domain.	('Tyr', 'Chemical', 'MESH:D014443', (56, 59))	('Mutations', 'Var', (0, 9))	('KIRP', 'Gene', (13, 17))
57396	33178590	Mutations in COADREAD and GBM were mainly located in the Sema domain (Figure 2B and Supplementary Table S3).	('Mutations', 'Var', (0, 9))	('Sema', 'Gene', (57, 61))	('Sema', 'Gene', '7869', (57, 61))	('COADREAD', 'Gene', (13, 21))
57399	33178590	For example, the 1,010-aa mutation was found in seven samples (six samples with X1010 splice, one with D1010fs) and occurred almost exclusively in LUAD (6/7) (Supplementary Figure S2B).	('D1010fs', 'Var', (103, 110))	('D1010fs', 'Mutation', 'p.D1010fsX', (103, 110))	('X1010 splice', 'Var', (80, 92))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
57402	33178590	The only other tumor with mutations at this position was LGG (one sample with X1010_splice), but its role was almost unknown to this cancer.	('LGG', 'Disease', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', (15, 20))	('X1010_splice', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
57403	33178590	The 1,148-aa mutation in the Pkinase-Tyr domain was also observed in seven samples [six samples with R1148Q (three SKCMs, one BLCA, one BRCA, one COADREAD), one sample with R1148* (one UCEC)].	('R1148*', 'Var', (173, 179))	('observed', 'Reg', (57, 65))	('Pkinase-Tyr', 'Enzyme', (29, 40))	('R1148Q', 'Var', (101, 107))	('R1148Q', 'Mutation', 'p.R1148Q', (101, 107))	('Tyr', 'Chemical', 'MESH:D014443', (37, 40))	('R1148*', 'SUBSTITUTION', 'None', (173, 179))
57405	33178590	The most mutated positions in KIRP (17 of 25 mutations) were located at the Pkinase Tyr domain, especially at the 1,250-aa position (four samples with M1250T) and the 1,092- to 1,094-aa position (three with V1092I, three with H1094Y).	('H1094Y', 'Var', (226, 232))	('V1092I', 'Var', (207, 213))	('V1092I', 'Mutation', 'p.V1092I', (207, 213))	('M1250T', 'Var', (151, 157))	('H1094Y', 'Mutation', 'p.H1094Y', (226, 232))	('Tyr', 'Chemical', 'MESH:D014443', (84, 87))	('M1250T', 'Mutation', 'p.M1250T', (151, 157))	('mutated', 'Reg', (9, 16))
57407	33178590	The most mutated positions in UCEC (3 of 78 mutations) were located at the Pkinase-Tyr domain at the 1,186-aa position (one with L1186F, one with L1186I, one with L1186R), but its oncogenic role was considered unknown.	('L1186F', 'Mutation', 'p.L1186F', (129, 135))	('Tyr', 'Chemical', 'MESH:D014443', (83, 86))	('L1186F', 'Var', (129, 135))	('L1186I', 'Mutation', 'p.L1186I', (146, 152))	('L1186R', 'Mutation', 'p.L1186R', (163, 169))	('L1186I', 'Var', (146, 152))	('L1186R', 'Var', (163, 169))	('mutated', 'Reg', (9, 16))
57408	33178590	D1228Y/A and T222K alterations were found in UCEC (one with D1228Y, one with D1228A, one with T222K) and known to be likely oncogenic and predicted oncogenic, respectively (Supplementary Figure S2D).	('D1228Y', 'SUBSTITUTION', 'None', (60, 66))	('T222K', 'Var', (13, 18))	('D1228A', 'Var', (77, 83))	('D1228Y', 'Var', (60, 66))	('D1228A', 'Mutation', 'p.D1228A', (77, 83))	('D1228Y', 'Mutation', 'p.D1228Y', (0, 6))	('T222K', 'Mutation', 'p.T222K', (94, 99))	('D1228Y', 'SUBSTITUTION', 'None', (0, 6))	('D1228Y', 'Var', (0, 6))	('UCEC', 'Disease', (45, 49))	('D1228Y', 'Mutation', 'p.D1228Y', (60, 66))	('T222K', 'Mutation', 'p.T222K', (13, 18))
57410	33178590	Next, we analyzed the clinical targeted therapy implications of MET mutation using cBioPortal, which could provide the annotation of variants from different databases, including COSMIC, Cancer Hotspots method, CIViC, My Cancer Genome, and OncoKB.	('MET', 'Gene', (64, 67))	('CIViC', 'Disease', 'None', (210, 215))	('MET', 'Gene', '79811', (64, 67))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CIViC', 'Disease', (210, 215))	('Cancer', 'Disease', (220, 226))	('Cancer', 'Disease', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('variants', 'Var', (133, 141))
57411	33178590	Thus, for the clinical targeted therapy implications, each MET somatic mutation could be classified into four levels as defined by OncoKB: level 2 (seven mutations), level 3B (one mutation), level 4 (13 mutations), and level NA (290 mutations) (Figure 4A and Supplementary Table S2).	('MET', 'Gene', '79811', (59, 62))	('MET', 'Gene', (59, 62))	('mutations', 'Var', (154, 163))
57418	33178590	Among the 311 samples with MET mutations mentioned above, 129 also harbored MET CNVs (108 with gain, nine with amplification, and 12 with shallow deletion).	('mutations', 'Var', (31, 40))	('MET', 'Gene', (27, 30))	('MET', 'Gene', '79811', (76, 79))	('MET', 'Gene', (76, 79))	('gain', 'PosReg', (95, 99))	('MET', 'Gene', '79811', (27, 30))
57420	33178590	As shown in Figure 5A and Figures 1A,B, KIRP harbored a very high proportion of gain and was also the cancer type with higher MET expression.	('MET', 'Gene', '79811', (126, 129))	('KIRP', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MET', 'Gene', (126, 129))	('gain', 'PosReg', (80, 84))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (102, 108))
57425	33178590	MET alterations were observed most commonly in UCEC (10.21%), SKCM (10.14%), and KIRP (9.89%), in which mutations were more common.	('SKCM', 'Disease', (62, 66))	('MET', 'Gene', '79811', (0, 3))	('alterations', 'Var', (4, 15))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (47, 51))	('observed', 'Reg', (21, 29))	('KIRP', 'Disease', (81, 85))
57426	33178590	Other cancer types with dominant MET mutations but at much lower mutation rates included LUAD (3.53%), BLCA (3.89%), COADREAD (3.2%), UCS (3.51%), and PAAD (0.54%).	('COADREAD', 'Disease', (117, 125))	('LUAD', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('UCS', 'Disease', (134, 137))	('PAAD', 'Phenotype', 'HP:0006725', (151, 155))	('PAAD', 'Disease', (151, 155))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('BLCA', 'Disease', (103, 107))	('MET', 'Gene', '79811', (33, 36))	('cancer', 'Disease', (6, 12))	('MET', 'Gene', (33, 36))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
57429	33178590	Approximately half of the mutations (29 of 67 mutations) in the Pkinase-Tyr domain also had MET copy gain, while nearly half of the mutations (44 of 90 mutations) in the other function-unknown domain were accompanied by amplification, gain, and shallow deletion.	('Pkinase-Tyr', 'Gene', (64, 75))	('copy', 'MPA', (96, 100))	('mutations', 'Var', (46, 55))	('MET', 'Gene', (92, 95))	('mutations', 'Var', (132, 141))	('gain', 'PosReg', (101, 105))	('amplification', 'MPA', (220, 233))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('mutations', 'Var', (26, 35))	('gain', 'PosReg', (235, 239))	('MET', 'Gene', '79811', (92, 95))
57436	33178590	Moreover, when the survival association analysis was performed only for MET mutation status, MET mutations were associated with poor prognosis in LUAD (Figure 7D).	('mutations', 'Var', (97, 106))	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('MET', 'Gene', '79811', (93, 96))	('LUAD', 'Disease', (146, 150))	('MET', 'Gene', '79811', (72, 75))	('MET', 'Gene', (93, 96))	('MET', 'Gene', (72, 75))
57438	33178590	UCEC, SKCM, and KIRP had the highest MET alteration, and mutations accounted for the major proportion.	('MET', 'Gene', (37, 40))	('mutations', 'Var', (57, 66))	('MET', 'Gene', '79811', (37, 40))
57439	33178590	While mutations in UCEC and SKCM were most commonly located in the Sema domain and the other function-unknown domain, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is more important for treatment selection.	('KIRP', 'Gene', (131, 135))	('located', 'Reg', (52, 59))	('Sema', 'Gene', (67, 71))	('mutations', 'Var', (118, 127))	('Sema', 'Gene', '7869', (67, 71))	('Tyr', 'Chemical', 'MESH:D014443', (174, 177))	('mutations', 'Var', (6, 15))	('UCEC', 'Gene', (19, 23))
57441	33178590	Other cancer types, including LUAD, BLCA, COADREAD, and UCS harbored similar characteristics; all their alteration frequency was between 4 and 6%, and mutation was the primary alteration.	('BLCA', 'Disease', (36, 40))	('LUAD', 'Disease', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('COADREAD', 'Disease', (42, 50))	('UCS', 'Disease', (56, 59))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
57442	33178590	Mutations in LUAD are mainly X1010_splices, which are in exon 14, and mutations in this region are known for targeted therapy in clinical practice in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('LUAD', 'Gene', (13, 17))	('X1010_splices', 'Var', (29, 42))	('NSCLC', 'Disease', (150, 155))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
57450	33178590	In addition, the prognostic role of MET in LUAD was quite clear, and both high expression and amplification of MET were significantly associated with poor prognosis.	('associated', 'Reg', (134, 144))	('amplification', 'Var', (94, 107))	('high', 'Var', (74, 78))	('MET', 'Gene', '79811', (111, 114))	('MET', 'Gene', (111, 114))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))
57453	33178590	Compared with other cancer types, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is known for targeted therapy with TKIs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Tyr', 'Chemical', 'MESH:D014443', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('mutations', 'Var', (34, 43))
57456	33178590	In addition, high expression of MET was discovered in KIRP, and most mutations in KIRP were oncogenic and likely oncogenic; however, there was no association observed between MET expression and patient prognosis in this dataset, although some reports indicated otherwise.	('MET', 'Gene', '79811', (175, 178))	('mutations', 'Var', (69, 78))	('patient', 'Species', '9606', (194, 201))	('MET', 'Gene', (175, 178))	('KIRP', 'Gene', (82, 86))	('MET', 'Gene', '79811', (32, 35))	('MET', 'Gene', (32, 35))
57457	33178590	This paradox could be due to the absence of well-known responsive mutations and the presence of alternative compensatory pathways interacting with MET pathways, such as the MAPK/ERK and PI3K/AKT pathways, which inspired further research on combinatorial therapy strategies in KIRP.	('mutations', 'Var', (66, 75))	('MET', 'Gene', '79811', (147, 150))	('AKT', 'Gene', '207', (191, 194))	('MET', 'Gene', (147, 150))	('AKT', 'Gene', (191, 194))	('ERK', 'Gene', '2048', (178, 181))	('ERK', 'Gene', (178, 181))
57462	33178590	However, several recent reports have showed that passenger mutations may also have critical functional roles in driving cancer, with some authors describing them as mini drivers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('mutations', 'Var', (59, 68))
57463	33178590	They found that the aggregated impact of putative passenger mutations could provide significant predictive power to distinguish cancer from non-cancer phenotypes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('non-cancer', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (144, 150))	('non-cancer', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (128, 134))
57464	33178590	The above content implied to us that in some types of cancers, such as UCEC, even most of these mutations belonged to the unknown class; more efforts are needed to determine the meanings of these mutations, which might be found to also have important functional roles in driving tumorigenesis.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Disease', (54, 61))	('UCEC', 'Disease', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Disease', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (196, 205))
57465	33178590	In addition, several reports have showed that some gene mutations, like BRAF mutation and ERBB2 mutation, were associated with MSI status in several cancer types.	('cancer', 'Disease', (149, 155))	('MSI status', 'Disease', (127, 137))	('BRAF', 'Gene', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutation', 'Var', (77, 85))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (90, 95))	('BRAF', 'Gene', '673', (72, 76))
57485	33178590	Some alterations are more involved in the development of tumors, while others participate more in targeted therapy.	('involved', 'Reg', (26, 34))	('participate', 'Reg', (78, 89))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
57632	30197062	In endometrioid endometrial cancer, OS was significantly worse in metachronous cases compared to non-metachronous cases (HR 6.17, P < 0.001).	('endometrioid endometrial cancer', 'Disease', (3, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('metachronous', 'Var', (66, 78))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (3, 34))	('endometrial cancer', 'Phenotype', 'HP:0012114', (16, 34))	('worse', 'NegReg', (57, 62))
57636	30197062	Similarly, in early-stage endometrial cancer, metachronous cases were significantly associated with decreased OS compared to non-metachronous cases (HR for stage I-II: 5.29, P < 0.001).	('endometrial cancer', 'Disease', 'MESH:D016889', (26, 44))	('metachronous cases', 'Var', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('decreased', 'NegReg', (100, 109))	('endometrial cancer', 'Disease', (26, 44))	('endometrial cancer', 'Phenotype', 'HP:0012114', (26, 44))
57643	30197062	Due to lack of prior studies examining the tumor factor-specific significance of metachronous uterine malignancy, it remains unknown as to why metachronicity impacts survival more in tumors that are low-grade, early-stage, and of endometrioid histology compared to tumors that are high-grade, advanced-stage, and of non-endometrioid histology.	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumor', 'Disease', (43, 48))	('tumors', 'Disease', (183, 189))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('uterine malignancy', 'Phenotype', 'HP:0010784', (94, 112))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('survival', 'MPA', (166, 174))	('low-grade', 'Var', (199, 208))	('metachronous uterine malignancy', 'Disease', 'MESH:D016609', (81, 112))	('impacts', 'Reg', (158, 165))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (183, 188))	('endometrioid', 'Disease', (230, 242))	('metachronous uterine malignancy', 'Disease', (81, 112))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumors', 'Disease', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
57653	30197062	Radiotherapy is generally known, however, to induce enhanced short-term immune function via various mechanisms such as increased immunogenic cell death but the long-term effects are not known.	('death', 'Disease', (146, 151))	('Radiotherapy', 'Var', (0, 12))	('enhanced', 'PosReg', (52, 60))	('death', 'Disease', 'MESH:D003643', (146, 151))
57656	30197062	This observation is likely due to the fact that women with lower grade cervical cancers have more favorable survival and are more likely to be cured of their disease and become cancer survivors, with the potential to develop metachronous uterine malignancy several years remote from their cervical cancer diagnosis.	('lower grade', 'Var', (59, 70))	('cancer', 'Disease', (177, 183))	('cervical cancer', 'Disease', 'MESH:D002583', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('women', 'Species', '9606', (48, 53))	('uterine malignancy', 'Phenotype', 'HP:0010784', (238, 256))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('metachronous uterine malignancy', 'Disease', 'MESH:D016609', (225, 256))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cervical cancers', 'Disease', (71, 87))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cervical cancers', 'Disease', 'MESH:D002583', (71, 87))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('more', 'PosReg', (93, 97))	('cervical cancer', 'Disease', (289, 304))	('cervical cancer', 'Disease', 'MESH:D002583', (289, 304))	('metachronous uterine malignancy', 'Disease', (225, 256))	('develop', 'PosReg', (217, 224))	('cancer', 'Disease', (298, 304))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
57685	32939323	Lung cancer patients with positive Siglec-15 expression showed significantly short survival rates in progression-free survival concomitant with reduced infiltration of CD20 + B, and dendritic cells by immunohistochemistry.	('short', 'NegReg', (77, 82))	('reduced', 'NegReg', (144, 151))	('patients', 'Species', '9606', (12, 20))	('positive', 'Var', (26, 34))	('Siglec-15', 'Gene', (35, 44))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('CD20', 'Gene', '54474', (168, 172))	('CD20', 'Gene', (168, 172))	('Lung cancer', 'Disease', (0, 11))	('progression-free survival', 'CPA', (101, 126))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('expression', 'Var', (45, 55))	('infiltration', 'MPA', (152, 164))	('Siglec-15', 'Gene', '284266', (35, 44))
57716	32939323	We investigated the copy number alterations (CNA) and mutations of Siglec-15 in different cancers.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (54, 63))	('copy number alterations', 'Var', (20, 43))	('Siglec-15', 'Gene', '284266', (67, 76))	('Siglec-15', 'Gene', (67, 76))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
57751	32939323	Genetic and epigenetic changes play a critical role in regulating cancer development and immune tolerance.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Genetic', 'Var', (0, 7))	('immune tolerance', 'CPA', (89, 105))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('epigenetic changes', 'Var', (12, 30))	('cancer', 'Disease', (66, 72))
57753	32939323	We found that patients with high Siglec-15 expression were accompanied by gene alterations in OV, HNSC, sarcoma (SARC), UCEC, BLCA, BRCA, SKCM, and lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) (Figure 2a, Supplementary Figure S2a).	('neoplasm', 'Phenotype', 'HP:0002664', (157, 165))	('alterations', 'Reg', (79, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (180, 195))	('patients', 'Species', '9606', (14, 22))	('HNSC', 'Disease', (98, 102))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (180, 195))	('OV', 'Phenotype', 'HP:0012887', (94, 96))	('lymphoid neoplasm', 'Disease', (148, 165))	('SARC', 'Phenotype', 'HP:0100242', (113, 117))	('B-cell lymphoma', 'Disease', (180, 195))	('Siglec-15', 'Gene', (33, 42))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('high', 'Var', (28, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (187, 195))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (148, 165))	('sarcoma', 'Disease', (104, 111))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (148, 165))	('Siglec-15', 'Gene', '284266', (33, 42))	('expression', 'MPA', (43, 53))
57754	32939323	The trends in Siglec-15 genetic alteration were consistent with its mRNA levels in these cancers.	('Siglec-15', 'Gene', (14, 23))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('genetic alteration', 'Var', (24, 42))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('Siglec-15', 'Gene', '284266', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
57773	32939323	High Siglec-15 expression predicted worse outcomes in LUAD, BRCA-basal, BRCA-Her2+ ,and STAD (Figure 3d).	('High', 'Var', (0, 4))	('BRCA', 'Phenotype', 'HP:0003002', (72, 76))	('Her2', 'Gene', (77, 81))	('Siglec-15', 'Gene', '284266', (5, 14))	('Her2', 'Gene', '2064', (77, 81))	('expression', 'MPA', (15, 25))	('Siglec-15', 'Gene', (5, 14))	('LUAD', 'Phenotype', 'HP:0030078', (54, 58))	('BRCA', 'Phenotype', 'HP:0003002', (60, 64))	('STAD', 'Disease', (88, 92))	('LUAD', 'Disease', (54, 58))	('BRCA-basal', 'Disease', (60, 70))
57774	32939323	Furthermore, high Siglec-15 expression was associated with poor OS and FP in LUAD; poor OS in BRCA-basal; poor RFS in BRCA-Her2+; poor OS and PPS in STAD-intestinal; and poor OS in STAD-mixed.	('Siglec-15', 'Gene', (18, 27))	('high', 'Var', (13, 17))	('BRCA', 'Phenotype', 'HP:0003002', (94, 98))	('Her2', 'Gene', (123, 127))	('expression', 'MPA', (28, 38))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('Her2', 'Gene', '2064', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('PPS', 'Chemical', '-', (142, 145))	('Siglec-15', 'Gene', '284266', (18, 27))
57791	32939323	Siglec-15 was positively associated with naive B cells, neutrophils, and activated mast cells and negatively associated with follicular helper T cells in metastatic SKCM in GSE8401 compared to the associations in primary SKCM.	('positively', 'PosReg', (14, 24))	('follicular helper T cells', 'CPA', (125, 150))	('associated', 'Interaction', (109, 119))	('associated', 'Interaction', (25, 35))	('negatively', 'NegReg', (98, 108))	('Siglec-15', 'Gene', '284266', (0, 9))	('GSE8401', 'Var', (173, 180))	('Siglec-15', 'Gene', (0, 9))	('metastatic SKCM', 'Disease', (154, 169))
57793	32939323	These results suggest opposite correlation patterns in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) in GSE26886; however, the results were not significant.	('adenocarcinoma', 'Disease', (112, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (112, 126))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('esophageal squamous cell carcinoma', 'Disease', (55, 89))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('GSE26886', 'Var', (136, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
57813	32939323	And PI3 K was significantly positively associated with Siglec-15 expression (Pearson r = 0.54, p = .01).	('expression', 'MPA', (65, 75))	('Siglec-15', 'Gene', (55, 64))	('PI3 K', 'Var', (4, 9))	('Siglec-15', 'Gene', '284266', (55, 64))
57815	32939323	PI3 K was highly expressed in the Siglec-15 high group (p < .05).	('Siglec-15', 'Gene', (34, 43))	('Siglec-15', 'Gene', '284266', (34, 43))	('PI3', 'Var', (0, 3))
57846	32939323	For example, mutant PD-L1 with structural variations leads to aberrant PD-L1 expression and immunosuppression.	('mutant', 'Var', (13, 19))	('expression', 'MPA', (77, 87))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', (20, 25))	('PD-L1', 'Gene', '29126', (71, 76))	('leads to', 'Reg', (53, 61))	('PD-L1', 'Gene', '29126', (20, 25))
57847	32939323	JAK2/PD-L1/PD-L2 (9p24.1) amplifications can also bring about constitutive overexpression of PD-L1 and a significant response to checkpoint inhibitors.	('PD-L1', 'Gene', '29126', (93, 98))	('overexpression', 'PosReg', (75, 89))	('PD-L1', 'Gene', (5, 10))	('JAK2', 'Gene', '3717', (0, 4))	('response to checkpoint inhibitors', 'MPA', (117, 150))	('PD-L1', 'Gene', '29126', (5, 10))	('JAK2', 'Gene', (0, 4))	('bring about', 'Reg', (50, 61))	('PD-L1', 'Gene', (93, 98))	('PD-L2', 'Gene', (11, 16))	('PD-L2', 'Gene', '80380', (11, 16))	('amplifications', 'Var', (26, 40))
57849	32939323	Preliminary analysis suggested that Siglec-15 expression was genetically and epigenetically regulated through CNA and promoter methylation.	('expression', 'MPA', (46, 56))	('Siglec-15', 'Gene', (36, 45))	('Siglec-15', 'Gene', '284266', (36, 45))	('promoter methylation', 'Var', (118, 138))
57866	32939323	There is an increasing trend for CXCR3 and MMP9 in patients with overexpressed Siglec-15, which may recruit Treg.	('overexpressed', 'Var', (65, 78))	('Siglec-15', 'Gene', (79, 88))	('CXCR3', 'Gene', '2833', (33, 38))	('patients', 'Species', '9606', (51, 59))	('MMP9', 'Gene', (43, 47))	('CXCR3', 'Gene', (33, 38))	('MMP9', 'Gene', '4318', (43, 47))	('Siglec-15', 'Gene', '284266', (79, 88))
57883	32722287	Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Mutations', 'Var', (51, 60))
57885	32722287	Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome.	('Cancer', 'Disease', (17, 23))	('matrisome genes', 'Gene', (118, 133))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (92, 101))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('copy number alterations', 'Var', (64, 87))
57888	32722287	In recent years, The Cancer Genome Atlas (TCGA) has provided researchers with an unmatched set of genomics, epigenomics, transcriptomics, and clinical data, enabling disruptive discoveries of driver mutations and oncogenic signaling pathways, probing the immune landscape of tumors pathways, or correlating genomic alterations to response to anti-cancer therapies.	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('tumors', 'Disease', (275, 281))	('probing', 'Reg', (243, 250))	('Cancer', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (347, 353))	('cancer', 'Disease', 'MESH:D009369', (347, 353))	('mutations', 'Var', (199, 208))	('oncogenic signaling pathways', 'Pathway', (213, 241))
57894	32722287	Used to annotate proteomics data of murine or human tumors, it has revealed that compositional and quantitative alterations of the matrisome contribute to tumor progression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('murine', 'Species', '10090', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Disease', (52, 58))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('human', 'Species', '9606', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('alterations', 'Var', (112, 123))	('contribute', 'Reg', (141, 151))	('compositional', 'MPA', (81, 94))
57899	32722287	However, while mutations in ECM genes have been linked to a plethora of diseases and syndromes, no study has focused on determining the presence and extent of genomic alterations and mutations in ECM genes in cancers, a crucial piece of information to further understanding of the tumor microenvironment (TME).	('plethora', 'Phenotype', 'HP:0001050', (60, 68))	('mutations', 'Var', (15, 24))	('ECM genes', 'Gene', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancers', 'Disease', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))	('linked', 'Reg', (48, 54))
57901	32722287	For our analysis, we retrieved data on 1014 of the 1027 human matrisome genes for 6740 patients and surveyed the nature and potential consequences of 4433 copy number alterations (CNAs) and 4497 mutations affecting matrisome genes (Table 2).	('matrisome genes', 'Gene', (62, 77))	('4497', 'Var', (190, 194))	('human', 'Species', '9606', (56, 61))	('copy number alterations', 'Var', (155, 178))	('patients', 'Species', '9606', (87, 95))
57903	32722287	We further identified common core matrisome and matrisome-associated genes altered across multiple cancer types, and within these genes, we identified sequences encoding protein domains that accumulate more frequent mutations, which hints at the potential functional consequences these mutations could have on the multi-faceted roles of the ECM in cancer initiation and progression.	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('mutations', 'Var', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', (348, 354))
57904	32722287	Last, we report the identification of matrisome genes whose mutational burden correlates with overall survival, demonstrating the potential prognostic value of analyzing genomic features of the matrisome to predict cancer patient outcome.	('matrisome genes', 'Gene', (38, 53))	('correlates', 'Reg', (78, 88))	('mutational burden', 'Var', (60, 77))	('cancer', 'Disease', (215, 221))	('overall survival', 'MPA', (94, 110))	('patient', 'Species', '9606', (222, 229))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
57908	32722287	Further breakdown of the data per matrisome gene category (Figure S2) shows the same general outlook: matrisome genes seem particularly tolerant of copy number alterations, with minor tumor-specific differences in the amount and type of CNAs within the matrisome categories.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('matrisome genes', 'Gene', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('copy number alterations', 'Var', (148, 171))
57912	32722287	This suggests that either or both a lower selective pressure on these mutations by, for example, immune cells and/or a higher fitness as local mutators that act as a buffer to the preservation of the global genomic information might act on matrisome sequences at the genomic level.	('fitness', 'Disease', 'MESH:D012640', (126, 133))	('mutations', 'Var', (70, 79))	('fitness', 'Disease', (126, 133))
57914	32722287	Of note, for three cancer types, cutaneous melanoma, stomach adenocarcinoma, and endometrial carcinoma, we found a subset of mutations in matrisome genes found in more than five patients (Table S2C).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('mutations', 'Var', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('endometrial carcinoma', 'Disease', (81, 102))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('stomach adenocarcinoma', 'Disease', (53, 75))	('cancer', 'Disease', (19, 25))	('patients', 'Species', '9606', (178, 186))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('matrisome genes', 'Gene', (138, 153))	('cutaneous melanoma', 'Disease', (33, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (33, 51))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (53, 75))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (81, 102))
57915	32722287	In light of our findings on CNAs, we can speculate that the selective pressure on these mutations might be counteracted and dispersed by the high number of matrisome gene paralogs, which might further point to a role for matrisome gene mutations as local mutators or interactors rather than cancer drivers.	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('mutations', 'Var', (88, 97))	('mutations', 'Var', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
57916	32722287	While most of the mutations identified were specific to only one patient or to a few patients within a single tumor type (Table S2), we could nonetheless identify potential "hotspot" mutations, defined as occurring in at least five patients per tumor type, and in at least two different tumor types, for six genes (Figure S4).	('patient', 'Species', '9606', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('patients', 'Species', '9606', (232, 240))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', (287, 292))	('patient', 'Species', '9606', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (245, 250))	('patient', 'Species', '9606', (232, 239))	('mutations', 'Var', (18, 27))
57918	32722287	We further interrogated the molecular nature of the mutations and found that for all matrisome gene categories and for most cancer types, these were in majority (>~70%) transitions, i.e., the interchange of a purine for another (A/G) or of a pyrimidine for another (C/T) (Figure S5).	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (124, 130))	('interchange', 'Var', (192, 203))	('matrisome gene', 'Gene', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('purine', 'MPA', (209, 215))	('purine', 'Chemical', 'MESH:C030985', (209, 215))	('pyrimidine', 'Chemical', 'MESH:C030986', (242, 252))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
57920	32722287	Interestingly, for the former, the frequency of transversions, the replacement of a purine by a pyrimidine and a hallmark of the carcinogenic effects of smoking on genes, and the frequency of transitions were similar, and this was consistent across all matrisome gene categories (Figure S5).	('carcinogenic', 'Disease', 'MESH:D063646', (129, 141))	('purine', 'Chemical', 'MESH:C030985', (84, 90))	('replacement', 'MPA', (67, 78))	('carcinogenic', 'Disease', (129, 141))	('pyrimidine', 'Chemical', 'MESH:C030986', (96, 106))	('transversions', 'Var', (48, 61))
57922	32722287	When looking at the type of mutations affecting matrisome genes, we found that the majority of mutations across all cancer types were missense mutations (~50%), followed by silent mutations (~25%) (Figure 3C).	('missense mutations', 'Var', (134, 152))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (95, 104))
57924	32722287	In addition, when looking specifically at the frequency of mutation types per matrisome gene categories and cancer types, we observed that matrisome genes and particularly secreted factors presented frequent mutations affecting splicing sites in cervical squamous cell carcinomas and endocervical adenocarcinomas (CESC), esophageal carcinomas (ESCA), and uterine carcinosarcoma (UCS) (Figure S6).	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (321, 342))	('UCS', 'Phenotype', 'HP:0002891', (379, 382))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (321, 342))	('mutations', 'Var', (208, 217))	('carcinosarcoma', 'Disease', (363, 377))	('esophageal carcinomas', 'Disease', (321, 342))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('carcinosarcoma', 'Disease', 'MESH:D002296', (363, 377))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('splicing sites', 'MPA', (228, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (355, 377))	('matrisome genes', 'Gene', (139, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinomas', 'Phenotype', 'HP:0030731', (269, 279))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (255, 279))	('ESCA', 'Phenotype', 'HP:0011459', (344, 348))	('carcinomas', 'Phenotype', 'HP:0030731', (332, 342))	('cancer', 'Disease', (108, 114))	('cervical squamous cell carcinomas and endocervical adenocarcinomas', 'Disease', 'MESH:D002294', (246, 312))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
57925	32722287	This is of particular relevance, since there exist multiple examples of alternative splicing of ECM genes (e.g., fibronectin, tenascin) or growth factors resulting in the production of isoforms only reported to be expressed in pathological conditions such as wound healing and cancers, and these splice variants have been proposed to serve as biomarkers or anchors to selectively target drugs or biological agents to tumors.	('tenascin', 'Gene', (126, 134))	('tenascin', 'Gene', '3371', (126, 134))	('fibronectin', 'Gene', '2335', (113, 124))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (417, 422))	('cancers', 'Disease', (277, 284))	('ECM genes', 'Gene', (96, 105))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('tumors', 'Disease', 'MESH:D009369', (417, 423))	('tumors', 'Phenotype', 'HP:0002664', (417, 423))	('tumors', 'Disease', (417, 423))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('fibronectin', 'Gene', (113, 124))	('alternative splicing', 'Var', (72, 92))
57930	32722287	This is, for example, the case of mucin 16 (MUC16) or filaggrin (FLG), which are mutated in all 14 tumors analyzed, or of hemicentin 1 (HMCN1), mucin 5 B (MUC5B) or reelin (RELN) mutated in 12/14 tumors.	('MUC16', 'Gene', '94025', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('mucin 16', 'Gene', (34, 42))	('MUC16', 'Gene', (44, 49))	('hemicentin 1', 'Gene', '83872', (122, 134))	('RELN', 'Gene', '5649', (173, 177))	('reelin', 'Gene', '5649', (165, 171))	('MUC5B', 'Gene', '727897', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('mutated', 'Var', (179, 186))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('mucin 5 B', 'Gene', (144, 153))	('HMCN1', 'Gene', (136, 141))	('filaggrin', 'Gene', '2312', (54, 63))	('tumors', 'Disease', (196, 202))	('FLG', 'Gene', (65, 68))	('mutated', 'Var', (81, 88))	('hemicentin 1', 'Gene', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('MUC5B', 'Gene', (155, 160))	('tumors', 'Disease', (99, 105))	('reelin', 'Gene', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('filaggrin', 'Gene', (54, 63))	('mucin 16', 'Gene', '94025', (34, 42))	('FLG', 'Gene', '2312', (65, 68))	('RELN', 'Gene', (173, 177))	('mucin 5 B', 'Gene', '727897', (144, 153))	('HMCN1', 'Gene', '83872', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
57932	32722287	Interestingly, we observed again a differential distribution in the accumulation of mutations between core matrisome and matrisome-associated genes, with the latter (which includes the mucins) being more frequently represented at top position across all cancers considered.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('mucin', 'Gene', '100508689', (185, 190))	('matrisome-associated genes', 'Gene', (121, 147))	('mucin', 'Gene', (185, 190))	('mutations', 'Var', (84, 93))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cancers', 'Disease', (254, 261))	('cancers', 'Disease', 'MESH:D009369', (254, 261))
57936	32722287	Similarly, especially considering the impact on patient survival (see Figure 7), our data suggest that mutations within the mucin genes, especially MUC16 and MUC5B, are worth further assessment for their potential prognostic use, again expanding on observations from previous reports.	('mutations', 'Var', (103, 112))	('MUC16', 'Gene', (148, 153))	('MUC5B', 'Gene', '727897', (158, 163))	('mucin', 'Gene', '100508689', (124, 129))	('MUC5B', 'Gene', (158, 163))	('patient', 'Species', '9606', (48, 55))	('MUC16', 'Gene', '94025', (148, 153))	('mucin', 'Gene', (124, 129))
57938	32722287	Figure 7 depicts the prognostic value of two core matrisome genes, COL6A1 and LAMB3, and of two matrisome-associated genes, MUC5B and MUC16, whose mutational burden significantly correlated either negatively (Table 3A and Table 4A) or positively (Table 3B and Table 4B) with overall survival in at least two cancer types: colorectal cancer and melanoma for COL6A1, lung adenocarcinoma and stomach adenocarcinoma for LAMB3, melanoma and uterine corpus endometrial carcinoma for MUC16, and lung adenocarcinoma and uterine corpus endometrial carcinoma for MUC5B.	('stomach adenocarcinoma', 'Disease', (389, 411))	('carcinoma', 'Phenotype', 'HP:0030731', (375, 384))	('LAMB3', 'Gene', (416, 421))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (451, 472))	('MUC5B', 'Gene', '727897', (553, 558))	('colorectal cancer', 'Phenotype', 'HP:0003003', (322, 339))	('mutational', 'Var', (147, 157))	('melanoma', 'Disease', 'MESH:D008545', (344, 352))	('lung adenocarcinoma', 'Disease', (488, 507))	('endometrial carcinoma', 'Disease', (527, 548))	('cancer', 'Disease', (333, 339))	('MUC16', 'Gene', '94025', (477, 482))	('carcinoma', 'Phenotype', 'HP:0030731', (539, 548))	('MUC5B', 'Gene', (553, 558))	('LAMB3', 'Gene', '3914', (416, 421))	('MUC5B', 'Gene', '727897', (124, 129))	('LAMB3', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (498, 507))	('MUC16', 'Gene', '94025', (134, 139))	('melanoma', 'Disease', 'MESH:D008545', (423, 431))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (488, 507))	('COL6A1', 'Gene', (357, 363))	('COL6A1', 'Gene', '1291', (357, 363))	('lung adenocarcinoma', 'Disease', (365, 384))	('colorectal cancer', 'Disease', 'MESH:D015179', (322, 339))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (527, 548))	('cancer', 'Disease', (308, 314))	('endometrial carcinoma', 'Disease', (451, 472))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (488, 507))	('MUC5B', 'Gene', (124, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (365, 384))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (527, 548))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('MUC16', 'Gene', (477, 482))	('melanoma', 'Phenotype', 'HP:0002861', (344, 352))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('colorectal cancer', 'Disease', (322, 339))	('melanoma', 'Disease', (344, 352))	('LAMB3', 'Gene', '3914', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (389, 411))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (365, 384))	('MUC16', 'Gene', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (463, 472))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (451, 472))	('COL6A1', 'Gene', '1291', (67, 73))	('COL6A1', 'Gene', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (423, 431))	('melanoma', 'Disease', (423, 431))
57940	32722287	The same holds true for matrisome protein domains (Table S5B), though, from both the gene-centric and the domain-centric analyses, we observed that mutations in the tumor matrisome are much more likely to associate with increased overall survival (overall survival, approximately 61% of genes and 81% of domains reported in Table S5), supporting the idea that mutations in the tumor matrisome disrupt the organization of the tumor microenvironment and disadvantage neoplastic cells taking away structural cues they require for extensive growth, spreading, and metastasis.	('increased', 'PosReg', (220, 229))	('tumor', 'Disease', (425, 430))	('overall survival', 'CPA', (230, 246))	('mutations', 'Var', (148, 157))	('S5B', 'Gene', '5711', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (377, 382))	('S5B', 'Gene', (57, 60))	('disrupt', 'NegReg', (393, 400))	('organization of', 'CPA', (405, 420))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (425, 430))	('mutations', 'Var', (360, 369))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('tumor', 'Phenotype', 'HP:0002664', (425, 430))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('tumor', 'Disease', (165, 170))
57941	32722287	This observation may provide another explanation for the low recurrence of matrisome mutations found across tumors, though the lack of time coordinates within the TCGA data and their bulk rather than single cell structure prevented us from testing this further (see Section 4).	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutations', 'Var', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('matrisome', 'Gene', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
57943	32722287	We focused on the four genes, COL6A1, LAMB3, MUC5B, and MUC16, for which we showed that mutational burden had a prognostic value for patient survival (Figure 7) and interrogated a large collection of samples from patients and cells from 178 cohorts available via the cBioPortal (see Section 3).	('COL6A1', 'Gene', (30, 36))	('LAMB3', 'Gene', (38, 43))	('patient', 'Species', '9606', (213, 220))	('patient', 'Species', '9606', (133, 140))	('mutational', 'Var', (88, 98))	('LAMB3', 'Gene', '3914', (38, 43))	('MUC16', 'Gene', '94025', (56, 61))	('patients', 'Species', '9606', (213, 221))	('COL6A1', 'Gene', '1291', (30, 36))	('MUC5B', 'Gene', '727897', (45, 50))	('MUC5B', 'Gene', (45, 50))	('MUC16', 'Gene', (56, 61))
57944	32722287	We also observed an overall low occurrence and recurrence of CNAs and mutations for each of these genes (see the peak of the density plots around the 0 value in Figure S8A) and a higher number of studies with cases affected by CNAs or mutations for MUC5B and MUC16, than for COL6A1 and LAMB3 (Table S6A-D).	('affected', 'Reg', (215, 223))	('MUC5B', 'Gene', (249, 254))	('mutations', 'Var', (70, 79))	('MUC16', 'Gene', (259, 264))	('LAMB3', 'Gene', (286, 291))	('mutations', 'Var', (235, 244))	('COL6A1', 'Gene', '1291', (275, 281))	('COL6A1', 'Gene', (275, 281))	('CNAs', 'Gene', (227, 231))	('MUC16', 'Gene', '94025', (259, 264))	('LAMB3', 'Gene', '3914', (286, 291))	('MUC5B', 'Gene', '727897', (249, 254))
57946	32722287	Interestingly, we observed significant associations with survival for both MUC5B and MUC16 and a borderline association for COL6A1, which is similar to what we observed in the pan-cancer TCGA cohort (Figure 7), with MUC5B mutations associating with better survival and COL6A1 and MUC16 associating with poorer survival (Figure S8B).	('MUC16', 'Gene', '94025', (85, 90))	('MUC5B', 'Gene', '727897', (75, 80))	('MUC16', 'Gene', '94025', (280, 285))	('MUC5B', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('MUC5B', 'Gene', '727897', (216, 221))	('MUC16', 'Gene', (280, 285))	('MUC5B', 'Gene', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('COL6A1', 'Gene', (124, 130))	('COL6A1', 'Gene', (269, 275))	('COL6A1', 'Gene', '1291', (269, 275))	('mutations', 'Var', (222, 231))	('associations', 'Interaction', (39, 51))	('MUC16', 'Gene', (85, 90))	('COL6A1', 'Gene', '1291', (124, 130))	('cancer', 'Disease', (180, 186))	('better', 'PosReg', (249, 255))
57955	32722287	The prevalence of mutations in COL6A1, LAMB3, MUC5B, and MUC16 across 178 studies was evaluated via cBioPortal .	('LAMB3', 'Gene', '3914', (39, 44))	('MUC16', 'Gene', '94025', (57, 62))	('MUC16', 'Gene', (57, 62))	('COL6A1', 'Gene', (31, 37))	('COL6A1', 'Gene', '1291', (31, 37))	('MUC5B', 'Gene', '727897', (46, 51))	('LAMB3', 'Gene', (39, 44))	('MUC5B', 'Gene', (46, 51))	('mutations', 'Var', (18, 27))
57959	32722287	Hotspots mutations were defined as those occurring at least five times per tumor type in at least two different tumor types.	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (75, 80))
57962	32722287	This first survey of the genomic and mutational landscape of the cancer matrisome has uncovered the interesting, and yet perhaps unexpected, extent and consequences of copy number and mutational alterations of matrisome genes in a panel of 14 solid tumor types.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('matrisome genes', 'Gene', (210, 225))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', (249, 254))	('copy number', 'Var', (168, 179))	('mutational alterations', 'Var', (184, 206))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
57965	32722287	Further acknowledging that the number of CNAs and mutations in the cancer genome and the sample composition in terms of tumor/TME fractions are not linearly nor directly associated, the estimates we report for their interactions probably exceed their true extent.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (50, 59))	('interactions', 'Interaction', (216, 228))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
57969	32722287	One possibility is that mutations in matrisome genes, and more specifically located in sequences encoding protein domains, can affect protein/protein (e.g., ECM protein/ECM protein, ECM/growth factor, ECM/enzyme, ECM protein/ECM receptor) interactions and subsequently alter biochemical and mechanical signaling, leading to dysregulation of cellular phenotypes and eventually to cancer progression.	('cancer', 'Disease', (379, 385))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('leading to', 'Reg', (313, 323))	('dysregulation', 'MPA', (324, 337))	('protein/protein', 'Protein', (134, 149))	('cellular phenotypes', 'MPA', (341, 360))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('mutations', 'Var', (24, 33))	('alter', 'Reg', (269, 274))	('matrisome genes', 'Gene', (37, 52))	('affect', 'Reg', (127, 133))	('interactions', 'Interaction', (239, 251))
57970	32722287	Additionally, with recent reports highlighting the impact of the ECM on immune cells within the tumor microenvironment, mutations in matrisome genes could also result in the generation of neo-antigens and thus rewire the immune response.	('immune response', 'CPA', (221, 236))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('result in', 'Reg', (160, 169))	('neo-antigens', 'MPA', (188, 200))	('rewire', 'Reg', (210, 216))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('matrisome genes', 'Gene', (133, 148))
57971	32722287	We believe that our results are a starting point to the more extensive mapping of clinically relevant matrisome gene alterations and can be used to prioritize further investigations that may lead to significant translational applications to improve cancer patient care.	('alterations', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('matrisome gene', 'Gene', (102, 116))	('cancer', 'Disease', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('patient', 'Species', '9606', (256, 263))
57973	32722287	Frequency of CNAs and mutations in the matrisome genes COL6A1 (A), LAMB3 (B), MUC5B (C), MUC16 (D) in 180 different patient cohorts, representing 47500 cases available via cBioPortal, Table S7.	('MUC5B', 'Gene', '727897', (78, 83))	('MUC16', 'Gene', '94025', (89, 94))	('MUC5B', 'Gene', (78, 83))	('LAMB3', 'Gene', '3914', (67, 72))	('patient', 'Species', '9606', (116, 123))	('COL6A1', 'Gene', '1291', (55, 61))	('COL6A1', 'Gene', (55, 61))	('mutations', 'Var', (22, 31))	('MUC16', 'Gene', (89, 94))	('LAMB3', 'Gene', (67, 72))	('CNAs', 'Disease', (13, 17))
57974	32722287	Correlation of tumor purity with occurrence of CNAs and mutations in matrisome genes.	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('matrisome genes', 'Gene', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('CNAs', 'Disease', (47, 51))
57977	31440245	T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('destroy', 'NegReg', (85, 92))	('tumor', 'Disease', (57, 62))
57978	31440245	Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens.	('virulence of the immune system', 'MPA', (59, 89))	('increase', 'PosReg', (46, 54))	('cytotoxicity', 'Disease', 'MESH:D064420', (111, 123))	('cytotoxicity', 'Disease', (111, 123))	('increasing', 'PosReg', (93, 103))	('immunotherapy antibodies', 'Var', (17, 41))
57979	31440245	Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations.	('activate', 'PosReg', (86, 94))	('mutations', 'Var', (153, 162))	('patient', 'Species', '9606', (95, 102))
57980	31440245	Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells.	('increases', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutation-targeting', 'Var', (12, 30))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
57981	31440245	At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
57982	31440245	For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('TP53', 'Gene', (91, 95))	('HER2', 'Gene', '2064', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('breast tumors', 'Disease', (123, 136))	('breast tumors', 'Phenotype', 'HP:0100013', (123, 136))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('breast tumors', 'Disease', 'MESH:D001943', (123, 136))	('TP53', 'Gene', '7157', (91, 95))	('HER2', 'Gene', (31, 35))	('mutations', 'Var', (96, 105))	('mutated proteins', 'MPA', (65, 81))
57983	31440245	HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors.	('proteins', 'Protein', (38, 46))	('mutations', 'Var', (200, 209))	('neck tumors', 'Disease', 'MESH:D006258', (74, 85))	('TP53', 'Gene', '7157', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', (79, 85))	('head and neck tumors', 'Phenotype', 'HP:0012288', (65, 85))	('HPV', 'Gene', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('p53', 'Gene', '7157', (157, 160))	('mutations', 'Var', (220, 229))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (258, 264))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('neck tumors', 'Disease', (74, 85))	('TP53', 'Gene', (215, 219))	('p53', 'Gene', (157, 160))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('mutated', 'MPA', (30, 37))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
57986	31440245	Mutation neoantigens are critical for tumor control: T cells recognize mutant peptides bound to MHC alleles on tumor cells both in mice and humans and tumor mutational burden (TMB) predicts tumor response to anti-CTLA4 and anti-PD1 treatment.	('CTLA4', 'Gene', '1493', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PD1', 'Gene', (228, 231))	('PD1', 'Gene', '9825', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CTLA4', 'Gene', (213, 218))	('humans', 'Species', '9606', (140, 146))	('mutant', 'Var', (71, 77))	('mice', 'Species', '10090', (131, 135))	('TMB', 'Chemical', '-', (176, 179))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('MHC', 'Gene', (96, 99))
57987	31440245	Tumors that become resistant to pembrolizumab, an anti-PD1-therapy immunotherapy, often contain mutations in immune-related genes, including in interferon-receptor-associated Janus kinases and the antigen-presenting protein beta-2-microglobulin, suggesting that anti-PD1 therapeutic activity is mediated through neoantigen presentation and recognition.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PD1', 'Gene', (55, 58))	('PD1', 'Gene', '9825', (55, 58))	('PD1', 'Gene', '9825', (267, 270))	('pembrolizumab', 'Chemical', 'MESH:C582435', (32, 45))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('beta-2-microglobulin', 'Gene', '567', (224, 244))	('PD1', 'Gene', (267, 270))	('beta-2-microglobulin', 'Gene', (224, 244))	('mutations', 'Var', (96, 105))
57990	31440245	Together, these demonstrate that neoantigens encoding mutations can mediate the tumor-focused immune response and can be exploited as an exquisitely tumor-specific therapeutic target.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mediate', 'Reg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (149, 154))
57993	31440245	In addition to analysis of individual tumors, intra- and inter-indication analyses pinpoint re-occurring mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (105, 114))
57997	31440245	Missense mutations were mapped to human reference genome GRCh37 and filtered for those mutations present in at least two tumor samples.	('human', 'Species', '9606', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Missense mutations', 'Var', (0, 18))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
57999	31440245	Tumor mutational burden by indication: rather than examine mutation rates, Figure 1 shows the TMB as the number of proteins with non-synonymous point mutations in a tumor, grouped by cancer indication, along with the indication-specific median.	('non-synonymous point mutations', 'Var', (129, 159))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (183, 189))	('TMB', 'Chemical', '-', (94, 97))	('proteins', 'Protein', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Disease', (165, 170))
58006	31440245	Other indications with high median mutational burden show long tails (populations of tumors with many mutations), in particular melanoma and lung adenocarcinoma, but also lung squamous, bladder, and head and neck tumors.	('tumors', 'Disease', (213, 219))	('lung squamous', 'Disease', (171, 184))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('bladder', 'Disease', (186, 193))	('neck tumors', 'Disease', 'MESH:D006258', (208, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (102, 111))	('head and neck tumors', 'Phenotype', 'HP:0012288', (199, 219))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('particular melanoma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 160))	('neck tumors', 'Disease', (208, 219))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('long tail', 'Phenotype', 'HP:0002831', (58, 67))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('tumors', 'Disease', (85, 91))
58007	31440245	While MSI tumors are uncommon in breast cancer, there is curiously a clear population of breast tumors with significantly more mutations.	('MSI tumors', 'Disease', 'MESH:D009369', (6, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MSI tumors', 'Disease', (6, 16))	('breast tumors', 'Phenotype', 'HP:0100013', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('breast tumors', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('mutations', 'Var', (127, 136))	('breast tumors', 'Disease', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
58011	31440245	Normal breast tumors have the lowest median, 19 mutations, while luminal A tumors show a tight symmetrical distribution around the median, 25 mutations.	('A tumors', 'Disease', (73, 81))	('A tumors', 'Disease', 'MESH:D009369', (73, 81))	('breast tumors', 'Phenotype', 'HP:0100013', (7, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('breast tumors', 'Disease', 'MESH:D001943', (7, 20))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (48, 57))	('breast tumors', 'Disease', (7, 20))
58012	31440245	Interestingly, the percentage of tumors containing p53 mutations roughly tracks the median number of mutations in each class, highest in basal and HER2 positive tumors and lowest in luminal A tumors.	('p53', 'Gene', (51, 54))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', (192, 198))	('HER2', 'Gene', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('A tumors', 'Disease', (190, 198))	('mutations', 'Var', (55, 64))	('tumors', 'Disease', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('HER2', 'Gene', '2064', (147, 151))	('p53', 'Gene', '7157', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('A tumors', 'Disease', 'MESH:D009369', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
58018	31440245	In agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have p53 mutations, vs. 86% of the HPV negative tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (129, 138))	('tumors', 'Disease', (168, 174))	('p53', 'Gene', (125, 128))	('p53', 'Gene', (67, 70))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('p53', 'Gene', '7157', (125, 128))	('p53', 'Gene', '7157', (67, 70))	('HPV', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
58019	31440245	This suggests that the presence of HPV removes the need to mutate p53.	('mutate', 'Var', (59, 65))	('HPV', 'Gene', (35, 38))	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (66, 69))
58023	31440245	In colon tumors, the MSI-H tumors contain a median of 944 mutations vs. 93 and 86 in the MSI-L and MSS tumors, respectively.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (58, 67))	('MSS tumors', 'Disease', 'MESH:D013132', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('colon tumors', 'Disease', 'MESH:D015179', (3, 15))	('MSS tumors', 'Disease', (99, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('colon tumors', 'Disease', (3, 15))	('colon tumors', 'Phenotype', 'HP:0100273', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('MSI-H tumors', 'Disease', 'MESH:D009369', (21, 33))	('MSI-H tumors', 'Disease', (21, 33))
58024	31440245	The number of tumors with PIK3CA mutations is similar across the three sub-groups.	('PIK3CA', 'Gene', '5290', (26, 32))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('PIK3CA', 'Gene', (26, 32))
58025	31440245	However, similar to the HPV positive tumors, the percentage of MSI-H tumors with p53 mutations is much lower, here suggesting that the MSI-H status lessens the need of p53 mutations for oncogenesis.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MSI-H tumors', 'Disease', (63, 75))	('MSI-H tumors', 'Disease', 'MESH:D009369', (63, 75))	('MSI-H', 'Disease', 'MESH:D000848', (135, 140))	('p53', 'Gene', '7157', (168, 171))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('HPV positive tumors', 'Disease', (24, 43))	('HPV positive tumors', 'Disease', 'MESH:D030361', (24, 43))	('MSI-H', 'Disease', (63, 68))	('mutations', 'Var', (85, 94))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('MSI-H', 'Disease', (135, 140))	('p53', 'Gene', (168, 171))	('MSI-H', 'Disease', 'MESH:D000848', (63, 68))
58030	31440245	Recent clinical trials have shown increased benefit of anti-PD1 and anti-CTLA4 antibodies for the treatment of non-small-cell lung cancer (NSCLC) tumors with high TMB, defined as tumors with >10 mutations per megabase or as tumors with great than a median of 158 mutations.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('TMB', 'Chemical', '-', (163, 166))	('CTLA4', 'Gene', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('non-small-cell lung cancer (NSCLC) tumors', 'Disease', 'MESH:D002289', (111, 152))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('PD1', 'Gene', '9825', (60, 63))	('PD1', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('high TMB', 'Var', (158, 166))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CTLA4', 'Gene', '1493', (73, 78))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('tumors', 'Disease', (146, 152))
58031	31440245	The percentage of tumors with TP53 protein mutations is almost three-fold higher in current smokers than in never-smokers, 61% vs. 23%, respectively.	('TP53', 'Gene', (30, 34))	('higher', 'PosReg', (74, 80))	('mutations', 'Var', (43, 52))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('TP53', 'Gene', '7157', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
58032	31440245	Further examining the association of TP53 mutations, Figure 3, right, shows the relationship between TP53 mutations and TMB.	('TMB', 'Chemical', '-', (120, 123))	('TP53', 'Gene', '7157', (101, 105))	('relationship', 'Interaction', (80, 92))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('TMB', 'Disease', (120, 123))
58033	31440245	The tumors with TP53 mutations have over twice the number of mutated proteins compared to tumors with non-mutated TP53, 285 vs. 121 mutated proteins, respectively.	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (114, 118))	('mutated proteins', 'MPA', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('TP53', 'Gene', '7157', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('TP53', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
58034	31440245	Conversely, the rate of mutated KRAS is almost twice as large in the TP53 non-mutated tumors, 41% vs. 21%, respectively.	('mutated', 'Var', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('KRAS', 'Gene', (32, 36))	('tumors', 'Disease', (86, 92))	('KRAS', 'Gene', '3845', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))
58039	31440245	HLA allele B08, for example, is predicted to strongly bind (<10 nM) the peptide containing mutation NBPF10 p.E3455K, a mutation found in uterine carcinosarcoma and prostate tumors.	('p.E3455K', 'Var', (107, 115))	('NBPF10', 'Gene', '100132406', (100, 106))	('p.E3455K', 'Mutation', 'p.E3455K', (107, 115))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (137, 159))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('bind', 'Interaction', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('carcinosarcoma and prostate tumors', 'Disease', 'MESH:D002296', (145, 179))	('NBPF10', 'Gene', (100, 106))
58041	31440245	Most of the re-occurring mutations are predicted to bind one or more common HLA allele with binding affinity 500 nM or stronger, suggesting candidate patient subsets for investigation of each re-occurring mutation.	('binding', 'Interaction', (92, 99))	('mutations', 'Var', (25, 34))	('patient', 'Species', '9606', (150, 157))
58042	31440245	The IDH1 p.R132H mutation is found primarily in lower grade glioma, and found in 42% of these tumors.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glioma', 'Disease', (60, 66))	('p.R132H', 'Var', (9, 16))	('IDH1', 'Gene', (4, 8))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('p.R132H', 'Mutation', 'rs121913500', (9, 16))
58043	31440245	Other mutations, such as PIK3CA p.E545K, KRAS p.G12D, and KRAS p.G12V, occur in many indications.	('KRAS', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (58, 62))	('KRAS', 'Gene', '3845', (41, 45))	('PIK3CA', 'Gene', (25, 31))	('p.G12V', 'Mutation', 'rs121913529', (63, 69))	('PIK3CA', 'Gene', '5290', (25, 31))	('p.E545K', 'Var', (32, 39))	('p.G12D', 'Mutation', 'rs121913529', (46, 52))	('p.E545K', 'Mutation', 'rs104886003', (32, 39))	('KRAS', 'Gene', (41, 45))
58045	31440245	When ranked from most to less frequent, the most common mutations in an indication occur in 50% (thyroid) to <1% (renal clear cell) of the tumors.	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
58046	31440245	Of the indications considered here, only thyroid, melanoma, pancreatic, and lower grade glioma tumors have a mutation found in more than 20% of the tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('pancreatic', 'Disease', 'MESH:D010195', (60, 70))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('glioma tumors', 'Disease', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('pancreatic', 'Disease', (60, 70))	('glioma tumors', 'Disease', 'MESH:D005910', (88, 101))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('mutation', 'Var', (109, 117))
58047	31440245	When examining the cumulative sum of the first five mutations, one finds that contributions of mutations two through five are large for the profiled pancreatic and uterine cancers: over 80 and 40% of the profiled pancreatic and uterine tumors, respectively, have one of the five most frequent mutations.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('uterine cancers', 'Phenotype', 'HP:0010784', (164, 179))	('pancreatic', 'Disease', (149, 159))	('mutations', 'Var', (293, 302))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('pancreatic', 'Disease', 'MESH:D010195', (213, 223))	('uterine tumors', 'Phenotype', 'HP:0010784', (228, 242))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('cancers', 'Disease', (172, 179))	('pancreatic', 'Disease', (213, 223))	('tumors', 'Disease', (236, 242))	('uterine tumor', 'Phenotype', 'HP:0010784', (228, 241))	('pancreatic', 'Disease', 'MESH:D010195', (149, 159))
58048	31440245	The three most frequent mutations in pancreatic tumors are KRAS p.G12D, G12V, and G12R, demonstrating the importance of this aberration for pancreatic tumor oncogenicity.	('KRAS', 'Gene', '3845', (59, 63))	('G12V', 'Var', (72, 76))	('G12R', 'Mutation', 'rs121913530', (82, 86))	('KRAS', 'Gene', (59, 63))	('p.G12D', 'Mutation', 'rs121913529', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (37, 53))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (140, 156))	('G12R', 'Var', (82, 86))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (37, 54))	('pancreatic tumor', 'Disease', (140, 156))	('p.G12D', 'Var', (64, 70))	('pancreatic tumor', 'Disease', 'MESH:D010190', (37, 53))	('pancreatic tumor', 'Disease', 'MESH:D010190', (140, 156))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic tumors', 'Disease', 'MESH:D010190', (37, 54))	('pancreatic tumors', 'Disease', (37, 54))	('G12V', 'SUBSTITUTION', 'None', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
58049	31440245	Conversely, the most frequent uterine tumor mutations are found in different genes, including TP53, PIK3CA, ZNF814, and KRAS, suggesting engagement of alternative pathways.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('KRAS', 'Gene', '3845', (120, 124))	('ZNF814', 'Gene', (108, 114))	('uterine tumor', 'Phenotype', 'HP:0010784', (30, 43))	('TP53', 'Gene', '7157', (94, 98))	('PIK3CA', 'Gene', (100, 106))	('TP53', 'Gene', (94, 98))	('frequent uterine tumor', 'Phenotype', 'HP:0000130', (21, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (120, 124))	('PIK3CA', 'Gene', '5290', (100, 106))	('ZNF814', 'Gene', '730051', (108, 114))
58050	31440245	While not reviewed here, there are re-occurring mutations in other indications, such as uveal melanoma and diffuse intrinsic pontine glioma (DIPG) tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('intrinsic pontine glioma (DIPG) tumors', 'Disease', 'MESH:D000080443', (115, 153))	('uveal melanoma', 'Disease', (88, 102))	('mutations', 'Var', (48, 57))
58051	31440245	Cancer mutations are found in tumor cells and absent in non-tumorous cells.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (30, 35))	('mutations', 'Var', (7, 16))
58052	31440245	Thus, as targets, mutations are, by definition, uniquely found in the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mutations', 'Var', (18, 27))
58053	31440245	Some of the mutations are expressed, processed, and presented on tumor HLA molecules to T cells; those mutation-containing peptides that are recognized by T cells are neoantigens.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
58055	31440245	The number of mutations, and particularly the number of clonal immunogenic mutations, predicts tumor response to immune-strengthening therapeutics, such as anti-CLTA4 and anti-PD(L)1 mAbs.	('predicts', 'Reg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PD(L)1', 'Gene', (176, 182))	('PD(L)1', 'Gene', '29126', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (95, 100))
58056	31440245	Tumors with exceptionally high mutational burden respond favorably to immune-strengthening: pembrolizumab, an anti-PD-1 mAb, has been approved to treat MSI-H or mismatch repair deficient solid tumors, regardless of tumor site or histology.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mismatch', 'Var', (161, 169))	('deficient solid tumors', 'Disease', 'MESH:D009369', (177, 199))	('MSI-H', 'Disease', 'MESH:D000848', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('pembrolizumab', 'Chemical', 'MESH:C582435', (92, 105))	('deficient solid tumors', 'Disease', (177, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', (193, 198))	('MSI-H', 'Disease', (152, 157))
58057	31440245	Thus, Figure 1, and the subclasses in Figures 2, 3, identifies the tumors and indications:those with higher mutation burden:potentially more likely to respond to general immune strengthening agents (those agents not targeting specific mutations).	('more', 'PosReg', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutation', 'Var', (108, 116))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('respond', 'MPA', (151, 158))
58059	31440245	Mutations are identified in a patient's tumor using next-generation sequencing and bioinformatics, prioritized for vaccine inclusion using criteria including mutation clonality and peptide HLA binding affinity, manufactured, and administered with an adjuvant, potentially as part of combination therapy.	('patient', 'Species', '9606', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
58063	31440245	However, there are mutations found frequently in specific indications, such as IDH1 p.R132H in lower grade glioma.	('p.R132H', 'Mutation', 'rs121913500', (84, 91))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH1', 'Gene', (79, 83))	('p.R132H', 'Var', (84, 91))	('glioma', 'Disease', (107, 113))
58064	31440245	BRAF p.V600E, KRAS p.G12D, and KRAS p.G12V are frequent in multiple indications.	('KRAS', 'Gene', (31, 35))	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('KRAS', 'Gene', '3845', (14, 18))	('p.V600E', 'Var', (5, 12))	('KRAS', 'Gene', '3845', (31, 35))	('BRAF', 'Gene', '673', (0, 4))	('p.G12D', 'Mutation', 'rs121913529', (19, 25))	('BRAF', 'Gene', (0, 4))	('p.G12V', 'Mutation', 'rs121913529', (36, 42))	('KRAS', 'Gene', (14, 18))
58065	31440245	Other mutations, such as PIK3CA p.E545K, are less frequently found in a single indication but are found in the tumors of many indications.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('PIK3CA', 'Gene', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('PIK3CA', 'Gene', '5290', (25, 31))	('p.E545K', 'Var', (32, 39))	('p.E545K', 'Mutation', 'rs104886003', (32, 39))
58067	31440245	The five most frequent mutations in each indication typically account for more than 30% of the tumors in pancreatic, thyroid, lower grade glioma, melanoma, and uterine cancers.	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('account', 'Reg', (62, 69))	('cancers', 'Disease', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioma', 'Disease', (138, 144))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('pancreatic', 'Disease', 'MESH:D010195', (105, 115))	('mutations', 'Var', (23, 32))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('uterine cancers', 'Phenotype', 'HP:0010784', (160, 175))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('thyroid', 'Disease', (117, 124))	('pancreatic', 'Disease', (105, 115))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
58071	31440245	Using the impressive public domain TCGA dataset, this work shows the presence of non-synonymous single-nucleotide mutations across a broad panel of tumor indications and potential immunotherapy application.	('tumor', 'Disease', (148, 153))	('non-synonymous single-nucleotide mutations', 'Var', (81, 123))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))
58072	31440245	As previously described, melanoma and lung cancers have higher numbers of mutations relative to other tumors.	('melanoma and lung cancers', 'Disease', 'MESH:D008175', (25, 50))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('mutations', 'Var', (74, 83))	('lung cancers', 'Phenotype', 'HP:0100526', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
58075	31440245	Mutation rates vary among molecularly-defined tumor sub-groups: breast basal tumors have, on average, more mutations than luminal A tumors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('A tumors', 'Disease', 'MESH:D009369', (130, 138))	('mutations', 'Var', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('A tumors', 'Disease', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('basal tumors', 'Phenotype', 'HP:0002671', (71, 83))	('breast basal tumors', 'Disease', 'MESH:D001943', (64, 83))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('breast basal tumors', 'Disease', (64, 83))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
58076	31440245	Smoking and TP53 mutations are associated with high tumor mutation burden in lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', (12, 16))	('lung cancers', 'Disease', 'MESH:D008175', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (77, 89))	('TP53', 'Gene', '7157', (12, 16))	('high tumor', 'Disease', (47, 57))	('lung cancers', 'Disease', (77, 89))	('high tumor', 'Disease', 'MESH:D009369', (47, 57))	('mutations', 'Var', (17, 26))
58077	31440245	Finally, re-occurring mutations can be found in the profiled tumors: BRAF p.V600E is found in many thyroid tumors and melanomas and mutations such as PIK3CA p.E454K can be found at appreciable levels across multiple indications.	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('PIK3CA', 'Gene', '5290', (150, 156))	('p.E454K', 'Var', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))	('tumors', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('thyroid tumors and melanomas', 'Disease', 'MESH:D013959', (99, 127))	('p.V600E', 'Mutation', 'rs113488022', (74, 81))	('tumors', 'Disease', (107, 113))	('p.V600E', 'Var', (74, 81))	('p.E454K', 'Mutation', 'p.E454K', (157, 164))	('PIK3CA', 'Gene', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('found', 'Reg', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
58085	31307426	In contrast, for patients with carcinosarcoma, total mortality risk was significantly decreased with EBRT, brachytherapy, and combination radiotherapy compared with no radiotherapy.	('brachytherapy', 'Var', (107, 120))	('carcinosarcoma', 'Disease', 'MESH:D002296', (31, 45))	('mortality', 'MPA', (53, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('EBRT', 'Var', (101, 105))	('decreased', 'NegReg', (86, 95))	('patients', 'Species', '9606', (17, 25))	('carcinosarcoma', 'Disease', (31, 45))	('EBRT', 'Chemical', '-', (101, 105))
58112	31307426	The SEER database was examined to identify patients with primary uterine sarcoma according to codes of the International Classification of Diseases for Oncology (ICD-O) for anatomic sites (PRIMSITE = C54.0-C54.3, C54.8-C54.9, C55.9) who underwent total hysterectomy (SURGPRIF = 40, 50).	('Oncology', 'Phenotype', 'HP:0002664', (152, 160))	('C54.0-C54.3', 'Var', (200, 211))	('patients', 'Species', '9606', (43, 51))	('sarcoma', 'Disease', (73, 80))	('C54.8-C54.9', 'Var', (213, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (65, 80))	('C55.9', 'Var', (226, 231))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
58145	31307426	In contrast, for patients with carcinosarcoma, the risk of overall mortality was significantly decreased with EBRT alone (aHR = 0.72, 95% CI: 0.53, 0.99, P = 0.042), brachytherapy alone (aHR = 0.55, 95% CI: 0.37, 0.80, P = 0.002), and combination radiotherapy (aHR = 0.47, 95% CI: 0.29, 0.77, P = 0.003) as compared with no radiotherapy (Table 2).	('decreased', 'NegReg', (95, 104))	('carcinosarcoma', 'Disease', 'MESH:D002296', (31, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('brachytherapy', 'Var', (166, 179))	('EBRT', 'Chemical', '-', (110, 114))	('patients', 'Species', '9606', (17, 25))	('carcinosarcoma', 'Disease', (31, 45))	('combination radiotherapy', 'Var', (235, 259))
58146	31307426	In addition, for patients with carcinosarcoma, the risk of cancer-specific mortality was significantly decreased with brachytherapy alone (aHR = 0.51, 95% CI: 0.31, 0.84, P = 0.009), combination radiotherapy (aHR = 0.53, 95% CI: 0.29, 0.95, P = 0.034) as compared to no radiotherapy (Table 2).	('carcinosarcoma', 'Disease', 'MESH:D002296', (31, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('decreased', 'NegReg', (103, 112))	('combination radiotherapy', 'Var', (183, 207))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (17, 25))	('carcinosarcoma', 'Disease', (31, 45))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
58152	31307426	For patients with carcinosarcoma, propensity score matching showed the risk of overall mortality was significantly decreased with EBRT alone (aHR = 0.65, 95% CI: 0.45, 0.93, P = 0.020), brachytherapy alone (aHR = 0.62, 95% CI: 0.40, 0.95, P = 0.029), and combination radiotherapy (aHR = 0.47, 95% CI: 0.26, 0.85, P = 0.013) as compared with no radiotherapy (Table 3).	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('EBRT', 'Chemical', '-', (130, 134))	('brachytherapy', 'Var', (186, 199))	('carcinosarcoma', 'Disease', 'MESH:D002296', (18, 32))	('decreased', 'NegReg', (115, 124))	('patients', 'Species', '9606', (4, 12))	('combination radiotherapy', 'Var', (255, 279))	('carcinosarcoma', 'Disease', (18, 32))
58172	31307426	The locoregional failure rate was lower for patients who received adjuvant radiotherapy than for those who did not (17.5% vs. 28.5%, P = 0.107), and adjuvant radiotherapy was associated with longer locoregional recurrence-free survival in patients who did not undergo pelvic lymph node dissection (52.7% vs. 18.7%, P < 0.001).	('locoregional failure rate', 'CPA', (4, 29))	('patients', 'Species', '9606', (44, 52))	('lower', 'NegReg', (34, 39))	('patients', 'Species', '9606', (239, 247))	('adjuvant', 'Var', (149, 157))	('locoregional recurrence-free survival', 'CPA', (198, 235))	('longer', 'PosReg', (191, 197))
58177	31307426	analyzed the SEER data of 1855 patients with uterine carcinosarcoma and found that lymphadenectomy was associated with improved OS in patients with stage I-III disease as compared to no lymphadenectomy.	('carcinosarcoma', 'Disease', (53, 67))	('OS', 'Chemical', '-', (128, 130))	('patients', 'Species', '9606', (134, 142))	('carcinosarcoma', 'Disease', 'MESH:D002296', (53, 67))	('II disease', 'Disease', (157, 167))	('patients', 'Species', '9606', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (45, 67))	('improved', 'PosReg', (119, 127))	('II disease', 'Disease', 'MESH:D005776', (157, 167))	('lymphadenectomy', 'Var', (83, 98))
58179	31307426	For women who received adjuvant radiotherapy as compared to those who did not, the 5-year OS rates were 41.5 and 33.2%, respectively (P < 0.001), and uterine-specific survival rates were 56.0 and 50.8%, respectively (P = 0.005).	('uterine-specific survival', 'CPA', (150, 175))	('women', 'Species', '9606', (4, 9))	('radiotherapy', 'Var', (32, 44))	('OS', 'Chemical', '-', (90, 92))
58180	31307426	Radiotherapy was associated with better OS in patients with stage I-III disease (HR = 0.87, P = 0.03), and with better OS (HR = 0.63, P < 0.001) and uterine-specific survival (HR = 0.63, P = 0.004) in patients with stage IV disease.	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (46, 54))	('II disease', 'Disease', 'MESH:D005776', (69, 79))	('Radiotherapy', 'Var', (0, 12))	('uterine-specific survival', 'CPA', (149, 174))	('OS', 'Chemical', '-', (40, 42))	('II disease', 'Disease', (69, 79))	('OS', 'Chemical', '-', (119, 121))	('better', 'PosReg', (33, 39))	('better', 'PosReg', (112, 118))
58203	31096664	Etiological factors such as obesity, persistent anovulatory cycles, nulliparity and exogenous estrogen exposure are intrinsically associated with the malignancy.	('nulliparity', 'Var', (68, 79))	('malignancy', 'Disease', (150, 160))	('obesity', 'Phenotype', 'HP:0001513', (28, 35))	('obesity', 'Disease', 'MESH:D009765', (28, 35))	('malignancy', 'Disease', 'MESH:D009369', (150, 160))	('obesity', 'Disease', (28, 35))	('associated', 'Reg', (130, 140))
58266	31096664	In this study, we have analyzed the expression profile of HMGA genes in two different EEC samples series in order to access the potential of HMGA expression as a biomarker and, additionally, gain some insight on its tumor biology, since it is already known that alterations in HMGA expression are crucial for cancer development and progression.	('tumor', 'Disease', (216, 221))	('alterations', 'Var', (262, 273))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('HMGA', 'Gene', (277, 281))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('EEC', 'Phenotype', 'HP:0012114', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancer', 'Disease', (309, 315))
58288	31096664	Additionally, among EEC samples expressing HMGA2, protein levels were barely detected when compared with endometrium serous carcinoma or with endometrium benign lesions, such as glandular dysplasia and intraepithelial neoplasia.	('glandular dysplasia', 'Disease', (178, 197))	('serous carcinoma', 'Disease', (117, 133))	('HMGA2', 'Var', (43, 48))	('serous carcinoma', 'Disease', 'MESH:D018284', (117, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('glandular dysplasia', 'Disease', 'MESH:D002277', (178, 197))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (202, 227))	('neoplasia', 'Phenotype', 'HP:0002664', (218, 227))	('intraepithelial neoplasia', 'Disease', (202, 227))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (202, 227))	('EEC', 'Phenotype', 'HP:0012114', (20, 23))
58367	30299262	The morcellation resulted in a tissue spill on various intraabdominal organs such as ovaries, liver, and omentum, and it did not matter which surgical technique (vaginal, laparoscopic or open) was used.	('morcellation', 'Var', (4, 16))	('resulted in', 'Reg', (17, 28))	('ovaries', 'Disease', (85, 92))	('ovaries', 'Disease', 'MESH:D010051', (85, 92))
58409	30956779	Inhibitors against CTLA-4, PD-1, and PD-L1 proteins are in clinical use and have been responsible for long-lasting responses in different types of cancer.	('CTLA-4', 'Gene', '1493', (19, 25))	('PD-L1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('PD-1', 'Gene', (27, 31))	('Inhibitors', 'Var', (0, 10))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('proteins', 'Protein', (43, 51))	('CTLA-4', 'Gene', (19, 25))	('cancer', 'Disease', (147, 153))
58455	30956779	Specifically, SKCM_1 denotes the SKCM patients (n = 258) in the cluster with apparently higher immune gene expression signature, whereas SKCM_2 denotes the SKCM patients (n = 177) in the other cluster with an apparently lower immune gene expression signature.	('higher', 'PosReg', (88, 94))	('SKCM', 'Disease', (33, 37))	('patients', 'Species', '9606', (161, 169))	('SKCM_1', 'Var', (14, 20))	('patients', 'Species', '9606', (38, 46))	('immune gene expression signature', 'MPA', (95, 127))
58492	30956779	Although it is beyond the scope of the current study, in the future we plan to perform a thorough interrogation on the relationship between this global immune gene signature and oncogenic pathways, copy number alterations, mutational load, and established clinicopathological characteristics, such as tumor metastasis, grade, and stage.	('tumor metastasis', 'Disease', 'MESH:D009362', (301, 317))	('mutational load', 'Var', (223, 238))	('grade', 'CPA', (319, 324))	('tumor metastasis', 'Disease', (301, 317))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('copy number alterations', 'Var', (198, 221))
58503	30956779	POLE was commonly mutated in endometrial and colorectal cancer, while MSI tumors frequently occurred in endometrial, stomach, and colon cancer.	('endometrial', 'Disease', (104, 115))	('MSI tumors', 'Disease', 'MESH:D009369', (70, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('stomach', 'Disease', (117, 124))	('mutated', 'Var', (18, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('colorectal cancer', 'Disease', (45, 62))	('endometrial', 'Disease', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MSI tumors', 'Disease', (70, 80))	('occurred', 'Reg', (92, 100))	('colon cancer', 'Disease', (130, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
58526	29854405	Advanced age, nulliparity, polycystic ovary syndrome, family history, and prolonged estrogen exposure are well-known risk factors for endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (134, 152))	('ovary syndrome', 'Phenotype', 'HP:0000137', (38, 52))	('endometrial cancer', 'Disease', 'MESH:D016889', (134, 152))	('polycystic ovary syndrome', 'Disease', (27, 52))	('polycystic ovary', 'Phenotype', 'HP:0000147', (27, 43))	('nulliparity', 'Var', (14, 25))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (27, 52))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('endometrial cancer', 'Disease', (134, 152))
58601	29434664	RT to the abdomen-pelvis is associated with a high risk of permanent amenorrhoea and can damage the uterus and uterine vessels, affecting the ability of a woman to carry a pregnancy to term.	('damage', 'Reg', (89, 95))	('uterus', 'CPA', (100, 106))	('affecting', 'Reg', (128, 137))	('RT to', 'Var', (0, 5))	('high risk of permanent amenorrhoea', 'Phenotype', 'HP:0008209', (46, 80))	('amenorrhoea', 'Disease', (69, 80))	('permanent amenorrhoea', 'Phenotype', 'HP:0000869', (59, 80))	('amenorrhoea', 'Disease', 'MESH:C537962', (69, 80))	('woman', 'Species', '9606', (155, 160))	('uterine vessels', 'CPA', (111, 126))
58621	29434664	Alkylating agents are gonadotoxic chemotherapeutic agents and have most consistently been associated with ovarian failure in a dose-dependent manner.	('Alkylating', 'Var', (0, 10))	('ovarian failure', 'Phenotype', 'HP:0008209', (106, 121))	('ovarian failure', 'Disease', 'MESH:D010049', (106, 121))	('associated', 'Reg', (90, 100))	('ovarian failure', 'Disease', (106, 121))
58671	29434664	It is well established that women with germline mutation BRCA genes have an increased lifetime risk of developing ovarian and breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('germline mutation', 'Var', (39, 56))	('BRCA', 'Gene', '672', (57, 61))	('women', 'Species', '9606', (28, 33))	('BRCA', 'Gene', (57, 61))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (114, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
58673	29434664	Although women with BRCA mutations are more likely to develop breast cancer at a younger age than ovarian cancer, the decision to opt for bilateral risk-reducing mastectomy (BRRM) and risk-reducing salpingo-oophorectomy (RRSO) should be performed according to evidenced-based knowledge of the risks and benefits of prophylactic surgical procedures.	('BRCA', 'Gene', '672', (20, 24))	('mutations', 'Var', (25, 34))	('ovarian cancer', 'Disease', 'MESH:D010051', (98, 112))	('women', 'Species', '9606', (9, 14))	('BRCA', 'Gene', (20, 24))	('ovarian cancer', 'Disease', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('develop', 'PosReg', (54, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
58674	29434664	For sure, RRSO is recommended to prevent ovarian cancer/fallopian tube cancer in BRCA mutation carriers by 40 years of age or after completion of childbearing.	('BRCA', 'Gene', (81, 85))	('ovarian cancer', 'Disease', (41, 55))	('fallopian tube cancer', 'Phenotype', 'HP:0030394', (56, 77))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (56, 77))	('fallopian tube cancer', 'Disease', (56, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutation', 'Var', (86, 94))	('BRCA', 'Gene', '672', (81, 85))
58676	29434664	In fact, BRCA germline mutations seem to be related to a lower ovarian reserve - and thus a shorter reproductive lifespan - compared to women without BRCA mutations.	('BRCA', 'Gene', (150, 154))	('reproductive lifespan -', 'CPA', (100, 123))	('BRCA', 'Gene', '672', (9, 13))	('women', 'Species', '9606', (136, 141))	('BRCA', 'Gene', (9, 13))	('ovarian reserve -', 'CPA', (63, 80))	('shorter', 'NegReg', (92, 99))	('germline mutations', 'Var', (14, 32))	('BRCA', 'Gene', '672', (150, 154))	('lower', 'NegReg', (57, 62))
58698	27001612	We previously reported that Hmga1 transgenic mice develop uterine tumors with complete penetrance.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Hmga1', 'Gene', '15361', (28, 33))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('uterine tumor', 'Phenotype', 'HP:0010784', (58, 71))	('Hmga1', 'Gene', (28, 33))	('transgenic mice', 'Species', '10090', (34, 49))	('develop', 'PosReg', (50, 57))	('transgenic', 'Var', (34, 44))	('uterine tumors', 'Phenotype', 'HP:0010784', (58, 72))
58702	27001612	Here, we report for the first time that uterine tumor growth is impaired in Hmga1a transgenic mice crossed on to an Mmp-2 deficient background.	('Mmp-2', 'Gene', (116, 121))	('transgenic', 'Var', (83, 93))	('tumor', 'Disease', (48, 53))	('uterine tumor', 'Phenotype', 'HP:0010784', (40, 53))	('impaired', 'NegReg', (64, 72))	('Hmga1a', 'Gene', (76, 82))	('Hmga1a', 'Gene', '15361', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Mmp-2', 'Gene', '17390', (116, 121))	('transgenic mice', 'Species', '10090', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
58707	27001612	Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies.	('uterine cancer', 'Phenotype', 'HP:0010784', (100, 114))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('uterine cancers', 'Phenotype', 'HP:0010784', (100, 115))	('HMGA1', 'Gene', (38, 43))	('targeting', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
58727	27001612	We also discovered that Hmga1a transgenic mice develop aggressive lymphoid tumors and uterine sarcomas by 9 months of age with complete penetrance.	('aggressive lymphoid tumors', 'Disease', 'MESH:D001523', (55, 81))	('lymphoid tumor', 'Phenotype', 'HP:0002665', (66, 80))	('Hmga1a', 'Gene', (24, 30))	('Hmga1a', 'Gene', '15361', (24, 30))	('aggressive lymphoid tumors', 'Disease', (55, 81))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('develop', 'PosReg', (47, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('sarcomas', 'Disease', (94, 102))	('lymphoid tumors', 'Phenotype', 'HP:0002665', (66, 81))	('transgenic', 'Var', (31, 41))	('transgenic mice', 'Species', '10090', (31, 46))
58752	27001612	First, we generated mice that are transgenic for Hmga1a and heterozygous for the Mmp-2 alleles (Mmp-2+/-).	('mice', 'Species', '10090', (20, 24))	('Mmp-2', 'Gene', '17390', (96, 101))	('Mmp-2', 'Gene', (96, 101))	('Hmga1a', 'Gene', '15361', (49, 55))	('Hmga1a', 'Gene', (49, 55))	('transgenic', 'Species', '10090', (34, 44))	('transgenic', 'Var', (34, 44))	('Mmp-2', 'Gene', '17390', (81, 86))	('Mmp-2', 'Gene', (81, 86))
58753	27001612	The Hmga1a transgenic-Mmp-2+/- males were then crossed again with Mmp-2-/- mice to generate mice that are transgenic for Hmga1a and homozygous null for Mmp-2 (designated Hmga1a-Mmp-2-/-).	('Mmp-2', 'Gene', '17390', (66, 71))	('Mmp-2', 'Gene', '17390', (152, 157))	('Mmp-2', 'Gene', (152, 157))	('Mmp-2', 'Gene', (66, 71))	('transgenic', 'Species', '10090', (11, 21))	('Mmp-2', 'Gene', '17390', (177, 182))	('Mmp-2', 'Gene', (177, 182))	('mice', 'Species', '10090', (92, 96))	('transgenic', 'Var', (106, 116))	('Hmga1a', 'Gene', '15361', (121, 127))	('Hmga1a', 'Gene', (121, 127))	('Hmga1a', 'Gene', (4, 10))	('Hmga1a', 'Gene', '15361', (4, 10))	('transgenic', 'Species', '10090', (106, 116))	('Hmga1a', 'Gene', (170, 176))	('Hmga1a', 'Gene', '15361', (170, 176))	('mice', 'Species', '10090', (75, 79))	('Mmp-2', 'Gene', '17390', (22, 27))	('Mmp-2', 'Gene', (22, 27))
58768	27001612	Of note, absolute spleen weights and relative spleen weights, which reflect the lymphoid tumor burdens, showed a trend towards decreasing size in Hmga1a transgenics that were deficient for Mmp-2, although this did not reach statistical significance in the small samples sizes studied (Supplementary Fig.	('size', 'MPA', (138, 142))	('Mmp-2', 'Gene', '17390', (189, 194))	('Mmp-2', 'Gene', (189, 194))	('transgenic', 'Species', '10090', (153, 163))	('lymphoid tumor', 'Phenotype', 'HP:0002665', (80, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('lymphoid tumor', 'Disease', (80, 94))	('decreasing', 'NegReg', (127, 137))	('lymphoid tumor', 'Disease', 'MESH:D009369', (80, 94))	('transgenics', 'Var', (153, 164))	('Hmga1a', 'Gene', '15361', (146, 152))	('Hmga1a', 'Gene', (146, 152))
58805	27001612	A subset of MMPs has tumor-suppressor effects, and inhibitors could potentially enhance tumor progression.	('MMPs', 'Gene', '17386;4313;17390;17394;4318;17395;4322;17386;17388', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('enhance', 'PosReg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (88, 93))	('inhibitors', 'Var', (51, 61))	('MMPs', 'Gene', (12, 16))
58827	27001612	Finally, we show that growth of uterine sarcomas is impaired in Hmga1 transgenics that are deficient in Mmp-2, providing additional evidence that targeting this pathway could be beneficial in the treatment of a subset of uterine cancers.	('transgenic', 'Species', '10090', (70, 80))	('impaired', 'NegReg', (52, 60))	('Hmga1', 'Gene', '15361', (64, 69))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('Hmga1', 'Gene', (64, 69))	('Mmp-2', 'Gene', '17390', (104, 109))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('uterine cancer', 'Phenotype', 'HP:0010784', (221, 235))	('cancers', 'Disease', (229, 236))	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('Mmp-2', 'Gene', (104, 109))	('transgenics', 'Var', (70, 81))	('growth', 'CPA', (22, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('uterine cancers', 'Phenotype', 'HP:0010784', (221, 236))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('beneficial', 'PosReg', (178, 188))	('sarcomas', 'Disease', (40, 48))
58830	27001612	HMGA1a            high mobility group A1 gene MMP-2 matrix metalloproteinase-2 RT-PCR real time polymerase chain reaction Deficiency of Mmp-2 impairs uterine tumorigenesis in Hmga1 transgenic mice HMGA1 is overexpressed in aggressive human uterine carcinosarcomas and serous carcinomas HMGA1 and MMP-2 are positively correlated in a subset of human carcinosarcomas HMGA1 occupies the MMP-2 promoter in human carcinosarcoma cells Targeting the HMGA1 pathways could disrupt progression of aggressive uterine tumors	('carcinosarcoma', 'Disease', 'MESH:D002296', (349, 363))	('tumor', 'Disease', 'MESH:D009369', (506, 511))	('high mobility group A1', 'Gene', '15361', (18, 40))	('carcinosarcomas', 'Disease', 'MESH:D002296', (349, 364))	('Mmp-2', 'Gene', '17390', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (356, 364))	('carcinosarcomas', 'Disease', (248, 263))	('carcinosarcomas and serous carcinomas', 'Disease', 'MESH:D002296', (248, 285))	('human', 'Species', '9606', (343, 348))	('Mmp-2', 'Gene', (136, 141))	('disrupt', 'NegReg', (464, 471))	('high mobility group A1', 'Gene', (18, 40))	('tumor', 'Phenotype', 'HP:0002664', (506, 511))	('carcinosarcoma', 'Disease', (408, 422))	('tumors', 'Phenotype', 'HP:0002664', (506, 512))	('carcinosarcomas', 'Disease', (349, 364))	('transgenic mice', 'Species', '10090', (181, 196))	('carcinosarcoma', 'Disease', 'MESH:D002296', (408, 422))	('Hmga1', 'Gene', '15361', (175, 180))	('Hmga1', 'Gene', (175, 180))	('carcinosarcomas', 'Disease', 'MESH:D002296', (248, 263))	('Deficiency', 'Var', (122, 132))	('tumors', 'Disease', (506, 512))	('carcinosarcoma', 'Disease', (248, 262))	('tumor', 'Disease', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('uterine tumors', 'Phenotype', 'HP:0010784', (498, 512))	('sarcomas', 'Phenotype', 'HP:0100242', (255, 263))	('carcinomas', 'Phenotype', 'HP:0030731', (275, 285))	('human', 'Species', '9606', (234, 239))	('uterine tumor', 'Phenotype', 'HP:0010784', (150, 163))	('human', 'Species', '9606', (402, 407))	('carcinosarcoma', 'Disease', 'MESH:D002296', (248, 262))	('tumor', 'Disease', (506, 511))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (240, 262))	('carcinosarcoma', 'Disease', (349, 363))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('uterine tumor', 'Phenotype', 'HP:0010784', (498, 511))	('impairs', 'NegReg', (142, 149))	('tumors', 'Disease', 'MESH:D009369', (506, 512))
58835	27905822	an ultramutated group containing as many as 232 x 10-6 mutations/Mb in conjunction with alteration in DNA polymerase epsilon (POLE) (n = 17) a hypermutated group with 18 x 10-6 mutations/Mb and microsatellite instability (n = 65) copy number low (endometrioid) tumors with 2.9 x 10-6 mutations/Mb (n = 90) copy number low (serous) tumors with a low mutation rate of 2.3 x 10-6 mutations/Mb but somatic copy number alterations such as MYC, ErbB2, and CCNE1 amplification (n = 60).	('MYC', 'Gene', '4609', (434, 437))	('tumors', 'Disease', 'MESH:D009369', (331, 337))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('ErbB2', 'Gene', (439, 444))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('CCNE1', 'Gene', '898', (450, 455))	('CCNE1', 'Gene', (450, 455))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('MYC', 'Gene', (434, 437))	('ErbB2', 'Gene', '2064', (439, 444))	('tumors', 'Phenotype', 'HP:0002664', (331, 337))	('mutations/Mb', 'Var', (55, 67))	('tumors', 'Disease', (331, 337))
58841	27905822	Tumor immunogenicity is also inherently enhanced by the mutational diversity that occurs in the absence of functional POLE proofreading or mismatch repair mechanisms resulting in microsatellite instability (MSI) due to either germline (Lynch syndrome) or somatic (Lynch-like) alterations in mismatch repair genes (MSH2, MSH6, MLH1, PMS2) or somatic silencing of the MLH1 promoter.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MLH1', 'Gene', '4292', (326, 330))	('MLH1', 'Gene', '4292', (366, 370))	('Lynch syndrome', 'Disease', (236, 250))	('enhanced', 'PosReg', (40, 48))	('Lynch syndrome', 'Disease', 'MESH:D003123', (236, 250))	('mutational', 'Var', (56, 66))	('PMS2', 'Gene', '5395', (332, 336))	('MSI', 'Disease', 'None', (207, 210))	('MSH2', 'Gene', (314, 318))	('microsatellite instability', 'MPA', (179, 205))	('MSI', 'Disease', (207, 210))	('MSH6', 'Gene', (320, 324))	('MLH1', 'Gene', (326, 330))	('Tumor immunogenicity', 'CPA', (0, 20))	('MLH1', 'Gene', (366, 370))	('alterations', 'Var', (276, 287))	('silencing', 'NegReg', (349, 358))	('MSH6', 'Gene', '2956', (320, 324))	('MSH2', 'Gene', '4436', (314, 318))	('PMS2', 'Gene', (332, 336))
58842	27905822	Accordingly, hypermutated tumors generally display favorable survival outcome.	('tumors', 'Disease', (26, 32))	('hypermutated', 'Var', (13, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
58847	27905822	This was first noted among 41 consecutive patients (78% colorectal, 10% biliary, 5% endometrial, 5% small bowel, and 2% gastric carcinoma) treated with the checkpoint inhibitor pembrolizumab at 10 mg/kg every 14 days over a median follow-up of 36 weeks: median overall survival was 5 months in mismatch repair proficient tumors but not reached in mismatch repair deficient tumors.	('deficient tumors', 'Disease', (363, 379))	('deficient tumors', 'Disease', 'MESH:D009369', (363, 379))	('mismatch repair proficient', 'Var', (294, 320))	('gastric carcinoma', 'Disease', 'MESH:D013274', (120, 137))	('tumors', 'Disease', (373, 379))	('tumors', 'Disease', 'MESH:D009369', (373, 379))	('tumors', 'Phenotype', 'HP:0002664', (373, 379))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('tumors', 'Disease', 'MESH:D009369', (321, 327))	('gastric carcinoma', 'Disease', (120, 137))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('pembrolizumab', 'Chemical', 'MESH:C582435', (177, 190))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (120, 137))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('tumors', 'Disease', (321, 327))
58849	27905822	In a study of 63 endometrial cancers, neoantigen load as well as CD3+ and CD8+ tumor-associated lymphocytes were greater in POLE-mutated and MSI tumors relative to microsatellite-stable tumors.	('neoantigen load', 'MPA', (38, 53))	('tumor', 'Disease', (186, 191))	('MSI tumors', 'Disease', (141, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('CD8', 'Gene', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('endometrial cancers', 'Disease', (17, 36))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('endometrial cancers', 'Disease', 'MESH:D016889', (17, 36))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MSI tumors', 'Disease', 'MESH:D009369', (141, 151))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('greater', 'PosReg', (113, 120))	('CD8', 'Gene', '925', (74, 77))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('endometrial cancer', 'Phenotype', 'HP:0012114', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('POLE-mutated', 'Var', (124, 136))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
58858	27905822	As endometrial cancers rank among the most frequent to harbor microsatellite instability (22-33%) relative to colorectal (20%), cervical (8%), esophageal (7%), and breast cancers (0%-2%), immunotherapy with checkpoint inhibition has the potential to represent one of the most promising advances in the treatment of endometrial cancer in recent years.	('endometrial cancer', 'Phenotype', 'HP:0012114', (315, 333))	('microsatellite instability', 'Var', (62, 88))	('endometrial cancer', 'Disease', 'MESH:D016889', (315, 333))	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('breast cancers', 'Disease', 'MESH:D001943', (164, 178))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('breast cancers', 'Disease', (164, 178))	('endometrial cancers', 'Disease', (3, 22))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('endometrial cancers', 'Disease', 'MESH:D016889', (3, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('endometrial cancer', 'Disease', (315, 333))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
58885	28541634	Univariate analysis determined that hazard ratios (HRs) for disease progression for SUVmax (>=8.33), MTV2.5 (>=63.92 mL), and TLG2.5 (>=396.16) were 1.930 (95% confidence interval [CI]=0.793-4.701), 3.264 (95% CI=1.466-7.268), and 2.692 (95% CI=1.224-5.924), respectively.	('TLG2.5', 'Var', (126, 132))	('MTV2.5', 'Var', (101, 107))	('MTV', 'Chemical', '-', (101, 104))	('disease', 'Disease', (60, 67))	('TLG', 'Chemical', '-', (126, 129))
58897	28541634	The maximum standardized uptake value (SUVmax) measured by 18F-FDG PET/CT, reflecting tumor aggressiveness, may be a predictor of poor prognosis in numerous malignancies.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('18F-FDG', 'Var', (59, 66))	('tumor aggressiveness', 'Disease', (86, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (92, 106))	('18F-FDG', 'Chemical', 'MESH:D019788', (59, 66))	('numerous malignancies', 'Disease', 'MESH:D009369', (148, 169))	('standardized uptake value', 'MPA', (12, 37))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (86, 106))	('numerous malignancies', 'Disease', (148, 169))
58933	28541634	Using the time-dependent ROC curve for primary tumors, optimal cutoff values for predicting 3-year disease progression were 8.33 (area under the curve [AUC]=0.541; sensitivity, 75.4%; specificity, 49.5%), 63.92 mL (AUC=0.755; sensitivity, 66.2%; specificity, 85%), and 396.16 g (AUC=0.747; sensitivity, 64.4%; specificity, 83.5%) for SUVmax, MTV2.5, and TLG2.5, respectively.	('396.16 g', 'Var', (269, 277))	('primary tumors', 'Disease', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MTV', 'Chemical', '-', (342, 345))	('TLG', 'Chemical', '-', (354, 357))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('primary tumors', 'Disease', 'MESH:D009369', (39, 53))
58934	28541634	Optimal cutoff values for predicting the 3-year death were 8.33 (AUC=0.584; sensitivity, 77.7%; specificity, 51.2%), 63.92 mL (AUC=0.726; sensitivity, 62%; specificity, 81.2%), and 396.16 g (AUC=0.724; sensitivity, 61.7%; specificity, 81%) for SUVmax, MTV2.5, and TLG2.5, respectively (Table 2, Fig.	('396.16 g', 'Var', (181, 189))	('death', 'Disease', 'MESH:D003643', (48, 53))	('MTV', 'Chemical', '-', (252, 255))	('death', 'Disease', (48, 53))	('TLG', 'Chemical', '-', (264, 267))
58940	28541634	MTV2.5 (p=0.008) and TLG2.5 (p=0.016) were significant prognostic predictors of OS, whereas SUVmax (p=0.913) was not.	('TLG', 'Chemical', '-', (21, 24))	('MTV2.5', 'Var', (0, 6))	('MTV', 'Chemical', '-', (0, 3))	('TLG2.5', 'Gene', (21, 27))
58946	28541634	Similarly, the 3-year OS rates in patients with low vs. high SUVmax, MTV2.5, and TLG2.5 were 71.4% vs. 45.6% (p=0.147), 71.0% vs. 31.3% (p=0.011), and 70.9% vs. 31.7% (p=0.013), respectively.	('MTV', 'Chemical', '-', (69, 72))	('TLG', 'Chemical', '-', (81, 84))	('SUVmax', 'Gene', (61, 67))	('patients', 'Species', '9606', (34, 42))	('MTV2.5', 'Var', (69, 75))	('low', 'Var', (48, 51))
58952	28541634	Most previously published studies investigating the prognostic role of 18F-FDG PET/CT in endometrial cancers included only a small percentage (0%-14.3%) of patients with UCS, and the most common histology was an endometrioid adenocarcinoma.	('patients', 'Species', '9606', (156, 164))	('UCS', 'Disease', (170, 173))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('endometrial cancer', 'Phenotype', 'HP:0012114', (89, 107))	('endometrial cancers', 'Disease', 'MESH:D016889', (89, 108))	('endometrial cancers', 'Disease', (89, 108))	('endometrioid adenocarcinoma', 'Disease', (212, 239))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (212, 239))	('UCS', 'Phenotype', 'HP:0002891', (170, 173))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (212, 239))	('18F-FDG', 'Var', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('18F-FDG', 'Chemical', 'MESH:D019788', (71, 78))	('common', 'Reg', (188, 194))
58953	28541634	High SUVmax of primary endometrial cancer showed significantly worse disease-free survival (DFS) or OS rates than those with a low SUVmax.	('endometrial cancer', 'Disease', 'MESH:D016889', (23, 41))	('OS rates', 'CPA', (100, 108))	('worse', 'NegReg', (63, 68))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('endometrial cancer', 'Disease', (23, 41))	('disease-free survival', 'CPA', (69, 90))	('endometrial cancer', 'Phenotype', 'HP:0012114', (23, 41))
58967	28541634	There are currently several methods to delineate tumor volume in 18F-FDG PET/CT, including manual drawing and automatic and semiautomatic methods using an isocontour threshold based on a fixed SUVmax percentage, a specific SUV (e.g., 2.5 and 3.0), or a background-level threshold; however, there is currently no consensus on the best method.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('18F-FDG', 'Var', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('18F-FDG', 'Chemical', 'MESH:D019788', (65, 72))	('tumor', 'Disease', (49, 54))	('semiautomatic', 'Disease', (124, 137))	('semiautomatic', 'Disease', 'None', (124, 137))
58985	27926484	In addition, in a meta-analysis of non-female cancer patients from TCGA datasets and 12 independent studies, hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/metastasis-free survival (MFS)/progression-free survival (PFS) were pooled to assess the prognostic value of high H19 expression.	('MFS', 'Disease', (275, 278))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('MFS', 'Disease', 'MESH:D008382', (275, 278))	('H19', 'Gene', '283120', (363, 366))	('high', 'Var', (358, 362))	('H19', 'Gene', (363, 366))
58987	27926484	Multivariate Cox regression analysis showed that high H19 expression could independently predict a poorer prognosis in cervical cancer patients (HR=4.099, p<0.05).	('patients', 'Species', '9606', (135, 143))	('expression', 'MPA', (58, 68))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('cervical cancer', 'Disease', (119, 134))	('H19', 'Gene', '283120', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (49, 53))	('H19', 'Gene', (54, 57))
58988	27926484	In the meta-analysis, patients with high H19 expression showed a poorer outcome in non-female cancer (p<0.05).	('H19', 'Gene', '283120', (41, 44))	('H19', 'Gene', (41, 44))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('high', 'Var', (36, 40))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
58989	27926484	These results suggest that high lncRNA H19 expression is predictive of an unfavorable prognosis in two female cancers (uterine corpus endometrioid cancer and cervical cancer) as well as in non-female cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (127, 153))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (167, 173))	('cervical cancer', 'Disease', (158, 173))	('cervical cancer', 'Disease', 'MESH:D002583', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (134, 153))	('corpus endometrioid cancer', 'Disease', (127, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('H19', 'Gene', (39, 42))	('cancer', 'Disease', (110, 116))	('cancers', 'Disease', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('H19', 'Gene', '283120', (39, 42))	('cancer', 'Disease', (200, 206))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', (147, 153))	('expression', 'MPA', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
58997	27926484	We evaluated the prognostic power of high lncRNA H19 expression for female cancers and pooled the prognostic ability of high H19 expression in non-female cancers according to TCGA datasets and the available literature.	('H19', 'Gene', '283120', (49, 52))	('H19', 'Gene', (49, 52))	('high', 'Var', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Disease', (75, 82))	('H19', 'Gene', (125, 128))	('H19', 'Gene', '283120', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
59002	27926484	There were no significant differences in clinicopathological variables between patients with high H19 expression and those with low H19 expression in patients with uterine corpus endometrioid cancer, cervical cancer, uterine carcinosarcoma, breast cancer, and ovarian cancer (p > 0.05; Supplementary Table S1-S6).	('ovarian cancer', 'Disease', (260, 274))	('patients', 'Species', '9606', (150, 158))	('H19', 'Gene', '283120', (98, 101))	('ovarian cancer', 'Phenotype', 'HP:0100615', (260, 274))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (172, 198))	('high', 'Var', (93, 97))	('carcinosarcoma', 'Disease', (225, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('H19', 'Gene', (132, 135))	('corpus endometrioid cancer', 'Disease', (172, 198))	('carcinosarcoma', 'Disease', 'MESH:D002296', (225, 239))	('cervical cancer', 'Disease', (200, 215))	('cervical cancer', 'Disease', 'MESH:D002583', (200, 215))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (179, 198))	('ovarian cancer', 'Disease', 'MESH:D010051', (260, 274))	('expression', 'MPA', (102, 112))	('H19', 'Gene', '283120', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (217, 239))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('breast cancer', 'Disease', (241, 254))	('patients', 'Species', '9606', (79, 87))	('H19', 'Gene', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
59011	27926484	However, high H19 expression was associated with a shorter relapse-free survival (RFS; HR = 2.261, 95% CI = 1.077 - 4.747, p = 0.0310) in cervical cancer patients when compared with patients with low H19 expression (Figure 1C-1D).	('H19', 'Gene', '283120', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('H19', 'Gene', (14, 17))	('shorter', 'NegReg', (51, 58))	('H19', 'Gene', '283120', (200, 203))	('patients', 'Species', '9606', (154, 162))	('H19', 'Gene', (200, 203))	('patients', 'Species', '9606', (182, 190))	('relapse-free survival', 'CPA', (59, 80))	('cervical cancer', 'Disease', (138, 153))	('cervical cancer', 'Disease', 'MESH:D002583', (138, 153))	('high', 'Var', (9, 13))
59018	27926484	Because the above results suggested that high H19 expression could predict an unfavorable prognosis in some female cancer patients, we next assessed whether it had prognostic ability in patients with non-female cancer (Pan-cancer excluding the female cancers, including 25 cancers).	('non-female', 'Disease', (200, 210))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('cancers', 'Disease', (273, 280))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('expression', 'MPA', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('Pan-cancer', 'Disease', 'MESH:C537931', (219, 229))	('H19', 'Gene', (46, 49))	('patients', 'Species', '9606', (186, 194))	('H19', 'Gene', '283120', (46, 49))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('patients', 'Species', '9606', (122, 130))	('cancers', 'Disease', (251, 258))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('high', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('Pan-cancer', 'Disease', (219, 229))
59028	27926484	Under a random-effect model, non-female cancer patients with high H19 expression had shorter OS than those with low H19 expression (Figure 3; pooling HR = 1.33, 95 % CI = 1.11 - 1.59, p = 0.002).	('shorter', 'NegReg', (85, 92))	('H19', 'Gene', '283120', (66, 69))	('H19', 'Gene', (66, 69))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('H19', 'Gene', '283120', (116, 119))	('expression', 'Var', (70, 80))	('H19', 'Gene', (116, 119))
59030	27926484	With a random-effect model, shorter OS was observed in non-female cancer patients with high H19 expression than those with low H19 expression (Figure 4; pooling HR = 1.31, 95 % CI = 1.09 - 1.59, p = 0.004).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (73, 81))	('H19', 'Gene', '283120', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('H19', 'Gene', '283120', (127, 130))	('H19', 'Gene', (92, 95))	('expression', 'Var', (96, 106))	('cancer', 'Disease', (66, 72))	('H19', 'Gene', (127, 130))
59031	27926484	These results suggested that high H19 expression could predict inferior clinical outcomes on OS time in non-female cancer patients.	('high', 'Var', (29, 33))	('H19', 'Gene', (34, 37))	('cancer', 'Disease', (115, 121))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('inferior', 'NegReg', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('patients', 'Species', '9606', (122, 130))	('OS time', 'Disease', (93, 100))	('H19', 'Gene', '283120', (34, 37))
59033	27926484	As shown in Figure 5, there was no heterogeneity (p' = 0.54, I2 = 0 %; p' = 0.80, I2 = 0 %) in DFS or DFS/RFS/MFS/PFS.	('MFS', 'Disease', 'MESH:D008382', (110, 113))	('MFS', 'Disease', (110, 113))	('DFS', 'Var', (95, 98))
59037	27926484	These results suggested that high H19 expression could predict an adverse prognosis on DFS or DFS/RFS/MFS/PFS in non-female cancer patients, and predict adverse OS and DFS/RFS/MFS/PFS in non-female cancer patients by pooling meta-analysis.	('high', 'Var', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('H19', 'Gene', (34, 37))	('DFS', 'Var', (87, 90))	('cancer', 'Disease', (124, 130))	('MFS', 'Disease', (176, 179))	('predict', 'Reg', (145, 152))	('cancer', 'Disease', (198, 204))	('expression', 'MPA', (38, 48))	('H19', 'Gene', '283120', (34, 37))	('patients', 'Species', '9606', (205, 213))	('MFS', 'Disease', 'MESH:D008382', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('MFS', 'Disease', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('MFS', 'Disease', 'MESH:D008382', (176, 179))
59048	27926484	In order to assess the potential prognostic value of H19 expression in female cancers, we analyzed six datasets for female cancers from TCGA, and discovered that high expression of H19 had an unfavorable prognostic influence on OS and RFS in uterine corpus endometrioid cancer and cervical cancer, but not in breast cancer and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', 'MESH:D001943', (309, 322))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('breast cancer', 'Disease', (309, 322))	('high expression', 'Var', (162, 177))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('ovarian cancer', 'Disease', 'MESH:D010051', (327, 341))	('RFS', 'Disease', (235, 238))	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (250, 276))	('H19', 'Gene', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('H19', 'Gene', (53, 56))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (257, 276))	('H19', 'Gene', '283120', (181, 184))	('corpus endometrioid cancer', 'Disease', (250, 276))	('ovarian cancer', 'Disease', (327, 341))	('breast cancer', 'Phenotype', 'HP:0003002', (309, 322))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cervical cancer', 'Disease', (281, 296))	('cervical cancer', 'Disease', 'MESH:D002583', (281, 296))	('cancers', 'Disease', (123, 130))	('ovarian cancer', 'Phenotype', 'HP:0100615', (327, 341))	('H19', 'Gene', '283120', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
59051	27926484	Consistent with some reports that H19 expression could serve as a poor prognostic factor, our results further indicated that high expression of H19 predicted an unfavorable prognosis in non-female cancer patients.	('H19', 'Gene', '283120', (144, 147))	('H19', 'Gene', (34, 37))	('patients', 'Species', '9606', (204, 212))	('H19', 'Gene', '283120', (34, 37))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('H19', 'Gene', (144, 147))	('predicted', 'Reg', (148, 157))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('high', 'Var', (125, 129))
59056	27926484	In conclusion, we found that high lncRNA H19 expression predicted an inferior prognosis in two female cancers (uterine corpus endometrioid cancer and cervical cancer), as well as in non-female cancer patients.	('corpus endometrioid cancer', 'Disease', 'MESH:D016889', (119, 145))	('cancer', 'Disease', (193, 199))	('cervical cancer', 'Disease', (150, 165))	('cervical cancer', 'Disease', 'MESH:D002583', (150, 165))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('H19', 'Gene', '283120', (41, 44))	('corpus endometrioid cancer', 'Disease', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('high', 'Var', (29, 33))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (126, 145))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (102, 108))	('inferior', 'NegReg', (69, 77))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (45, 55))	('H19', 'Gene', (41, 44))
59146	27057865	It is reported that the risk factors of uterine carcinosarcoma include estrogen, nulliparity, tamoxifen, and pelvic radiation.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (40, 62))	('carcinosarcoma', 'Disease', 'MESH:D002296', (48, 62))	('carcinosarcoma', 'Disease', (48, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('tamoxifen', 'Chemical', 'MESH:D013629', (94, 103))	('nulliparity', 'Var', (81, 92))
59164	27057865	Final diagnosis of carcinosarcoma was confirmed by hematoxylin and eosin (H&E) staining and immunohistochemical analysis showing positive p63, pan-cytokeratin (CK), vimentin (VIM), CD99, and Bcl-2 (Figure 4B-F).	('positive', 'Var', (129, 137))	('carcinosarcoma', 'Disease', (19, 33))	('vimentin', 'Gene', (165, 173))	('H&E', 'Chemical', '-', (74, 77))	('p63', 'Gene', '8626', (138, 141))	('VIM', 'Gene', '7431', (175, 178))	('p63', 'Gene', (138, 141))	('CD99', 'Gene', (181, 185))	('Bcl-2', 'Gene', (191, 196))	('carcinosarcoma', 'Disease', 'MESH:D002296', (19, 33))	('Bcl-2', 'Gene', '596', (191, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('and', 'Gene', (187, 190))	('eosin', 'Chemical', 'MESH:D004801', (67, 72))	('hematoxylin', 'Chemical', 'MESH:D006416', (51, 62))	('VIM', 'Gene', (175, 178))	('CD99', 'Gene', '4267', (181, 185))	('vimentin', 'Gene', '7431', (165, 173))
59196	27057136	LMS was found to possess features typically observed in malignant solid tumors, such as extensive chromosomal abnormalities, overexpression of cell cycle-related genes, hypomethylation spreading through large genomic regions, and frequent hypermethylation at the polycomb group target genes and protocadherin genes.	('LMS', 'Phenotype', 'HP:0100243', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('chromosomal abnormalities', 'Disease', (98, 123))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (98, 123))	('malignant solid tumors', 'Disease', 'MESH:D009369', (56, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('malignant solid tumors', 'Disease', (56, 78))	('hypomethylation', 'Var', (169, 184))	('hypermethylation', 'Var', (239, 255))	('overexpression', 'PosReg', (125, 139))	('LMS', 'Disease', (0, 3))
59220	27057136	Detection of copy neutral loss of heterozygosity (CNLOH) and copy number alterations (gain and loss) was performed using CNVpartition V3.0.7.0 (Illumina) and R-GADA (R-genome alteration detection analysis), respectively, with default parameters.	('alterations', 'Var', (73, 84))	('loss of heterozygosity', 'NegReg', (26, 48))	('R-GADA', 'Chemical', '-', (158, 164))	('copy number alterations', 'Var', (61, 84))
59227	27057136	This array platform uses logR ratio (LRR) and B allele frequency (BAF) as metrics to detect copy number changes.	('BAF', 'Gene', '8815', (66, 69))	('logR', 'MPA', (25, 29))	('copy number changes', 'Var', (92, 111))	('BAF', 'Gene', (66, 69))
59232	27057136	We regarded the sum of the ratio of the copy number altering changes (gain and loss) detected by R-GADA and that of copy neutral changes (CN-LOH) detected by CNV partition as the approximate ratio of chromosomal abnormalities in this study.	('copy', 'Var', (40, 44))	('loss', 'NegReg', (79, 83))	('chromosomal abnormalities', 'Disease', (200, 225))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (200, 225))	('R-GADA', 'Chemical', '-', (97, 103))
59240	27057136	Somatic mutations in the FH gene (encoding fumarate hydratase) and in the MED12 gene (encoding mediator complex subunit 12) have been identified in 1.3% of sporadic and 70% of unselected uterine LMs, respectively.	('MED12', 'Gene', (74, 79))	('MED12', 'Gene', '9968', (74, 79))	('fumarate hydratase', 'Gene', (43, 61))	('FH', 'Gene', '2271', (25, 27))	('uterine LMs', 'Disease', (187, 198))	('mutations', 'Var', (8, 17))	('mediator complex subunit 12', 'Gene', '9968', (95, 122))	('mediator complex subunit 12', 'Gene', (95, 122))	('identified', 'Reg', (134, 144))	('fumarate hydratase', 'Gene', '2271', (43, 61))
59242	27057136	Therefore, not only mutations in specific genes but also chromosomal abnormalities are likely involved in genetic causes of LM and should be further explored.	('involved', 'Reg', (94, 102))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (57, 82))	('mutations', 'Var', (20, 29))	('chromosomal abnormalities', 'Disease', (57, 82))
59250	27057136	Scatter plots (Figure 4(d)) of the average beta values for the same probe set also showed that LMS was globally hypomethylated compared to LM and NM, which is consistent with the global hypomethylation known to occur in most malignant tumors.	('malignant tumors', 'Disease', (225, 241))	('malignant tumors', 'Disease', 'MESH:D018198', (225, 241))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('hypomethylated', 'Var', (112, 126))	('LMS', 'Phenotype', 'HP:0100243', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
59251	27057136	We confirmed the hypomethylation of LINE1 elements in LMS by the combined bisulfite restriction analysis (Figure 4(e) and Supplementary Material, Figure S2).	('LMS', 'Disease', (54, 57))	('hypomethylation', 'Var', (17, 32))	('bisulfite', 'Chemical', 'MESH:C042345', (74, 83))	('LMS', 'Phenotype', 'HP:0100243', (54, 57))
59252	27057136	CpG sites within CpG islands (CGIs), the majority of which are unmethylated, were found to be more frequently hypermethylated (4.5%) than those outside of CGIs (2.5% in open sea) and to be much less frequently hypomethylated (4.6%) than those outside CGIs (16.7% in shores and shelves, and 28.1% in open sea) (Figures 4(l)-4(n) and Table 2).	('open sea', 'Disease', (299, 307))	('open sea', 'Disease', 'MESH:D009041', (169, 177))	('open sea', 'Disease', (169, 177))	('open sea', 'Disease', 'MESH:D009041', (299, 307))	('hypermethylated', 'Var', (110, 125))
59255	27057136	Hypermethylation of the subset of PcG genes encoding developmental regulators is considered to potentially contribute to the stem-like state of cancer.	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PcG genes', 'Gene', (34, 43))	('stem-like state', 'CPA', (125, 140))	('cancer', 'Disease', (144, 150))	('contribute', 'Reg', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
59260	27057136	Taken together, the annotations for differentially methylated regions in LMS compared to NM demonstrate that LMS exhibits epigenomic features such as hypermethylation at the PcG target gene and protocadherin gene loci and hypomethylation within large blocks that are known to be common among malignant solid tumors (Supplementary Material, Figure S4).	('hypomethylation', 'Var', (222, 237))	('LMS', 'Phenotype', 'HP:0100243', (73, 76))	('malignant solid tumors', 'Disease', 'MESH:D009369', (292, 314))	('LMS', 'Disease', (109, 112))	('malignant solid tumors', 'Disease', (292, 314))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('LMS', 'Phenotype', 'HP:0100243', (109, 112))	('hypermethylation', 'Var', (150, 166))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))
59282	25610676	A 26-year-old G4P2A2 Caucasian woman consulted our emergency department after being diagnosed with a uterine malignancy in Turkey after curettage for menorrhagia.	('menorrhagia', 'Disease', (150, 161))	('malignancy', 'Disease', (109, 119))	('menorrhagia', 'Phenotype', 'HP:0000132', (150, 161))	('G4P2A2', 'Var', (14, 20))	('menorrhagia', 'Disease', 'MESH:D008595', (150, 161))	('woman', 'Species', '9606', (31, 36))	('uterine malignancy', 'Phenotype', 'HP:0010784', (101, 119))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))	('Turkey', 'Species', '9103', (123, 129))
59344	22138373	In a randomized phase III trial, the combination of cisplatin and ifosfamide was associated with a higher response rate (54% v 36%) and an improved median progression-free survival (PFS) compared to ifosfamide when used alone as first line therapy.	('ifosfamide', 'Chemical', 'MESH:D007069', (199, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('ifosfamide', 'Chemical', 'MESH:D007069', (66, 76))	('progression-free survival', 'CPA', (155, 180))	('improved', 'PosReg', (139, 147))	('response', 'MPA', (106, 114))	('cisplatin', 'Var', (52, 61))
59445	16895611	There are three types of endometrial stromal tumors: endometrial stromal nodule, low-grade ESS (LGESS), and high-grade ESS (HGESS).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (25, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('endometrial stromal tumors', 'Disease', (25, 51))	('endometrial stromal nodule', 'Disease', (53, 79))	('low-grade', 'Var', (81, 90))	('high-grade ESS', 'Disease', (108, 122))
59527	33543003	Likewise, ECM remodeling via metalloproteinases and impaired or ectopic interaction with ECM receptors such as CD44 are reportedly major Pan-Cancer drivers of dissemination and resistance to therapy.	('CD44', 'Gene', (111, 115))	('metalloproteinases', 'Enzyme', (29, 47))	('ectopic', 'Var', (64, 71))	('Pan-Cancer', 'Disease', (137, 147))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CD44', 'Gene', '960', (111, 115))	('Pan-Cancer', 'Disease', 'MESH:D009369', (137, 147))
59534	33543003	We further show that different tumors share similar matrisome organization under similar master regulatory mechanisms, suggestive of common microenvironmental needs, and that matrisome expression has significant impact on Pan-Cancer and tumor-specific patient survival and offers possibilities for therapeutic interventions.	('patient', 'Species', '9606', (252, 259))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (237, 242))	('Pan-Cancer', 'Disease', (222, 232))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (31, 36))	('expression', 'Var', (185, 195))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('Pan-Cancer', 'Disease', 'MESH:D009369', (222, 232))	('Cancer', 'Phenotype', 'HP:0002664', (226, 232))	('matrisome', 'Gene', (175, 184))	('impact', 'Reg', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
59571	33543003	The master regulators identified were typically hub proteins (such as TP53 and P300), governing large networks of TFs as expected, and the number of drivers in a cancer type correlated linearly with the number of TFs they controlled (Suppl Fig.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('TP53', 'Gene', '7157', (70, 74))	('TF', 'Gene', '2152', (213, 215))	('P300', 'Var', (79, 83))	('TP53', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('TF', 'Gene', '2152', (114, 116))
59578	33543003	In general, pathway activation by mutations (at least two cancer-specific master regulators carrying oncogenic mutations in the same pathway) was infrequent, though in some tumors (BLCA, COAD, LUAD, READ and UCEC) it accounted for the majority of active pathways.	('COAD', 'Disease', 'MESH:D029424', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('COAD', 'Disease', (187, 191))	('LUAD', 'Disease', (193, 197))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (58, 64))	('READ', 'Disease', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (34, 43))
59627	33543003	Pan-Cancer drivers were filtered so that, for each cancer, their frequency of mutation in the tumor of interest was > average frequency of mutation of the same driver in the whole Pan-Cancer cohort.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Pan-Cancer', 'Disease', 'MESH:D009369', (180, 190))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', (94, 99))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Pan-Cancer', 'Disease', (0, 10))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Pan-Cancer', 'Disease', (180, 190))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Pan-Cancer', 'Disease', 'MESH:D009369', (0, 10))
59628	33543003	Cancer-specific drivers were filtered so that their frequency of mutation in the tumor of interest was >5%, well above the lower limit of intermediate-frequency drivers and the Pan-Cancer frequency of mutation in drivers (4.16%).	('Pan-Cancer', 'Disease', (177, 187))	('Pan-Cancer', 'Disease', 'MESH:D009369', (177, 187))	('Cancer', 'Disease', (181, 187))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutation', 'Var', (65, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
59669	33324570	In the SEER database of patients with uterine sarcoma, registered from 2004 to 2015 according to the International Classification of Tumor Diseases Third Edition (ICD-O-3), the included site codes were c54.0-C54.3, C54.8, and C54.9; these were histologically coded as 8800/3-8950/3, 8963/3, and 8982/3-8991/3, respectively.	('C54.8', 'Var', (215, 220))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('Tumor', 'Phenotype', 'HP:0002664', (133, 138))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (38, 53))	('c54.0-C54.3', 'Var', (202, 213))	('sarcoma', 'Disease', (46, 53))	('C54.9', 'Var', (226, 231))	('8800/3-8950/3', 'Var', (268, 281))	('Tumor Diseases', 'Disease', 'MESH:D009369', (133, 147))	('patients', 'Species', '9606', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('Tumor Diseases', 'Disease', (133, 147))
59690	33324570	Multivariate analysis results showed that, in general, early death and cancer-specific mortality risk was higher among black patients; older patients (51-67 years old, at the age of 68 or higher); those with larger tumors (98-148 mm, 149 mm or higher), higher FIGO staging (II, III, IV), or higher histological grade (GIII-GIV); those with tumors like endometrial stromal sarcoma, mixed epithelial and mesenchymal tumors, or other types of uterine sarcomas(except for leiomyosarcoma, endometrial stromal sarcoma and mixed epithelial and mesenchymal tumors); those who did not undergo surgery, radiotherapy, or chemotherapy; and those with brain metastases.	('tumors', 'Disease', (549, 555))	('higher', 'Var', (253, 259))	('death', 'Disease', 'MESH:D003643', (61, 66))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (402, 420))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (414, 420))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (537, 555))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (440, 455))	('endometrial stromal sarcoma', 'Disease', (352, 379))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('leiomyosarcoma', 'Disease', (468, 482))	('metastases', 'Disease', (645, 655))	('tumors', 'Disease', (215, 221))	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (125, 133))	('tumors', 'Disease', 'MESH:D009369', (549, 555))	('sarcoma', 'Phenotype', 'HP:0100242', (475, 482))	('endometrial stromal sarcoma', 'Disease', (484, 511))	('cancer', 'Disease', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('mesenchymal tumors', 'Disease', (402, 420))	('sarcoma', 'Phenotype', 'HP:0100242', (372, 379))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mesenchymal tumors', 'Disease', (537, 555))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('death', 'Disease', (61, 66))	('tumors', 'Disease', (340, 346))	('sarcomas', 'Disease', 'MESH:D012509', (448, 456))	('tumors', 'Phenotype', 'HP:0002664', (414, 420))	('sarcomas', 'Phenotype', 'HP:0100242', (448, 456))	('sarcoma', 'Phenotype', 'HP:0100242', (504, 511))	('mortality', 'Disease', (87, 96))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (468, 482))	('sarcomas', 'Disease', (448, 456))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (468, 482))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (352, 379))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('tumors', 'Phenotype', 'HP:0002664', (549, 555))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('higher', 'PosReg', (106, 112))	('tumors', 'Disease', (414, 420))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (484, 511))	('tumor', 'Phenotype', 'HP:0002664', (549, 554))	('sarcoma', 'Phenotype', 'HP:0100242', (448, 455))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('metastases', 'Disease', 'MESH:D009362', (645, 655))
59722	33324570	constructed an effective diagnostic model for uterine leiomyosarcoma using seven serum miRNA (Mir-4430, Mir-6511b-5p, Mir-191-5p, Mir-451A, Mir-4485-5p, Mir-4635, and Mir-1246) with high diagnostic performance for preoperative screening of uterine sarcoma, and proved that serum miRNA could be used as a preoperative biomarker.	('Mir-191', 'Gene', '406966', (118, 125))	('Mir-4430', 'Gene', (94, 102))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (46, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('Mir-4485', 'Gene', (140, 148))	('Mir-4430', 'Gene', '100616136', (94, 102))	('leiomyosarcoma', 'Disease', (54, 68))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('Mir-451A', 'Gene', (130, 138))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (240, 255))	('Mir-1246', 'Gene', (167, 175))	('sarcoma', 'Disease', (61, 68))	('Mir-6511b-5p', 'Var', (104, 116))	('Mir-4635', 'Gene', (153, 161))	('Mir-1246', 'Gene', '100302142', (167, 175))	('sarcoma', 'Disease', 'MESH:D012509', (248, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Mir-451A', 'Gene', '574411', (130, 138))	('sarcoma', 'Disease', (248, 255))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (54, 68))	('Mir-191', 'Gene', (118, 125))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (54, 68))	('Mir-4485', 'Gene', '100616263', (140, 148))	('Mir-4635', 'Gene', '100616479', (153, 161))
59854	31833846	This process, known as immunoediting, involves tumor stimulation of innate and adaptive immune responses resulting either in successful elimination of tumor or propagation of tumor variants with the capacity to escape or ultimately evade immune attack.	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('variants', 'Var', (181, 189))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
59867	31833846	Her2/neu, P53), (iv) splice variant antigens (e.g.	('splice variant', 'Var', (21, 35))	('Her2/neu', 'Gene', '2064', (0, 8))	('P53', 'Gene', (10, 13))	('P53', 'Gene', '7157', (10, 13))	('Her2/neu', 'Gene', (0, 8))
59883	31833846	Interference with inhibitory immune checkpoint signaling enhances antitumor responses by restoring T-cell function.	('T-cell function', 'CPA', (99, 114))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('enhances', 'PosReg', (57, 65))	('Interference', 'Var', (0, 12))	('restoring', 'PosReg', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
59887	31833846	These findings led to the first site-agnostic drug approval by the U.S. Food and Drug Administration for treatment-refractory solid tumors with PD-L1 expression, microsatellite instability or DNA mismatch repair deficiencies.	('microsatellite instability', 'Disease', (162, 188))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('microsatellite instability', 'Disease', 'MESH:D053842', (162, 188))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('PD-L1', 'Gene', (144, 149))	('DNA mismatch repair deficiencies', 'Var', (192, 224))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
59934	31833846	It is likely that a combination of PD-L1 expression, BRCA mutation status and presence of mismatch repair deficiency will better define candidates for immune checkpoint blockade.	('BRCA', 'Gene', (53, 57))	('PD-L1', 'Gene', (35, 40))	('BRCA', 'Gene', '672', (53, 57))	('deficiency', 'Var', (106, 116))
59936	31833846	This approach is of particular interest in patients with BRCA mutations, as combination treatment with niraparib (a PARPi) and pembrolizumab has demonstrated ORR as high as 45%.	('patients', 'Species', '9606', (43, 51))	('niraparib', 'Chemical', 'MESH:C545685', (103, 112))	('BRCA', 'Gene', '672', (57, 61))	('combination', 'Interaction', (76, 87))	('BRCA', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('pembrolizumab', 'Chemical', 'MESH:C582435', (127, 140))
59944	31833846	With the advent of newer technologies including transduction of chimeric antigen receptors and TCRs, the repertoire of potential targets for ACT in ovarian cancer has grown exponentially.	('TCR', 'Gene', '6962', (95, 98))	('chimeric', 'Var', (64, 72))	('ovarian cancer', 'Disease', (148, 162))	('TCR', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ovarian cancer', 'Phenotype', 'HP:0100615', (148, 162))	('ovarian cancer', 'Disease', 'MESH:D010051', (148, 162))
59950	31833846	Therefore, additional strategies in on-going clinical trials in ovarian cancer include combination with DNA methyltransferase inhibitor to enhance antigen expression and viral mimicry (NCT03017131), incorporation of a decoy dominant negative receptor for TGFbetaRII (NCT02650986), and the use of CD4TCR to generate CD4+ T cells for promoting CD8+ T-cell persistence.	('CD4', 'Gene', (296, 299))	('CD4', 'Gene', '920', (315, 318))	('CD8', 'Gene', (342, 345))	('antigen expression', 'MPA', (147, 165))	('ovarian cancer', 'Disease', 'MESH:D010051', (64, 78))	('CD4', 'Gene', '920', (296, 299))	('NCT02650986', 'Var', (267, 278))	('CD8', 'Gene', '925', (342, 345))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('promoting', 'PosReg', (332, 341))	('TGFbeta', 'Gene', (255, 262))	('NCT03017131', 'Var', (185, 196))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))	('ovarian cancer', 'Disease', (64, 78))	('CD4', 'Gene', (315, 318))	('enhance', 'PosReg', (139, 146))	('TGFbeta', 'Gene', '7039', (255, 262))
59953	31833846	These categories include ultra-mutated, hypermutated, copy number high and copy number low endometrial carcinomas.	('copy number low', 'Var', (75, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('endometrial carcinomas', 'Disease', (91, 113))	('hypermutated', 'Disease', (40, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (91, 113))	('ultra-mutated', 'Disease', (25, 38))	('copy number high', 'Var', (54, 70))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (91, 113))
59954	31833846	Similar to ovarian cancer, the presence of tumor infiltrating lymphocytes is associated with a favorable prognosis, reduced recurrence risk and is an independent risk factor for improved overall survival.	('improved', 'PosReg', (178, 186))	('reduced', 'NegReg', (116, 123))	('recurrence risk', 'MPA', (124, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('overall', 'MPA', (187, 194))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', (43, 48))	('ovarian cancer', 'Disease', (11, 25))	('presence', 'Var', (31, 39))
59958	31833846	Frequent DNA transcription errors in trinucleotide repeat sequences of tumor cells, known as high microsatellite instability (MSI-H), further characterize this phenotype.	('errors', 'Var', (27, 33))	('microsatellite instability', 'Disease', (98, 124))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('trinucleotide', 'Chemical', '-', (37, 50))	('microsatellite instability', 'Disease', 'MESH:D053842', (98, 124))
59959	31833846	MMR-deficient tumors including ultramutated and hypermutated endometrial cancers further exhibit higher TIL infiltration and PD-L1 expression compared to microsatellite-stable tumors, suggesting therapeutic benefit to immune checkpoint blockade in this subpopulation.	('higher', 'PosReg', (97, 103))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (0, 20))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('endometrial cancer', 'Phenotype', 'HP:0012114', (61, 79))	('TIL', 'Gene', '7096', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('PD-L1', 'Gene', (125, 130))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('TIL', 'Gene', (104, 107))	('hypermutated', 'Var', (48, 60))	('endometrial cancers', 'Disease', 'MESH:D016889', (61, 80))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('endometrial cancers', 'Disease', (61, 80))	('MMR-deficient tumors', 'Disease', (0, 20))	('ultramutated', 'Var', (31, 43))	('tumors', 'Disease', (176, 182))	('expression', 'MPA', (131, 141))	('tumors', 'Disease', 'MESH:D009369', (14, 20))
59963	31833846	The endometrial cancer cohort of KEYNOTE-028 evaluating pembrolizumab in solid tumors with PD-L1 positivity demonstrated 13% objective response rate with a median duration of 24.6 weeks, comparable with traditional chemotherapy regimens.	('endometrial cancer', 'Phenotype', 'HP:0012114', (4, 22))	('PD-L1', 'Gene', (91, 96))	('endometrial cancer', 'Disease', 'MESH:D016889', (4, 22))	('pembrolizumab', 'Chemical', 'MESH:C582435', (56, 69))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('positivity', 'Var', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('endometrial cancer', 'Disease', (4, 22))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
59993	31833846	These preliminary findings support the rationale for several active trials evaluating immune checkpoint inhibition with concurrent chemotherapy and radiation for locally advanced or persistent cervical cancer (NCT03277482, NCT02635360, NCT03738228).	('cervical cancer', 'Disease', 'MESH:D002583', (193, 208))	('NCT02635360', 'Var', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('locally advanced', 'Disease', (162, 178))	('NCT03738228', 'Var', (236, 247))	('NCT03277482', 'Var', (210, 221))	('cervical cancer', 'Disease', (193, 208))
59995	31833846	The first clinical trial using ACT were published by Stevanovic and colleagues using a single infusion of HPV E6 and E7 reactive tumor infiltrating lymphocytes after lymphodepletion.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('HPV E6', 'Var', (106, 112))	('tumor', 'Disease', (129, 134))	('HPV', 'Species', '10566', (106, 109))
60003	31833846	Single-agent checkpoint blockade in murine models of ovarian cancer is associated with upregulation of alternative checkpoint blockade pathways, however simultaneous blockade of PD-1 and LAG-3 has a synergistic effect on CD8 cell function.	('CD8', 'Gene', '925', (221, 224))	('LAG-3', 'Gene', '16768', (187, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('LAG-3', 'Gene', (187, 192))	('murine', 'Species', '10090', (36, 42))	('ovarian cancer', 'Disease', (53, 67))	('PD-1', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('blockade', 'Var', (166, 174))	('alternative checkpoint blockade pathways', 'Pathway', (103, 143))	('CD8', 'Gene', (221, 224))	('upregulation', 'PosReg', (87, 99))
60079	31324031	Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (74, 95))	('c-MYC', 'Gene', '4609', (284, 289))	('mutation', 'Var', (123, 131))	('CCNE1', 'Gene', '898', (274, 279))	('CCNE1', 'Gene', (274, 279))	('amplification', 'Var', (228, 241))	('TP53', 'Gene', '7157', (118, 122))	('ECS', 'Chemical', '-', (5, 8))	('TP53', 'Gene', (118, 122))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (74, 95))	('c-MYC', 'Gene', (284, 289))	('endometrial carcinoma', 'Disease', (74, 95))	('accompanied', 'Reg', (151, 162))
60080	31324031	However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', '7157', (261, 265))	('ARID1A', 'Gene', '8289', (223, 229))	('ARID1A', 'Gene', (223, 229))	('PI3', 'Gene', '5266', (212, 215))	('TP53', 'Gene', (261, 265))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('PI3', 'Gene', (212, 215))	('mutations', 'Var', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PTEN', 'Gene', (206, 210))	('tumors', 'Disease', (75, 81))	('PTEN', 'Gene', '5728', (206, 210))
60123	31324031	Four molecular groups have been defined for ECs: the hypermutated (mismatch repair deficiency), the ultramutated (POLE mutated), the copy-number low, and the copy-number high groups.	('deficiency', 'Disease', 'MESH:D007153', (83, 93))	('deficiency', 'Disease', (83, 93))	('copy-number', 'Var', (133, 144))
60126	31324031	Thus, in the study by McConechy et al., most tumors had a molecular profile similar to endometrial serous carcinoma (characterized by the presence of TP53, FBXW7, and PPP2R1A mutations and the absence of ARID1A, CTNNB1, KRAS, or PTEN mutations), while part of the tumors displayed an endometrioid carcinoma-like mutation profile characterized by the presence of ARID1A, CTNNB1, KRAS, and PTEN mutations.	('carcinoma', 'Disease', (106, 115))	('TP53', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (378, 382))	('CTNNB1', 'Gene', (370, 376))	('CTNNB1', 'Gene', (212, 218))	('PTEN', 'Gene', '5728', (229, 233))	('tumors', 'Disease', (264, 270))	('mutations', 'Var', (175, 184))	('ARID1A', 'Gene', '8289', (362, 368))	('FBXW7', 'Gene', '55294', (156, 161))	('PTEN', 'Gene', '5728', (388, 392))	('KRAS', 'Gene', (378, 382))	('PPP2R1A', 'Gene', '5518', (167, 174))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Disease', 'MESH:D002277', (297, 306))	('carcinoma', 'Disease', 'MESH:D002277', (106, 115))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('TP53', 'Gene', '7157', (150, 154))	('PPP2R1A', 'Gene', (167, 174))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (284, 306))	('endometrial serous carcinoma', 'Disease', (87, 115))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('CTNNB1', 'Gene', '1499', (370, 376))	('ARID1A', 'Gene', (204, 210))	('CTNNB1', 'Gene', '1499', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('KRAS', 'Gene', '3845', (220, 224))	('FBXW7', 'Gene', (156, 161))	('mutations', 'Var', (393, 402))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('PTEN', 'Gene', (229, 233))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('carcinoma', 'Disease', (297, 306))	('ARID1A', 'Gene', '8289', (204, 210))	('ARID1A', 'Gene', (362, 368))	('KRAS', 'Gene', (220, 224))	('PTEN', 'Gene', (388, 392))
60131	31324031	Most of the endometrioid-like ECSs also showed TP53 mutations, implying that TP53 could be involved in the progression of part of the copy-number low endometrioid-like carcinomas to ECSs, as we have previously reported in undifferentiated endometrial carcinoma.	('mutations', 'Var', (52, 61))	('involved', 'Reg', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('carcinomas', 'Disease', (168, 178))	('undifferentiated endometrial carcinoma', 'Disease', 'MESH:D002277', (222, 260))	('ECS', 'Chemical', '-', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('TP53', 'Gene', '7157', (47, 51))	('undifferentiated endometrial carcinoma', 'Disease', (222, 260))	('ECS', 'Chemical', '-', (182, 185))	('copy-number low', 'Var', (134, 149))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', (47, 51))	('carcinomas', 'Disease', 'MESH:D002277', (168, 178))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (239, 260))
60134	31324031	Previous studies combining aberrant expression of p53 and mutational analysis estimated a TP53 mutation prevalence of 50-60%.	('TP53', 'Gene', '7157', (90, 94))	('p53', 'Gene', '7157', (50, 53))	('TP53', 'Gene', (90, 94))	('p53', 'Gene', (50, 53))	('mutation', 'Var', (95, 103))
60135	31324031	However, subsequent studies using Next Generation Sequencing (NGS) techniques have shown that the true frequency of TP53 mutation in ECS is very high, between 64% and 91%.	('TP53', 'Gene', '7157', (116, 120))	('TP53', 'Gene', (116, 120))	('mutation', 'Var', (121, 129))	('ECS', 'Chemical', '-', (133, 136))
60136	31324031	In effect, TP53 mutations are the most frequent molecular alterations in ECS (Table 1).	('ECS', 'Disease', (73, 76))	('TP53', 'Gene', '7157', (11, 15))	('frequent', 'Reg', (39, 47))	('TP53', 'Gene', (11, 15))	('ECS', 'Chemical', '-', (73, 76))	('mutations', 'Var', (16, 25))
60137	31324031	The lack of nuclear p53 expression is most commonly detected with indel or nonsense mutations, while missense mutations usually lead to diffuse nuclear p53 immunostaining.	('missense mutations', 'Var', (101, 119))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('lack', 'NegReg', (4, 8))	('expression', 'MPA', (24, 34))	('p53', 'Gene', (152, 155))	('indel', 'Var', (66, 71))	('p53', 'Gene', '7157', (152, 155))	('nonsense mutations', 'Var', (75, 93))	('nuclear', 'MPA', (12, 19))	('lead to', 'Reg', (128, 135))
60138	31324031	In the DNA binding domain, 32% of mutations are located on known hotspot residues, and the most frequent are the R248Q and R273C/H (12% and 7%, respectively) followed by H179R/D, H193R/Y, and S241Y (5% each), .	('R248Q', 'Var', (113, 118))	('H179R', 'Var', (170, 175))	('H193R', 'SUBSTITUTION', 'None', (179, 184))	('S241Y', 'Var', (192, 197))	('H193R', 'Var', (179, 184))	('S241Y', 'Mutation', 'rs28934573', (192, 197))	('R248Q', 'Mutation', 'rs11540652', (113, 118))	('H179R', 'SUBSTITUTION', 'None', (170, 175))	('R273C', 'Var', (123, 128))	('R273C', 'SUBSTITUTION', 'None', (123, 128))
60139	31324031	The carcinomatous and sarcomatous components show a concordance of 85% for the p53 protein overexpression and 96% for the TP53 gene mutation, which points to a monoclonal origin of both components (Figure 1).	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('p53', 'Gene', (79, 82))	('TP53', 'Gene', (122, 126))	('p53', 'Gene', '7157', (79, 82))	('overexpression', 'PosReg', (91, 105))	('carcinomatous', 'Disease', 'MESH:D055756', (4, 17))	('carcinomatous', 'Disease', (4, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))	('sarcomatous component', 'Disease', 'MESH:D018316', (22, 43))	('TP53', 'Gene', '7157', (122, 126))	('mutation', 'Var', (132, 140))	('sarcomatous component', 'Disease', (22, 43))
60140	31324031	p16 overexpression (in-block diffuse expression) occurs in about 60% of ECS simultaneously with TP53 mutations.	('ECS', 'Disease', (72, 75))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('p16', 'Gene', (0, 3))	('ECS', 'Chemical', '-', (72, 75))	('overexpression', 'PosReg', (4, 18))	('p16', 'Gene', '1029', (0, 3))	('TP53', 'Gene', '7157', (96, 100))
60142	31324031	In addition to TP53, ECSs show mutations in other genes that are also more frequently affected in endometrial serous carcinoma (ESC) than in endometrial endometrioid carcinoma (EEC).	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (98, 126))	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (141, 175))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('endometrial serous carcinoma', 'Disease', (98, 126))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (153, 175))	('affected', 'Reg', (86, 94))	('endometrial endometrioid carcinoma', 'Disease', (141, 175))	('ECS', 'Chemical', '-', (21, 24))
60143	31324031	Accordingly, mutations of FBXW7 and PPP2R1A have been reported in 19% to 39% and 1% to 38%, respectively, in different series.	('mutations', 'Var', (13, 22))	('FBXW7', 'Gene', (26, 31))	('PPP2R1A', 'Gene', (36, 43))	('PPP2R1A', 'Gene', '5518', (36, 43))	('reported', 'Reg', (54, 62))	('FBXW7', 'Gene', '55294', (26, 31))
60144	31324031	Regarding the BRCA1 and BRCA2 genes, the frequency of ECS in patients carrying germinal BRCA1/2 mutations has been analyzed in different studies.	('BRCA1', 'Gene', '672', (14, 19))	('BRCA1', 'Gene', (88, 93))	('BRCA2', 'Gene', '675', (24, 29))	('BRCA1', 'Gene', (14, 19))	('patients', 'Species', '9606', (61, 69))	('ECS', 'Chemical', '-', (54, 57))	('BRCA1/2', 'Gene', (88, 95))	('BRCA1', 'Gene', '672', (88, 93))	('BRCA2', 'Gene', (24, 29))	('BRCA1/2', 'Gene', '672;675', (88, 95))	('mutations', 'Var', (96, 105))
60145	31324031	The estimated relative risk for mutation carriers is approximately 2% per year, most importantly among serous carcinoma.	('serous carcinoma', 'Disease', 'MESH:D018284', (103, 119))	('mutation', 'Var', (32, 40))	('serous carcinoma', 'Disease', (103, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))
60146	31324031	A recent series has reported that BRCA1/2 were found mutated in 18% and 27%, respectively of ECS, although in the TCGA (The Cancer Genome Atlas Program) series, only BRCA2 mutations were detected and at a lower frequency (5%).	('ECS', 'Disease', (93, 96))	('ECS', 'Chemical', '-', (93, 96))	('BRCA2', 'Gene', '675', (166, 171))	('BRCA1/2', 'Gene', '672;675', (34, 41))	('mutated', 'Var', (53, 60))	('Cancer Genome Atlas', 'Disease', (124, 143))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (124, 143))	('BRCA1/2', 'Gene', (34, 41))	('BRCA2', 'Gene', (166, 171))
60148	31324031	found an excess of mutations in genes encoding histone H2A and H2B, as well as a significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes.	('H2B', 'Gene', '8349', (63, 66))	('mutations', 'Var', (19, 28))	('H2B', 'Gene', (63, 66))	('histone H2A', 'Protein', (47, 58))
60149	31324031	Thus, mutations in histone H2A/H2B genes were significantly enriched in carcinosarcomas (CSs) compared with carcinomas (mutations in 21.2% of CSs and 5.2% of uterine and ovarian epithelial tumor).	('ovarian epithelial tumor', 'Disease', 'MESH:D000077216', (170, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ovarian epithelial tumor', 'Disease', (170, 194))	('ovarian epithelial tumor', 'Phenotype', 'HP:0025318', (170, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('H2B', 'Gene', (31, 34))	('CSs', 'Disease', (142, 145))	('epithelial tumor', 'Phenotype', 'HP:0031492', (178, 194))	('carcinomas', 'Disease', (108, 118))	('carcinomas', 'Disease', 'MESH:D002277', (108, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('H2B', 'Gene', '8349', (31, 34))	('carcinosarcomas', 'Disease', 'MESH:D002296', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutations', 'Var', (6, 15))	('carcinosarcomas', 'Disease', (72, 87))
60150	31324031	These findings implicate mutations in histone H2A/H2B genes in ECS.	('mutations', 'Var', (25, 34))	('ECS', 'Chemical', '-', (63, 66))	('H2B', 'Gene', '8349', (50, 53))	('ECS', 'Disease', (63, 66))	('implicate', 'Reg', (15, 24))	('H2B', 'Gene', (50, 53))
60151	31324031	have reported forkhead box A2 (FOXA2) mutations in 15.1% of ECS.	('FOXA2', 'Gene', '3170', (31, 36))	('forkhead box A2', 'Gene', (14, 29))	('FOXA2', 'Gene', (31, 36))	('ECS', 'Disease', (60, 63))	('ECS', 'Chemical', '-', (60, 63))	('forkhead box A2', 'Gene', '3170', (14, 29))	('mutations', 'Var', (38, 47))
60152	31324031	FOXA2 had not previously been implicated in ECSs and was predominated by frameshift and nonsense mutations.	('frameshift', 'Var', (73, 83))	('ECS', 'Chemical', '-', (44, 47))	('nonsense mutations', 'Var', (88, 106))	('FOXA2', 'Gene', '3170', (0, 5))	('FOXA2', 'Gene', (0, 5))
60153	31324031	Sequencing of FOXA2 in 160 primary endometrial carcinomas revealed somatic mutations in 5.7% of serous, 22.7% of clear cell, 9% of endometrioid, and 11.1% of mixed endometrial carcinomas, the majority of which were frameshift mutations.	('FOXA2', 'Gene', (14, 19))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (35, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('endometrial carcinomas', 'Disease', (164, 186))	('serous', 'Disease', (96, 102))	('FOXA2', 'Gene', '3170', (14, 19))	('endometrioid', 'Disease', (131, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (164, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('endometrial carcinomas', 'Disease', (35, 57))	('clear cell', 'Disease', (113, 123))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (164, 186))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (35, 56))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (164, 186))	('frameshift mutations', 'Var', (215, 235))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (35, 57))	('mutations', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
60155	31324031	Similarly to ESC, ECS is characterized by aneuploidy and a high frequency of copy number variations (CNVs).	('aneuploidy', 'Disease', (42, 52))	('ECS', 'Disease', (18, 21))	('ECS', 'Chemical', '-', (18, 21))	('aneuploidy', 'Disease', 'MESH:D000782', (42, 52))	('copy number variations', 'Var', (77, 99))
60160	31324031	In other tumors, for example, ovarian high-grade serous carcinoma, amplification of CCNE1 is associated with a worse prognosss and resistance to chemotherapy.	('serous carcinoma', 'Disease', (49, 65))	('CCNE1', 'Gene', (84, 89))	('serous carcinoma', 'Disease', 'MESH:D018284', (49, 65))	('amplification', 'Var', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('ovarian high', 'Phenotype', 'HP:0008209', (30, 42))	('associated', 'Reg', (93, 103))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('CCNE1', 'Gene', '898', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
60165	31324031	Thus, ECS patients with ERBB2 amplification could benefit from anti-HER2 (human epidermal growth factor receptor 2) therapies, such as Trastuzumab.	('Trastuzumab', 'Chemical', 'MESH:D000068878', (135, 146))	('ECS', 'Chemical', '-', (6, 9))	('HER2', 'Gene', (68, 72))	('amplification', 'Var', (30, 43))	('ERBB2', 'Gene', (24, 29))	('epidermal growth factor receptor 2', 'Gene', (80, 114))	('ERBB2', 'Gene', '2064', (24, 29))	('benefit', 'PosReg', (50, 57))	('HER2', 'Gene', '2064', (68, 72))	('epidermal growth factor receptor 2', 'Gene', '2064', (80, 114))	('patients', 'Species', '9606', (10, 18))	('human', 'Species', '9606', (74, 79))	('ECS', 'Disease', (6, 9))
60168	31324031	detected ZNF217 amplification in 87% of gynecological CS.	('gynecological CS', 'Disease', (40, 56))	('ZNF217', 'Gene', '7764', (9, 15))	('ZNF217', 'Gene', (9, 15))	('amplification', 'Var', (16, 29))
60171	31324031	reported EGFR amplification by FISH in 19% of tumors, while in studies with smaller sample size, EGFR (epidermal growth factor receptor) protein overexpression has been reported in 45% to 82% of ECS, where a higher level of expression was seen in the sarcomatous component.	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('ECS', 'Chemical', '-', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcomatous component', 'Disease', 'MESH:D018316', (251, 272))	('EGFR', 'Gene', '1956', (97, 101))	('sarcomatous component', 'Disease', (251, 272))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('tumors', 'Disease', (46, 52))	('amplification', 'Var', (14, 27))	('ECS', 'Disease', (195, 198))
60173	31324031	URI1 amplification was also associated with poor survival and reduced response to adjuvant treatment.	('amplification', 'Var', (5, 18))	('URI1', 'Gene', (0, 4))	('URI1', 'Gene', '8725', (0, 4))	('poor', 'NegReg', (44, 48))	('response to adjuvant treatment', 'MPA', (70, 100))	('reduced', 'NegReg', (62, 69))
60174	31324031	Likewise, in a cultured cell model, overexpression of URI1 induced ATM (ATM Serine/Threonine Kinase) expression and resistance to cisplatin.	('URI1', 'Gene', (54, 58))	('resistance', 'CPA', (116, 126))	('ATM', 'Gene', '472', (72, 75))	('ATM', 'Gene', '472', (67, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('ATM Serine/Threonine Kinase', 'Gene', (72, 99))	('ATM Serine/Threonine Kinase', 'Gene', '472', (72, 99))	('induced', 'Reg', (59, 66))	('URI1', 'Gene', '8725', (54, 58))	('expression', 'MPA', (101, 111))	('overexpression', 'Var', (36, 50))	('ATM', 'Gene', (72, 75))	('ATM', 'Gene', (67, 70))
60176	31324031	Mutations in genes encoding for the kinase or regulatory proteins of the PI3K/AKT (phosphatidylinositol 3-kinase/(Protein Kinase B) pathway have been detected in up to 67% of ECS.	('ECS', 'Chemical', '-', (175, 178))	('PI3', 'Gene', (73, 76))	('AKT', 'Gene', '207', (78, 81))	('Protein Kinase B', 'Gene', (114, 130))	('Protein Kinase B', 'Gene', '2185', (114, 130))	('Mutations', 'Var', (0, 9))	('PI3', 'Gene', '5266', (73, 76))	('ECS', 'Disease', (175, 178))	('AKT', 'Gene', (78, 81))	('detected', 'Reg', (150, 158))
60177	31324031	Moreover, multiple PI3K/AKT pathway proteins have been found mutated in one tumor.	('AKT', 'Gene', (24, 27))	('PI3', 'Gene', '5266', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PI3', 'Gene', (19, 22))	('mutated', 'Var', (61, 68))	('AKT', 'Gene', '207', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
60178	31324031	PIK3CA mutations have been found in 11% to 40% of the tumors.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PIK3CA', 'Gene', '5290', (0, 6))	('found', 'Reg', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))	('mutations', 'Var', (7, 16))
60179	31324031	Unlike for TP53, with mutations concentrated on HotSpot regions, the mutations in PIK3CA are found scattered in the different functional domains.	('mutations', 'Var', (69, 78))	('PIK3CA', 'Gene', (82, 88))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('PIK3CA', 'Gene', '5290', (82, 88))
60180	31324031	In addition to the traditional PIK3CA hotspots in exons 9 and 20, a smaller portion of ECS has mutations in exon 1, in the adaptor binding domain, helical domain, and C2 domain which increase kinase enzymatic activity.	('exon 1', 'Gene', (108, 114))	('ECS', 'Chemical', '-', (87, 90))	('increase', 'PosReg', (183, 191))	('PIK3CA', 'Gene', (31, 37))	('kinase enzymatic activity', 'MPA', (192, 217))	('PIK3CA', 'Gene', '5290', (31, 37))	('mutations', 'Var', (95, 104))
60181	31324031	The importance of mutations in this pathway comes from the fact that PI3KCA mutations have been detected in both the carcinoma and sarcoma components of the primary tumor and also in the metastatic tumor.	('PI3', 'Gene', (69, 72))	('detected', 'Reg', (96, 104))	('mutations', 'Var', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('sarcoma component', 'Disease', 'MESH:D012509', (131, 148))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('PI3', 'Gene', '5266', (69, 72))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (117, 138))	('sarcoma component', 'Disease', (131, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (165, 170))
60184	31324031	Phosphatase And Tensin Homolog (PTEN) mutations are not as frequent as PIK3CA, but they are present in approximately 20% of ECS: 17% and 19% in the series reported by McConechy et al.	('ECS', 'Disease', (124, 127))	('ECS', 'Chemical', '-', (124, 127))	('PIK3CA', 'Gene', '5290', (71, 77))	('PTEN', 'Gene', (32, 36))	('Phosphatase And Tensin Homolog', 'Gene', (0, 30))	('PTEN', 'Gene', '5728', (32, 36))	('mutations', 'Var', (38, 47))	('Phosphatase And Tensin Homolog', 'Gene', '5728', (0, 30))	('PIK3CA', 'Gene', (71, 77))
60185	31324031	reported that 47% of ECS carried PTEN mutation, but their series included only 17 cases.	('PTEN', 'Gene', (33, 37))	('ECS', 'Chemical', '-', (21, 24))	('mutation', 'Var', (38, 46))	('PTEN', 'Gene', '5728', (33, 37))
60186	31324031	PTEN and PIK3CA mutations frequently coexist in the same ECS.	('mutations', 'Var', (16, 25))	('ECS', 'Chemical', '-', (57, 60))	('PIK3CA', 'Gene', (9, 15))	('PTEN', 'Gene', (0, 4))	('PIK3CA', 'Gene', '5290', (9, 15))	('PTEN', 'Gene', '5728', (0, 4))
60187	31324031	Other genes with less frequency of mutations in the PI3K/AKT pathway in ECSs include Phosphatidylinositol 3-Kinase Regulatory Subunit 1 (PIK3R1) (10-17%), PIK3R2, AKT1, AKT2, and AKT3 (less than 5% for each gene).	('mutations', 'Var', (35, 44))	('AKT3', 'Gene', '10000', (179, 183))	('PI3', 'Gene', (52, 55))	('AKT', 'Gene', (163, 166))	('ECS', 'Chemical', '-', (72, 75))	('AKT2', 'Gene', '208', (169, 173))	('AKT', 'Gene', '207', (57, 60))	('AKT1', 'Gene', '207', (163, 167))	('AKT3', 'Gene', (179, 183))	('PIK3R1', 'Gene', (137, 143))	('AKT', 'Gene', (179, 182))	('PIK3R2', 'Gene', (155, 161))	('AKT', 'Gene', (169, 172))	('AKT2', 'Gene', (169, 173))	('AKT1', 'Gene', (163, 167))	('AKT', 'Gene', '207', (163, 166))	('AKT', 'Gene', (57, 60))	('PIK3R2', 'Gene', '5296', (155, 161))	('AKT', 'Gene', '207', (179, 182))	('PI3', 'Gene', '5266', (52, 55))	('PIK3R1', 'Gene', '5295', (137, 143))	('AKT', 'Gene', '207', (169, 172))
60188	31324031	AT-Rich Interaction Domain 1A (ARID1A) and Catenin Beta 1 (CTNNB1) are commonly mutated in EEC, and ARID1A mutations occur also in 10% to 15% of ECS, leading usually to loss of of protein expression, while mutations in CTNNB1 are infrequent in ECS.	('CTNNB1', 'Gene', '1499', (59, 65))	('AT-Rich Interaction Domain 1A', 'Gene', (0, 29))	('ECS', 'Chemical', '-', (244, 247))	('mutations', 'Var', (107, 116))	('ECS', 'Chemical', '-', (145, 148))	('loss', 'NegReg', (169, 173))	('ARID1A', 'Gene', '8289', (31, 37))	('CTNNB1', 'Gene', (219, 225))	('ARID1A', 'Gene', (31, 37))	('of of protein expression', 'MPA', (174, 198))	('ARID1A', 'Gene', '8289', (100, 106))	('Catenin Beta 1', 'Gene', (43, 57))	('ARID1A', 'Gene', (100, 106))	('AT-Rich Interaction Domain 1A', 'Gene', '8289', (0, 29))	('Catenin Beta 1', 'Gene', '1499', (43, 57))	('CTNNB1', 'Gene', (59, 65))	('CTNNB1', 'Gene', '1499', (219, 225))
60189	31324031	KRAS mutations were found in 12% and Cadherin 4 (CDH4) mutations in 18%.	('CDH4', 'Gene', (49, 53))	('mutations', 'Var', (55, 64))	('mutations', 'Var', (5, 14))	('Cadherin 4', 'Gene', '1002', (37, 47))	('CDH4', 'Gene', '1002', (49, 53))	('found', 'Reg', (20, 25))	('KRAS', 'Gene', (0, 4))	('Cadherin 4', 'Gene', (37, 47))	('KRAS', 'Gene', '3845', (0, 4))
60192	31324031	In sporadic EC, MMR-def is detected in 15-30% of cases, although a higher frequency has been detected among high-grade endometrioid carcinomas (45-63%), most frequently due to MLH1 promotor methylation.	('methylation', 'Var', (190, 201))	('endometrioid carcinomas', 'Disease', (119, 142))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (119, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (119, 142))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (119, 142))	('MMR-def', 'Disease', (16, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('MLH1', 'Gene', '4292', (176, 180))	('MLH1', 'Gene', (176, 180))
60193	31324031	In addition, between 2-6% of endometrial carcinoma occurs in the context of Lynch syndrome due to germline mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('Lynch syndrome', 'Disease', (76, 90))	('due', 'Reg', (91, 94))	('Lynch syndrome', 'Disease', 'MESH:D003123', (76, 90))	('germline mutations', 'Var', (98, 116))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (29, 50))	('occurs', 'Reg', (51, 57))	('endometrial carcinoma', 'Disease', (29, 50))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (29, 50))
60195	31324031	MLH1 promoter methylation is probably the major cause for MMR-def in most tumors, and accordingly, MLH1 was epigenetically silenced in the two samples with MMR-def in the TCGA series.	('MLH1', 'Gene', '4292', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MLH1', 'Gene', (99, 103))	('MLH1', 'Gene', '4292', (0, 4))	('cause', 'Reg', (48, 53))	('MLH1', 'Gene', (0, 4))	('silenced', 'NegReg', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('epigenetically', 'Var', (108, 122))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('MMR-def', 'Disease', (58, 65))	('tumors', 'Disease', (74, 80))
60196	31324031	Mutations in DNA Polymerase Epsilon, Catalytic Subunit (POLE) are present in some ECS, both of the most common HotSpot-mutations (P286R and V114L) have been identified in individual cases of ECS.	('P286R', 'Var', (130, 135))	('present', 'Reg', (66, 73))	('ECS', 'Disease', (191, 194))	('V114L', 'Var', (140, 145))	('P286R', 'Mutation', 'rs1476441129', (130, 135))	('V114L', 'Mutation', 'rs750420143', (140, 145))	('ECS', 'Chemical', '-', (191, 194))	('ECS', 'Disease', (82, 85))	('ECS', 'Chemical', '-', (82, 85))
60213	31324031	Finally, lower cancer-specific survival has been associated with upregulation of miR-184 and downregulation of let-7b-5p and miR-124.	('cancer', 'Disease', (15, 21))	('miR-184', 'Gene', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('let-7b', 'Gene', '406884', (111, 117))	('miR-184', 'Gene', '406960', (81, 88))	('let-7b', 'Gene', (111, 117))	('lower', 'NegReg', (9, 14))	('upregulation', 'PosReg', (65, 77))	('downregulation', 'NegReg', (93, 107))	('miR-124', 'Var', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
60214	31324031	Similarly to other types of cancers, ECS displays abnormal DNA methylation patterns including genome-wide hypomethylation and site-specific hypermethylation, associated with increased expression of DNA methyltransferases (DNMT1, DNMT3a), when compared to the normal endometrium.	('cancers', 'Disease', (28, 35))	('hypomethylation', 'Var', (106, 121))	('DNMT3a', 'Gene', '1788', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('DNMT3a', 'Gene', (229, 235))	('DNMT1', 'Gene', (222, 227))	('ECS', 'Chemical', '-', (37, 40))	('DNMT1', 'Gene', '1786', (222, 227))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('expression', 'MPA', (184, 194))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('increased', 'PosReg', (174, 183))	('hypermethylation', 'Var', (140, 156))
60221	31324031	Accordingly, the frequency of PTEN mutations was higher in the first group.	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))	('mutations', 'Var', (35, 44))
60222	31324031	A constant characteristic of ECS is the aberrant DNA methylation of miR-200 genes (see discussion in Section 7.	('aberrant', 'Var', (40, 48))	('ECS', 'Chemical', '-', (29, 32))	('DNA', 'MPA', (49, 52))	('miR-200', 'Gene', (68, 75))	('miR-200', 'Chemical', '-', (68, 75))
60236	31324031	A role of the WNT pathway in the transition from an epithelial to a mesenchymal status is demonstrated by the fact that up to 23% of ECS showed nuclear beta-catenin, not associated with CTNNB1 mutation, in the sarcomatous but not in the carcinomatous component.	('sarcomatous', 'Disease', (210, 221))	('CTNNB1', 'Gene', '1499', (186, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('beta-catenin', 'Gene', (152, 164))	('beta-catenin', 'Gene', '1499', (152, 164))	('CTNNB1', 'Gene', (186, 192))	('ECS', 'Chemical', '-', (133, 136))	('carcinomatous component', 'Disease', 'MESH:D055756', (237, 260))	('sarcomatous', 'Disease', 'MESH:D018316', (210, 221))	('mutation', 'Var', (193, 201))	('carcinomatous component', 'Disease', (237, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
60245	31324031	In this sense, experimental studies have demonstrated a major role of ZEB1 in transcriptional repression and of SNAI1 and, to a lesser extent, SNAI2 in the epigenetic silencing through DNA hypermethylation of miR-200 genes.	('miR-200', 'Gene', (209, 216))	('miR-200', 'Chemical', '-', (209, 216))	('ZEB1', 'Gene', (70, 74))	('transcriptional repression', 'MPA', (78, 104))	('SNAI1', 'Gene', '6615', (112, 117))	('SNAI2', 'Gene', '6591', (143, 148))	('SNAI2', 'Gene', (143, 148))	('DNA hypermethylation', 'Var', (185, 205))	('SNAI1', 'Gene', (112, 117))	('epigenetic', 'MPA', (156, 166))	('ZEB1', 'Gene', '6935', (70, 74))
60276	31324031	Molecular observations suggest that, although infrequent, endometrioid carcinomas associated with mutations in PTEN or PIK3CA are more prone to acquire TP53 mutations than those associated with MMR-def, POLE, or CTNNB1 mutations.	('endometrioid carcinomas', 'Disease', (58, 81))	('PTEN', 'Gene', (111, 115))	('PIK3CA', 'Gene', (119, 125))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (58, 80))	('PTEN', 'Gene', '5728', (111, 115))	('PIK3CA', 'Gene', '5290', (119, 125))	('TP53', 'Gene', '7157', (152, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (58, 81))	('CTNNB1', 'Gene', (212, 218))	('mutations', 'Var', (98, 107))	('mutations', 'Var', (157, 166))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (58, 81))	('TP53', 'Gene', (152, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('acquire', 'PosReg', (144, 151))	('CTNNB1', 'Gene', '1499', (212, 218))
60277	31324031	Mutations in TP53 seem to be essential, but not sufficient, to ECS development, since they are as frequent in ECS as in endometrial serous carcinoma.	('ECS', 'Disease', (110, 113))	('TP53', 'Gene', (13, 17))	('ECS', 'Chemical', '-', (110, 113))	('ECS', 'Chemical', '-', (63, 66))	('frequent', 'Reg', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('Mutations', 'Var', (0, 9))	('endometrial serous carcinoma', 'Disease', (120, 148))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (120, 148))	('TP53', 'Gene', '7157', (13, 17))	('ECS', 'Disease', (63, 66))
60278	31324031	Although it is not clear what triggers EMT in tumors with TP53 mutation, a common characteristic of all ECS is the switching of cadherins, the overexpression EMT-TF, and the down-regulation of miR-200 genes.	('ECS', 'Chemical', '-', (104, 107))	('cadherin', 'Gene', '999;1009;1000;1002', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mutation', 'Var', (63, 71))	('miR-200 genes', 'Gene', (193, 206))	('down-regulation', 'NegReg', (174, 189))	('miR-200', 'Chemical', '-', (193, 200))	('tumors', 'Disease', (46, 52))	('cadherin', 'Gene', (128, 136))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
60279	31324031	Probably, the crosstalk of different EMT-TF and the differential regulation of miR-200 genes by transcriptional repression or by epigenetic silencing through DNA hypermethylation play a major role in fixing the mesenchymal phenotype.	('hypermethylation', 'Var', (162, 178))	('miR-200', 'Gene', (79, 86))	('miR-200', 'Chemical', '-', (79, 86))	('mesenchymal phenotype', 'CPA', (211, 232))	('epigenetic silencing', 'Var', (129, 149))
60284	31324031	Although the relatively low-frequency of ECS hinders efforts to design specific clinical trials, there are promising areas of research, such as the use of immunotherapy in tumors with POLE mutations, MMR-def, and high TMB, and also the use of Poly (ADP-ribose) polymerase (PARP) inhibitors in tumors with homologous recombination deficiency, especially due to germline or somatic BRCA mutations.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('BRCA', 'Gene', (380, 384))	('deficiency', 'Disease', (330, 340))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('germline', 'Var', (360, 368))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('TMB', 'Chemical', '-', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('ECS', 'Chemical', '-', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('deficiency', 'Disease', 'MESH:D007153', (330, 340))	('clinical', 'Species', '191496', (80, 88))	('tumors', 'Disease', (293, 299))	('BRCA', 'Gene', '672', (380, 384))	('mutations', 'Var', (385, 394))
60321	29439179	The Cancer Genome Atlas (TCGA) study of endometrioid and serous carcinomas found mutations in several genes (e.g., TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, CTNNB1, KRAS and POLE), but more importantly, identified four major genomically defined classes of tumor (POLE-ultramutated, microsatellite instability-hypermutated [MSI-H], copy-number-low, and copy-number-high).	('serous carcinomas', 'Disease', (57, 74))	('copy-number-low', 'Var', (325, 340))	('FBXW7', 'Gene', (144, 149))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (81, 90))	('tumor', 'Disease', (250, 255))	('MSI-H', 'Disease', 'MESH:D000848', (317, 322))	('microsatellite instability-hypermutated', 'MPA', (276, 315))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('PIK3CA', 'Gene', '5290', (127, 133))	('TP53', 'Gene', (115, 119))	('PPP2R1A', 'Gene', '5518', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('serous carcinomas', 'Disease', 'MESH:D018284', (57, 74))	('CTNNB1', 'Gene', '1499', (151, 157))	('PTEN', 'Gene', (121, 125))	('FBXW7', 'Gene', '55294', (144, 149))	('PPP2R1A', 'Gene', (135, 142))	('KRAS', 'Gene', '3845', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('copy-number-high', 'Var', (346, 362))	('PTEN', 'Gene', '5728', (121, 125))	('KRAS', 'Gene', (159, 163))	('TP53', 'Gene', '7157', (115, 119))	('PIK3CA', 'Gene', (127, 133))	('CTNNB1', 'Gene', (151, 157))	('MSI-H', 'Disease', (317, 322))	('Cancer Genome Atlas', 'Disease', (4, 23))
60324	29439179	Abnormal DNA ploidy was associated with higher grade, non-endometrioid histotype, and poorer survival (particularly in mismatch repair-deficient tumors).	('non-endometrioid', 'Disease', (54, 70))	('survival', 'MPA', (93, 101))	('Abnormal DNA ploidy', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('poorer', 'NegReg', (86, 92))	('deficient tumors', 'Disease', (135, 151))	('higher', 'Disease', (40, 46))	('mismatch', 'Var', (119, 127))	('deficient tumors', 'Disease', 'MESH:D009369', (135, 151))
60326	29439179	Uterine carcinosarcomas also frequently harbor mutations in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous carcinomas.	('KRAS', 'Gene', (100, 104))	('harbor', 'Reg', (40, 46))	('FBXW7', 'Gene', (89, 94))	('PIK3CA', 'Gene', '5290', (72, 78))	('TP53', 'Gene', (60, 64))	('serous carcinomas', 'Disease', (134, 151))	('carcinosarcomas', 'Disease', (8, 23))	('mutations', 'Var', (47, 56))	('PPP2R1A', 'Gene', '5518', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('FBXW7', 'Gene', '55294', (89, 94))	('PTEN', 'Gene', (66, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('PIK3CA', 'Gene', (72, 78))	('TP53', 'Gene', '7157', (60, 64))	('PPP2R1A', 'Gene', (80, 87))	('serous carcinomas', 'Disease', 'MESH:D018284', (134, 151))	('KRAS', 'Gene', '3845', (100, 104))	('PTEN', 'Gene', '5728', (66, 70))	('carcinosarcomas', 'Disease', 'MESH:D002296', (8, 23))
60328	29439179	Copy-number-high tumors, which are characterized by TP53 mutations and alterations associated with cell cycle deregulation, comprise some high-grade endometrioid adenocarcinomas and clear cell carcinomas, and all serous cancers.	('serous cancers', 'Disease', 'MESH:D009369', (213, 227))	('tumors', 'Disease', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('mutations', 'Var', (57, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('endometrioid adenocarcinomas', 'Disease', (149, 177))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('TP53', 'Gene', (52, 56))	('serous cancers', 'Disease', (213, 227))	('alterations', 'Var', (71, 82))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (149, 177))	('clear cell carcinomas', 'Disease', (182, 203))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TP53', 'Gene', '7157', (52, 56))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (182, 203))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (149, 176))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
60330	29439179	POLE-mutated endometrial carcinomas are typically characterized by: high grade; tumor-infiltrating lymphocytes and/or peritumoral lymphocytes; morphologic heterogeneity/ambiguity; and bizarre/giant tumor cell nuclei.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (13, 34))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (13, 35))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('giant tumor', 'Disease', 'MESH:D005870', (192, 203))	('giant tumor', 'Disease', (192, 203))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('POLE-mutated', 'Var', (0, 12))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))	('endometrial carcinomas', 'Disease', (13, 35))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (13, 35))
60331	29439179	Endometrioid histotype is most frequent, although POLE mutations have also been reported in clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas.	('Endometrioid', 'Disease', (0, 12))	('carcinosarcomas', 'Disease', 'MESH:D002296', (148, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('mutations', 'Var', (55, 64))	('carcinosarcomas', 'Disease', (148, 163))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (115, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('clear cell carcinomas', 'Disease', (92, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('undifferentiated carcinomas', 'Disease', (115, 142))	('reported', 'Reg', (80, 88))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (92, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
60334	29439179	P53 immunohistochemistry does not correlate perfectly with TP53 copy number changes, and its use in these algorithms may therefore misclassify some copy-number-high tumors.	('P53', 'Gene', (60, 63))	('TP53', 'Gene', (59, 63))	('misclassify', 'Reg', (131, 142))	('copy-number-high', 'Var', (148, 164))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('P53', 'Gene', '7157', (60, 63))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('TP53', 'Gene', '7157', (59, 63))
60348	29439179	Genomically, these tumors harbor mutations in POLE, SMARCA4, ARID1B, CTNNB1, PPP2R1A, or TP53.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('ARID1B', 'Gene', '57492', (61, 67))	('TP53', 'Gene', (89, 93))	('TP53', 'Gene', '7157', (89, 93))	('CTNNB1', 'Gene', '1499', (69, 75))	('harbor', 'Reg', (26, 32))	('mutations', 'Var', (33, 42))	('SMARCA4', 'Gene', (52, 59))	('POLE', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PPP2R1A', 'Gene', (77, 84))	('CTNNB1', 'Gene', (69, 75))	('SMARCA4', 'Gene', '6597', (52, 59))	('PPP2R1A', 'Gene', '5518', (77, 84))	('ARID1B', 'Gene', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
60357	29439179	Mutations in KRAS, NRAS, and chromatin remodeling genes (ARID1A, ARID1B, SMARCA4) have been reported in mesonephric carcinomas.	('mesonephric carcinomas', 'Disease', 'MESH:D002277', (104, 126))	('ARID1B', 'Gene', (65, 71))	('NRAS', 'Gene', (19, 23))	('NRAS', 'Gene', '4893', (19, 23))	('SMARCA4', 'Gene', (73, 80))	('Mutations', 'Var', (0, 9))	('SMARCA4', 'Gene', '6597', (73, 80))	('ARID1B', 'Gene', '57492', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('mesonephric carcinomas', 'Disease', (104, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('ARID1A', 'Gene', '8289', (57, 63))	('KRAS', 'Gene', (13, 17))	('ARID1A', 'Gene', (57, 63))	('KRAS', 'Gene', '3845', (13, 17))	('reported', 'Reg', (92, 100))
60358	29439179	MSI-H endometrial carcinomas can be effectively identified by assessing morphologic features (described above) and DNA mismatch repair deficiencies in histologic material with immunohistochemistry using antibodies directed against MLH1, PMS2, MSH2, and MSH6.	('MLH1', 'Gene', '4292', (231, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('MLH1', 'Gene', (231, 235))	('MSH2', 'Gene', (243, 247))	('MSH2', 'Gene', '4436', (243, 247))	('MSI-H endometrial carcinomas', 'Disease', 'MESH:D016889', (0, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('PMS2', 'Gene', (237, 241))	('MSI-H endometrial carcinomas', 'Disease', (0, 28))	('PMS2', 'Gene', '5395', (237, 241))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (6, 27))	('deficiencies', 'Var', (135, 147))	('MSH6', 'Gene', (253, 257))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (6, 28))	('MSH6', 'Gene', '2956', (253, 257))
60360	29439179	The identification of a POLE mutation in patients with endometrial cancer (based on morphologic features of the tumor, as described above, and POLE sequencing) may help these patients avoid overtreatment given their excellent prognosis.	('mutation', 'Var', (29, 37))	('endometrial cancer', 'Disease', (55, 73))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('endometrial cancer', 'Phenotype', 'HP:0012114', (55, 73))	('endometrial cancer', 'Disease', 'MESH:D016889', (55, 73))	('tumor', 'Disease', (112, 117))
60361	29439179	POLE-mutated and MSI-H tumors are also amenable to immunotherapy (as discussed below).	('MSI-H tumors', 'Disease', (17, 29))	('POLE-mutated', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('MSI-H tumors', 'Disease', 'MESH:D009369', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
60363	29439179	The ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) algorithm involves immunohistochemistry for DNA mismatch repair proteins, sequencing of mismatch-repair-proficient tumors for POLE mutations, and immunohistochemistry for p53 in the POLE-wild-type tumors.	('tumors', 'Disease', (270, 276))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('p53', 'Gene', (244, 247))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('p53', 'Gene', '7157', (244, 247))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (204, 213))	('Endometrial Cancer', 'Disease', 'MESH:D016889', (53, 71))	('Endometrial Cancer', 'Disease', (53, 71))	('Endometrial Cancer', 'Phenotype', 'HP:0012114', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
60365	29439179	The copy-number-high group of endometrial carcinomas identified in TCGA study includes high-grade endometrioid adenocarcinomas and serous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('copy-number-high', 'Var', (4, 20))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (30, 52))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (30, 51))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (98, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('TCGA', 'Gene', (67, 71))	('endometrioid adenocarcinomas', 'Disease', (98, 126))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (98, 125))	('endometrial carcinomas', 'Disease', (30, 52))	('serous carcinomas', 'Disease', 'MESH:D018284', (131, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('serous carcinomas', 'Disease', (131, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (30, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
60368	29439179	However, a recent study of copy-number-high endometrial carcinomas showed significant differences between high-grade endometrioid adenocarcinomas and serous carcinomas with respect to their stage distributions and sites of recurrence.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('serous carcinomas', 'Disease', 'MESH:D018284', (150, 167))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (44, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('serous carcinomas', 'Disease', (150, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (44, 65))	('endometrial carcinomas', 'Disease', (44, 66))	('differences', 'Reg', (86, 97))	('copy-number-high', 'Var', (27, 43))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (117, 145))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (117, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (44, 66))	('endometrioid adenocarcinomas', 'Disease', (117, 145))
60374	29439179	A recent study exploring factors associated with poor outcomes in women with low-grade, early-stage endometrial carcinomas found that in patients with endometrioid adenocarcinomas, CTNNB1 mutations were found to be independent predictors of poorer recurrence-free survival.	('CTNNB1', 'Gene', '1499', (181, 187))	('endometrioid adenocarcinomas', 'Disease', (151, 179))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (100, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('CTNNB1', 'Gene', (181, 187))	('patients', 'Species', '9606', (137, 145))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (151, 179))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (100, 122))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (151, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('mutations', 'Var', (188, 197))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (100, 121))	('women', 'Species', '9606', (66, 71))	('endometrial carcinomas', 'Disease', (100, 122))
60375	29439179	In this study, 84% of tumors with CTNNB1 mutations showed nuclear expression of beta catenin (the protein product of CTNNB1) by immunohistochemistry.	('mutations', 'Var', (41, 50))	('CTNNB1', 'Gene', '1499', (117, 123))	('beta catenin', 'Gene', (80, 92))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('CTNNB1', 'Gene', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('CTNNB1', 'Gene', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('nuclear expression', 'MPA', (58, 76))	('CTNNB1', 'Gene', '1499', (34, 40))	('beta catenin', 'Gene', '1499', (80, 92))	('tumors', 'Disease', (22, 28))
60378	29439179	POLE-mutated and mismatch repair-deficient tumors exhibit tumor-infiltrating lymphocytes, high levels of neoantigens, and expression of immune checkpoint regulators, such as programmed death receptor-1 (PD-1) or its ligand, PDL-1, which are thought to promote escape from immune surveillance.	('deficient tumors exhibit tumor', 'Disease', (33, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mismatch', 'Var', (17, 25))	('PD-1', 'Gene', (203, 207))	('PDL-1', 'Gene', '29126', (224, 229))	('neoantigens', 'MPA', (105, 116))	('POLE-mutated', 'Var', (0, 12))	('PD-1', 'Gene', '5133', (203, 207))	('deficient tumors exhibit tumor', 'Disease', 'MESH:D009369', (33, 63))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('PDL-1', 'Gene', (224, 229))
60379	29439179	Immune checkpoint blockade with the anti-PD1 antibody pembrolizumab has shown responses in patients with POLE-mutated and mismatch repair-deficient endometrial cancer, and pembrolizumab has been approved by the FDA for metastatic cancers exhibiting mismatch repair deficiency.	('POLE-mutated', 'Var', (105, 117))	('patients', 'Species', '9606', (91, 99))	('deficient endometrial cancer', 'Disease', (138, 166))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('pembrolizumab', 'Chemical', 'MESH:C582435', (54, 67))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('endometrial cancer', 'Phenotype', 'HP:0012114', (148, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancers', 'Disease', (230, 237))	('deficient endometrial cancer', 'Disease', 'MESH:D016889', (138, 166))	('PD1', 'Gene', '5133', (41, 44))	('PD1', 'Gene', (41, 44))	('pembrolizumab', 'Chemical', 'MESH:C582435', (172, 185))
60381	29439179	KRAS mutations are common in endometrial cancer, and are associated with mucinous differentiation.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mucinous differentiation', 'Disease', (73, 97))	('endometrial cancer', 'Disease', 'MESH:D016889', (29, 47))	('endometrial cancer', 'Disease', (29, 47))	('mutations', 'Var', (5, 14))	('common', 'Reg', (19, 25))	('endometrial cancer', 'Phenotype', 'HP:0012114', (29, 47))	('KRAS', 'Gene', (0, 4))	('associated', 'Reg', (57, 67))	('KRAS', 'Gene', '3845', (0, 4))
60382	29439179	ERBB2 amplifications are also identified in endometrial serous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('ERBB2', 'Gene', '2064', (0, 5))	('amplifications', 'Var', (6, 20))	('ERBB2', 'Gene', (0, 5))	('endometrial serous carcinomas', 'Disease', 'MESH:D016889', (44, 73))	('endometrial serous carcinomas', 'Disease', (44, 73))	('identified', 'Reg', (30, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
60459	31026023	Known diagnostic markers for renal clear cell carcinoma, namely CA9 and CA12, were associated with renal clear cell carcinoma.	('renal clear cell carcinoma', 'Disease', (99, 125))	('CA9', 'Gene', '768', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (29, 55))	('associated', 'Reg', (83, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('renal clear cell carcinoma', 'Disease', (29, 55))	('CA9', 'Gene', (64, 67))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (99, 125))	('CA12', 'Var', (72, 76))
60462	31026023	Unexpectedly, in the absence of a healthy tissue class corresponding to a primary tumor type, some important genes for the cancer reflect biological characteristics of the progenitor healthy tissue, such as DPPA3/5 for testicular germline cancers, and TYR and MLANA for uveal melanomas.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('uveal melanomas', 'Disease', (270, 285))	('uveal melanomas', 'Phenotype', 'HP:0007716', (270, 285))	('melanomas', 'Phenotype', 'HP:0002861', (276, 285))	('DPPA3', 'Gene', '359787', (207, 212))	('tumor', 'Disease', (82, 87))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancers', 'Disease', (239, 246))	('TYR', 'Chemical', 'MESH:D014443', (252, 255))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('TYR', 'Var', (252, 255))	('uveal melanomas', 'Disease', 'MESH:C536494', (270, 285))	('DPPA3', 'Gene', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('testicular germline', 'Disease', (219, 238))	('MLANA', 'Var', (260, 265))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('cancer', 'Disease', (123, 129))
60498	29625050	Oncogenic Signaling Pathways in The Cancer Genome Atlas Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types.	('Cancer Genome Atlas', 'Disease', (36, 55))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (36, 55))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Disease', (299, 304))	('signaling pathways', 'Pathway', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('tumors', 'Disease', (299, 305))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('alterations', 'Var', (64, 75))	('tumor', 'Disease', (310, 315))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('cell', 'CPA', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
60499	29625050	Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, NRF2, PI-3-Kinase/Akt, RTK-RAS, TGFbeta signaling, P53 and beta-catenin/WNT.	('Akt', 'Gene', (286, 289))	('NRF2', 'Gene', (268, 272))	('beta-catenin', 'Gene', (327, 339))	('P53', 'Gene', '7157', (319, 322))	('beta-catenin', 'Gene', '1499', (327, 339))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (120, 139))	('tumors', 'Disease', (97, 103))	('TGFbeta', 'Gene', (300, 307))	('Myc', 'Gene', '4609', (256, 259))	('Akt', 'Gene', '207', (286, 289))	('TGFbeta', 'Gene', '7040', (300, 307))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Cancer Genome Atlas', 'Disease', (120, 139))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutations', 'Var', (6, 15))	('RTK-RAS', 'Pathway', (291, 298))	('cell cycle', 'Pathway', (237, 247))	('NRF2', 'Gene', '4780', (268, 272))	('Myc', 'Gene', (256, 259))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('P53', 'Gene', (319, 322))	('Notch', 'Gene', (261, 266))	('canonical pathways', 'Pathway', (217, 235))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Hippo', 'Gene', (249, 254))	('Notch', 'Gene', '4853', (261, 266))
60503	29625050	An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.	('000 tumors', 'Disease', 'MESH:D009369', (77, 87))	('alterations', 'Reg', (185, 196))	('genetic alterations', 'Var', (26, 45))	('000 tumors', 'Disease', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('TCGA', 'Gene', (100, 104))
60504	29625050	Cancer is a disease in which cells have acquired the ability to divide and grow uncontrollably,, usually through genetic alterations in specific genes.	('Cancer', 'Disease', (0, 6))	('genetic alterations', 'Var', (113, 132))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
60509	29625050	In these cases, many mutations, even when they occur in cancer genes, may have no functional effect.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (21, 30))
60511	29625050	Certain pathways, such as RTK-RAS signaling or the cell cycle pathway, are altered at high frequencies across many different tumor types, whereas other pathways are altered in more specific subsets of malignancies (e.g., alterations in the oxidative stress response pathway are strongly associated with squamous histologies).	('malignancies', 'Disease', (201, 213))	('altered', 'Reg', (165, 172))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('alterations', 'Var', (221, 232))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('oxidative stress', 'Phenotype', 'HP:0025464', (240, 256))	('altered', 'Reg', (75, 82))	('cell cycle pathway', 'Pathway', (51, 69))	('malignancies', 'Disease', 'MESH:D009369', (201, 213))	('RTK-RAS', 'MPA', (26, 33))	('associated', 'Reg', (287, 297))	('oxidative stress response pathway', 'Pathway', (240, 273))
60518	29625050	We evaluated 10 canonical signaling pathways with frequent genetic alterations, starting with key cancer genes explored in these pathways in previous TCGA publications, and focused on pathway members likely to be cancer drivers (functional contributors) or therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alterations', 'Var', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (98, 104))	('canonical signaling pathways', 'Pathway', (16, 44))	('cancer', 'Disease', (213, 219))	('genetic alterations', 'Var', (59, 78))
60522	29625050	The selected genes in the ten pathways were then assessed for recurrent alterations within and across different tumor types as follows (Figure 1B): Alterations of pathway members were classified as activating events (usually specific recurrent missense mutations, i.e., hotspot mutations, amplifications or fusions involving oncogenes) or inactivating events (truncating mutations, specific recurrent missense or inframe mutations, deletions, as well as fusions and promoter hypermethylation of tumor suppressor genes).	('tumor', 'Disease', 'MESH:D009369', (495, 500))	('missense', 'Var', (401, 409))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('promoter hypermethylation', 'Var', (466, 491))	('tumor', 'Disease', (495, 500))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('deletions', 'Var', (432, 441))	('truncating', 'Disease', (360, 370))	('missense mutations', 'Var', (244, 262))	('tumor', 'Disease', (112, 117))	('fusions', 'Var', (454, 461))
60524	29625050	In order to identify likely functional variants, we then used recurrence across tumor samples at the residue level (linear and 3D mutational hotspots,, see Methods) and prior knowledge about specific variants via the OncoKB knowledge base, which contains information about the oncogenic effects and treatment implications of variants in >400 cancer genes.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Disease', (342, 348))	('tumor', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('variants', 'Var', (325, 333))	('variants', 'Var', (39, 47))
60525	29625050	Epigenetic silencing through promoter DNA hypermethylation of tumor suppressor genes was evaluated using the RESET algorithm (see Methods).	('promoter DNA hypermethylation', 'Var', (29, 58))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
60527	29625050	The resulting comprehensive dataset of different types of alterations across many tumor types form the basis of all subsequent analyses regarding pathways, patterns of co-occurrence and mutual exclusivity, as well as potential therapeutic implications.	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('alterations', 'Var', (58, 69))
60530	29625050	Despite the fact that non-recurrent and not previously known alterations were filtered out as likely passenger events and were not included in the alteration frequencies, the microsatellite instability (MSI) and polymerase epsilon (POLE) mutant subtypes of gastrointestinal and uterine tumors, which had the highest mutation burden, also had the highest overall frequencies of pathway alterations.	('alterations', 'Reg', (385, 396))	('uterine tumors', 'Phenotype', 'HP:0010784', (278, 292))	('MSI', 'Disease', 'None', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('gastrointestinal', 'Disease', 'MESH:D005767', (257, 273))	('tumors', 'Disease', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('MSI', 'Disease', (203, 206))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('mutant', 'Var', (238, 244))	('gastrointestinal', 'Disease', (257, 273))	('microsatellite instability', 'MPA', (175, 201))
60531	29625050	This is possibly due to the frequent inactivating mutations introduced by the predominant mutation mechanisms in these tumor types  The RTK-RAS pathway was the signaling pathway with the highest median frequency of alterations (46% of samples) across all cancer types.	('tumor', 'Disease', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('RTK-RAS pathway', 'Pathway', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('mutation', 'Var', (90, 98))
60538	29625050	Particularly interesting gene alterations across tumor types were observed in the RTK-RAS pathway.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('RTK-RAS pathway', 'Pathway', (82, 97))	('gene alterations', 'Var', (25, 41))
60540	29625050	KRAS alterations were most common in pancreatic carcinoma (PAAD, 72%), genomically stable colorectal cancer (69%), and lung adenocarcinoma (33%) (Figure 4B).	('KRAS', 'Gene', '3845', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('KRAS', 'Gene', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('pancreatic carcinoma', 'Disease', (37, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('alterations', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung adenocarcinoma', 'Disease', (119, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (37, 57))	('colorectal cancer', 'Disease', (90, 107))	('common', 'Reg', (27, 33))
60541	29625050	BRAF alterations (predominantly known hotspot mutations) were found in melanoma and thyroid carcinoma, altered in 51% and 62% of samples, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (84, 101))	('BRAF', 'Gene', '673', (0, 4))	('alterations', 'Var', (5, 16))	('melanoma and thyroid carcinoma', 'Disease', 'MESH:D008545', (71, 101))	('BRAF', 'Gene', (0, 4))
60542	29625050	EGFR alterations were predominantly found in glioblastoma (GBM, 50%), low grade glioma IDHwt (52%), HPV-negative head and neck cancer (HNSC HPV-, 13%), lung adenocarcinoma (13%), and esophagogastric squamous carcinoma (14%), while ERBB2 alterations were found most commonly in breast cancer and chromosomally unstable esophagogastric carcinoma (STES CIN 26% altered), as well as cervical carcinoma (CESC 23% altered).	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('found', 'Reg', (36, 41))	('glioblastoma', 'Disease', (45, 57))	('alterations', 'Var', (5, 16))	('esophagogastric carcinoma', 'Phenotype', 'HP:0011459', (318, 343))	('ERBB2', 'Gene', '2064', (231, 236))	('cervical carcinoma', 'Disease', 'MESH:D002575', (379, 397))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('breast cancer', 'Disease', (277, 290))	('IDH', 'Gene', (87, 90))	('chromosomally unstable esophagogastric carcinoma', 'Disease', 'MESH:D000789', (295, 343))	('CIN', 'Disease', 'MESH:D007674', (350, 353))	('carcinoma', 'Phenotype', 'HP:0030731', (388, 397))	('head and neck cancer', 'Phenotype', 'HP:0012288', (113, 133))	('glioma', 'Disease', (80, 86))	('chromosomally unstable esophagogastric carcinoma', 'Disease', (295, 343))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', (152, 171))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (199, 217))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('IDH', 'Gene', '3417', (87, 90))	('esophagogastric squamous carcinoma', 'Phenotype', 'HP:0011459', (183, 217))	('neck cancer', 'Disease', 'MESH:D006258', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('neck cancer', 'Disease', (122, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('alterations', 'Var', (237, 248))	('CIN', 'Disease', (350, 353))	('STES', 'Chemical', '-', (345, 349))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (152, 171))	('esophagogastric squamous carcinoma', 'Disease', (183, 217))	('esophagogastric squamous carcinoma', 'Disease', 'MESH:D002294', (183, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('cervical carcinoma', 'Disease', (379, 397))	('EGFR', 'Gene', '1956', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))	('ERBB2', 'Gene', (231, 236))
60543	29625050	While most of the alterations described here were previously reported as functional contributors, we identified relatively rare potentially oncogenic alterations in SOS1 (<1%).	('SOS1', 'Gene', (165, 169))	('alterations', 'Var', (150, 161))	('alterations', 'Var', (18, 29))	('SOS1', 'Gene', '6654', (165, 169))
60545	29625050	Specific germline mutations in this gene are involved in Noonan syndrome, and recurrent somatic mutations in SOS1 were recently identified in otherwise RAS-pathway driver-negative lung adenocarcinoma samples.	('Noonan syndrome', 'Disease', 'MESH:D009634', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('SOS1', 'Gene', (109, 113))	('lung adenocarcinoma', 'Disease', (180, 199))	('involved', 'Reg', (45, 53))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (180, 199))	('SOS1', 'Gene', '6654', (109, 113))	('Noonan syndrome', 'Disease', (57, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))	('germline mutations', 'Var', (9, 27))
60546	29625050	We identified recurrent (hotspot) mutations (A90V/T, N233Y/S) and other known activating mutations (M269I/V, G434R, R552S/K/G/M, E846K) in SOS1 in a total of 1% of lung adenocarcinoma samples, 1% of uterine carcinomas, independent of subtype, and at lower frequencies in several other cancer types (Figure 4C).	('uterine carcinomas', 'Phenotype', 'HP:0010784', (199, 217))	('E846K', 'Var', (129, 134))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (199, 216))	('R552S', 'SUBSTITUTION', 'None', (116, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (164, 183))	('SOS1', 'Gene', (139, 143))	('G434R', 'Mutation', 'rs397517148', (109, 114))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (164, 183))	('M269I', 'SUBSTITUTION', 'None', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('carcinomas', 'Disease', 'MESH:D002277', (207, 217))	('G434R', 'Var', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('cancer', 'Disease', (285, 291))	('M269I', 'Var', (100, 105))	('R552S', 'Var', (116, 121))	('N233Y', 'SUBSTITUTION', 'None', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('N233Y', 'Var', (53, 58))	('A90V', 'Var', (45, 49))	('SOS1', 'Gene', '6654', (139, 143))	('E846K', 'Mutation', 'rs397517159', (129, 134))	('carcinomas', 'Disease', (207, 217))	('lung adenocarcinoma', 'Disease', (164, 183))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('A90V', 'SUBSTITUTION', 'None', (45, 49))
60548	29625050	A more detailed analysis of RAS pathway alterations is published separately, including a description of downstream transcriptional changes due to malfunctioning Ras signaling and results suggesting that multiple hits in the Ras pathway are capable of increasing overall Ras activity in RAS wildtype tumors.	('hits', 'Var', (212, 216))	('Ras', 'Gene', (224, 227))	('tumors', 'Disease', (299, 305))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('increasing', 'PosReg', (251, 261))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('Ras', 'Enzyme', (270, 273))
60550	29625050	Several pathways are featured in more detail as separate publications, including: 1) PI3K pathway: aberrations in the PI3K pathway were found predominantly as activating events in PIK3CA (less commonly in PIK3CB) and inactivating events in PTEN or PIK3R1 with PIK3CA and PTEN alterations being most commonly found in head and neck cancer, breast cancer, gastrointestinal and gynecological tumors; 2) TGFbeta pathway: The TGFbeta pathway had the highest alteration rate in pancreatic and gastrointestinal cancers, while renal and brain cancers, among others, had almost no alterations in this pathway; and 3) MYC pathway: MYC pathway alterations were most common in tumor types with amplification of chromosome 8, which contains MYC, such as breast cancer, ovarian cancer (OV), and others.	('gastrointestinal', 'Disease', (354, 370))	('TGFbeta', 'Gene', (421, 428))	('MYC', 'Gene', (608, 611))	('PIK3CA', 'Gene', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('alterations', 'Reg', (633, 644))	('tumor', 'Disease', 'MESH:D009369', (665, 670))	('TGFbeta', 'Gene', '7040', (421, 428))	('ovarian cancer', 'Disease', 'MESH:D010051', (756, 770))	('gastrointestinal', 'Disease', 'MESH:D005767', (354, 370))	('PIK3R1', 'Gene', '5295', (248, 254))	('tumors', 'Disease', (389, 395))	('PIK3CB', 'Gene', (205, 211))	('pancreatic and gastrointestinal cancers', 'Disease', 'MESH:D010190', (472, 511))	('common', 'Reg', (655, 661))	('cancer', 'Phenotype', 'HP:0002664', (748, 754))	('MYC', 'Gene', '4609', (728, 731))	('MYC', 'Gene', (621, 624))	('PIK3CB', 'Gene', '5291', (205, 211))	('gastrointestinal', 'Disease', (487, 503))	('breast cancer', 'Phenotype', 'HP:0003002', (339, 352))	('renal and brain cancers', 'Disease', 'MESH:D007680', (519, 542))	('tumors', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('tumor', 'Phenotype', 'HP:0002664', (665, 670))	('PIK3CA', 'Gene', '5290', (180, 186))	('MYC', 'Gene', '4609', (608, 611))	('gastrointestinal', 'Disease', 'MESH:D005767', (487, 503))	('PTEN', 'Gene', (240, 244))	('PTEN', 'Gene', (271, 275))	('ovarian cancer', 'Disease', (756, 770))	('breast cancer', 'Disease', 'MESH:D001943', (339, 352))	('ovarian cancer', 'Phenotype', 'HP:0100615', (756, 770))	('breast cancer', 'Phenotype', 'HP:0003002', (741, 754))	('breast cancer', 'Disease', (339, 352))	('PIK3CA', 'Gene', '5290', (260, 266))	('tumor', 'Disease', (389, 394))	('MYC', 'Gene', '4609', (621, 624))	('PIK3R1', 'Gene', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('TGFbeta', 'Gene', (400, 407))	('PTEN', 'Gene', '5728', (240, 244))	('PTEN', 'Gene', '5728', (271, 275))	('tumor', 'Disease', 'MESH:D009369', (389, 394))	('breast cancer', 'Disease', 'MESH:D001943', (741, 754))	('breast cancer', 'Disease', (741, 754))	('cancers', 'Phenotype', 'HP:0002664', (504, 511))	('cancers', 'Phenotype', 'HP:0002664', (535, 542))	('MYC', 'Gene', (728, 731))	('TGFbeta', 'Gene', '7040', (400, 407))	('head and neck cancer', 'Phenotype', 'HP:0012288', (317, 337))	('amplification', 'Var', (682, 695))	('neck cancer', 'Disease', 'MESH:D006258', (326, 337))	('PIK3CA', 'Gene', (180, 186))	('neck cancer', 'Disease', (326, 337))	('tumors', 'Phenotype', 'HP:0002664', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (504, 510))	('cancer', 'Phenotype', 'HP:0002664', (535, 541))	('tumor', 'Disease', (665, 670))
60559	29625050	Indeed, numerous alterations affecting Rb-mediated cell cycle control were found co-occurring with TP53 mutations.	('TP53', 'Gene', '7157', (99, 103))	('Rb-mediated', 'MPA', (39, 50))	('mutations', 'Var', (104, 113))	('TP53', 'Gene', (99, 103))
60560	29625050	These included amplification of CCNE1, mutation of CDKN2A, RB1 loss, and amplification of CDK6 and E2F3 (Figure S4B).	('CDKN2A', 'Gene', '1029', (51, 57))	('RB1', 'Gene', (59, 62))	('CCNE1', 'Gene', (32, 37))	('CCNE1', 'Gene', '898', (32, 37))	('mutation', 'Var', (39, 47))	('amplification', 'Reg', (15, 28))	('CDK6', 'Gene', '1021', (90, 94))	('RB1', 'Gene', '5925', (59, 62))	('E2F3', 'Gene', '1871', (99, 103))	('CDK6', 'Gene', (90, 94))	('E2F3', 'Gene', (99, 103))	('CDKN2A', 'Gene', (51, 57))	('loss', 'NegReg', (63, 67))	('amplification', 'Var', (73, 86))
60561	29625050	Interestingly, TP53 mutations were found mutually exclusive with CDKN2A deletion, consistent with the latter invariably affecting both p16, regulating the cell cycle, and ARF, promoting p53-dependent apoptosis.	('CDKN2A', 'Gene', '1029', (65, 71))	('affecting', 'Reg', (120, 129))	('promoting', 'PosReg', (176, 185))	('regulating', 'Reg', (140, 150))	('p16', 'Gene', '1029', (135, 138))	('cell cycle', 'CPA', (155, 165))	('TP53', 'Gene', '7157', (15, 19))	('p53', 'Gene', (186, 189))	('TP53', 'Gene', (15, 19))	('p53', 'Gene', '7157', (186, 189))	('ARF', 'Disease', 'MESH:D058186', (171, 174))	('ARF', 'Disease', (171, 174))	('CDKN2A', 'Gene', (65, 71))	('p16', 'Gene', (135, 138))	('mutations', 'Var', (20, 29))	('deletion', 'Var', (72, 80))
60564	29625050	Overall, these results indicate that p53 signaling and cell cycle control are frequently co-altered across multiple tumor types, either through two independent events (e.g., mutations of TP53 and RB1), or through a single alteration that is able to affect both pathways (e.g., CDKN2A deletion).	('deletion', 'Var', (284, 292))	('CDKN2A', 'Gene', (277, 283))	('TP53', 'Gene', '7157', (187, 191))	('RB1', 'Gene', '5925', (196, 199))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('CDKN2A', 'Gene', '1029', (277, 283))	('cell cycle', 'CPA', (55, 65))	('TP53', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p53', 'Gene', (37, 40))	('affect', 'Reg', (249, 255))	('p53', 'Gene', '7157', (37, 40))	('mutations', 'Var', (174, 183))	('tumor', 'Disease', (116, 121))	('RB1', 'Gene', (196, 199))	('co-altered', 'Reg', (89, 99))
60566	29625050	Here, gain of function mutations and amplifications of the NFE2L2 gene (encoding for NRF2) significantly co-occurred with PIK3CA amplification and tended to co-occur with PIK3CA mutations and PIK3CB amplification (Figure 6C).	('NRF2', 'Gene', (85, 89))	('PIK3CA', 'Gene', (122, 128))	('PIK3CA', 'Gene', (171, 177))	('PIK3CB', 'Gene', (192, 198))	('PIK3CA', 'Gene', '5290', (171, 177))	('PIK3CB', 'Gene', '5291', (192, 198))	('PIK3CA', 'Gene', '5290', (122, 128))	('NFE2L2', 'Gene', '4780', (59, 65))	('mutations', 'Var', (23, 32))	('gain of function', 'PosReg', (6, 22))	('NRF2', 'Gene', '4780', (85, 89))	('NFE2L2', 'Gene', (59, 65))
60567	29625050	Interestingly, even though NFE2L2 amplification was largely mutually exclusive with loss of STK11 (a.k.a.	('STK11', 'Gene', '6794', (92, 97))	('NFE2L2', 'Gene', '4780', (27, 33))	('NFE2L2', 'Gene', (27, 33))	('loss', 'Var', (84, 88))	('STK11', 'Gene', (92, 97))
60568	29625050	LKB1), the latter significantly co-occurred with loss of function mutations of KEAP1, a negative regulator of NFE2L2.	('mutations', 'Var', (66, 75))	('NFE2L2', 'Gene', (110, 116))	('LKB1', 'Gene', (0, 4))	('KEAP1', 'Gene', (79, 84))	('LKB1', 'Gene', '6794', (0, 4))	('loss of function', 'NegReg', (49, 65))	('NFE2L2', 'Gene', '4780', (110, 116))	('KEAP1', 'Gene', '9817', (79, 84))
60569	29625050	Co-occurring NRF2-PI3K pathway alterations were most frequent in lung tumors (both squamous cell and adenocarcinoma), esophageal carcinomas, head and neck squamous cell carcinoma and uterine carcinoma, independent of subtype (Figure 6D).	('carcinoma', 'Disease', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('lung tumors', 'Disease', 'MESH:D008175', (65, 76))	('carcinoma', 'Disease', (169, 178))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (183, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('neck squamous cell carcinoma', 'Disease', (150, 178))	('lung tumors', 'Phenotype', 'HP:0100526', (65, 76))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (150, 178))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('carcinoma', 'Disease', 'MESH:D002277', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Disease', 'MESH:D002277', (106, 115))	('carcinoma', 'Disease', (191, 200))	('lung tumors', 'Disease', (65, 76))	('adenocarcinoma', 'Disease', (101, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('carcinoma', 'Disease', 'MESH:D002277', (169, 178))	('NRF2', 'Gene', '4780', (13, 17))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (118, 139))	('alterations', 'Var', (31, 42))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (118, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (101, 115))	('frequent', 'Reg', (53, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinoma', 'Disease', 'MESH:D002277', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('carcinoma', 'Disease', (129, 138))	('esophageal carcinomas', 'Disease', (118, 139))	('NRF2', 'Gene', (13, 17))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (141, 178))
60570	29625050	In these tumor types, alterations in NFE2L2 and KEAP1 were recurrent and almost perfectly mutually exclusive and they frequently co-occurred with PIK3CA activation or STK11 loss (Figure 6E).	('PIK3CA', 'Gene', '5290', (146, 152))	('STK11', 'Gene', (167, 172))	('NFE2L2', 'Gene', (37, 43))	('co-occurred', 'Reg', (129, 140))	('activation', 'PosReg', (153, 163))	('KEAP1', 'Gene', '9817', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('STK11', 'Gene', '6794', (167, 172))	('KEAP1', 'Gene', (48, 53))	('tumor', 'Disease', (9, 14))	('loss', 'NegReg', (173, 177))	('alterations', 'Var', (22, 33))	('PIK3CA', 'Gene', (146, 152))	('NFE2L2', 'Gene', '4780', (37, 43))
60575	29625050	In particular, alterations promoting EGFR activation (gain of function mutations, fusion, and amplification) were involved in the highest number of significant pairs.	('gain of function', 'PosReg', (54, 70))	('alterations', 'Var', (15, 26))	('EGFR', 'Gene', '1956', (37, 41))	('mutations', 'Var', (71, 80))	('activation', 'PosReg', (42, 52))	('EGFR', 'Gene', (37, 41))
60576	29625050	EGFR amplification was significantly mutually exclusive with activation of its paralog growth factor receptor Her2 (ERBB2, Figure 6H - Box 1) and with key drivers of the RAS pathway, including oncogenic mutations in BRAF and KRAS as well as loss of NF1 and RASA1 (Figure 6G).	('RASA1', 'Gene', (257, 262))	('amplification', 'Var', (5, 18))	('KRAS', 'Gene', '3845', (225, 229))	('Her2', 'Gene', (110, 114))	('RAS', 'Pathway', (170, 173))	('KRAS', 'Gene', (225, 229))	('EGFR', 'Gene', (0, 4))	('ERBB2', 'Gene', (116, 121))	('NF1', 'Gene', '4763', (249, 252))	('mutations', 'Var', (203, 212))	('RASA1', 'Gene', '5921', (257, 262))	('ERBB2', 'Gene', '2064', (116, 121))	('loss', 'Var', (241, 245))	('NF1', 'Gene', (249, 252))	('activation', 'PosReg', (61, 71))	('BRAF', 'Gene', '673', (216, 220))	('BRAF', 'Gene', (216, 220))	('EGFR', 'Gene', '1956', (0, 4))	('Her2', 'Gene', '2064', (110, 114))
60577	29625050	Since oncogenic EGFR can be synthetically lethal with mutated KRAS and can mediate resistance to BRAF inhibition in colon cancer and melanoma, these results suggest a similar antagonistic interaction with loss of NF1 or RASA1.	('KRAS', 'Gene', (62, 66))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('NF1', 'Gene', (213, 216))	('mutated', 'Var', (54, 61))	('EGFR', 'Gene', '1956', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('colon cancer', 'Disease', (116, 128))	('BRAF', 'Gene', (97, 101))	('RASA1', 'Gene', '5921', (220, 225))	('mediate', 'Reg', (75, 82))	('EGFR', 'Gene', (16, 20))	('RASA1', 'Gene', (220, 225))	('KRAS', 'Gene', '3845', (62, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('NF1', 'Gene', '4763', (213, 216))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRAF', 'Gene', '673', (97, 101))
60578	29625050	Overall, alterations of either of these genes were recurrent across multiple tumor types, although almost never in the same patient (Figure 6H - Box 2).	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('alterations', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patient', 'Species', '9606', (124, 131))	('tumor', 'Disease', (77, 82))
60579	29625050	On the other hand, in glioblastoma and IDH wild-type low grade glioma, EGFR amplifications were highly co-occurrent with either EGFR mutations or gene fusions (Figure 6H - Box 3) or with focal amplifications of chromosome 4q12, where both KIT and PDGFRA are located (Figure 6H - Box 4).	('PDGFRA', 'Gene', '5156', (247, 253))	('PDGFRA', 'Gene', (247, 253))	('glioblastoma', 'Disease', (22, 34))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('gene fusions', 'Var', (146, 158))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('amplifications', 'Var', (76, 90))	('EGFR', 'Gene', '1956', (71, 75))	('mutations', 'Var', (133, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('IDH', 'Gene', (39, 42))	('co-occurrent', 'Reg', (103, 115))	('EGFR', 'Gene', (71, 75))	('IDH', 'Gene', '3417', (39, 42))	('glioma', 'Disease', (63, 69))
60580	29625050	It should be noted that the majority of EGFR and PDGFRA fusions were found coincident with amplifications in these genes, indicating that, potentially, in these cases the same structural variant was detected as both a copy number gain and a fusion.	('fusions', 'Var', (56, 63))	('copy number gain', 'Disease', (218, 234))	('PDGFRA', 'Gene', (49, 55))	('PDGFRA', 'Gene', '5156', (49, 55))	('copy number gain', 'Disease', 'MESH:D015430', (218, 234))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))
60581	29625050	Interestingly, co-amplification of EGFR and PDGFRA has been proposed to be an early event in glioblastoma development, where the two receptors heterodimerize under EGF stimulation and respond to EGFR-inhibitors.	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('EGFR', 'Gene', (195, 199))	('co-amplification', 'Var', (15, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('glioblastoma', 'Disease', (93, 105))	('heterodimerize', 'MPA', (143, 157))	('respond', 'Reg', (184, 191))	('PDGFRA', 'Gene', '5156', (44, 50))	('EGFR', 'Gene', '1956', (195, 199))	('PDGFRA', 'Gene', (44, 50))
60583	29625050	A relatively small number of alterations in a subset of tumor types are currently biomarkers for standard care targeted therapies, and a larger number are potential biomarkers for investigational therapies, some with promising clinical results.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('alterations', 'Var', (29, 40))
60585	29625050	Overall, 52% of tumors had at least one potentially actionable alteration in the ten signaling pathways, and 57% had at least one actionable alteration when including genes outside of these pathways, most notably BRCA1/2 and IDH1/2 (all numbers referenced below include these additional genes).	('BRCA1/2', 'Gene', '672;675', (213, 220))	('IDH1/2', 'Gene', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('ten signaling pathways', 'Pathway', (81, 103))	('BRCA1/2', 'Gene', (213, 220))	('tumors', 'Disease', (16, 22))	('alteration', 'Var', (63, 73))	('IDH1/2', 'Gene', '3417;3418', (225, 231))
60586	29625050	Apart from the Her2-enriched breast cancer samples, most of which have a standard care targeted therapy, melanoma was the tumor type with the highest fraction of tumors with a Level 1 or 2A alteration (46%) (Figure 7A), mainly due to frequent BRAF mutations (Figure 7B), followed by esophagogastric cancers (ERBB2 amplifications).	('mutations', 'Var', (248, 257))	('tumor', 'Disease', (162, 167))	('Her2', 'Gene', '2064', (15, 19))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('ERBB2', 'Gene', (308, 313))	('Her2', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('esophagogastric cancers', 'Disease', (283, 306))	('breast cancer', 'Disease', (29, 42))	('esophagogastric cancers', 'Disease', 'MESH:C537006', (283, 306))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ERBB2', 'Gene', '2064', (308, 313))	('BRAF', 'Gene', '673', (243, 247))	('BRAF', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumors', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
60587	29625050	Luminal A breast cancer was the tumor type with the highest frequency of biomarkers with promising investigational data (Level 3A), driven by the high prevalence of PIK3CA, AKT1 and ERBB2 mutations.	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('PIK3CA', 'Gene', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('breast cancer', 'Disease', (10, 23))	('ERBB2', 'Gene', '2064', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ERBB2', 'Gene', (182, 187))	('PIK3CA', 'Gene', '5290', (165, 171))	('AKT1', 'Gene', '207', (173, 177))	('mutations', 'Var', (188, 197))	('tumor', 'Disease', (32, 37))	('AKT1', 'Gene', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
60588	29625050	Several tumor types had frequent mutations that are biomarkers for drug sensitivity in other cancer types (Level 3B), including endometrial cancer, where PIK3CA mutations are common.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('PIK3CA', 'Gene', (154, 160))	('drug sensitivity', 'Phenotype', 'HP:0020174', (67, 83))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('endometrial cancer', 'Disease', (128, 146))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', (140, 146))	('PIK3CA', 'Gene', '5290', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('endometrial cancer', 'Phenotype', 'HP:0012114', (128, 146))	('tumor', 'Disease', (8, 13))	('endometrial cancer', 'Disease', 'MESH:D016889', (128, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
60596	29625050	By a similar consideration linking actionable alterations of targets to their inhibitors, a combination of HER2 and PI3K inhibitors might be beneficial across multiple tumor types, in particular Her2-enriched breast cancer (17%), uterine carcinosarcoma (UCS, 7%), chromosomally unstable endometrioid carcinoma (UCEC CN high, 7%), and cervical adenocarcinoma (7%) (Figure 7D).	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (230, 252))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (287, 309))	('HER2', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cervical adenocarcinoma', 'Disease', 'MESH:D002575', (334, 357))	('Her2', 'Gene', '2064', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('endometrioid carcinoma', 'Disease', (287, 309))	('tumor', 'Disease', (168, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('Her2', 'Gene', (195, 199))	('cervical adenocarcinoma', 'Disease', (334, 357))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('carcinosarcoma', 'Disease', (238, 252))	('HER2', 'Gene', '2064', (107, 111))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('breast cancer', 'Disease', (209, 222))	('alterations', 'Var', (46, 57))	('carcinosarcoma', 'Disease', 'MESH:D002296', (238, 252))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (287, 309))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
60598	29625050	While there are many steps from the observation of combinations of genetic alterations to valid combination therapies, this survey indicates the wide landscape of potential tumor-type specific novel therapeutic combinations that can be explored in experimental and clinical contexts.	('genetic alterations', 'Var', (67, 86))	('tumor-type', 'Disease', 'MESH:D009369', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor-type', 'Disease', (173, 183))	('alterations', 'Var', (75, 86))
60604	29625050	They also underscore the potential for discovering previously uncharacterized alterations in pathway genes that occur at low frequencies and might otherwise remain statistically unnoticeable (see SOS1, Figure 4).	('SOS1', 'Gene', (196, 200))	('alterations', 'Var', (78, 89))	('SOS1', 'Gene', '6654', (196, 200))	('pathway genes', 'Gene', (93, 106))
60608	29625050	While the NRF2 pathway does not have therapies directly targeting any of the pathway members included in this study, alterations in NRF2 pathway members (NFE2L2 and KEAP1) are used as part of the inclusion criteria in the Phase 2 trial of a TORC1/2 inhibitor.	('alterations', 'Var', (117, 128))	('NFE2L2', 'Gene', '4780', (154, 160))	('NRF2', 'Gene', '4780', (132, 136))	('NRF2', 'Gene', (10, 14))	('KEAP1', 'Gene', (165, 170))	('NFE2L2', 'Gene', (154, 160))	('NRF2', 'Gene', (132, 136))	('TORC1/2', 'Gene', (241, 248))	('TORC1/2', 'Gene', '23373;200186', (241, 248))	('NRF2', 'Gene', '4780', (10, 14))	('KEAP1', 'Gene', '9817', (165, 170))
60609	29625050	Not all apparently functional mutations, however, represent therapeutic targets, as illustrated, e.g., by the unusually large number of mutations in the MSI-H and POLE-mutated tumor subtypes, of which only a small fraction plausibly dominate oncogenesis..	('MSI-H', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('MSI-H', 'Disease', 'MESH:D000848', (153, 158))	('mutations', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
60611	29625050	However, there is a growing corpus of promising preclinical data indicating such combinations can be effective, such as the combination of MDM2 and CDK4 inhibitors, and the combination of PI3K inhibitors and HER2 inhibitors in HER2-positive / PIK3CA mutant breast cancer patients, even when single gene-therapy approaches (e.g.	('PI3K', 'Var', (188, 192))	('MDM2', 'Gene', (139, 143))	('CDK4', 'Gene', '1019', (148, 152))	('HER2', 'Gene', '2064', (227, 231))	('PIK3CA', 'Gene', (243, 249))	('HER2', 'Gene', (208, 212))	('HER2', 'Gene', '2064', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('PIK3CA', 'Gene', '5290', (243, 249))	('MDM2', 'Gene', '4193', (139, 143))	('breast cancer', 'Disease', (257, 270))	('patients', 'Species', '9606', (271, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('CDK4', 'Gene', (148, 152))	('HER2', 'Gene', (227, 231))
60626	29625050	The cancer hotspots algorithm that we used identifies recurrent alterations based on a cohort of 24,592 tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', (104, 109))	('alterations', 'Var', (64, 75))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
60628	29625050	For Genes within ROIs, copy number variants consistent with the role of the gene (amplification of OGs and deletions of TSGs) were retained.	('TSG', 'Gene', (120, 123))	('deletions', 'Var', (107, 116))	('TSG', 'Gene', '57045', (120, 123))	('ROIs', 'Gene', (17, 21))
60629	29625050	CDKN2A promoter methylation was assessed using Illumina Infinium HumanMethylation450 probe cg13601799 located within Exon 1a of CDKN2A (p16INK4a).	('CDKN2A', 'Gene', '1029', (128, 134))	('p16INK4a', 'Gene', (136, 144))	('cg13601799', 'Var', (91, 101))	('CDKN2A', 'Gene', (0, 6))	('p16INK4a', 'Gene', '1029', (136, 144))	('CDKN2A', 'Gene', (128, 134))	('CDKN2A', 'Gene', '1029', (0, 6))
60630	29625050	We described the selection of this probe for CDKN2A methylation calling in a prior report.	('CDKN2A', 'Gene', (45, 51))	('methylation', 'Var', (52, 63))	('CDKN2A', 'Gene', '1029', (45, 51))
60631	29625050	We required a Log2(foreground/background) log-ratio of 2 or greater for the U probe to ensure that the U signal was derived from tumor cells and not from contaminating normal cells in the case of a tumor with CDKN2A deletion.	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('CDKN2A', 'Gene', '1029', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('CDKN2A', 'Gene', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('deletion', 'Var', (216, 224))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (129, 134))
60633	29625050	Out of these 627, 471 were called to have high level deletion for CDKN2A (-2 in GISTIC calls) and 120 had low level deletion for this gene (-1 in GISTIC calls), validating this approach.	('CDKN2A', 'Gene', (66, 72))	('deletion', 'Var', (53, 61))	('CDKN2A', 'Gene', '1029', (66, 72))
60634	29625050	Epigenetic DNA hypermethylation events at promoters of tumor suppressor genes that are associated with decreased gene expression were systematically identified using the RESET bioinformatic tool (Saghafinia, Mina, et al.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Mina', 'Gene', (208, 212))	('Mina', 'Gene', '84864', (208, 212))	('gene expression', 'MPA', (113, 128))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('Epigenetic', 'Var', (0, 10))
60647	29625050	For our pathway analyses, we included only the fusions that (a) involved at least one gene labeled as TSG in one of our pathway templates, or (b) involved at least one gene labeled as OG in one of our pathway templates and such that the fusion is labeled as oncogenic, likely oncogenic or predicted oncogenic in OncoKB.	('TSG', 'Gene', '57045', (102, 105))	('fusion', 'Var', (237, 243))	('TSG', 'Gene', (102, 105))
60649	29625050	We also included epigenetic silencing of CDKN2A based on DNA methylation analysis of the gene promoter and the epigenetic silencing of 15 additional genes uncovered by RESET.	('CDKN2A', 'Gene', '1029', (41, 47))	('epigenetic silencing', 'Var', (17, 37))	('CDKN2A', 'Gene', (41, 47))
60666	29480840	PNETs of the genital tract are rare; they can share some genetic rearrangements such as translocations involving the EWS-FLI1 genes, as in peripheral PNET or also CIC-DUX4.	('EWS', 'Gene', '2130', (117, 120))	('EWS', 'Gene', (117, 120))	('CIC', 'Gene', (163, 166))	('DUX4', 'Gene', '100288687', (167, 171))	('PNETs', 'Phenotype', 'HP:0030065', (0, 5))	('FLI1', 'Gene', (121, 125))	('FLI1', 'Gene', '2313', (121, 125))	('translocations', 'Var', (88, 102))	('peripheral PNET', 'Disease', (139, 154))	('CIC', 'Gene', '23152', (163, 166))	('DUX4', 'Gene', (167, 171))
60672	29480840	In the case series of uterine PNETs collected by Euscher et al, CD99 was positive in 7 of 9 cases tested for the marker; all 12 cases were tested for the typical EWSR1 rearrangement, but yielded negative results.	('tested', 'Reg', (139, 145))	('CD99', 'Gene', (64, 68))	('EWSR1', 'Gene', (162, 167))	('PNETs', 'Phenotype', 'HP:0030065', (30, 35))	('rearrangement', 'Var', (168, 181))	('CD99', 'Gene', '4267', (64, 68))	('EWSR1', 'Gene', '2130', (162, 167))
60696	29480840	The new immunohistochemistry is also summarized in Table 2; FISH (fluorescence in situ hybridization) study demonstrated negativity for EWS (Ewing sarcoma), a 22q12 translocation, WT1, and CIC rearrangement (with BAC Bacteria Artificial Chromosome probe library RP11).	('22q12 translocation', 'Var', (159, 178))	('CIC', 'Gene', (189, 192))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('CIC', 'Gene', '23152', (189, 192))	('WT1', 'Gene', '7490', (180, 183))	('Ewing sarcoma', 'Gene', '2130', (141, 154))	('Ewing sarcoma', 'Gene', (141, 154))	('rearrangement', 'Var', (193, 206))	('WT1', 'Gene', (180, 183))	('EWS', 'Gene', '2130', (136, 139))	('EWS', 'Gene', (136, 139))
60712	29480840	EWSR1 can often form a chimeric couple with FLI 1 (11q24) (85%) or ERG (21q22) (5-10%).	('11q24', 'Var', (51, 56))	('EWSR1', 'Gene', '2130', (0, 5))	('ERG', 'Var', (67, 70))	('FLI 1', 'Gene', (44, 49))	('EWSR1', 'Gene', (0, 5))	('form', 'Reg', (16, 20))	('FLI 1', 'Gene', '2313', (44, 49))
60721	29480840	Most MRTs, including tumors arising in the brain, called atypical teratoid/rhabdoid tumors [AT/RTs], host inactivating mutations in SMARCB1 (INI-1; SNF5; BAF47).	('SMARCB1', 'Gene', (132, 139))	('SMARCB1', 'Gene', '6598', (132, 139))	('SNF5', 'Gene', (148, 152))	('AT', 'Disease', 'None', (92, 94))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('BAF47', 'Gene', '6598', (154, 159))	('inactivating mutations', 'Var', (106, 128))	('rhabdoid tumors', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (75, 90))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumors', 'Disease', (21, 27))	('SNF5', 'Gene', '6598', (148, 152))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('BAF47', 'Gene', (154, 159))	('INI-1', 'Gene', '6598', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('INI-1', 'Gene', (141, 146))
60722	29480840	Other MRTs of the ovaries, without the SMARCB1 alteration, harbor a similar mutation involving the SMARCA4 gene (also called BRG1) as also occurs in SCCOHT, so both can be denominated MRTOs.	('SMARCA4', 'Gene', (99, 106))	('SMARCA4', 'Gene', '6597', (99, 106))	('BRG1', 'Gene', '6597', (125, 129))	('SMARCB1', 'Gene', '6598', (39, 46))	('ovaries', 'Disease', 'MESH:D010051', (18, 25))	('SMARCB1', 'Gene', (39, 46))	('ovaries', 'Disease', (18, 25))	('mutation', 'Var', (76, 84))	('BRG1', 'Gene', (125, 129))
60778	29515415	The pathology report described a moderately differentiated uterine leiomyosarcoma (G2) according to TNM classification (p T1b [10 cm], L0, Nx, V0, R0, G2).	('leiomyosarcoma', 'Disease', (67, 81))	('TNM', 'Gene', '10178', (100, 103))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (67, 81))	('p T1b [10 cm]', 'Var', (120, 133))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (67, 81))	('TNM', 'Gene', (100, 103))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
60880	29400015	Obesity is also a risk factor for developing breast cancer, for which tamoxifen is commonly used as an adjuvant therapy.	('Obesity', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('tamoxifen', 'Chemical', 'MESH:D013629', (70, 79))
60910	29137450	The four subgroups were: POLE-ultramutated (POLE), microsatellite instability-hypermutated (MSI), copy number low-microsatellite stable (CNL), and copy number high-serous-like (CNH).	('MSI', 'Disease', (92, 95))	('microsatellite', 'MPA', (51, 65))	('copy number', 'Var', (147, 158))	('MSI', 'Disease', 'None', (92, 95))	('copy number low-microsatellite', 'Var', (98, 128))
60912	29137450	The MSI subgroup is characterized by MSI and has a high mutation burden with frequent MLH1 promoter methylation.	('MSI', 'Disease', 'None', (4, 7))	('MSI', 'Disease', (37, 40))	('MSI', 'Disease', (4, 7))	('methylation', 'Var', (100, 111))	('MLH1', 'Gene', '4292', (86, 90))	('MLH1', 'Gene', (86, 90))	('MSI', 'Disease', 'None', (37, 40))
60914	29137450	The CNL subgroup has low histological grade and frequent CTNNB1 mutations without MSI or TP53 mutations.	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('MSI', 'Disease', (82, 85))	('CTNNB1', 'Gene', '1499', (57, 63))	('mutations', 'Var', (64, 73))	('MSI', 'Disease', 'None', (82, 85))	('CTNNB1', 'Gene', (57, 63))
60915	29137450	PTEN mutations are very common in the MSI and CNL subgroups and infrequent in the CNH subgroup.	('MSI', 'Disease', 'None', (38, 41))	('mutations', 'Var', (5, 14))	('CNL', 'Disease', (46, 49))	('MSI', 'Disease', (38, 41))	('common', 'Reg', (24, 30))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
60916	29137450	The CNH subgroup is defined by the presence of somatic TP53 mutations, and included nearly all uterine serous carcinomas and ~25% of high-grade endometrioid tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('endometrioid tumors', 'Disease', (144, 163))	('TP53', 'Gene', '7157', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('TP53', 'Gene', (55, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('serous carcinomas', 'Disease', 'MESH:D018284', (103, 120))	('serous carcinomas', 'Disease', (103, 120))	('endometrioid tumors', 'Disease', 'MESH:D016889', (144, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mutations', 'Var', (60, 69))	('CNH', 'Disease', (4, 7))
60919	29137450	Serous ECs are characterized by genomic instability, high rates of somatic mutations in the TP53, PPP2R1A, FBXW7, PIK3CA, PIK3R1, PTEN, SPOP, CHD4, and TAF1 genes frequent amplification and/or overexpression of the ERBB2/HER2 receptor tyrosine kinase, and dysregulated expression of cyclin E, c-MYC, p16, E-cadherin, claudin-3, claudin-4, L1CAM and EpCAM.	('PIK3CA', 'Gene', '5290', (114, 120))	('PPP2R1A', 'Gene', '5518', (98, 105))	('TAF1', 'Gene', '6872', (152, 156))	('p16', 'Gene', '1029', (300, 303))	('EC', 'Phenotype', 'HP:0012114', (7, 9))	('dysregulated', 'Reg', (256, 268))	('FBXW7', 'Gene', '55294', (107, 112))	('claudin-4', 'Gene', '1364', (328, 337))	('TP53', 'Gene', (92, 96))	('PPP2R1A', 'Gene', (98, 105))	('claudin-3', 'Gene', '1365', (317, 326))	('PIK3R1', 'Gene', (122, 128))	('ERBB2', 'Gene', (215, 220))	('amplification', 'PosReg', (172, 185))	('HER2', 'Gene', '2064', (221, 225))	('E-cadherin', 'Gene', (305, 315))	('E-cadherin', 'Gene', '999', (305, 315))	('ECs', 'Chemical', 'MESH:C001390', (7, 10))	('PIK3CA', 'Gene', (114, 120))	('EpCAM', 'Gene', (349, 354))	('PTEN', 'Gene', (130, 134))	('EpCAM', 'Gene', '4072', (349, 354))	('L1CAM', 'Gene', '3897', (339, 344))	('overexpression', 'PosReg', (193, 207))	('ERBB2', 'Gene', '2064', (215, 220))	('TAF1', 'Gene', (152, 156))	('expression', 'MPA', (269, 279))	('TP53', 'Gene', '7157', (92, 96))	('FBXW7', 'Gene', (107, 112))	('c-MYC', 'Gene', '4609', (293, 298))	('PIK3R1', 'Gene', '5295', (122, 128))	('PTEN', 'Gene', '5728', (130, 134))	('SPOP', 'Gene', (136, 140))	('CHD4', 'Gene', (142, 146))	('HER2', 'Gene', (221, 225))	('c-MYC', 'Gene', (293, 298))	('CHD4', 'Gene', '1108', (142, 146))	('mutations', 'Var', (75, 84))	('L1CAM', 'Gene', (339, 344))	('p16', 'Gene', (300, 303))	('cyclin E', 'Protein', (283, 291))	('claudin-4', 'Gene', (328, 337))	('claudin-3', 'Gene', (317, 326))
60923	29137450	These include: the high mutational profiles, TP53 mutation, PTEN loss, and ARID1A mutations.	('loss', 'NegReg', (65, 69))	('TP53', 'Gene', (45, 49))	('ARID1A', 'Gene', (75, 81))	('PTEN', 'Gene', (60, 64))	('mutations', 'Var', (82, 91))	('PTEN', 'Gene', '5728', (60, 64))	('ARID1A', 'Gene', '8289', (75, 81))	('TP53', 'Gene', '7157', (45, 49))	('mutation', 'Var', (50, 58))
60924	29137450	PTEN loss of function in EC, frequent in all TCGA subgroups except CNH, may confer a homologous recombination (HR) deficiency phenotype, similar to that seen in deleterious germline BRCA1 and BRCA2 mutations.	('homologous recombination', 'MPA', (85, 109))	('BRCA1', 'Gene', '672', (182, 187))	('BRCA1', 'Gene', (182, 187))	('EC', 'Phenotype', 'HP:0012114', (25, 27))	('mutations', 'Var', (198, 207))	('(HR) deficiency', 'Disease', 'MESH:D001919', (110, 125))	('BRCA2', 'Gene', (192, 197))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('loss of function', 'NegReg', (5, 21))	('BRCA2', 'Gene', '675', (192, 197))
60927	29137450	Cell line data from colorectal and endometrial cancers suggest MSI tumors may harbor mutations in other genes involved in HR repair of double strand DNA breaks, e.g., MRE11A and RAD50.	('MSI tumors', 'Disease', 'MESH:D009369', (63, 73))	('RAD50', 'Gene', (178, 183))	('RAD50', 'Gene', '10111', (178, 183))	('colorectal', 'Disease', 'MESH:D015179', (20, 30))	('MSI tumors', 'Disease', (63, 73))	('MRE11A', 'Gene', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('endometrial cancer', 'Phenotype', 'HP:0012114', (35, 53))	('colorectal', 'Disease', (20, 30))	('harbor', 'Reg', (78, 84))	('mutations', 'Var', (85, 94))	('endometrial cancers', 'Disease', 'MESH:D016889', (35, 54))	('endometrial cancers', 'Disease', (35, 54))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('MRE11A', 'Gene', '4361', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
60928	29137450	ARID1A mutations are present in ~40% of MSI and CNL endometrioid tumors.	('CNL endometrioid tumors', 'Disease', (48, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('ARID1A', 'Gene', '8289', (0, 6))	('CNL endometrioid tumors', 'Disease', 'MESH:D016889', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('ARID1A', 'Gene', (0, 6))	('MSI', 'Disease', 'None', (40, 43))	('MSI', 'Disease', (40, 43))	('mutations', 'Var', (7, 16))
60936	29137450	Data to date suggest that cancers with a dependence on G2/M DNA repair may be susceptible to inhibition with DNA repair inhibitors.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('G2/M', 'Var', (55, 59))
60942	29137450	Silencing of both ERalpha and PR by aberrant promoter methylation is reported in cell lines and patient samples with hypermethylation of the ERalpha-promoter C reported in over 90% and PR-promoter B in 70% of cases.	('hypermethylation', 'Var', (117, 133))	('ERalpha', 'Gene', (141, 148))	('Silencing', 'NegReg', (0, 9))	('patient', 'Species', '9606', (96, 103))	('ERalpha', 'Gene', '2099', (141, 148))	('ERalpha', 'Gene', (18, 25))	('aberrant', 'Var', (36, 44))	('ERalpha', 'Gene', '2099', (18, 25))
60946	29137450	There was a statistically marginal benefit for the small subset of patients with catenin-beta 1 CTNNB1 mutations.	('mutations', 'Var', (103, 112))	('CTNNB1', 'Gene', '1499', (96, 102))	('patients', 'Species', '9606', (67, 75))	('CTNNB1', 'Gene', (96, 102))	('catenin-beta 1', 'Gene', '1499', (81, 95))	('catenin-beta 1', 'Gene', (81, 95))
60950	29137450	Exploratory biomarker work in this study and the everolimus/letrozole trial suggests that tumors harboring CTNNB1 mutations may be more likely to respond, although responses were also seen in tumors with wild type CTNNB1.	('letrozole', 'Chemical', 'MESH:D000077289', (60, 69))	('everolimus', 'Chemical', 'MESH:D000068338', (49, 59))	('CTNNB1', 'Gene', '1499', (107, 113))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('respond', 'MPA', (146, 153))	('CTNNB1', 'Gene', '1499', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('CTNNB1', 'Gene', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CTNNB1', 'Gene', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
60955	29137450	The PIK3CA-PIK3R1-PTEN axis is somatically mutated in at least 40% of serous ECs and over 70% of endometrioid EC.	('PTEN', 'Gene', (18, 22))	('endometrioid EC', 'Disease', (97, 112))	('ECs', 'Chemical', 'MESH:C001390', (77, 80))	('PTEN', 'Gene', '5728', (18, 22))	('serous ECs', 'Disease', (70, 80))	('PIK3CA-PIK3R1', 'Gene', '5290;5295', (4, 17))	('EC', 'Phenotype', 'HP:0012114', (110, 112))	('EC', 'Phenotype', 'HP:0012114', (77, 79))	('mutated', 'Var', (43, 50))	('PIK3CA-PIK3R1', 'Gene', (4, 17))
60956	29137450	A large fraction of PIK3CA mutations are located in exons 1-8, in addition to exons 9 and 20.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))
60961	29137450	A phase II trial (NCT01455493) of the PI3K/mTORC1/2 inhibitor, MK2206, in patients with advanced EC enrolled 56 patients, 3 patients had a confirmed clinical response and all 3 had one or more molecular abnormalities in PIK3CA, PTEN, or AKT.	('AKT', 'Gene', (237, 240))	('mTORC1/2', 'Gene', (43, 51))	('patients', 'Species', '9606', (124, 132))	('patients', 'Species', '9606', (74, 82))	('PTEN', 'Gene', (228, 232))	('patients', 'Species', '9606', (112, 120))	('molecular abnormalities', 'Disease', (193, 216))	('PIK3CA', 'Gene', (220, 226))	('MK2206', 'Chemical', 'MESH:C548887', (63, 69))	('PTEN', 'Gene', '5728', (228, 232))	('PIK3CA', 'Gene', '5290', (220, 226))	('AKT', 'Gene', '207', (237, 240))	('mTORC1/2', 'Gene', '74343;382056', (43, 51))	('molecular abnormalities', 'Disease', 'MESH:C567116', (193, 216))	('EC', 'Phenotype', 'HP:0012114', (97, 99))	('MK2206', 'Var', (63, 69))
60975	29137450	Further characterization of the immunological landscape of the copy-number low, copy-number high, and TP53 mutant high-risk ECs may result in additional patient-tailored immunological therapies.	('ECs', 'Chemical', 'MESH:C001390', (124, 127))	('copy-number low', 'Var', (63, 78))	('TP53', 'Gene', (102, 106))	('copy-number high', 'Var', (80, 96))	('mutant', 'Var', (107, 113))	('result in', 'Reg', (132, 141))	('EC', 'Phenotype', 'HP:0012114', (124, 126))	('patient', 'Species', '9606', (153, 160))	('TP53', 'Gene', '7157', (102, 106))
60984	29137450	Although the hypotheses are controversial, metformin may exert anti-tumorigenic activity through indirect effects on the metabolic milieu via cation-selective transporters and direct effects on the tumor through inhibition of mitochondrial complex 1 and subsequent AMPK activation and mTOR pathway inhibition.	('tumor', 'Disease', (68, 73))	('mitochondrial complex 1', 'Enzyme', (226, 249))	('metabolic milieu', 'MPA', (121, 137))	('mTOR', 'Gene', (285, 289))	('cation-selective transporters', 'MPA', (142, 171))	('metformin', 'Var', (43, 52))	('mTOR', 'Gene', '2475', (285, 289))	('metformin', 'Chemical', 'MESH:D008687', (43, 52))	('AMPK', 'Pathway', (265, 269))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('activation', 'PosReg', (270, 280))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('inhibition', 'NegReg', (298, 308))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (198, 203))	('inhibition', 'NegReg', (212, 222))
61002	29137450	TCGA has shown that amplification of HER2 and somatic mutations of PIK3CA, the p110 kinase subunit of PI3K, often co-occur in serous/serous-like EC.	('PIK3CA', 'Gene', '5290', (67, 73))	('HER2', 'Gene', (37, 41))	('mutations', 'Var', (54, 63))	('serous/serous-like EC', 'Disease', (126, 147))	('HER2', 'Gene', '2064', (37, 41))	('co-occur', 'Reg', (114, 122))	('EC', 'Phenotype', 'HP:0012114', (145, 147))	('PIK3CA', 'Gene', (67, 73))
61007	29137450	Thus, dual HER2/PIK3CA blockade may represent a novel therapeutic option for EC patients harboring tumors with HER2 gene amplification and mutated PIK3CA.	('HER2', 'Gene', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('patients', 'Species', '9606', (80, 88))	('HER2', 'Gene', '2064', (111, 115))	('PIK3CA', 'Gene', '5290', (16, 22))	('PIK3CA', 'Gene', (147, 153))	('HER2', 'Gene', '2064', (11, 15))	('mutated', 'Var', (139, 146))	('PIK3CA', 'Gene', (16, 22))	('PIK3CA', 'Gene', '5290', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('EC', 'Phenotype', 'HP:0012114', (77, 79))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('HER2', 'Gene', (11, 15))	('gene amplification', 'Var', (116, 134))	('tumors', 'Disease', (99, 105))
61011	29137450	When the pathway is disrupted, such as somatic mutations in pathway members or CTNNB1, CTNNB1 is not targeted for degradation, avoids phosphorylation, and accumulates in the cytoplasm, ultimately entering the nucleus and leading to CTNNB1-mediated transcription.	('CTNNB1', 'Gene', '1499', (79, 85))	('phosphorylation', 'MPA', (134, 149))	('CTNNB1', 'Gene', '1499', (87, 93))	('leading to', 'Reg', (221, 231))	('avoids', 'NegReg', (127, 133))	('mutations', 'Var', (47, 56))	('entering', 'Reg', (196, 204))	('CTNNB1', 'Gene', '1499', (232, 238))	('CTNNB1', 'Gene', (87, 93))	('CTNNB1', 'Gene', (79, 85))	('accumulates', 'PosReg', (155, 166))	('CTNNB1', 'Gene', (232, 238))
61016	29137450	CTNNB1 mutations occur in 52% of the CNL EC subgroup identified in the TCGA.	('CTNNB1', 'Gene', '1499', (0, 6))	('CNL EC', 'Disease', (37, 43))	('EC', 'Phenotype', 'HP:0012114', (41, 43))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
61017	29137450	Alterations are uncommon among serous tumors and are present at low frequency in MSI+ tumors.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('serous tumors', 'Disease', (31, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('Alterations', 'Var', (0, 11))	('MSI+ tumors', 'Disease', 'MESH:D009369', (81, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('MSI+ tumors', 'Disease', (81, 92))	('serous tumors', 'Disease', 'MESH:D018284', (31, 44))
61018	29137450	Several studies have suggested that CTNNB1 mutations are associated with a worse prognosis in early-stage low grade EC.	('early-stage low grade EC', 'Disease', (94, 118))	('CTNNB1', 'Gene', (36, 42))	('CTNNB1', 'Gene', '1499', (36, 42))	('mutations', 'Var', (43, 52))	('associated', 'Reg', (57, 67))	('EC', 'Phenotype', 'HP:0012114', (116, 118))
61020	29137450	Dysregulation of ubiquitin mediated proteosomal degradation of cellular proteins is often observed in human cancers.	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', (108, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('observed', 'Reg', (90, 98))	('human', 'Species', '9606', (102, 107))
61021	29137450	Recent whole exome sequencing studies in EC have uncovered frequent somatic alterations in the FBXW7 and SPOP genes, which encode ubiquitin ligase adaptor proteins and are more commonly seen in the CNH TCGA subgroup.	('alterations', 'Var', (76, 87))	('FBXW7', 'Gene', '55294', (95, 100))	('FBXW7', 'Gene', (95, 100))	('EC', 'Phenotype', 'HP:0012114', (41, 43))	('SPOP', 'Gene', (105, 109))
61025	29137450	Comprehensive sequencing studies in EC have shown that FBXW7 mutations are more abundant in serous (15%-29%) and serous-like (21%) cancers, than in either clear cell (7%-13%) or endometrioid (10%-27%) ECs.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('ECs', 'Chemical', 'MESH:C001390', (201, 204))	('cancers', 'Disease', (131, 138))	('abundant', 'Reg', (80, 88))	('FBXW7', 'Gene', '55294', (55, 60))	('mutations', 'Var', (61, 70))	('serous', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('EC', 'Phenotype', 'HP:0012114', (201, 203))	('FBXW7', 'Gene', (55, 60))	('EC', 'Phenotype', 'HP:0012114', (36, 38))	('serous-like', 'Disease', (113, 124))
61026	29137450	The presence of FBXW7 mutations in concurrent cases of serous EC and serous endometrial intraepithelial carcinoma suggests these are early genetic events for this subtype.	('FBXW7', 'Gene', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('EC', 'Phenotype', 'HP:0012114', (62, 64))	('serous endometrial intraepithelial carcinoma', 'Disease', 'MESH:D016889', (69, 113))	('serous endometrial intraepithelial carcinoma', 'Phenotype', 'HP:0012887', (69, 113))	('serous endometrial intraepithelial carcinoma', 'Disease', (69, 113))	('mutations', 'Var', (22, 31))	('FBXW7', 'Gene', '55294', (16, 21))	('serous EC', 'Disease', (55, 64))
61027	29137450	In addition, FBXW7 is also mutated in 20% of undifferentiated uterine carcinomas and in 23% of uterine carcinosarcomas.	('carcinosarcomas', 'Disease', 'MESH:D002296', (103, 118))	('mutated', 'Var', (27, 34))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (62, 80))	('carcinosarcomas', 'Disease', (103, 118))	('FBXW7', 'Gene', '55294', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Disease', (70, 80))	('carcinomas', 'Disease', 'MESH:D002277', (70, 80))	('FBXW7', 'Gene', (13, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))
61031	29137450	SPOP mutations have been documented in 7%-8% of serous ECs, 5% of serous-like ECs, 0-9% of endometrioid ECs, and 8% of clear cell ECs.	('EC', 'Phenotype', 'HP:0012114', (78, 80))	('SPOP', 'Gene', (0, 4))	('serous ECs', 'Disease', (48, 58))	('mutations', 'Var', (5, 14))	('ECs', 'Chemical', 'MESH:C001390', (78, 81))	('EC', 'Phenotype', 'HP:0012114', (104, 106))	('EC', 'Phenotype', 'HP:0012114', (55, 57))	('serous-like ECs', 'Disease', (66, 81))	('ECs', 'Chemical', 'MESH:C001390', (130, 133))	('EC', 'Phenotype', 'HP:0012114', (130, 132))	('ECs', 'Chemical', 'MESH:C001390', (55, 58))	('ECs', 'Chemical', 'MESH:C001390', (104, 107))
61032	29137450	The majority of SPOP mutations in EC and in prostate cancer localize to the MATH domain, which binds proteins that are targeted for ubiquitination and proteasomal degradation.	('EC', 'Phenotype', 'HP:0012114', (34, 36))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('prostate cancer', 'Disease', (44, 59))	('ubiquitination', 'Disease', 'MESH:C563003', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('ubiquitination', 'Disease', (132, 146))	('SPOP', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
61033	29137450	The MATH domain of SPOP functions in an analogous manner to the WD repeats of FBXW7, leading to the speculation that missense mutations in the MATH domain are likely to be dominant-negative or loss-of-function mutants that disrupt the binding of SPOP to one or more of its protein substrates.	('SPOP', 'Protein', (246, 250))	('disrupt', 'NegReg', (223, 230))	('FBXW7', 'Gene', (78, 83))	('FBXW7', 'Gene', '55294', (78, 83))	('WD', 'Disease', 'MESH:D006527', (64, 66))	('missense mutations', 'Var', (117, 135))	('loss-of-function', 'NegReg', (193, 209))	('binding', 'Interaction', (235, 242))
61034	29137450	Functional studies of the SPOP mutations that have been found in EC are at a very early stage, but thus far indicate that a subset of SPOP mutants have an impaired ability to regulate ERalpha.	('SPOP', 'Gene', (134, 138))	('ability', 'MPA', (164, 171))	('EC', 'Phenotype', 'HP:0012114', (65, 67))	('mutants', 'Var', (139, 146))	('ERalpha', 'Gene', '2099', (184, 191))	('ERalpha', 'Gene', (184, 191))	('impaired', 'NegReg', (155, 163))	('SPOP', 'Gene', (26, 30))
61035	29137450	Recent work by Barberi et al., 2015 indicates that SPOP mutations in prostate cancer lead to defects in HR and confer sensitivity to PARP inhibition.	('PARP', 'Gene', (133, 137))	('defects', 'NegReg', (93, 100))	('mutations', 'Var', (56, 65))	('SPOP', 'Gene', (51, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('PARP', 'Gene', '142', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Disease', (69, 84))
61036	29137450	Whole-exome sequencing analysis of a small number of primary serous endometrial tumors (n=13), followed by targeted gene sequencing in a larger cohort of serous ECs, identified frequent somatic mutations in CHD4 (17%), which encodes a subunit of the NuRD-chromatin-remodeling complex.	('CHD4', 'Gene', (207, 211))	('serous endometrial tumors', 'Phenotype', 'HP:0012887', (61, 86))	('EC', 'Phenotype', 'HP:0012114', (161, 163))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (194, 203))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('CHD4', 'Gene', '1108', (207, 211))	('ECs', 'Chemical', 'MESH:C001390', (161, 164))	('serous endometrial tumors', 'Disease', 'MESH:D016889', (61, 86))	('serous endometrial tumors', 'Disease', (61, 86))
61037	29137450	A confirmatory study also noted frequent deletion of a small segment of chromosome 19 containing MBD3, another subunit of the NuRD-chromatin-modification complex, and frequent mutations in TAF1.	('mutations', 'Var', (176, 185))	('MBD3', 'Gene', (97, 101))	('deletion', 'Var', (41, 49))	('TAF1', 'Gene', '6872', (189, 193))	('TAF1', 'Gene', (189, 193))	('MBD3', 'Gene', '53615', (97, 101))
61039	29137450	Le Gallo et al., have reported TAF1 mutations in nearly 10% of clear cell EC.	('clear cell EC', 'Disease', (63, 76))	('mutations', 'Var', (36, 45))	('TAF1', 'Gene', '6872', (31, 35))	('TAF1', 'Gene', (31, 35))	('EC', 'Phenotype', 'HP:0012114', (74, 76))
61040	29137450	Lower frequency mutations in several other chromatin remodeling genes including EP300 (8%), and ARID1A (6%) have been noted in serous ECs.	('serous ECs', 'Disease', (127, 137))	('ARID1A', 'Gene', '8289', (96, 102))	('mutations', 'Var', (16, 25))	('ARID1A', 'Gene', (96, 102))	('ECs', 'Chemical', 'MESH:C001390', (134, 137))	('EP300', 'Gene', (80, 85))	('EC', 'Phenotype', 'HP:0012114', (134, 136))
61041	29137450	ARID1a, a component of the SWI/SNF chromatin remodeling complex, is also frequently mutated in endometrioid ECs including all TCGA subgroups except CNH, up to 40% by different databases.	('ARID1a', 'Gene', '8289', (0, 6))	('ARID1a', 'Gene', (0, 6))	('endometrioid ECs', 'Disease', (95, 111))	('mutated', 'Var', (84, 91))	('EC', 'Phenotype', 'HP:0012114', (108, 110))	('ECs', 'Chemical', 'MESH:C001390', (108, 111))
61043	29137450	Therapeutic inhibition of EZH2 is now in early evaluation and could be targeted to ARID1a mutant EC.	('ARID1a', 'Gene', (83, 89))	('EZH2', 'Gene', '2146', (26, 30))	('EZH2', 'Gene', (26, 30))	('mutant', 'Var', (90, 96))	('ARID1a', 'Gene', '8289', (83, 89))	('EC', 'Phenotype', 'HP:0012114', (97, 99))
61051	28193280	Recently, the deregulated expression of full-length ALK has been observed in some primary solid tumors, but little is known about its involvement in the tumorigenesis of uterine carcinosarcomas (UCSs).	('expression', 'MPA', (26, 36))	('primary solid tumors', 'Disease', 'MESH:D009369', (82, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('primary solid tumors', 'Disease', (82, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('carcinosarcomas', 'Disease', 'MESH:D002296', (178, 193))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('deregulated', 'Var', (14, 25))	('observed', 'Reg', (65, 73))	('carcinosarcomas', 'Disease', (178, 193))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (170, 192))	('ALK', 'Gene', (52, 55))
61054	28193280	In cell lines, ALK promoter activity was significantly increased by transfection of Sox11 and N-myc, which are known to contribute to neuronal properties.	('N-myc', 'Gene', '4613', (94, 99))	('transfection', 'Var', (68, 80))	('increased', 'PosReg', (55, 64))	('N-myc', 'Gene', (94, 99))	('Sox11', 'Gene', (84, 89))	('ALK', 'Protein', (15, 18))
61056	28193280	Overexpression of p65 also led to transactivation of Twist1 gene, known as an EMT inducer.	('Twist1', 'Gene', '7291', (53, 59))	('p65', 'Var', (18, 21))	('transactivation', 'MPA', (34, 49))	('Twist1', 'Gene', (53, 59))
61057	28193280	Finally, treatment of the stable ALK-overexpressing cells with doxorubicin resulted in inhibition of apoptosis with progressive increase in the expression ratio of both pAkt and bcl2 relative to total Akt and bax, respectively.	('inhibition', 'NegReg', (87, 97))	('increase', 'PosReg', (128, 136))	('doxorubicin', 'Var', (63, 74))	('bcl2', 'Gene', '596', (178, 182))	('bax', 'Gene', '581', (209, 212))	('Akt', 'Gene', (201, 204))	('Akt', 'Gene', (170, 173))	('Akt', 'Gene', '207', (201, 204))	('apoptosis', 'CPA', (101, 110))	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('bcl2', 'Gene', (178, 182))	('bax', 'Gene', (209, 212))	('expression ratio', 'MPA', (144, 160))	('Akt', 'Gene', '207', (170, 173))
61079	28193280	Anti-N-myc, anti-Twist1, and anti-Histone H1 antibodies were from Abcam (Cambridge, MA, USA).	('N-myc', 'Gene', (5, 10))	('N-myc', 'Gene', '4613', (5, 10))	('Twist1', 'Gene', '7291', (17, 23))	('anti-Histone', 'Var', (29, 41))	('Twist1', 'Gene', (17, 23))
61081	28193280	Anti-bcl-2 and anti-p21waf1 antibodies were from Dako (Glostrup, Denmark).	('bcl-2', 'Gene', (5, 10))	('bcl-2', 'Gene', '596', (5, 10))	('anti-p21waf1', 'Var', (15, 27))
61099	28193280	Lung carcinoma tissues with ALK overexpression due to a gene abnormality were used as positive control.	('carcinoma', 'Disease', (5, 14))	('carcinoma', 'Disease', 'MESH:D002277', (5, 14))	('gene abnormality', 'Var', (56, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))
61101	28193280	Riboprobes for ALK containing nucleotides 3946 to 4633 of the ALK gene were generated by in vitro transcription using full length ALK cDNA, and ISH assays were performed using the GenPoint Tyramide Signal Amplification System (Dako) as described previously.	('Tyramide', 'Chemical', '-', (189, 197))	('nucleotides 3946 to 4633', 'Var', (30, 54))	('ALK', 'Gene', (62, 65))
61103	28193280	Transient transfection of N-myc, but not c-myc, resulted in activation of the ALK promoter, in particular the shortest reporter constructs (-146/+30 bp) (Fig.	('ALK promoter', 'Gene', (78, 90))	('c-myc', 'Gene', '4609', (41, 46))	('c-myc', 'Gene', (41, 46))	('activation', 'PosReg', (60, 70))	('-146/+30 bp', 'Var', (140, 151))	('N-myc', 'Gene', '4613', (26, 31))	('N-myc', 'Gene', (26, 31))
61112	28193280	These two independent stable clones showed high proliferation rates, particularly in the exponential growth phase, along with decreased amounts of p21waf1, but not cyclin A and p27kip1 (Additional file 2: Figure S2A and B).	('decreased', 'NegReg', (126, 135))	('amounts', 'MPA', (136, 143))	('p27kip1', 'Gene', (177, 184))	('cyclin A', 'Gene', (164, 172))	('p27kip1', 'Gene', '1027', (177, 184))	('cyclin A', 'Gene', '890', (164, 172))	('p21waf1', 'Var', (147, 154))
61116	28193280	Given that cytokines including NF-kappaB effectively and reproducibly induce EMT, we next examined whether p65 can affect expression of Snail, Slug, and Twist1, all of which are EMT-related genes.	('Twist1', 'Gene', '7291', (153, 159))	('expression', 'MPA', (122, 132))	('Snail', 'Gene', (136, 141))	('affect', 'Reg', (115, 121))	('Slug', 'Gene', (143, 147))	('Snail', 'Gene', '6615', (136, 141))	('NF-kappaB', 'Gene', '4790', (31, 40))	('Twist1', 'Gene', (153, 159))	('EMT', 'CPA', (77, 80))	('p65', 'Var', (107, 110))	('NF-kappaB', 'Gene', (31, 40))	('Slug', 'Gene', '6591', (143, 147))
61122	28193280	ChIP assay also revealed that increased amount of p65 caused its recruitment to the region of -101 to +62 bp within the promoter lacking putative NF-kappaB-binding sites (Fig.	('recruitment', 'MPA', (65, 76))	('p65', 'Var', (50, 53))	('NF-kappaB', 'Gene', '4790', (146, 155))	('increased', 'PosReg', (30, 39))	('NF-kappaB', 'Gene', (146, 155))
61123	28193280	Finally, knockdown of endogenous p65 resulted in a decrease in Twist1 expression in H251-ALK#16 cells (Fig.	('knockdown', 'Var', (9, 18))	('Twist1', 'Gene', (63, 69))	('p65', 'Gene', (33, 36))	('H251-ALK#16', 'Gene', (84, 95))	('H251-ALK#16', 'Gene', '238', (84, 95))	('expression', 'MPA', (70, 80))	('decrease', 'NegReg', (51, 59))	('Twist1', 'Gene', '7291', (63, 69))
61150	28193280	Several lines of evidence from our present study support the conclusion that Twist1 expression is under the transcriptional control of p65 : i) rapid induction of Twist1 expression by treatment of cells with TNF-alpha; ii) up-regulation of Twist1 expression at both mRNA and protein levels by transfection of p65 in Ishikawa cells; iii) activation of the Twist1 promoter by p65 at the proximal region (-101 to +62 bp), which is independent of NF-kappaB-binding sites, suggesting its association with the basic transcriptional machinery at the promoter; iv) decreased Twist1 expression by knockdown of endogenous p65 in H251-ALK#16 cells; v) and significant positive correlation of Twist1 score with both ALK and pAkt IHC scores in clinical UCS samples.	('H251-ALK#16', 'Gene', (619, 630))	('decreased', 'NegReg', (557, 566))	('expression', 'MPA', (574, 584))	('clinical', 'Species', '191496', (731, 739))	('Akt', 'Gene', (713, 716))	('Twist1', 'Gene', (240, 246))	('up-regulation', 'PosReg', (223, 236))	('Akt', 'Gene', '207', (713, 716))	('NF-kappaB', 'Gene', (443, 452))	('Twist1', 'Gene', '7291', (240, 246))	('Twist1', 'Gene', (355, 361))	('NF-kappaB', 'Gene', '4790', (443, 452))	('TNF-alpha', 'Gene', '7124', (208, 217))	('Twist1', 'Gene', (681, 687))	('Twist1', 'Gene', (77, 83))	('Twist1', 'Gene', '7291', (355, 361))	('TNF-alpha', 'Gene', (208, 217))	('knockdown', 'Var', (588, 597))	('Twist1', 'Gene', '7291', (681, 687))	('Twist1', 'Gene', (567, 573))	('Twist1', 'Gene', '7291', (77, 83))	('Twist1', 'Gene', (163, 169))	('H251-ALK#16', 'Gene', '238', (619, 630))	('Twist1', 'Gene', '7291', (163, 169))	('Twist1', 'Gene', '7291', (567, 573))
61151	28193280	Although we could not demonstrate immunoreactivity for phosphorylated NF-kappaB/p65 (pp65) in UCS tissues, because of a lack of the available antibody, it appears that the ALK-mediated Akt/NF-kappaB/Twist1 pathway may participate in an initial stage that regulates morphological alterations toward the sarcomatous phenotype in UCSs, since induction of Akt was found to activate NF-kappaB/p65-dependent transcription, probably through repression of IkappaBalpha expression.	('sarcomatous', 'Disease', (302, 313))	('IkappaBalpha', 'Gene', (448, 460))	('induction', 'Var', (339, 348))	('Akt', 'Gene', (352, 355))	('IkappaBalpha', 'Gene', '4792', (448, 460))	('NF-kappaB', 'Gene', '4790', (378, 387))	('NF-kappaB', 'Gene', '4790', (189, 198))	('NF-kappaB', 'Gene', (378, 387))	('Twist1', 'Gene', '7291', (199, 205))	('NF-kappaB', 'Gene', '4790', (70, 79))	('Akt', 'Gene', '207', (185, 188))	('sarcomatous', 'Disease', 'MESH:D018316', (302, 313))	('NF-kappaB', 'Gene', (189, 198))	('NF-kappaB', 'Gene', (70, 79))	('Akt', 'Gene', '207', (352, 355))	('activate', 'PosReg', (369, 377))	('Akt', 'Gene', (185, 188))	('Twist1', 'Gene', (199, 205))
61300	25767563	Interestingly, in various other solid tumour types such as germ cell tumour, gestational trophoblastic disease, rectal cancer, presence of lung metastasis is a risk factor to CNS involvement.	('tumour', 'Disease', (69, 75))	('rectal cancer', 'Disease', 'MESH:D012004', (112, 125))	('rectal cancer', 'Disease', (112, 125))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('lung metastasis', 'Disease', (139, 154))	('rectal cancer', 'Phenotype', 'HP:0100743', (112, 125))	('lung metastasis', 'Disease', 'MESH:D009362', (139, 154))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('CNS involvement', 'Disease', (175, 190))	('germ cell tumour', 'Phenotype', 'HP:0100728', (59, 75))	('gestational trophoblastic disease', 'Disease', 'MESH:D006828', (77, 110))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Disease', (38, 44))	('presence', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gestational trophoblastic disease', 'Disease', (77, 110))
61323	25767563	Eribulin inhibits microtubules via a mechanism that is distinct from other microtubule-targeting agents such as taxanes.	('Eribulin', 'Var', (0, 8))	('microtubules', 'MPA', (18, 30))	('taxanes', 'Chemical', 'MESH:D043823', (112, 119))	('inhibits', 'NegReg', (9, 17))
61352	23935632	Two 5' UTR variants dominate PLAC1 expression (Figure 1).	('variants', 'Var', (11, 19))	('PLAC1', 'Gene', '10761', (29, 34))	('PLAC1', 'Gene', (29, 34))
61392	23935632	Indirect support for this idea comes from experiments in MCF-7 and BT-549 breast cancer cells showing that PLAC1 knockdown significantly reduces cell motility, proliferation, and invasiveness.	('breast cancer', 'Disease', (74, 87))	('reduces', 'NegReg', (137, 144))	('PLAC1', 'Gene', '10761', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('proliferation', 'CPA', (160, 173))	('MCF-7', 'CellLine', 'CVCL:0031', (57, 62))	('knockdown', 'Var', (113, 122))	('BT-549', 'CellLine', 'CVCL:1092', (67, 73))	('cell motility', 'CPA', (145, 158))	('PLAC1', 'Gene', (107, 112))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('invasiveness', 'CPA', (179, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
61583	18645019	We previously showed that all female HMGA1a transgenic mice develop malignant uterine tumors, indicating that HMGA1a causes uterine cancer in vivo.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (132, 138))	('uterine tumor', 'Phenotype', 'HP:0010784', (78, 91))	('uterine cancer', 'Phenotype', 'HP:0010784', (124, 138))	('HMGA1a', 'Gene', (37, 43))	('transgenic', 'Var', (44, 54))	('transgenic mice', 'Species', '10090', (44, 59))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('malignant uterine tumors', 'Disease', 'MESH:D014594', (68, 92))	('malignant uterine tumors', 'Disease', (68, 92))	('uterine tumors', 'Phenotype', 'HP:0010784', (78, 92))	('develop', 'PosReg', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
61592	18645019	These preclinical studies suggest that cyclooxygenase inhibitors could play a role in preventing tumor onset or progression in uterine cancers with dysregulation of the HMGA1a-COX-2 pathway.	('COX-2', 'Gene', '19225', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('uterine cancers', 'Phenotype', 'HP:0010784', (127, 142))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', (97, 102))	('dysregulation', 'Var', (148, 161))	('uterine cancer', 'Phenotype', 'HP:0010784', (127, 141))	('COX-2', 'Gene', (176, 181))
61599	18645019	Preclinical studies of therapeutic interventions for uterine cancer recently became possible with the generation of HMGA1a transgenic mice, which develop malignant uterine tumors with complete penetrance.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (61, 67))	('HMGA1a', 'Gene', (116, 122))	('uterine cancer', 'Phenotype', 'HP:0010784', (53, 67))	('develop', 'PosReg', (146, 153))	('transgenic mice', 'Species', '10090', (123, 138))	('malignant uterine tumors', 'Disease', (154, 178))	('malignant uterine tumors', 'Disease', 'MESH:D014594', (154, 178))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('uterine tumor', 'Phenotype', 'HP:0010784', (164, 177))	('transgenic', 'Var', (123, 133))	('uterine tumors', 'Phenotype', 'HP:0010784', (164, 178))
61621	18645019	At 8 weeks of age, HMGA1a transgenic mice (10 in each arm) were randomly assigned to one of three groups: control, sulindac, or celecoxib.	('sulindac', 'Chemical', 'MESH:D013467', (115, 123))	('transgenic mice', 'Species', '10090', (26, 41))	('HMGA1a', 'Gene', (19, 25))	('transgenic', 'Var', (26, 36))	('celecoxib', 'Chemical', 'MESH:D000068579', (128, 137))
61628	18645019	To determine if cyclooxygenase inhibitors could prevent the development or progression of uterine cancer, the mice were fed a diet supplemented with either sulindac, a COX-1/COX-2 inhibitor (320 ppm, n = 10), celecoxib, a specific COX-2 inhibitor (800 ppm; n = 10), or control (n = 10), starting at 8 weeks of age.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('COX-1', 'Gene', (168, 173))	('sulindac', 'Chemical', 'MESH:D013467', (156, 164))	('celecoxib', 'Chemical', 'MESH:D000068579', (209, 218))	('320 ppm', 'Var', (191, 198))	('COX-2', 'Gene', (231, 236))	('COX-2', 'Gene', '19225', (231, 236))	('uterine cancer', 'Phenotype', 'HP:0010784', (90, 104))	('COX-1', 'Gene', '17708', (168, 173))	('mice', 'Species', '10090', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('COX-2', 'Gene', '19225', (174, 179))	('COX-2', 'Gene', (174, 179))	('800 ppm', 'Var', (248, 255))
61637	18645019	At this later time point (36 weeks), it is possible that the oncogenic influence from the potent HMGA1a transgene allows tumor cells to escape the inhibitory effects of the drugs.	('oncogenic', 'MPA', (61, 70))	('escape', 'MPA', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('HMGA1a', 'Gene', (97, 103))	('tumor', 'Disease', (121, 126))	('transgene', 'Var', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
61666	18645019	MMMTs represent approximately 5% of all uterine cancers and have a 5 year survival of 40-50% for all stages.	('cancers', 'Disease', (48, 55))	('MMMTs', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('uterine cancer', 'Phenotype', 'HP:0010784', (40, 54))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('uterine cancers', 'Phenotype', 'HP:0010784', (40, 55))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
61680	18645019	Nonetheless, a recent clinical trial with lung cancer demonstrated benefit in selected patients on celecoxib and no cardiovascular toxicity.	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('celecoxib', 'Chemical', 'MESH:D000068579', (99, 108))	('celecoxib', 'Var', (99, 108))	('lung cancer', 'Disease', (42, 53))	('benefit', 'PosReg', (67, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cardiovascular toxicity', 'Disease', 'MESH:D002318', (116, 139))	('patients', 'Species', '9606', (87, 95))	('cardiovascular toxicity', 'Disease', (116, 139))
61681	18645019	Thus, the current challenge is to identify selected patients who could benefit from COX-2 inhibitors and to develop next generation agents that lack toxicity.	('COX-2', 'Gene', '19225', (84, 89))	('COX-2', 'Gene', (84, 89))	('toxicity', 'Disease', 'MESH:D064420', (149, 157))	('toxicity', 'Disease', (149, 157))	('inhibitors', 'Var', (90, 100))	('patients', 'Species', '9606', (52, 60))
61687	18645019	Importantly, COX-2 inhibitors have lower toxicity than the chemotherapeutic agents currently used to treat advanced stage uterine cancers.	('uterine cancers', 'Phenotype', 'HP:0010784', (122, 137))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('toxicity', 'Disease', 'MESH:D064420', (41, 49))	('toxicity', 'Disease', (41, 49))	('cancers', 'Disease', (130, 137))	('inhibitors', 'Var', (19, 29))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('lower', 'NegReg', (35, 40))	('COX-2', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('COX-2', 'Gene', '19225', (13, 18))	('uterine cancer', 'Phenotype', 'HP:0010784', (122, 136))
61773	33787622	Several other trials evaluate immunotherapeutic agents alone or in combination with conventional chemotherapy or targeted therapies already used in sarcomas (NCT02997358, NCT04200443, NCT02203760, NCT03463408, NCT03282344).	('sarcomas', 'Disease', 'MESH:D012509', (148, 156))	('sarcomas', 'Disease', (148, 156))	('NCT03463408', 'Var', (197, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('NCT02203760', 'Var', (184, 195))	('NCT02997358', 'Var', (158, 169))	('NCT03282344', 'Var', (210, 221))	('NCT04200443', 'Var', (171, 182))
61792	33173410	Genes encoding HNF1B transcription factors are prone to various types of mutations, causing the occurrence and progression of various diseases, including diabetes, renal insufficiency, and various malignant tumors.	('diabetes', 'Disease', (154, 162))	('malignant tumors', 'Disease', 'MESH:D009369', (197, 213))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('renal insufficiency', 'Disease', (164, 183))	('HNF1B', 'Gene', '6928', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('HNF1B', 'Gene', (15, 20))	('renal insufficiency', 'Disease', 'MESH:D051437', (164, 183))	('renal insufficiency', 'Phenotype', 'HP:0000083', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('causing', 'Reg', (84, 91))	('malignant tumors', 'Disease', (197, 213))	('mutations', 'Var', (73, 82))
61793	33173410	In the present study, we evaluated expression and mutations of HNF1B in different types of cancer from The Cancer Genome Atlas (TCGA) database.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HNF1B', 'Gene', '6928', (63, 68))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('HNF1B', 'Gene', (63, 68))
61799	33173410	The cBio cancer genomics portal was used to explore mutations and copy-number alterations of HNF1B in the TCGA pan-cancer studies.	('mutations', 'Var', (52, 61))	('HNF1B', 'Gene', (93, 98))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (9, 15))	('copy-number alterations', 'Var', (66, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('HNF1B', 'Gene', '6928', (93, 98))
61813	33173410	As shown in Figure 2A, the mutation types of HNF1B included missense mutations, truncating mutations, in-frame mutations and other mutations.	('truncating', 'MPA', (80, 90))	('HNF1B', 'Gene', (45, 50))	('missense mutations', 'Var', (60, 78))	('in-frame mutations', 'Var', (102, 120))	('HNF1B', 'Gene', '6928', (45, 50))
61815	33173410	Additionally, cancer patients with HNF1B mutations are more susceptible to many other gene mutations, including TP53, TTN, MUC16, CSMD3, SYNE1, ZFHX4, LRP1B, XIRP2, PCLO, FLG, FAT4, DNAH5, HYDIN, PIK3CA, USH2A, HMCN1, RYR2, CSMD1, FAT3 and KMT2D (Figure 2C).	('ZFHX4', 'Gene', (144, 149))	('SYNE1', 'Gene', (137, 142))	('MUC16', 'Gene', '94025', (123, 128))	('HNF1B', 'Gene', (35, 40))	('DNAH5', 'Gene', '1767', (182, 187))	('PIK3CA', 'Gene', (196, 202))	('LRP1B', 'Gene', (151, 156))	('XIRP2', 'Gene', (158, 163))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', '7157', (112, 116))	('PCLO', 'Gene', (165, 169))	('HYDIN', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('FAT3', 'Gene', (231, 235))	('SYNE1', 'Gene', '23345', (137, 142))	('TTN', 'Gene', '7273', (118, 121))	('mutations', 'Var', (41, 50))	('HMCN1', 'Gene', (211, 216))	('FLG', 'Gene', (171, 174))	('ZFHX4', 'Gene', '79776', (144, 149))	('FAT4', 'Gene', '79633', (176, 180))	('TTN', 'Gene', (118, 121))	('CSMD3', 'Gene', '114788', (130, 135))	('KMT2D', 'Gene', '8085', (240, 245))	('MUC16', 'Gene', (123, 128))	('CSMD1', 'Gene', '64478', (224, 229))	('DNAH5', 'Gene', (182, 187))	('CSMD1', 'Gene', (224, 229))	('FAT3', 'Gene', '120114', (231, 235))	('FLG', 'Gene', '2312', (171, 174))	('LRP1B', 'Gene', '53353', (151, 156))	('USH2A', 'Gene', (204, 209))	('PIK3CA', 'Gene', '5290', (196, 202))	('HMCN1', 'Gene', '83872', (211, 216))	('CSMD3', 'Gene', (130, 135))	('PCLO', 'Gene', '27445', (165, 169))	('TP53', 'Gene', (112, 116))	('cancer', 'Disease', (14, 20))	('XIRP2', 'Gene', '129446', (158, 163))	('FAT4', 'Gene', (176, 180))	('RYR2', 'Gene', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('HYDIN', 'Gene', '54768', (189, 194))	('KMT2D', 'Gene', (240, 245))	('RYR2', 'Gene', '6262', (218, 222))	('USH2A', 'Gene', '7399', (204, 209))	('HNF1B', 'Gene', '6928', (35, 40))
61833	33173410	As shown in Figure 6A, CD8+ T cell levels were negatively associated with overall survival in the low HNF1B expression group of kidney renal papillary cell carcinoma (KIRP, HR=3.76, P=0.00305) and uveal melanoma (UVM, HR=2.99, P=0.0479).	('CD8', 'Gene', (23, 26))	('kidney renal papillary cell carcinoma', 'Disease', (128, 165))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (135, 165))	('CD8', 'Gene', '925', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (128, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (197, 211))	('low', 'Var', (98, 101))	('HNF1B', 'Gene', '6928', (102, 107))	('uveal melanoma', 'Disease', (197, 211))	('HNF1B', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('negatively', 'NegReg', (47, 57))	('overall', 'MPA', (74, 81))
61835	33173410	In the low HNF1B expression group of liver hepatocellular carcinoma (LIHC), CD8+ T cells were revealed to be positively associated with overall survival.	('liver hepatocellular carcinoma', 'Disease', (37, 67))	('associated', 'Reg', (120, 130))	('HNF1B', 'Gene', '6928', (11, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('low', 'Var', (7, 10))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 67))	('overall', 'MPA', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('HNF1B', 'Gene', (11, 16))
61847	33173410	Moreover, it has been reported that the single nucleotide polymorphism (SNP) of HNF1B can affect the susceptibility of endometrial tumors.	('affect', 'Reg', (90, 96))	('endometrial tumors', 'Disease', 'MESH:D016889', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HNF1B', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('endometrial tumors', 'Disease', (119, 137))	('single nucleotide polymorphism', 'Var', (40, 70))	('HNF1B', 'Gene', '6928', (80, 85))
61848	33173410	conducted gene sequencing studies on endometrial cancer patients and control groups and found that HNF1B gene SNP (rs4430796, G A) can reduce the incidence of endometrial cancer.	('rs4430796', 'Var', (115, 124))	('patients', 'Species', '9606', (56, 64))	('rs4430796', 'Mutation', 'rs4430796', (115, 124))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('endometrial cancer', 'Disease', (37, 55))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('HNF1B', 'Gene', '6928', (99, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('HNF1B', 'Gene', (99, 104))	('reduce', 'NegReg', (135, 141))
61851	33173410	Most HNF1B mutations are clustered in the first 4 exons of the gene.	('HNF1B', 'Gene', (5, 10))	('mutations', 'Var', (11, 20))	('HNF1B', 'Gene', '6928', (5, 10))
61853	33173410	A total of 106 HNF1B gene mutations, including gene deletion (34%), missense mutation (31%), frameshift deletion or insertion mutation (15%), nonsense mutation (11%) and splicing point mutation (8%) have been reported.	('frameshift deletion', 'Var', (93, 112))	('gene deletion', 'Var', (47, 60))	('HNF1B', 'Gene', '6928', (15, 20))	('HNF1B', 'Gene', (15, 20))	('insertion mutation', 'Var', (116, 134))	('splicing', 'MPA', (170, 178))	('nonsense mutation', 'Var', (142, 159))	('missense mutation', 'Var', (68, 85))
61854	33173410	According to these results, our study found that HNF1B mutations occurred widely in human cancers and that the most common type is missense mutations.	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HNF1B', 'Gene', (49, 54))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('missense mutations', 'Var', (131, 149))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('HNF1B', 'Gene', '6928', (49, 54))
61855	33173410	Additionally, patients with HNF1B mutations are more prone to mutations in other genes, such as TP53, TTN and MUC16.	('TTN', 'Gene', (102, 105))	('mutations', 'Var', (62, 71))	('MUC16', 'Gene', (110, 115))	('TP53', 'Gene', (96, 100))	('TTN', 'Gene', '7273', (102, 105))	('prone', 'Reg', (53, 58))	('MUC16', 'Gene', '94025', (110, 115))	('patients', 'Species', '9606', (14, 22))	('HNF1B', 'Gene', '6928', (28, 33))	('mutations', 'Var', (34, 43))	('TP53', 'Gene', '7157', (96, 100))	('HNF1B', 'Gene', (28, 33))
61867	33173410	HNF1B mutations are widely observed in tumors and interact with different genes in different cancer types, which may be the cause of the distinct prognostic values in cancers.	('interact', 'Reg', (50, 58))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancers', 'Disease', (167, 174))	('HNF1B', 'Gene', '6928', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('HNF1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (6, 15))
61946	27931750	Key findings of this study include more early-stage disease and less distant metastatic disease in tamoxifen-related uterine carcinosarcomas when compared to tamoxifen-unrelated uterine carcinosarcomas.	('uterine carcinosarcoma', 'Disease', (178, 200))	('carcinosarcomas', 'Disease', (186, 201))	('uterine carcinosarcoma', 'Disease', 'MESH:D002296', (178, 200))	('distant metastatic disease', 'CPA', (69, 95))	('carcinosarcomas', 'Disease', 'MESH:D002296', (125, 140))	('more', 'PosReg', (35, 39))	('age', 'Gene', '5973', (48, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (158, 167))	('less', 'NegReg', (64, 68))	('tamoxifen-related', 'Var', (99, 116))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (117, 139))	('carcinosarcomas', 'Disease', (125, 140))	('uterine carcinosarcoma', 'Disease', (117, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('uterine carcinosarcoma', 'Disease', 'MESH:D002296', (117, 139))	('carcinosarcomas', 'Disease', 'MESH:D002296', (186, 201))	('tamoxifen', 'Chemical', 'MESH:D013629', (99, 108))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (178, 200))	('age', 'Gene', (48, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))
61968	27931750	Because gynecologic malignancy with the PIK3CA/AKT/mTOR pathway alteration is known to be associated with better prognosis, this may be a possible biological plausibility to support a high proportion of early-stage disease in tamoxifen-related uterine carcinosarcoma.	('mTOR', 'Gene', (51, 55))	('AKT', 'Gene', (47, 50))	('malignancy', 'Disease', (20, 30))	('uterine carcinosarcoma', 'Disease', (244, 266))	('PIK3CA', 'Gene', (40, 46))	('tamoxifen', 'Chemical', 'MESH:D013629', (226, 235))	('age', 'Gene', '5973', (211, 214))	('PIK3CA', 'Gene', '5290', (40, 46))	('better', 'PosReg', (106, 112))	('AKT', 'Gene', '207', (47, 50))	('alteration', 'Var', (64, 74))	('uterine carcinosarcoma', 'Disease', 'MESH:D002296', (244, 266))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (244, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('age', 'Gene', (211, 214))	('mTOR', 'Gene', '2475', (51, 55))	('malignancy', 'Disease', 'MESH:D009369', (20, 30))
62008	32419250	8  Copy number variations have been detected in the anti-apoptotic members MCL1 and BCL2L1 across 26 human cancers, including gynaecologic cancers.	('BCL2L1', 'Gene', (84, 90))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('BCL2L1', 'Gene', '598', (84, 90))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('MCL1', 'Gene', (75, 79))	('MCL1', 'Gene', '4170', (75, 79))	('detected', 'Reg', (36, 44))	('cancers', 'Disease', (139, 146))	('anti-apoptotic', 'Gene', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Copy number variations', 'Var', (3, 25))	('human', 'Species', '9606', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
62009	32419250	9  Furthermore, overexpression of MCL1 is thought to promote chemotherapy resistance and prolong cell survival in breast cancer and ovarian cancer.	('ovarian cancer', 'Disease', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('MCL1', 'Gene', '4170', (34, 38))	('cell survival', 'CPA', (97, 110))	('MCL1', 'Gene', (34, 38))	('overexpression', 'Var', (16, 30))	('prolong', 'PosReg', (89, 96))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('chemotherapy resistance', 'CPA', (61, 84))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))	('breast cancer', 'Disease', (114, 127))	('promote', 'PosReg', (53, 60))
62010	32419250	10 ,  11  However, loss of the representative pro-apoptosis members BAX, BIM and BBC3 is also a common trend in oncogenesis, facilitating tumour formation and progression through genomic deletion, silencing and mutation in several cancers.	('facilitating', 'PosReg', (125, 137))	('BIM', 'Gene', (73, 76))	('BAX', 'Gene', (68, 71))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('BAX', 'Gene', '581', (68, 71))	('loss', 'NegReg', (19, 23))	('cancers', 'Disease', (231, 238))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('silencing', 'Var', (197, 206))	('progression', 'CPA', (159, 170))	('BBC3', 'Gene', (81, 85))	('BBC3', 'Gene', '27113', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('mutation', 'Var', (211, 219))	('tumour', 'Disease', (138, 144))	('BIM', 'Gene', '10018', (73, 76))
62012	32419250	Previous research on the BCL2 family has been mostly concerned with overexpression or copy number variation and seldom with long-distance regulation, and the distal regulation of the BCL2 family in gynaecologic cancers remains ambiguous.	('BCL2', 'Gene', '596', (183, 187))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', (211, 218))	('BCL2', 'Gene', (25, 29))	('BCL2', 'Gene', (183, 187))	('overexpression', 'MPA', (68, 82))	('copy number variation', 'Var', (86, 107))	('BCL2', 'Gene', '596', (25, 29))
62022	32419250	Finally, we identified genetic alterations in the BCL2 family network across gynaecologic cancers.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BCL2', 'Gene', '596', (50, 54))	('genetic alterations', 'Var', (23, 42))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('BCL2', 'Gene', (50, 54))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
62026	32419250	8  Overall survival and BCL2 family gene alterations in pan-cancers, including somatic mutations, amplification, deep deletion and DNA methylation, were measured through the cBioPortal database.	('BCL2', 'Gene', '596', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('BCL2', 'Gene', (24, 28))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('amplification', 'Var', (98, 111))	('deep deletion', 'Var', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
62031	32419250	26  To explore and affirm the chromatin state of BCL2 family gene loci in gynaecologic cancer, we compared differential chromatin-accessibility (ATAC-seq) data sets from the UCSC Xena browser with published histone modification ChIP-seq datasets from gynaecologic tumour samples, including EP300, TEAD4, H3K4me1 and H3K27ac (Table S1).	('tumour', 'Disease', (264, 270))	('cancer', 'Disease', (87, 93))	('EP300', 'Gene', (290, 295))	('BCL2', 'Gene', '596', (49, 53))	('EP300', 'Gene', '2033', (290, 295))	('H3K27ac', 'Var', (316, 323))	('TEAD4', 'Gene', '7004', (297, 302))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('BCL2', 'Gene', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('TEAD4', 'Gene', (297, 302))	('H3K4me1', 'Var', (304, 311))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('UCS', 'Phenotype', 'HP:0002891', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
62038	32419250	To provide a well-calibrated regulatory network, each member with a >=30% alteration frequency was retained according to an established workflow with modifications in the BCL2 family regulation network.	('BCL2', 'Gene', (171, 175))	('BCL2', 'Gene', '596', (171, 175))	('alteration', 'Var', (74, 84))
62041	32419250	The fifteen members of the BCL2 family that are expressed in gynaecologic cancers (BCL2, BCL2L1, BCL2L2, MCL1, BAX, BAK1, BAD, BOK, BCL2L11, BMF, BID, NOXA, HRK, BBC3 and BIK) present aberrant expression in many cancers and may be associated with chromosomal translocations, gene amplification, upregulated gene transcription, altered post-translational processing and tumour progression.	('BID', 'Gene', '637', (146, 149))	('BCL2', 'Gene', '596', (83, 87))	('BCL2L11', 'Gene', '10018', (132, 139))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('BAK1', 'Gene', (116, 120))	('BCL2L1', 'Gene', (89, 95))	('BIK', 'Gene', '638', (171, 174))	('cancers', 'Disease', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (369, 375))	('BCL2L2', 'Gene', (97, 103))	('BCL2', 'Gene', (132, 136))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('BIK', 'Gene', (171, 174))	('expression', 'MPA', (193, 203))	('tumour', 'Disease', 'MESH:D009369', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumour', 'Disease', (369, 375))	('MCL1', 'Gene', (105, 109))	('BBC3', 'Gene', '27113', (162, 166))	('BOK', 'Gene', '666', (127, 130))	('BCL2L1', 'Gene', '598', (132, 138))	('BCL2', 'Gene', (27, 31))	('BCL2', 'Gene', '596', (97, 101))	('BCL2L11', 'Gene', (132, 139))	('BCL2', 'Gene', (83, 87))	('gene transcription', 'MPA', (307, 325))	('BMF', 'Gene', (141, 144))	('BAX', 'Gene', '581', (111, 114))	('BAX', 'Gene', (111, 114))	('BCL2', 'Gene', '596', (89, 93))	('BBC3', 'Gene', (162, 166))	('MCL1', 'Gene', '4170', (105, 109))	('NOXA', 'Gene', '5366', (151, 155))	('gene amplification', 'Var', (275, 293))	('BMF', 'Gene', '90427', (141, 144))	('HRK', 'Gene', '8739', (157, 160))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('BCL2L2', 'Gene', '599', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('BCL2L1', 'Gene', '598', (89, 95))	('BCL2', 'Gene', (97, 101))	('cancers', 'Disease', (212, 219))	('NOXA', 'Gene', (151, 155))	('BCL2L1', 'Gene', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('BCL2', 'Gene', '596', (132, 136))	('BCL2', 'Gene', (89, 93))	('BID', 'Gene', (146, 149))	('upregulated', 'PosReg', (295, 306))	('HRK', 'Gene', (157, 160))	('BOK', 'Gene', (127, 130))	('BCL2', 'Gene', '596', (27, 31))	('BAK1', 'Gene', '578', (116, 120))
62043	32419250	The gene alteration frequencies of the BCL2 family, including mutations, deletions and amplifications, are shown (Figure 1A; Tables S3).	('BCL2', 'Gene', '596', (39, 43))	('deletions', 'Var', (73, 82))	('BCL2', 'Gene', (39, 43))
62044	32419250	The data show that gene alteration frequencies in the BCL2 family were more widely found in gynaecologic cancer than many other cancers.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gene alteration frequencies', 'Var', (19, 46))	('BCL2', 'Gene', '596', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('found', 'Reg', (83, 88))	('BCL2', 'Gene', (54, 58))	('cancer', 'Disease', (128, 134))
62045	32419250	In general, BCL2 family amplification was more frequent than deep deletion and missense mutations across pan-cancer.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('frequent', 'Reg', (47, 55))	('BCL2', 'Gene', '596', (12, 16))	('deep deletion', 'Var', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BCL2', 'Gene', (12, 16))
62062	32419250	The open peaks of the BCL2 family in gynaecologic cancer exhibited a wide genomic distribution that overlapped the promoters, intergenic regions and introns (Figures [Link], [Link], [Link], [Link], [Link], [Link], [Link], [Link], [Link]).	('[Link]', 'Var', (174, 180))	('cancer', 'Disease', (50, 56))	('BCL2', 'Gene', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('[Link]', 'Var', (182, 188))	('[Link]', 'Var', (206, 212))	('[Link]', 'Var', (214, 220))	('[Link]', 'Var', (198, 204))	('[Link]', 'Var', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('BCL2', 'Gene', '596', (22, 26))	('[Link]', 'Var', (222, 228))
62073	32419250	The results demonstrate that the dysregulation of BCL2 family expression in gynaecologic cancer is associated with promoter DNA methylation.	('dysregulation', 'Var', (33, 46))	('BCL2', 'Gene', '596', (50, 54))	('expression', 'MPA', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('promoter DNA methylation', 'Var', (115, 139))	('cancer', 'Disease', (89, 95))	('BCL2', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
62075	32419250	Kaplan-Meier analysis indicated that gene alteration in BOK was significantly associated with favourable prognosis in OV (P < .1), which is consistent with the results of the genetic alteration analysis (Figure 1).	('associated', 'Reg', (78, 88))	('BOK', 'Gene', (56, 59))	('OV', 'Phenotype', 'HP:0012887', (118, 120))	('BOK', 'Gene', '666', (56, 59))	('gene alteration', 'Var', (37, 52))
62077	32419250	Nevertheless, gene alterations in BAD and BIK were associated with poor survival in UCEC (BAD, P < .05; BIK, P < .01).	('BIK', 'Gene', (42, 45))	('BIK', 'Gene', (104, 107))	('UCEC', 'Disease', (84, 88))	('poor', 'NegReg', (67, 71))	('BAD', 'Gene', (34, 37))	('BIK', 'Gene', '638', (42, 45))	('gene alterations', 'Var', (14, 30))	('BIK', 'Gene', '638', (104, 107))
62082	32419250	The resulting networks from cBioportal analysis were highly structured across gynaecologic cancer types and were dominated by genetic alteration in BCL2 family members, including BCL2, BCL2L1, BAK1 and BAX.	('BCL2L1', 'Gene', '598', (185, 191))	('BCL2', 'Gene', '596', (185, 189))	('BCL2', 'Gene', '596', (148, 152))	('BCL2', 'Gene', (179, 183))	('genetic alteration', 'Var', (126, 144))	('cancer', 'Disease', (91, 97))	('BAX', 'Gene', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('BCL2', 'Gene', (185, 189))	('BAX', 'Gene', '581', (202, 205))	('BCL2', 'Gene', (148, 152))	('BCL2L1', 'Gene', (185, 191))	('BAK1', 'Gene', '578', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('BCL2', 'Gene', '596', (179, 183))	('BAK1', 'Gene', (193, 197))
62083	32419250	Furthermore, transformation-related protein 53 (TP53), transformation-related protein 63 (TP63), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and Myc-related translation/localization regulatory factor (MYC) were found to have frequent gene mutation or amplification/upregulation (Figure 6F-H).	('TP63', 'Gene', (90, 94))	('MYC', 'Gene', (237, 240))	('TP63', 'Gene', '8626', (90, 94))	('TP53', 'Gene', '7157', (48, 52))	('transformation-related protein 63', 'Gene', (55, 88))	('transformation-related protein 53', 'Gene', (13, 46))	('gene mutation', 'Var', (270, 283))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (97, 167))	('TP53', 'Gene', (48, 52))	('transformation-related protein 63', 'Gene', '8626', (55, 88))	('amplification/upregulation', 'MPA', (287, 313))	('MYC', 'Gene', '4609', (237, 240))	('transformation-related protein 53', 'Gene', '7157', (13, 46))	('Myc-related translation/localization regulatory factor', 'Gene', '4609', (181, 235))	('PIK3CA', 'Gene', (169, 175))	('PIK3CA', 'Gene', '5290', (169, 175))
62084	32419250	Importantly, we observed that both TP53 and PIK3CA had high-frequency mutations (Figure 6F-G), and simultaneously were significantly associated with genes for activators (BID), effectors (BAX and BAK1) and guardians (MCL1, BCL2 and BCL2L1) in BRCA, UCEC, UCS and OV.	('BCL2L1', 'Gene', (232, 238))	('associated', 'Interaction', (133, 143))	('TP53', 'Gene', '7157', (35, 39))	('BRCA', 'Gene', '672', (243, 247))	('PIK3CA', 'Gene', (44, 50))	('MCL1', 'Gene', (217, 221))	('BCL2', 'Gene', '596', (232, 236))	('BRCA', 'Gene', (243, 247))	('BCL2', 'Gene', '596', (223, 227))	('mutations', 'Var', (70, 79))	('BAX', 'Gene', (188, 191))	('UCEC', 'Disease', (249, 253))	('BAX', 'Gene', '581', (188, 191))	('TP53', 'Gene', (35, 39))	('BCL2L1', 'Gene', '598', (232, 238))	('MCL1', 'Gene', '4170', (217, 221))	('UCS', 'Phenotype', 'HP:0002891', (255, 258))	('BID', 'Gene', (171, 174))	('BCL2', 'Gene', (232, 236))	('BAK1', 'Gene', '578', (196, 200))	('BCL2', 'Gene', (223, 227))	('PIK3CA', 'Gene', '5290', (44, 50))	('BAK1', 'Gene', (196, 200))	('BRCA', 'Phenotype', 'HP:0003002', (243, 247))	('BID', 'Gene', '637', (171, 174))	('OV', 'Phenotype', 'HP:0012887', (263, 265))
62086	32419250	Fas-associated via death domain (FADD) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) were also highly specific connected in the BRCA network, while both phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) mutation in CESC, and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) mutation in UCEC controlled the expression of BCL2L1.	('mutation', 'Var', (274, 282))	('expression', 'MPA', (384, 394))	('BRCA', 'Phenotype', 'HP:0003002', (170, 174))	('tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta', 'Gene', '7534', (43, 118))	('BCL2L1', 'Gene', (398, 404))	('YWHAZ', 'Gene', '7534', (120, 125))	('controlled', 'Reg', (369, 379))	('death', 'Disease', 'MESH:D003643', (19, 24))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta', 'Gene', '5291', (195, 264))	('BRCA', 'Gene', '672', (170, 174))	('phosphoinositide-3-kinase regulatory subunit 1', 'Gene', '5295', (296, 342))	('PIK3R1', 'Gene', (344, 350))	('PIK3CB', 'Gene', (266, 272))	('PIK3CB', 'Gene', '5291', (266, 272))	('mutation', 'Var', (352, 360))	('BRCA', 'Gene', (170, 174))	('BCL2L1', 'Gene', '598', (398, 404))	('death', 'Disease', (19, 24))	('phosphoinositide-3-kinase regulatory subunit 1', 'Gene', (296, 342))	('PIK3R1', 'Gene', '5295', (344, 350))	('YWHAZ', 'Gene', (120, 125))
62089	32419250	Therefore, the BCL2 family protein network shows common features of co-mutations in TP53 and PIK3CA but varies in other genes for different types of gynaecologic cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('PIK3CA', 'Gene', '5290', (93, 99))	('cancer', 'Disease', (162, 168))	('co-mutations', 'Var', (68, 80))	('TP53', 'Gene', (84, 88))	('BCL2', 'Gene', '596', (15, 19))	('TP53', 'Gene', '7157', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PIK3CA', 'Gene', (93, 99))	('BCL2', 'Gene', (15, 19))
62099	32419250	Our observation that anti-apoptotic members are not widely expressed in gynaecologic cancers agrees with previous studies, and low expression level and deep deletion was also observed in some patient samples for anti-apoptotic members.	('patient', 'Species', '9606', (192, 199))	('deep deletion', 'Var', (152, 165))	('expression level', 'MPA', (131, 147))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
62102	32419250	41  These phenomena may be due to the enforced expression or activation of miRNAs that normally suppress BCL2 family expression, such as miR-15a or miR-16.1 targeting of BCL2; miR-29, miR-125 and miR-193 targeting of MCL1; or let-7 targeting of BCL2L2.	('BCL2', 'Gene', '596', (170, 174))	('BCL2', 'Gene', '596', (105, 109))	('suppress', 'NegReg', (96, 104))	('miR-16.1', 'Gene', '406950', (148, 156))	('MCL1', 'Gene', (217, 221))	('BCL2', 'Gene', (170, 174))	('miR-15a', 'Gene', (137, 144))	('BCL2L2', 'Gene', (245, 251))	('BCL2', 'Gene', (105, 109))	('miR-16.1', 'Gene', (148, 156))	('miR-193', 'Var', (196, 203))	('expression', 'MPA', (117, 127))	('MCL1', 'Gene', '4170', (217, 221))	('BCL2', 'Gene', '596', (245, 249))	('activation', 'PosReg', (61, 71))	('let-7', 'Gene', (226, 231))	('BCL2L2', 'Gene', '599', (245, 251))	('miR-29', 'Var', (176, 182))	('miR-15a', 'Gene', '406948', (137, 144))	('BCL2', 'Gene', (245, 249))	('miR-125', 'Var', (184, 191))
62108	32419250	15 ,  21 ,  38  BAD phosphorylation has recently been reported to promote tumour cell survival, and post-translational modification might therefore contribute to impaired pro-apoptotic proteins.	('impaired', 'NegReg', (162, 170))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('promote', 'PosReg', (66, 73))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('phosphorylation', 'Var', (20, 35))	('pro-apoptotic', 'MPA', (171, 184))
62112	32419250	6 ,  8  For example, in humans, multiple tumours mutations and deletions occur at higher frequency in BAX and BAK1, 14 ,  51 ,  52 ,  53  but mRNA upregulation serves as the main mechanism of BAX and BAK1 activation in gynaecologic cancer.	('BAX', 'Gene', '581', (192, 195))	('cancer', 'Disease', (232, 238))	('BAX', 'Gene', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumours', 'Disease', (41, 48))	('mutations', 'Var', (49, 58))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('BAK1', 'Gene', '578', (200, 204))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('mRNA', 'MPA', (142, 146))	('BAK1', 'Gene', (200, 204))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('BAX', 'Gene', (102, 105))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('BAX', 'Gene', '581', (102, 105))	('BAK1', 'Gene', '578', (110, 114))	('deletions', 'Var', (63, 72))	('upregulation', 'PosReg', (147, 159))	('BAK1', 'Gene', (110, 114))	('activation', 'PosReg', (205, 215))	('humans', 'Species', '9606', (24, 30))
62113	32419250	The alteration of pro-apoptotic genes indicates that dysregulated mechanisms may be influenced by epigenetic or distal enhancer-promoter contacts to control gene expression in gynaecologic cancer.	('influenced', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('epigenetic', 'Var', (98, 108))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
62116	32419250	In general, almost all methylation of BCL2 family genes obviously influenced gene expression.	('gene expression', 'MPA', (77, 92))	('methylation', 'Var', (23, 34))	('BCL2', 'Gene', (38, 42))	('influenced', 'Reg', (66, 76))	('BCL2', 'Gene', '596', (38, 42))
62117	32419250	The data suggest that BCL2L2, BCL2L11 and BBC3 might be affected by DNA methylation and gene amplification.	('BBC3', 'Gene', (42, 46))	('BBC3', 'Gene', '27113', (42, 46))	('BCL2L11', 'Gene', '10018', (30, 37))	('BCL2L2', 'Gene', '599', (22, 28))	('gene amplification', 'Var', (88, 106))	('BCL2L11', 'Gene', (30, 37))	('affected', 'Reg', (56, 64))	('BCL2L2', 'Gene', (22, 28))
62123	32419250	Therefore, we hypothesize that the co-mutation signature of TP53 and PIK3CA acts to stimulate the formation of chromatin loops of BCL2L1 gene loci to strengthen its transcriptional activity.	('formation', 'MPA', (98, 107))	('stimulate', 'PosReg', (84, 93))	('transcriptional activity', 'MPA', (165, 189))	('chromatin loops', 'MPA', (111, 126))	('strengthen', 'PosReg', (150, 160))	('BCL2L1', 'Gene', (130, 136))	('co-mutation', 'Var', (35, 46))	('BCL2L1', 'Gene', '598', (130, 136))	('TP53', 'Gene', '7157', (60, 64))	('PIK3CA', 'Gene', (69, 75))	('PIK3CA', 'Gene', '5290', (69, 75))	('TP53', 'Gene', (60, 64))
62126	32419250	The resulting network models showed specific differences in YWHAZ amplification in BRCA, PIK3CB amplification in CESC, PIK3R1 mutation in UCEC, and downregulation of XRCC6, NMT1 and CASP3 in OV, which suggests that the BCL2 family protein network can be used to identify different types of gynaecologic cancer.	('BRCA', 'Phenotype', 'HP:0003002', (83, 87))	('BCL2', 'Gene', '596', (219, 223))	('CESC', 'Disease', (113, 117))	('OV', 'Phenotype', 'HP:0012887', (191, 193))	('XRCC6', 'Gene', (166, 171))	('PIK3R1', 'Gene', '5295', (119, 125))	('BRCA', 'Gene', '672', (83, 87))	('cancer', 'Disease', (303, 309))	('BCL2', 'Gene', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('UCEC', 'Disease', (138, 142))	('downregulation', 'NegReg', (148, 162))	('NMT1', 'Gene', '4836', (173, 177))	('BRCA', 'Gene', (83, 87))	('CASP3', 'Gene', (182, 187))	('NMT1', 'Gene', (173, 177))	('YWHAZ', 'Gene', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('amplification', 'Var', (96, 109))	('CASP3', 'Gene', '836', (182, 187))	('PIK3R1', 'Gene', (119, 125))	('PIK3CB', 'Gene', (89, 95))	('PIK3CB', 'Gene', '5291', (89, 95))	('mutation', 'Var', (126, 134))	('XRCC6', 'Gene', '2547', (166, 171))	('YWHAZ', 'Gene', '7534', (60, 65))
62128	32419250	61  Mutation of PIK3CB, as the catalytic subunit in the PI3K signalling pathway, drives tumour cell growth and migration.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('drives', 'PosReg', (81, 87))	('PIK3CB', 'Gene', '5291', (16, 22))	('tumour', 'Disease', (88, 94))	('Mutation', 'Var', (4, 12))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('PIK3CB', 'Gene', (16, 22))
62130	32419250	63  Furthermore, co-mutation of PIK3R1 and PIK3CA is associated with oncogenesis and hyperactivity of the PI3K signal pathway in breast cancer, supporting an oncogenic role of the co-mutation pair.	('breast cancer', 'Disease', (129, 142))	('co-mutation', 'Var', (17, 28))	('PIK3CA', 'Gene', '5290', (43, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('PI3K signal pathway', 'Pathway', (106, 125))	('hyperactivity', 'Disease', 'MESH:D006948', (85, 98))	('hyperactivity', 'Disease', (85, 98))	('oncogenesis', 'CPA', (69, 80))	('associated', 'Reg', (53, 63))	('hyperactivity', 'Phenotype', 'HP:0000752', (85, 98))	('PIK3R1', 'Gene', '5295', (32, 38))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('PIK3R1', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('PIK3CA', 'Gene', (43, 49))
62145	32300630	Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma.	('BRCA2', 'Gene', '675', (147, 152))	('BRCA2', 'Gene', '675', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('variant', 'Var', (136, 143))	('variant', 'Var', (68, 75))	('serous carcinoma', 'Disease', 'MESH:D018297', (18, 34))	('olaparib', 'Chemical', 'MESH:C531550', (90, 98))	('serous carcinoma', 'Disease', 'MESH:D018297', (213, 229))	('serous carcinoma', 'Disease', (213, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('BRCA2', 'Gene', (147, 152))	('BRCA2', 'Gene', (62, 67))	('serous carcinoma', 'Disease', (18, 34))
62146	32300630	Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation.	('BRCA2', 'Gene', (97, 102))	('olaparib', 'Chemical', 'MESH:C531550', (21, 29))	('BRCA2', 'Gene', '675', (97, 102))	('serous carcinoma', 'Disease', 'MESH:D018297', (64, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('serous carcinoma', 'Disease', (64, 80))	('mutation', 'Var', (103, 111))
62147	32300630	Olaparib is a possible treatment option for uterine serous carcinomas with BRCA2 mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('BRCA2', 'Gene', (75, 80))	('serous carcinomas', 'Disease', (52, 69))	('mutations', 'Var', (81, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('BRCA2', 'Gene', '675', (75, 80))	('serous carcinomas', 'Disease', 'MESH:D018297', (52, 69))
62148	32300630	A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma.	('BRCA2', 'Gene', (33, 38))	('variant', 'Var', (22, 29))	('serous carcinoma', 'Disease', 'MESH:D018297', (99, 115))	('serous carcinoma', 'Disease', (99, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('BRCA2', 'Gene', '675', (33, 38))	('pathogenic', 'Reg', (11, 21))
62149	32300630	Here, we report, for the first time, a long-term clinical response to olaparib in a patient with uterine serous carcinoma and a germline pathogenic BRCA2 variant.	('BRCA2', 'Gene', (148, 153))	('serous carcinoma', 'Disease', 'MESH:D018297', (105, 121))	('serous carcinoma', 'Disease', (105, 121))	('BRCA2', 'Gene', '675', (148, 153))	('variant', 'Var', (154, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('olaparib', 'Chemical', 'MESH:C531550', (70, 78))	('patient', 'Species', '9606', (84, 91))
62163	32300630	The results revealed a BRCA2 loss-of-function mutation (p.l1859fs, c.5576_5579delTTAA).	('p.l1859fs', 'Mutation', 'p.l1859fs', (56, 65))	('p.l1859fs', 'Var', (56, 65))	('c.5576_5579delTTAA', 'Mutation', 'c.5576_5579delTTAA', (67, 85))	('BRCA2', 'Gene', (23, 28))	('BRCA2', 'Gene', '675', (23, 28))	('c.5576_5579delTTAA', 'Var', (67, 85))	('loss-of-function', 'NegReg', (29, 45))
62169	32300630	Due to limited therapeutic options and the somatic and germline BRCA2 mutations, olaparib was considered as a candidate for treatment.	('BRCA2', 'Gene', '675', (64, 69))	('olaparib', 'Chemical', 'MESH:C531550', (81, 89))	('mutations', 'Var', (70, 79))	('BRCA2', 'Gene', (64, 69))
62184	32300630	First, a BRCA2 pathogenic variant was secondarily identified via genomic sequencing of uterine serous carcinoma.	('BRCA2', 'Gene', (9, 14))	('serous carcinoma', 'Disease', 'MESH:D018297', (95, 111))	('pathogenic', 'Reg', (15, 25))	('serous carcinoma', 'Disease', (95, 111))	('variant', 'Var', (26, 33))	('BRCA2', 'Gene', '675', (9, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))
62187	32300630	The results of the somatic tumor panel led to a secondary finding of a germline BRCA2 mutation.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('BRCA2', 'Gene', (80, 85))	('tumor', 'Disease', (27, 32))	('BRCA2', 'Gene', '675', (80, 85))	('mutation', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
62189	32300630	It remains unclear whether mutations in BRCA1 and BRCA2 are associated with increased risks for endometrial cancer, and especially uterine serous carcinoma.	('mutations', 'Var', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('endometrial cancer', 'Disease', (96, 114))	('serous carcinoma', 'Disease', 'MESH:D018297', (139, 155))	('serous carcinoma', 'Disease', (139, 155))	('BRCA2', 'Gene', (50, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (96, 114))	('endometrial cancer', 'Phenotype', 'HP:0012114', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('BRCA1', 'Gene', '672', (40, 45))	('BRCA2', 'Gene', '675', (50, 55))	('associated', 'Reg', (60, 70))	('BRCA1', 'Gene', (40, 45))
62190	32300630	A case-controlled study found no differences in risks of endometrial cancer between individuals with and without BRCA1/2 mutations.	('mutations', 'Var', (121, 130))	('BRCA1', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('endometrial cancer', 'Disease', (57, 75))	('endometrial cancer', 'Disease', 'MESH:D016889', (57, 75))	('endometrial cancer', 'Phenotype', 'HP:0012114', (57, 75))	('BRCA1', 'Gene', '672', (113, 118))
62191	32300630	In contrast, studies show that patients with BRCA1 mutations undergoing risk-reducing salpingo-oophorectomy have increased risks of uterine serous carcinoma.	('mutations', 'Var', (51, 60))	('BRCA1', 'Gene', '672', (45, 50))	('BRCA1', 'Gene', (45, 50))	('patients', 'Species', '9606', (31, 39))	('serous carcinoma', 'Disease', 'MESH:D018297', (140, 156))	('serous carcinoma', 'Disease', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
62192	32300630	Conversely, the frequency of BRCA1/2 mutations has been reported to be higher among patients with uterine serous carcinoma than among those with all histologic types of endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('patients', 'Species', '9606', (84, 92))	('higher', 'Reg', (71, 77))	('endometrial cancer', 'Disease', (169, 187))	('BRCA1', 'Gene', '672', (29, 34))	('endometrial cancer', 'Phenotype', 'HP:0012114', (169, 187))	('mutations', 'Var', (37, 46))	('serous carcinoma', 'Disease', 'MESH:D018297', (106, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('serous carcinoma', 'Disease', (106, 122))	('endometrial cancer', 'Disease', 'MESH:D016889', (169, 187))	('BRCA1', 'Gene', (29, 34))
62193	32300630	A different study reported that among unselected 381 endometrial cancer patients who underwent cancer panel testing, 26 had serous carcinoma, and among them BRCA2 mutations were found in one patient with uterine serous carcinoma.	('patient', 'Species', '9606', (72, 79))	('found', 'Reg', (178, 183))	('endometrial cancer', 'Phenotype', 'HP:0012114', (53, 71))	('patient', 'Species', '9606', (191, 198))	('cancer', 'Disease', (65, 71))	('endometrial cancer', 'Disease', (53, 71))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA2', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('endometrial cancer', 'Disease', 'MESH:D016889', (53, 71))	('serous carcinoma', 'Disease', 'MESH:D018297', (212, 228))	('serous carcinoma', 'Disease', (212, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('BRCA2', 'Gene', '675', (157, 162))	('serous carcinoma', 'Disease', 'MESH:D018297', (124, 140))	('serous carcinoma', 'Disease', (124, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('mutations', 'Var', (163, 172))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (72, 80))
62194	32300630	A BRCA1 mutation was found in one of 289 patients with endometrioid carcinoma.	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (55, 77))	('patients', 'Species', '9606', (41, 49))	('BRCA1', 'Gene', '672', (2, 7))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (55, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('mutation', 'Var', (8, 16))	('found', 'Reg', (21, 26))	('BRCA1', 'Gene', (2, 7))	('endometrioid carcinoma', 'Disease', (55, 77))
62195	32300630	A meta-analysis demonstrated three out of 207 Caucasian women with uterine serous carcinoma had germline BRCA1/2 mutations.	('BRCA1', 'Gene', (105, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('mutations', 'Var', (113, 122))	('serous carcinoma', 'Disease', 'MESH:D018297', (75, 91))	('serous carcinoma', 'Disease', (75, 91))	('BRCA1', 'Gene', '672', (105, 110))	('women', 'Species', '9606', (56, 61))
62196	32300630	Accordingly, it is estimated that 1-3% of uterine serous carcinomas are associated with BRCA1/2 mutations.	('BRCA1', 'Gene', (88, 93))	('serous carcinomas', 'Disease', 'MESH:D018297', (50, 67))	('associated', 'Reg', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('BRCA1', 'Gene', '672', (88, 93))	('serous carcinomas', 'Disease', (50, 67))	('mutations', 'Var', (96, 105))
62197	32300630	Olaparib, the first poly (ADP-Ribose) polymerase (PARP) inhibitor, was approved by the Food and Drug Administration for the treatment of recurrent platinum-sensitive ovarian cancer with germline or somatic pathogenic BRCA1/2 mutations and also for patients with germline BRCA-positive, HER2-negatvie metastatic breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (311, 324))	('breast cancer', 'Disease', (311, 324))	('platinum-sensitive ovarian cancer', 'Disease', 'MESH:D003807', (147, 180))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('BRCA1', 'Gene', '672', (217, 222))	('platinum-sensitive ovarian cancer', 'Disease', (147, 180))	('HER2', 'Gene', '2064', (286, 290))	('PARP', 'Gene', '142', (50, 54))	('BRCA1', 'Gene', (217, 222))	('poly (ADP-Ribose) polymerase', 'Gene', '142', (20, 48))	('PARP', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('BRCA', 'Gene', '672', (271, 275))	('BRCA', 'Gene', '672', (217, 221))	('poly (ADP-Ribose) polymerase', 'Gene', (20, 48))	('patients', 'Species', '9606', (248, 256))	('HER2', 'Gene', (286, 290))	('breast cancer', 'Phenotype', 'HP:0003002', (311, 324))	('mutations', 'Var', (225, 234))	('BRCA', 'Gene', (271, 275))	('BRCA', 'Gene', (217, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))
62198	32300630	The efficacy of olaparib for the treatment of patients with metastatic pancreatic cancer with BRCA1/2 mutations was demonstrated in a randomized-controlled trial.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('patients', 'Species', '9606', (46, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('BRCA1', 'Gene', '672', (94, 99))	('mutations', 'Var', (102, 111))	('BRCA1', 'Gene', (94, 99))	('pancreatic cancer', 'Disease', (71, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))	('olaparib', 'Chemical', 'MESH:C531550', (16, 24))
62200	32300630	The efficacy of olaparib in endometrial cancer patients with germline BRCA1/2 mutations remains unknown.	('endometrial cancer', 'Disease', (28, 46))	('endometrial cancer', 'Phenotype', 'HP:0012114', (28, 46))	('BRCA1', 'Gene', '672', (70, 75))	('patients', 'Species', '9606', (47, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (28, 46))	('mutations', 'Var', (78, 87))	('BRCA1', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('olaparib', 'Chemical', 'MESH:C531550', (16, 24))
62201	32300630	To our knowledge, there has only been one case report showing a durable response (more than 15 months) to olaparib treatment in a patient with recurrent grade 1 endometrioid carcinoma with a germline BRCA2 mutation and a different somatic BRCA2 mutation.	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (161, 183))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (161, 183))	('patient', 'Species', '9606', (130, 137))	('BRCA2', 'Gene', (239, 244))	('BRCA2', 'Gene', (200, 205))	('olaparib', 'Chemical', 'MESH:C531550', (106, 114))	('endometrioid carcinoma', 'Disease', (161, 183))	('BRCA2', 'Gene', '675', (200, 205))	('BRCA2', 'Gene', '675', (239, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('germline', 'Var', (191, 199))	('mutation', 'Var', (245, 253))
62202	32300630	This case report was the first to show a 11-month clinical response to olaparib in a patient with uterine serous carcinoma with a germline pathogenic BRCA2 variant.	('patient', 'Species', '9606', (85, 92))	('olaparib', 'Chemical', 'MESH:C531550', (71, 79))	('variant', 'Var', (156, 163))	('BRCA2', 'Gene', (150, 155))	('serous carcinoma', 'Disease', 'MESH:D018297', (106, 122))	('serous carcinoma', 'Disease', (106, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('BRCA2', 'Gene', '675', (150, 155))
62204	32300630	Previous work has suggested that HRD and sensitivity to PARP inhibitors were tied to BRCA-associated cancer types in patients with BRCA1/2 mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('BRCA', 'Gene', (85, 89))	('PARP', 'Gene', '142', (56, 60))	('tied', 'Reg', (77, 81))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', (101, 107))	('HRD', 'Disease', (33, 36))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA', 'Gene', '672', (131, 135))	('BRCA', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PARP', 'Gene', (56, 60))	('BRCA1', 'Gene', (131, 136))	('patients', 'Species', '9606', (117, 125))	('BRCA', 'Gene', '672', (85, 89))	('HRD', 'Disease', 'None', (33, 36))
62205	32300630	showed HRD occurs in high-grade, non-endometrioid endometrial cancers (serous carcinoma and carcinosarcoma) and is related with pathogenic BRCA1 variants or high somatic copy-number losses of HR genes.	('endometrial cancers', 'Disease', 'MESH:D016889', (50, 69))	('HRD', 'Disease', 'None', (7, 10))	('endometrial cancers', 'Disease', (50, 69))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('BRCA1', 'Gene', '672', (139, 144))	('variants', 'Var', (145, 153))	('HR genes', 'Gene', (192, 200))	('serous carcinoma and carcinosarcoma', 'Disease', 'MESH:D002296', (71, 106))	('endometrial cancer', 'Phenotype', 'HP:0012114', (50, 68))	('high-grade', 'Disease', (21, 31))	('HRD', 'Disease', (7, 10))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('BRCA1', 'Gene', (139, 144))	('related', 'Reg', (115, 122))
62206	32300630	In their study, 24% (n = 6) of endometrial cancers were HR deficient, with either serous carcinoma or carcinosarcoma with a serous component, and two of them had pathogenic BRCA1 variants.	('pathogenic', 'Reg', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('variants', 'Var', (179, 187))	('serous carcinoma or carcinosarcoma', 'Disease', 'MESH:D002296', (82, 116))	('HR deficient', 'Disease', 'MESH:D001919', (56, 68))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('BRCA1', 'Gene', '672', (173, 178))	('endometrial cancers', 'Disease', 'MESH:D016889', (31, 50))	('endometrial cancer', 'Phenotype', 'HP:0012114', (31, 49))	('HR deficient', 'Disease', (56, 68))	('endometrial cancers', 'Disease', (31, 50))	('serous carcinoma or carcinosarcoma', 'Disease', (82, 116))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA1', 'Gene', (173, 178))
62207	32300630	also reported that, among 40 endometrial cancer patients with germline BRCA1/2 mutations, there were six with uterine serous carcinoma (3 BRCA1 and 3 BRCA2 mutations), five of whom were positive for loss of heterozygosity of the BRCA1/2 wild-type allele (3 BRCA1 and 2 BRCA2 mutations).	('BRCA1', 'Gene', '672', (138, 143))	('BRCA1', 'Gene', (138, 143))	('endometrial cancer', 'Phenotype', 'HP:0012114', (29, 47))	('mutations', 'Var', (79, 88))	('BRCA1', 'Gene', '672', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('endometrial cancer', 'Disease', (29, 47))	('BRCA1', 'Gene', (257, 262))	('BRCA2', 'Gene', (150, 155))	('endometrial cancer', 'Disease', 'MESH:D016889', (29, 47))	('serous carcinoma', 'Disease', 'MESH:D018297', (118, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('serous carcinoma', 'Disease', (118, 134))	('BRCA2', 'Gene', (269, 274))	('BRCA1', 'Gene', '672', (229, 234))	('BRCA1', 'Gene', '672', (71, 76))	('BRCA1', 'Gene', (229, 234))	('BRCA2', 'Gene', '675', (150, 155))	('BRCA1', 'Gene', (71, 76))	('BRCA2', 'Gene', '675', (269, 274))	('patients', 'Species', '9606', (48, 56))
62209	32300630	Although the frequency of germline BRCA1/2 mutations in patients with uterine serous carcinoma may not be high, olaparib could be an efficient treatment strategy for uterine serous carcinoma in cases involving HRD or germline BRCA1/2 mutations.	('patients', 'Species', '9606', (56, 64))	('olaparib', 'Chemical', 'MESH:C531550', (112, 120))	('BRCA1', 'Gene', (226, 231))	('HRD', 'Disease', 'None', (210, 213))	('BRCA1', 'Gene', '672', (35, 40))	('serous carcinoma', 'Disease', 'MESH:D018297', (78, 94))	('serous carcinoma', 'Disease', (78, 94))	('serous carcinoma', 'Disease', 'MESH:D018297', (174, 190))	('mutations', 'Var', (43, 52))	('serous carcinoma', 'Disease', (174, 190))	('BRCA1', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HRD', 'Disease', (210, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('BRCA1', 'Gene', '672', (226, 231))
62210	32300630	Finally, screening for germline BRCA1/2 mutations may be worthwhile.	('BRCA1', 'Gene', (32, 37))	('mutations', 'Var', (40, 49))	('BRCA1', 'Gene', '672', (32, 37))
62213	32300630	Germline or tumor DNA testing for pathogenic BRCA1/2 mutations in patients with uterine serous carcinoma might be beneficial, and olaparib could be a potential treatment option in patients with a germline pathogenic BRCA2 variant.	('olaparib', 'Chemical', 'MESH:C531550', (130, 138))	('BRCA1', 'Gene', '672', (45, 50))	('serous carcinoma', 'Disease', 'MESH:D018297', (88, 104))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('serous carcinoma', 'Disease', (88, 104))	('patients', 'Species', '9606', (180, 188))	('mutations', 'Var', (53, 62))	('BRCA1', 'Gene', (45, 50))	('BRCA2', 'Gene', (216, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('variant', 'Var', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('BRCA2', 'Gene', '675', (216, 221))	('patients', 'Species', '9606', (66, 74))
62214	32300630	Olaparib could be a promising candidate for the treatment of uterine serous carcinoma associated with germline BRCA2 mutations.	('serous carcinoma', 'Disease', (69, 85))	('mutations', 'Var', (117, 126))	('BRCA2', 'Gene', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('associated', 'Reg', (86, 96))	('BRCA2', 'Gene', '675', (111, 116))	('serous carcinoma', 'Disease', 'MESH:D018297', (69, 85))
62237	31599471	Within those 20 miRNAs, 7 (miR-4430, miR-6511b-5p, miR-451a, miR-4485-5p, miR-4635, miR-1246 and miR-191-5p) were selected as candidate miRNAs that had a cross-validation score greater than 0.75 and an absolute value of fold change (log2) >0.5.	('miR-4485', 'Gene', (61, 69))	('miR-4635', 'Gene', (74, 82))	('miR-1246', 'Gene', '100302142', (84, 92))	('miR-1246', 'Gene', (84, 92))	('miR-4430', 'Gene', (27, 35))	('miR-4635', 'Gene', '100616479', (74, 82))	('miR-191-5p', 'Gene', (97, 107))	('miR-451a', 'Gene', '574411', (51, 59))	('miR-451a', 'Gene', (51, 59))	('miR-6511b-5p', 'Var', (37, 49))	('miR-191-5p', 'Gene', '100302129', (97, 107))	('miR-4430', 'Gene', '100616136', (27, 35))	('miR-4485', 'Gene', '100616263', (61, 69))
62241	31599471	Based on the multiplied value of the AUC and a cross-validation score, the best combination was determined, which consisted of two miRNAs (miR-191-5p and miR-1246), and the diagnostic index (DI) of the model was defined as (DI = (-0.479) x miR-191-5p + (-0.380) x miR-1246 + 6.386).	('miR-191-5p', 'Gene', (240, 250))	('miR-1246', 'Gene', '100302142', (154, 162))	('miR-191-5p', 'Gene', '100302129', (240, 250))	('DI = (-0.479', 'Var', (224, 236))	('miR-191-5p', 'Gene', '100302129', (139, 149))	('miR-191-5p', 'Gene', (139, 149))	('miR-1246', 'Gene', '100302142', (264, 272))	('miR-1246', 'Gene', (154, 162))	('miR-1246', 'Gene', (264, 272))
62275	30740961	In particular, RT and CCRT appeared to increase the incidence of lymphedema.	('lymphedema', 'Disease', 'MESH:D008209', (65, 75))	('CCRT', 'Var', (22, 26))	('lymphedema', 'Phenotype', 'HP:0001004', (65, 75))	('lymphedema', 'Disease', (65, 75))
62279	30740961	However, the phase III Laparoscopic Approach to Cervical Cancer trial revealed that women undergoing MIS RH for early cervical cancer had higher rates of disease recurrence and worse survival than those who received abdominal RH.	('cervical cancer', 'Disease', (118, 133))	('women', 'Species', '9606', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('disease recurrence', 'CPA', (154, 172))	('cervical cancer', 'Disease', 'MESH:D002583', (118, 133))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Cervical Cancer', 'Disease', (48, 63))	('MIS RH', 'Var', (101, 107))	('higher', 'PosReg', (138, 144))	('Cervical Cancer', 'Disease', 'MESH:D002583', (48, 63))
62281	30740961	In particular, both tumor cut-through and spillage under CO2 pneumoperitoneum during laparoscopic intracorporeal colpotomy may contribute to tumor recurrence in a port site or unusual intraperitoneal sites.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cut-through', 'Var', (26, 37))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('CO2', 'Chemical', '-', (57, 60))	('contribute to', 'Reg', (127, 140))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
62298	30740961	Epidemiological study showed that antidyslipidemic statin agents is associated with reduced cancer-related mortality.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('antidyslipidemic', 'Var', (34, 50))	('reduced', 'NegReg', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
62308	30740961	Previous studies showed that germ-line BRCA mutations were found in 14.1% in non-mucinous ovarian cancer patients and more often in high grade serous carcinoma with approximately 22%-25%.	('BRCA', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mucinous ovarian cancer', 'Phenotype', 'HP:0031494', (81, 104))	('patients', 'Species', '9606', (105, 113))	('non-mucinous ovarian cancer', 'Disease', (77, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('non-mucinous ovarian cancer', 'Disease', 'MESH:D010051', (77, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('serous carcinoma', 'Disease', (143, 159))	('mutations', 'Var', (44, 53))	('found', 'Reg', (59, 64))	('BRCA', 'Gene', '672', (39, 43))	('serous carcinoma', 'Disease', 'MESH:D018284', (143, 159))
62309	30740961	It is well-known that BRCA mutation status influences the survival of patients with ovarian cancer and contribute to decision making and chemotherapy selection in the recurrence settings.	('patients', 'Species', '9606', (70, 78))	('ovarian cancer', 'Disease', (84, 98))	('survival', 'CPA', (58, 66))	('mutation', 'Var', (27, 35))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA', 'Gene', '672', (22, 26))	('contribute', 'Reg', (103, 113))	('influences', 'Reg', (43, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('BRCA', 'Gene', (22, 26))
62310	30740961	However, there are no data of BRCA1/2 mutations among Chinese ovarian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('BRCA1/2', 'Gene', (30, 37))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('patients', 'Species', '9606', (77, 85))	('ovarian cancer', 'Disease', (62, 76))	('mutations', 'Var', (38, 47))	('BRCA1/2', 'Gene', '672;675', (30, 37))
62311	30740961	Tingyan Shi reported that BRCA1/2 mutations were common in Chinese epithelial ovarian cancer patients (16.7%) with distinct mutational spectrum compared to Western populations, but she did not find any significant difference between germ-line BRCA1/2 mutation carriers and non-carriers in both PFS and OS (Supplementary Fig.	('BRCA1/2', 'Gene', '672;675', (243, 250))	('epithelial ovarian cancer', 'Disease', (67, 92))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (67, 92))	('mutation', 'Var', (251, 259))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BRCA1/2', 'Gene', (26, 33))	('BRCA1/2', 'Gene', (243, 250))	('BRCA1/2', 'Gene', '672;675', (26, 33))	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (34, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
62352	30740961	Thus, PARP inhibitors have now been approved for use in patients with recurrent BRCA1/2 mutant and platinum sensitive ovarian, peritoneal, and fallopian tube carcinomas.	('patients', 'Species', '9606', (56, 64))	('fallopian tube carcinomas', 'Disease', 'MESH:D005185', (143, 168))	('platinum sensitive ovarian', 'Disease', (99, 125))	('peritoneal', 'Disease', (127, 137))	('BRCA1/2', 'Gene', (80, 87))	('PARP', 'Gene', (6, 10))	('mutant', 'Var', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('BRCA1/2', 'Gene', '672;675', (80, 87))	('fallopian tube carcinomas', 'Disease', (143, 168))	('platinum', 'Chemical', 'MESH:D010984', (99, 107))	('PARP', 'Gene', '142', (6, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('fallopian tube carcinomas', 'Phenotype', 'HP:0030394', (143, 168))
62357	30740961	have shown that cancer immune microenvironment play an important role in clinical outcome and expression of PD-L1 in ovarian cancer is associated with poor prognosis of the patients.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('patients', 'Species', '9606', (173, 181))	('PD-L1 in ovarian cancer', 'Disease', 'MESH:D010300', (108, 131))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('associated', 'Reg', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('PD-L1 in ovarian cancer', 'Disease', (108, 131))	('expression', 'Var', (94, 104))
62371	30740961	In particular, the C1/Mesenchymal/Mes and C5/Proliferative/Stem-A GEMS is associated with poorer survival outcomes and high Epithelial-Mesenchymal Transition (EMT) scores; while the C3/Differentiated/Epi-A, C4/Differentiated/Epi-B, and C2/Immunoreactive/Epi-B show good prognosis and are associated with low EMT scores.	('C4/Differentiated/Epi-B', 'Var', (207, 230))	('Mes', 'Chemical', 'MESH:C004550', (34, 37))	('survival outcomes', 'CPA', (97, 114))	('C2/Immunoreactive/Epi-B', 'Gene', (236, 259))	('poorer', 'NegReg', (90, 96))	('C2/Immunoreactive/Epi-B', 'Gene', '717', (236, 259))	('high', 'PosReg', (119, 123))	('Mes', 'Chemical', 'MESH:C004550', (22, 25))	('low EMT', 'Phenotype', 'HP:0032198', (304, 311))	('Mes', 'Chemical', 'MESH:C004550', (135, 138))	('Epithelial-Mesenchymal Transition', 'CPA', (124, 157))	('C3/Differentiated/Epi-A', 'Var', (182, 205))
62400	30740961	With regard to chemotherapy and RT, a Chinese team is investigating on the efficacy of postoperative adjuvant chemotherapy (paclitaxel plus carboplatin) and RT for high-risk stage I endometrial cancer patients (NCT01820858); 2 clinical trials from Korea are studying on the efficacy of chemotherapy for advanced or recurrent endometrial cancer (docetaxel plus cisplatin, NCT01461759), and chemotherapy (docetaxel plus cisplatin) followed by RT in surgically treated women with stage II/III endometrioid and stage IB/II clear cell/serous carcinoma patients (NCT01461746).	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))	('serous carcinoma', 'Disease', 'MESH:D018284', (530, 546))	('endometrial cancer', 'Phenotype', 'HP:0012114', (182, 200))	('endometrial cancer', 'Disease', (325, 343))	('endometrial cancer', 'Disease', (182, 200))	('endometrial cancer', 'Disease', 'MESH:D016889', (325, 343))	('endometrial cancer', 'Disease', 'MESH:D016889', (182, 200))	('patients', 'Species', '9606', (201, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (537, 546))	('NCT01461746', 'Var', (557, 568))	('women', 'Species', '9606', (466, 471))	('docetaxel', 'Chemical', 'MESH:D000077143', (403, 412))	('cisplatin', 'Chemical', 'MESH:D002945', (418, 427))	('carboplatin', 'Chemical', 'MESH:D016190', (140, 151))	('serous carcinoma', 'Disease', (530, 546))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('docetaxel', 'Chemical', 'MESH:D000077143', (345, 354))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cisplatin', 'Chemical', 'MESH:D002945', (360, 369))	('patients', 'Species', '9606', (547, 555))	('endometrial cancer', 'Phenotype', 'HP:0012114', (325, 343))
62401	30740961	Four Chinese teams are studying on the effectiveness of levonorgestrel-releasing intrauterine system (LNG-IUS), metformin, and other treatment modalities as fertility-sparing treatment in early-stage endometrial cancer (LNG-IUS plus metformin, NCT02990728; LNG-IUS, NCT03463252; megestrol acetate, NCT03241914; and megestrol acetate plus metformin, NCT01968317).	('megestrol acetate', 'Chemical', 'MESH:D019290', (315, 332))	('endometrial cancer', 'Disease', (200, 218))	('metformin', 'Chemical', 'MESH:D008687', (112, 121))	('megestrol acetate', 'Chemical', 'MESH:D019290', (279, 296))	('NCT02990728', 'Var', (244, 255))	('endometrial cancer', 'Phenotype', 'HP:0012114', (200, 218))	('metformin', 'Chemical', 'MESH:D008687', (233, 242))	('endometrial cancer', 'Disease', 'MESH:D016889', (200, 218))	('levonorgestrel', 'Chemical', 'MESH:D016912', (56, 70))	('metformin', 'Chemical', 'MESH:D008687', (338, 347))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
62408	30740961	In addition, pazopanib maintenance therapy showed a disadvantage in OS in East Asian patients from AGO-OVAR16 versus placebo (hazard ratio=1.706; 95% confidence interval=1.010-2.883; p=0.0465).	('pazopanib', 'Chemical', 'MESH:C516667', (13, 22))	('patients', 'Species', '9606', (85, 93))	('disadvantage', 'NegReg', (52, 64))	('pazopanib', 'Gene', (13, 22))	('AGO-OVAR16', 'Var', (99, 109))
62431	30740961	LN density >15%, negative LN >25, and LODDS are associated with an impaired disease-free and OS.	('impaired disease-free', 'Disease', (67, 88))	('>15%', 'Var', (11, 15))	('LN density >15%', 'Var', (0, 15))	('LODDS', 'CPA', (38, 43))	('negative LN >25', 'Var', (17, 32))	('impaired disease-free', 'Disease', 'MESH:D008569', (67, 88))
62471	30740961	The function of DNA mismatch repair genes (MMR) is lost in 20%-30% of patients with endometrial cancer, displaying MSI as a consequence of somatic hypermethylation and silencing MLH1.	('patients', 'Species', '9606', (70, 78))	('hypermethylation', 'Var', (147, 163))	('silencing', 'Var', (168, 177))	('function', 'MPA', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('endometrial cancer', 'Disease', (84, 102))	('MLH1', 'Gene', '4292', (178, 182))	('endometrial cancer', 'Phenotype', 'HP:0012114', (84, 102))	('MLH1', 'Gene', (178, 182))	('endometrial cancer', 'Disease', 'MESH:D016889', (84, 102))
62513	29288495	The goal of this massive project was to comprehensively characterize multiple molecular aspects of 33 selected cancer types (Table 1; Figure 1), including DNA sequence (all exomes and low-pass genomes for a subset), copy number and methylation, mRNA and microRNA (miRNA) expression, and the expression of selected proteins.	('expression', 'MPA', (291, 301))	('methylation', 'Var', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('copy number', 'Var', (216, 227))	('proteins', 'Protein', (314, 322))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
62534	29288495	At the genomic level, malignancies appear to be divided into two broad categories reflecting divergent oncogenic processes: copy number-driven and mutation-driven.	('malignancies', 'Disease', 'MESH:D009369', (22, 34))	('malignancies', 'Disease', (22, 34))	('copy number-driven', 'Var', (124, 142))
62535	29288495	Malignancies in the PanCancer12 analysis with high levels of somatic copy number alterations were associated with early TP53 mutations, reflecting the importance of TP53 in regulating genomic stability, and included ovarian carcinoma, squamous cell carcinoma, breast invasive ductal carcinoma, uterine serous carcinoma, uterine carcinosarcoma, and pleomorphic adult sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (366, 374))	('Cancer', 'Disease', (23, 29))	('TP53', 'Gene', (165, 169))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (216, 233))	('Malignancies', 'Disease', (0, 12))	('ovarian carcinoma', 'Disease', (216, 233))	('squamous cell carcinoma', 'Disease', (235, 258))	('TP53', 'Gene', '7157', (120, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (276, 292))	('carcinosarcoma', 'Disease', (328, 342))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('carcinosarcoma', 'Disease', 'MESH:D002296', (328, 342))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (216, 233))	('TP53', 'Gene', '7157', (165, 169))	('mutations', 'Var', (125, 134))	('serous carcinoma', 'Disease', (302, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('pleomorphic adult sarcomas', 'Disease', (348, 374))	('TP53', 'Gene', (120, 124))	('pleomorphic adult sarcomas', 'Disease', 'MESH:D008228', (348, 374))	('serous carcinoma', 'Disease', 'MESH:D018284', (302, 318))	('breast invasive ductal carcinoma', 'Disease', (260, 292))	('Malignancies', 'Disease', 'MESH:D009369', (0, 12))	('breast invasive ductal carcinoma', 'Disease', 'MESH:D018270', (260, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (366, 373))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (235, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (320, 342))
62538	29288495	Common somatic copy number alterations across malignancies include amplification of regions containing oncogenes [CCND1, CCNE1, MYC, epidermal growth factor receptor (EGFR), ERBB2, MCL1, and MDM2], or genes involved in telomere maintenance, histone modification, or chromatin remodelling (TERC, RMRP, WHSC1L1, BRD4, KAT6A, KAT6B, NSD1, and PHF1), emphasizing the importance of epigenetic factors in tumourigenesis.	('copy', 'Var', (15, 19))	('PHF1', 'Gene', (340, 344))	('NSD1', 'Gene', (330, 334))	('MCL1', 'Gene', '4170', (181, 185))	('CCND1', 'Gene', '595', (114, 119))	('epidermal growth factor receptor', 'Gene', (133, 165))	('alterations', 'Var', (27, 38))	('KAT6A', 'Gene', (316, 321))	('MYC', 'Gene', (128, 131))	('CCND1', 'Gene', (114, 119))	('PHF1', 'Gene', '5252', (340, 344))	('epidermal growth factor receptor', 'Gene', '1956', (133, 165))	('ERBB2', 'Gene', (174, 179))	('malignancies', 'Disease', 'MESH:D009369', (46, 58))	('tumour', 'Phenotype', 'HP:0002664', (399, 405))	('NSD1', 'Gene', '64324', (330, 334))	('malignancies', 'Disease', (46, 58))	('BRD4', 'Gene', (310, 314))	('EGFR', 'Gene', (167, 171))	('MDM2', 'Gene', (191, 195))	('tumour', 'Disease', 'MESH:D009369', (399, 405))	('tumour', 'Disease', (399, 405))	('WHSC1L1', 'Gene', '54904', (301, 308))	('RMRP', 'Gene', (295, 299))	('ERBB2', 'Gene', '2064', (174, 179))	('KAT6B', 'Gene', (323, 328))	('CCNE1', 'Gene', (121, 126))	('WHSC1L1', 'Gene', (301, 308))	('MYC', 'Gene', '4609', (128, 131))	('MDM2', 'Gene', '4193', (191, 195))	('KAT6B', 'Gene', '23522', (323, 328))	('KAT6A', 'Gene', '7994', (316, 321))	('MCL1', 'Gene', (181, 185))	('BRD4', 'Gene', '23476', (310, 314))	('RMRP', 'Gene', '6023', (295, 299))	('CCNE1', 'Gene', '898', (121, 126))	('EGFR', 'Gene', '1956', (167, 171))
62539	29288495	Likewise, recurrent hotspot mutations in the chromatin modifier genes ARID1 and CTCF are frequent across multiple cancer lineages.	('multiple cancer', 'Disease', (105, 120))	('multiple cancer', 'Disease', 'MESH:D009369', (105, 120))	('CTCF', 'Gene', (80, 84))	('hotspot', 'PosReg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ARID1', 'Gene', (70, 75))	('CTCF', 'Gene', '10664', (80, 84))	('mutations', 'Var', (28, 37))
62541	29288495	For instance, in the multiplatform analysis, squamous cell carcinomas from the lung and head and neck clustered together with a subset of bladder carcinomas into a molecular subtype characterized by TP53 alterations, amplification of TP63, and high expression of immune-related and proliferation genes.	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (45, 69))	('TP53', 'Gene', '7157', (199, 203))	('expression', 'MPA', (249, 259))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (45, 69))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (138, 156))	('bladder carcinomas', 'Disease', 'MESH:D001749', (138, 156))	('amplification', 'Var', (217, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('bladder carcinomas', 'Disease', (138, 156))	('squamous cell carcinomas', 'Disease', (45, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('TP63', 'Gene', (234, 238))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (138, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('TP53', 'Gene', (199, 203))	('alterations', 'Var', (204, 215))	('TP63', 'Gene', '8626', (234, 238))	('immune-related', 'Gene', (263, 277))
62546	29288495	The main distinction within colorectal carcinoma is the increased frequency of hypermethylated and hypermutated DNA mismatch repair-deficient (resulting in microsatellite instability) and DNA polymerase-epsilon-deficient carcinomas in the right colon; otherwise, non-hypermutated carcinomas showed identical genomic, epigenomic and transcriptomic alterations, independently of rectal or colon origin.	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('carcinomas', 'Disease', (280, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (28, 48))	('epsilon-deficient carcinomas', 'Disease', 'MESH:D001321', (203, 231))	('carcinomas', 'Disease', 'MESH:D002277', (221, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('DNA mismatch', 'Gene', (112, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (221, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (280, 290))	('hypermethylated', 'Var', (79, 94))	('carcinomas', 'Disease', (221, 231))	('carcinomas', 'Disease', 'MESH:D002277', (280, 290))	('colorectal carcinoma', 'Disease', (28, 48))	('epsilon-deficient carcinomas', 'Disease', (203, 231))
62547	29288495	Interestingly, microsatellite-unstable colon cancers do show different histological features from microsatellite-stable cases.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('microsatellite-unstable', 'Var', (15, 38))	('colon cancers', 'Disease', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('colon cancers', 'Phenotype', 'HP:0003003', (39, 52))	('colon cancers', 'Disease', 'MESH:D015179', (39, 52))
62550	29288495	Indeed, the effort has identified numerous mutations that are present across disparate tumour types.	('mutations', 'Var', (43, 52))	('tumour', 'Disease', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
62551	29288495	Some of these alterations represent potentially attractive therapeutic targets, such as mutant BRAF, EGFR, or ARID1A.	('EGFR', 'Gene', '1956', (101, 105))	('BRAF', 'Gene', '673', (95, 99))	('EGFR', 'Gene', (101, 105))	('BRAF', 'Gene', (95, 99))	('mutant', 'Var', (88, 94))	('ARID1A', 'Gene', '8289', (110, 116))	('ARID1A', 'Gene', (110, 116))
62552	29288495	BRAF mutations have been found in multiple cancer types, including melanoma, thyroid carcinoma, and colorectal adenocarcinoma, as well as in a subset of pancreatic and lung adenocarcinomas.	('multiple cancer', 'Disease', (34, 49))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (77, 94))	('BRAF', 'Gene', '673', (0, 4))	('thyroid carcinoma', 'Disease', (77, 94))	('BRAF', 'Gene', (0, 4))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (168, 188))	('colorectal adenocarcinoma', 'Disease', (100, 125))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (77, 94))	('found', 'Reg', (25, 30))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (100, 125))	('mutations', 'Var', (5, 14))	('multiple cancer', 'Disease', 'MESH:D009369', (34, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('pancreatic and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (153, 188))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (168, 187))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
62553	29288495	The dramatic response of melanoma positive for BRAF p.V600E mutations to BRAF inhibitors such as vemurafenib or dabrafenib suggested that other malignancies harbouring the identical alteration might also respond.	('BRAF', 'Gene', '673', (73, 77))	('p.V600E', 'Var', (52, 59))	('melanoma', 'Disease', (25, 33))	('malignancies', 'Disease', 'MESH:D009369', (144, 156))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('dabrafenib', 'Chemical', 'MESH:C561627', (112, 122))	('vemurafenib', 'Chemical', 'MESH:D000077484', (97, 108))	('malignancies', 'Disease', (144, 156))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('BRAF', 'Gene', (73, 77))	('p.V600E', 'Mutation', 'rs113488022', (52, 59))
62554	29288495	Whereas BRAF inhibitors show promise in BRAF-mutated papillary thyroid carcinoma, patients with colorectal carcinomas with BRAF mutations (representing 10% of all colorectal adenocarcinoma) have shorter survival, and are less responsive to conventional chemotherapy than patients with other colorectal carcinomas.	('survival', 'MPA', (203, 211))	('BRAF', 'Gene', '673', (40, 44))	('BRAF', 'Gene', (40, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('BRAF', 'Gene', '673', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('mutations', 'Var', (128, 137))	('shorter', 'NegReg', (195, 202))	('BRAF', 'Gene', (8, 12))	('colorectal carcinomas', 'Disease', (291, 312))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (291, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (53, 80))	('papillary thyroid carcinoma', 'Disease', (53, 80))	('patients', 'Species', '9606', (82, 90))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (53, 80))	('colorectal carcinomas', 'Disease', (96, 117))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (96, 117))	('colorectal adenocarcinoma', 'Disease', (163, 188))	('patients', 'Species', '9606', (271, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (63, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (163, 188))
62555	29288495	In contrast to melanoma, which shows initial response rates of up to 80% prior to the development of resistance, colorectal adenocarcinomas with the identical BRAF p.V600E mutation respond to vemurafenib as a sole agent in <5% of cases.	('vemurafenib', 'Chemical', 'MESH:D000077484', (192, 203))	('BRAF', 'Gene', (159, 163))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (113, 139))	('p.V600E', 'Mutation', 'rs113488022', (164, 171))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('p.V600E', 'Var', (164, 171))	('colorectal adenocarcinomas', 'Disease', (113, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('BRAF', 'Gene', '673', (159, 163))
62574	29288495	oestrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67], although these have been somewhat slow to achieve widespread use.	('progesterone receptor', 'Gene', '5241', (25, 46))	('progesterone receptor', 'Gene', (25, 46))	('oestrogen', 'Protein', (0, 9))	('HER2', 'Gene', (53, 57))	('Ki67', 'Var', (63, 67))	('HER2', 'Gene', '2064', (53, 57))	('PR', 'Gene', '5241', (48, 50))
62584	29288495	Nuclear pleomorphism has long been appreciated as a prognostic indicator in many cancers, and is routinely evaluated as part of the grading of sarcoma, breast carcinoma, and other malignancies.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('breast carcinoma', 'Phenotype', 'HP:0003002', (152, 168))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('sarcoma', 'Disease', 'MESH:D012509', (143, 150))	('Nuclear pleomorphism', 'Var', (0, 20))	('malignancies', 'Disease', 'MESH:D009369', (180, 192))	('breast carcinoma', 'Disease', (152, 168))	('malignancies', 'Disease', (180, 192))	('sarcoma', 'Disease', (143, 150))	('breast carcinoma', 'Disease', 'MESH:D001943', (152, 168))
62677	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
62678	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
62716	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))	('cancer', 'Disease', (69, 75))
62755	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
62769	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
62777	29956810	In the present study, we found that high BMI (<=25) is potentially a risk factor for many types of cancer.	('types', 'Disease', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('risk', 'Reg', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('high', 'Var', (36, 40))
62779	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
62818	29983808	Low-grade endometrioid adenocarcinomas are often seen along with endometrial hyperplasia, but high-grade endometrioid adenocarcinomas have more solid sheets of less-differentiated tumour cells, which are no longer organised into glands, often associated with surrounded atrophic endometrium.	('atrophic', 'Disease', 'MESH:D020966', (270, 278))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (105, 133))	('high-grade', 'Var', (94, 104))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (10, 38))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (105, 132))	('atrophic', 'Disease', (270, 278))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (65, 88))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (10, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('endometrioid adenocarcinomas', 'Disease', (105, 133))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('endometrial hyperplasia', 'Disease', (65, 88))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (65, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('endometrioid adenocarcinomas', 'Disease', (10, 38))	('tumour', 'Disease', (180, 186))
62907	29398899	The medical record numbers for these cases were identified through the Ottawa Hospital Data Warehouse, according to the International Classification of Diseases (ICD 10-CA) codes for Malignant Neoplasm of Cervix Uteri, Corpus Uteri, and Uterus Unspecified (C54*, C55*, and C53*) and Diagnosis type 4 (Morphology) codes for Sarcoma or Leiomyosarcoma (88903, 88913, and 88963), Mullerian Tumor/Carcinosarcoma (89503, 89803, and 89813), Endometrial Stromal Sarcoma (89303), Sarcoma Uterus Not Otherwise Specified (88003), and Adenosarcoma (89333).	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (334, 348))	('89303', 'Var', (463, 468))	('88913', 'Var', (357, 362))	('Sarcoma', 'Phenotype', 'HP:0100242', (454, 461))	('C55*', 'SUBSTITUTION', 'None', (263, 267))	('Mullerian Tumor/Carcinosarcoma', 'Disease', (376, 406))	('Malignant Neoplasm', 'Disease', (183, 201))	('Neoplasm', 'Phenotype', 'HP:0002664', (193, 201))	('89813', 'Var', (426, 431))	('Sarcoma Uterus', 'Disease', (471, 485))	('Sarcoma Uterus', 'Disease', 'MESH:D014594', (471, 485))	('C53*', 'Var', (273, 277))	('Adenosarcoma', 'Disease', 'MESH:D018195', (523, 535))	('Unspecified', 'Species', '32644', (244, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (341, 348))	('89803', 'Var', (415, 420))	('89503', 'Var', (408, 413))	('88963', 'Var', (368, 373))	('89333', 'Var', (537, 542))	('C53*', 'SUBSTITUTION', 'None', (273, 277))	('C54*', 'SUBSTITUTION', 'None', (257, 261))	('Adenosarcoma', 'Disease', (523, 535))	('Sarcoma', 'Phenotype', 'HP:0100242', (323, 330))	('ICD', 'Disease', (162, 165))	('C54*', 'Var', (257, 261))	('Malignant Neoplasm', 'Disease', 'MESH:D009369', (183, 201))	('C55*', 'Var', (263, 267))	('88003', 'Var', (511, 516))	('Endometrial Stromal Sarcoma', 'Disease', (434, 461))	('Endometrial Stromal Sarcoma', 'Disease', 'MESH:D018203', (434, 461))	('Tumor', 'Phenotype', 'HP:0002664', (386, 391))	('88903', 'Var', (350, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (528, 535))	('Sarcoma', 'Phenotype', 'HP:0100242', (471, 478))	('ICD', 'Disease', 'OMIM:252500', (162, 165))	('Sarcoma or Leiomyosarcoma', 'Disease', (323, 348))	('Mullerian Tumor/Carcinosarcoma', 'Disease', 'MESH:D002296', (376, 406))	('Sarcoma or Leiomyosarcoma', 'Disease', 'MESH:D007890', (323, 348))	('Cervix Uteri', 'Phenotype', 'HP:0000139', (205, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (399, 406))
62908	29398899	Fibroid cases were identified with ICD10-CA codes (D25*).	('ICD', 'Disease', (35, 38))	('D25*', 'SUBSTITUTION', 'None', (51, 55))	('Fibroid', 'Disease', (0, 7))	('ICD', 'Disease', 'OMIM:252500', (35, 38))	('D25*', 'Var', (51, 55))
62980	29238287	Survival of patients with a LMS is strongly associated with the number of mitoses per 10 high power fields (x 100 magnification): 1-4, 98%; 5-9, 42%; >=10; 15%.	('associated', 'Reg', (44, 54))	('patients', 'Species', '9606', (12, 20))	('LMS', 'Disease', (28, 31))	('LMS', 'Phenotype', 'HP:0100243', (28, 31))	('mitoses', 'Var', (74, 81))
63080	29093822	EZH2 inhibition in ARID1A mutated clear cell and endometrioid ovarian and endometrioid endometrial cancers Clear cell carcinoma and endometrioid adenocarcinoma are histologic subtypes of ovarian and uterine cancer that demonstrate unique clinical behavior but share common underlying genomic aberrations and oncogenic pathways.	('uterine cancer', 'Phenotype', 'HP:0010784', (199, 213))	('ARID1A', 'Gene', (19, 25))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (132, 159))	('EZH2', 'Gene', '2146', (0, 4))	('endometrioid ovarian and endometrioid endometrial cancers', 'Disease', 'MESH:D016889', (49, 106))	('cancer', 'Disease', (207, 213))	('EZH2', 'Gene', (0, 4))	('clear cell', 'Disease', (34, 44))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('ARID1A', 'Gene', '8289', (19, 25))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (132, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('inhibition', 'NegReg', (5, 15))	('mutated', 'Var', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('Clear cell carcinoma', 'Disease', (107, 127))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('endometrial cancer', 'Phenotype', 'HP:0012114', (87, 105))	('cancer', 'Disease', (99, 105))	('Clear cell carcinoma', 'Disease', 'MESH:C538614', (107, 127))	('endometrioid adenocarcinoma', 'Disease', (132, 159))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
63081	29093822	ARID1A mutations are more frequently identified in these tumors, in comparison to other gynecologic histologies, and loss of ARID1A tumor suppressor function is thought to be an essential component of carcinogenic transformation.	('loss of ARID1A tumor', 'Disease', (117, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('loss of ARID1A tumor', 'Disease', 'MESH:D009369', (117, 137))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('ARID1A', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('identified', 'Reg', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('carcinogenic transformation', 'Disease', (201, 228))	('carcinogenic transformation', 'Disease', 'MESH:D020518', (201, 228))	('mutations', 'Var', (7, 16))
63082	29093822	Several therapeutic targets in ARID1A mutated cancers are in development, including EZH2 inhibitors.	('mutated', 'Var', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('ARID1A', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('EZH2', 'Gene', '2146', (84, 88))	('EZH2', 'Gene', (84, 88))
63084	29093822	EZH2 inhibition in ARID1A mutated tumors acts in a synthetically lethal manner to suppress cell growth and promote apoptosis, revealing a unique new therapeutic opportunity.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('EZH2', 'Gene', '2146', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('EZH2', 'Gene', (0, 4))	('cell growth', 'CPA', (91, 102))	('inhibition', 'NegReg', (5, 15))	('mutated', 'Var', (26, 33))	('suppress', 'NegReg', (82, 90))	('apoptosis', 'CPA', (115, 124))	('promote', 'PosReg', (107, 114))	('ARID1A', 'Gene', (19, 25))
63085	29093822	Several phase 1 and 2 clinical trials of EZH2 inhibitors are ongoing currently and there is considerable promise in translational trials for utilization of this new targeted therapy, both to capitalize on ARID1A loss of function and to increase sensitivity to platinum-based adjuvant chemotherapies.	('inhibitors', 'Var', (46, 56))	('loss of function', 'NegReg', (212, 228))	('EZH2', 'Gene', (41, 45))	('EZH2', 'Gene', '2146', (41, 45))	('platinum', 'Chemical', 'MESH:D010984', (260, 268))	('increase', 'PosReg', (236, 244))
63086	29093822	This review will synthesize the molecular carcinogenesis of these malignancies and their unique clinical behavior, as a foundation for an emerging frontier of targeted therapeutics - the synergistic inhibition of EZH2 in ARID1A mutated cancers.	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('EZH2', 'Gene', '2146', (213, 217))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('mutated', 'Var', (228, 235))	('cancers', 'Disease', (236, 243))	('EZH2', 'Gene', (213, 217))	('carcinogenesis', 'Disease', 'MESH:D063646', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('carcinogenesis', 'Disease', (42, 56))	('malignancies', 'Disease', (66, 78))	('ARID1A', 'Gene', (221, 227))	('synergistic', 'Var', (187, 198))
63112	29093822	The SWI/SNF complex plays a unique role in carcinogenesis and may be mutated in over 20% of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (43, 57))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('mutated', 'Var', (69, 76))	('carcinogenesis', 'Disease', (43, 57))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('human', 'Species', '9606', (92, 97))
63115	29093822	ARID1A mutations typically results in loss of protein function with implications for cell proliferation, differentiation and apoptosis - essential roles of a tumor suppressor gene.	('tumor', 'Disease', (158, 163))	('cell proliferation', 'CPA', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('ARID1A', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('protein function', 'MPA', (46, 62))	('loss', 'NegReg', (38, 42))	('mutations', 'Var', (7, 16))
63118	29093822	restored wild-type ARID1A expression in ovarian cancer cells harboring deleterious mutations and noted reactivation of protein function.	('expression', 'MPA', (26, 36))	('mutations', 'Var', (83, 92))	('ovarian cancer', 'Disease', 'MESH:D010051', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ovarian cancer', 'Disease', (40, 54))	('protein', 'Protein', (119, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))	('ARID1A', 'Gene', (19, 25))
63120	29093822	As the molecular characterization of solid malignancies expanded, it became evident that ARID1A mutations were most pronounced in gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('ARID1A', 'Gene', (89, 95))	('cancers', 'Disease', (142, 149))	('malignancies', 'Disease', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pronounced', 'Reg', (116, 126))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('malignancies', 'Disease', 'MESH:D009369', (43, 55))	('mutations', 'Var', (96, 105))
63121	29093822	Within ovarian cancer cohorts, mutation rates of 46-57% were identified in clear cell adenocarcinoma and 30% in endometrioid adenocarcinoma.	('endometrioid adenocarcinoma', 'Disease', (112, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (86, 100))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (112, 139))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (112, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (7, 21))	('mutation', 'Var', (31, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (7, 21))	('adenocarcinoma', 'Disease', (125, 139))	('adenocarcinoma', 'Disease', (86, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('ovarian cancer', 'Disease', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))
63122	29093822	This is contrasted with the absence of identifiable ARID1A mutations in high-grade serous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('serous carcinomas', 'Disease', 'MESH:D018284', (83, 100))	('serous carcinomas', 'Disease', (83, 100))	('ARID1A', 'Gene', (52, 58))	('mutations', 'Var', (59, 68))
63126	29093822	Loss of ARID1A is more frequent in endometriosis associated neoplasms, with loss of ARID1A immunohistochemical expression in 61% of endometriosis associated clear cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (157, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('endometriosis', 'Phenotype', 'HP:0030127', (132, 145))	('loss', 'Var', (76, 80))	('endometriosis', 'Phenotype', 'HP:0030127', (35, 48))	('ARID1A', 'Gene', (8, 14))	('neoplasms', 'Phenotype', 'HP:0002664', (60, 69))	('clear cell carcinomas', 'Disease', (157, 178))	('endometriosis', 'Disease', 'MESH:D004715', (35, 48))	('neoplasms', 'Disease', 'MESH:D009369', (60, 69))	('endometriosis', 'Disease', 'MESH:D004715', (132, 145))	('endometriosis', 'Disease', (35, 48))	('ARID1A', 'Gene', (84, 90))	('Loss', 'Var', (0, 4))	('endometriosis', 'Disease', (132, 145))	('neoplasms', 'Disease', (60, 69))
63127	29093822	While it is unclear if ARID1A mutations alone are sufficient to induce cancer progression, concurrent mutations in alternate pathways, including the PI3K/AKT pathway are frequent and appear to occur simultaneously to facilitate tumorigenesis.	('induce', 'Reg', (64, 70))	('facilitate', 'PosReg', (217, 227))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('ARID1A', 'Gene', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Disease', (71, 77))	('AKT', 'Gene', '207', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mutations', 'Var', (102, 111))	('mutations', 'Var', (30, 39))	('AKT', 'Gene', (154, 157))	('tumor', 'Disease', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
63128	29093822	ARID1A mutations are also found frequently among women with endometrial cancers, with mutation frequency of 40% in uterine endometrioid adenocarcinoma.	('women', 'Species', '9606', (49, 54))	('endometrial cancers', 'Disease', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('endometrial cancer', 'Phenotype', 'HP:0012114', (60, 78))	('endometrial cancers', 'Disease', 'MESH:D016889', (60, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (123, 150))	('endometrioid adenocarcinoma', 'Disease', (123, 150))	('ARID1A', 'Gene', (0, 6))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (123, 150))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('mutations', 'Var', (7, 16))
63131	29093822	These often occurred concurrently with inactivating PTEN mutations.	('PTEN', 'Gene', '5728', (52, 56))	('occurred', 'Reg', (12, 20))	('mutations', 'Var', (57, 66))	('PTEN', 'Gene', (52, 56))
63134	29093822	Conversely, in patient cohorts with high grade endometrioid and clear cell endometrial cancer, ARID1A mutations were not associated with clinical stage, depth of myometrial invasion, lymph node metastasis, or overall survival.	('patient', 'Species', '9606', (15, 22))	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))	('associated', 'Reg', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (102, 111))	('endometrial cancer', 'Disease', (75, 93))	('ARID1A', 'Gene', (95, 101))
63136	29093822	Women with low ARID1A expression more frequently had incomplete response to chemotherapy (p = 0.026) and were more likely to experience relapse after achieving a complete response (p = 0.07).	('ARID1A', 'Gene', (15, 21))	('Women', 'Species', '9606', (0, 5))	('low', 'Var', (11, 14))	('experience', 'Reg', (125, 135))	('expression', 'MPA', (22, 32))
63140	29093822	As ARID1A plays an integral role in cell-cycle control and DNA damage repair pathways, the loss of ARID1A function with concurrent dysfunction in p53, p21, MLH1, or the PI3K/AKT/mTOR pathway allow malignant progression, and have revealed several potential therapeutic targets in ARID1A mutated cancers.	('ARID1A', 'Gene', (99, 105))	('function', 'MPA', (106, 114))	('p53', 'Gene', (146, 149))	('mTOR', 'Gene', (178, 182))	('MLH1', 'Gene', (156, 160))	('p21', 'Gene', (151, 154))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('AKT', 'Gene', '207', (174, 177))	('loss', 'NegReg', (91, 95))	('dysfunction', 'Var', (131, 142))	('MLH1', 'Gene', '4292', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('mTOR', 'Gene', '2475', (178, 182))	('p21', 'Gene', '1026', (151, 154))	('allow', 'Reg', (191, 196))	('p53', 'Gene', '7157', (146, 149))	('malignant progression', 'CPA', (197, 218))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('AKT', 'Gene', (174, 177))
63142	29093822	Functional studies of ovarian cancer cell lines reveal numerous gene targets of the SWI/SNF complex which may be impacted by ARID1A mutation, including cyclins, c-myc, and the Polycomb complexes.	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('c-myc', 'Gene', (161, 166))	('ovarian cancer', 'Disease', (22, 36))	('ARID1A', 'Gene', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('c-myc', 'Gene', '4609', (161, 166))	('impacted', 'Reg', (113, 121))	('mutation', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
63144	29093822	EZH2 plays a role in cancer progression through several mechanisms, including gain-of-function and loss-of-function mutations, overexpression of EZH2, mutations in the H3K27 demethylase gene, and through antagonistic mutations in the SWI/SNF chromatin remodeling complex.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('EZH2', 'Gene', '2146', (0, 4))	('gain-of-function', 'PosReg', (78, 94))	('H3K27 demethylase', 'Gene', (168, 185))	('SWI/SNF', 'Gene', (234, 241))	('EZH2', 'Gene', (0, 4))	('EZH2', 'Gene', '2146', (145, 149))	('overexpression', 'PosReg', (127, 141))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (21, 27))	('EZH2', 'Gene', (145, 149))	('mutations', 'Var', (217, 226))	('loss-of-function', 'NegReg', (99, 115))	('mutations', 'Var', (151, 160))
63146	29093822	EZH2 overexpression manifests through histone hypermethylation, resulting in tumor proliferation, cell cycle dysregulation, metastatic spread, and angiogenesis.	('EZH2', 'Gene', '2146', (0, 4))	('cell cycle dysregulation', 'CPA', (98, 122))	('histone', 'MPA', (38, 45))	('EZH2', 'Gene', (0, 4))	('overexpression', 'PosReg', (5, 19))	('angiogenesis', 'CPA', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (98, 122))	('hypermethylation', 'Var', (46, 62))	('resulting', 'Reg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('metastatic spread', 'CPA', (124, 141))
63150	29093822	Additionally, these tumors are characterized by genomic instability and thus, epigenetic modification of gene expression may play a critical role in tumorigenesis.	('epigenetic modification', 'Var', (78, 101))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
63153	29093822	Overexpression has been associated with high proliferation rates and aggressive tumor subgroups of endometrial cancers .	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('endometrial cancers', 'Disease', 'MESH:D016889', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('endometrial cancers', 'Disease', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('aggressive tumor', 'Disease', 'MESH:D001523', (69, 85))	('aggressive tumor', 'Disease', (69, 85))	('Overexpression', 'Var', (0, 14))	('endometrial cancer', 'Phenotype', 'HP:0012114', (99, 117))	('high proliferation rates', 'CPA', (40, 64))
63155	29093822	Given the reversible epigenetic modifications which drive tumorigenesis, EZH2 methyltransferase activity is an ideal target for cancer therapeutics.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('epigenetic modifications', 'Var', (21, 45))	('EZH2', 'Gene', '2146', (73, 77))	('EZH2', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', (128, 134))
63159	29093822	Mechanistically, both ARID1A and EZH2 target PI3K-interacting protein 1 gene (PIK3IP1), with resultant silencing causing cell proliferation and promotion of anti-apoptotic effects through the PI3K-AKT pathway.	('silencing', 'Var', (103, 112))	('anti-apoptotic effects', 'CPA', (157, 179))	('AKT', 'Gene', '207', (197, 200))	('PIK3IP1', 'Gene', (78, 85))	('cell proliferation', 'CPA', (121, 139))	('AKT', 'Gene', (197, 200))	('EZH2', 'Gene', '2146', (33, 37))	('promotion', 'PosReg', (144, 153))	('EZH2', 'Gene', (33, 37))
63160	29093822	In a pivotal study by Bitler et al., it was demonstrated that targeted EZH2 inhibition triggers apoptosis in ARID1A mutated cells and upregulates PIK3IP1 expression, thereby suppressing cell growth.	('EZH2', 'Gene', (71, 75))	('inhibition', 'NegReg', (76, 86))	('mutated', 'Var', (116, 123))	('suppressing', 'NegReg', (174, 185))	('upregulates', 'PosReg', (134, 145))	('cell growth', 'CPA', (186, 197))	('PIK3IP1', 'Gene', (146, 153))	('apoptosis', 'CPA', (96, 105))	('EZH2', 'Gene', '2146', (71, 75))	('triggers', 'Reg', (87, 95))	('ARID1A', 'Gene', (109, 115))	('expression', 'MPA', (154, 164))
63161	29093822	This cooperation of ARID1A mutation and EZH2 targeted inhibition represents a synthetically lethal interaction.	('mutation', 'Var', (27, 35))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('ARID1A', 'Gene', (20, 26))
63162	29093822	This is particularly exciting in that drug-gene synthetic lethality often allows utilization of low concentrations of drugs, minimal toxicity, and limited treatment resistance (Table 2).	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('toxicity', 'Disease', (133, 141))	('drug-gene', 'Var', (38, 47))
63163	29093822	GSK126 was shown to be well tolerated in mouse xenograft models of ovarian CCC.	('ovarian CCC', 'Disease', (67, 78))	('GSK126', 'Chemical', 'MESH:C577920', (0, 6))	('mouse', 'Species', '10090', (41, 46))	('GSK126', 'Var', (0, 6))	('ovarian CCC', 'Disease', 'MESH:C535313', (67, 78))
63166	29093822	On a mechanistic level, immunohistochemical analysis showed decreased H3K27Me3 levels, increased PIK3IP1 activity, as well as cleaved caspase 3 in the GSK126 treated mice.	('increased', 'PosReg', (87, 96))	('PIK3IP1', 'Gene', (97, 104))	('decreased', 'NegReg', (60, 69))	('cleaved caspase', 'MPA', (126, 141))	('increased PIK3IP1 activity', 'Phenotype', 'HP:0003240', (87, 113))	('GSK126', 'Chemical', 'MESH:C577920', (151, 157))	('GSK126', 'Var', (151, 157))	('activity', 'MPA', (105, 113))	('mice', 'Species', '10090', (166, 170))	('H3K27Me3', 'Protein', (70, 78))
63171	29093822	EZH2 downregulation in ovarian cancer has been shown to sensitize tumor cells to cisplatin and EZH2 overexpression is associated with resistance to cisplatin through H3K27 tri-methylation of drug-resistance genes.	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('overexpression', 'PosReg', (100, 114))	('EZH2', 'Gene', '2146', (0, 4))	('tumor', 'Disease', (66, 71))	('EZH2', 'Gene', (0, 4))	('drug-resistance', 'Phenotype', 'HP:0020174', (191, 206))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))	('sensitize', 'Reg', (56, 65))	('EZH2', 'Gene', '2146', (95, 99))	('tri-methylation', 'Var', (172, 187))	('EZH2', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('H3K27 tri-methylation', 'Var', (166, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('downregulation', 'NegReg', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ovarian cancer', 'Disease', (23, 37))	('resistance', 'MPA', (134, 144))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))
63172	29093822	Translational research suggests that combination therapies utilizing platinum-based cytotoxic chemotherapy and EZH2 inhibitors, may be particularly potent and synergistic in ARID1A mutated tumors.	('ARID1A', 'Gene', (174, 180))	('mutated', 'Var', (181, 188))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('EZH2', 'Gene', '2146', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('EZH2', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('platinum', 'Chemical', 'MESH:D010984', (69, 77))
63173	29093822	Within non-Hodgkin's lymphoma tumors with EZH2 mutations, a combination of EPZ-6438 and traditional targeted chemotherapy prevented tumor growth.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (11, 29))	('prevented', 'NegReg', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('EZH2', 'Gene', '2146', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutations', 'Var', (47, 56))	("non-Hodgkin's lymphoma tumors", 'Disease', (7, 36))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('EZH2', 'Gene', (42, 46))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('tumor', 'Disease', (132, 137))	("non-Hodgkin's lymphoma tumors", 'Disease', 'MESH:D008228', (7, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
63175	29093822	Interestingly, EZH2 inhibition had varying effects in a preclinical study of non-small cell lung cancers, with increased sensitization to topoisomerase II inhibitors in the tumor subset demonstrating BRG1/SMARCA4 loss-of-function mutations or EGFR gain-of-function mutations.	('mutations', 'Var', (265, 274))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('lung cancers', 'Phenotype', 'HP:0100526', (92, 104))	('non-small cell lung cancers', 'Disease', (77, 104))	('mutations', 'Var', (230, 239))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (77, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('BRG1', 'Gene', '6597', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SMARCA4', 'Gene', (205, 212))	('EGFR', 'Gene', '1956', (243, 247))	('EZH2', 'Gene', (15, 19))	('EZH2', 'Gene', '2146', (15, 19))	('BRG1', 'Gene', (200, 204))	('sensitization', 'MPA', (121, 134))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (81, 104))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (77, 104))	('gain-of-function', 'PosReg', (248, 264))	('increased', 'PosReg', (111, 120))	('loss-of-function', 'NegReg', (213, 229))	('tumor', 'Disease', (173, 178))	('EGFR', 'Gene', (243, 247))	('SMARCA4', 'Gene', '6597', (205, 212))
63177	29093822	The potential therapeutic role of EZH2 inhibition in ARID1A mutated gynecologic cancers may represent a novel and exciting treatment paradigm in a subset of patients with limited treatment options.	('EZH2', 'Gene', '2146', (34, 38))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('EZH2', 'Gene', (34, 38))	('inhibition', 'NegReg', (39, 49))	('cancers', 'Disease', (80, 87))	('patients', 'Species', '9606', (157, 165))	('mutated', 'Var', (60, 67))	('ARID1A', 'Gene', (53, 59))
63178	29093822	Capitalizing on the concept of synthetic lethality induced in this population using EZH2 inhibitors, as well as the potential synergistic effects with platinum-based chemotherapies, may help translate into improved oncologic outcomes.	('improved', 'PosReg', (206, 214))	('inhibitors', 'Var', (89, 99))	('EZH2', 'Gene', '2146', (84, 88))	('platinum', 'Chemical', 'MESH:D010984', (151, 159))	('EZH2', 'Gene', (84, 88))
63179	29093822	Given the frequency of ARID1A mutations in patients with clear cell and endometrioid ovarian and uterine cancer, and the prognostic implications of loss of ARID1A expression, it is natural to explore the impact of EZH2 inhibition in these patient subsets.	('clear cell', 'Disease', (57, 67))	('patient', 'Species', '9606', (239, 246))	('loss', 'NegReg', (148, 152))	('ARID1A', 'Gene', (23, 29))	('patient', 'Species', '9606', (43, 50))	('endometrioid ovarian', 'Disease', 'MESH:D016889', (72, 92))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (43, 51))	('uterine cancer', 'Phenotype', 'HP:0010784', (97, 111))	('EZH2', 'Gene', '2146', (214, 218))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EZH2', 'Gene', (214, 218))	('endometrioid ovarian', 'Disease', (72, 92))	('ARID1A', 'Gene', (156, 162))
63185	29093822	Using both institutional genomic data, and data from the NCI sponsored cancer genome atlas, ARID1A mutations were frequently identified as mutated tumor suppressor genes, in clear cell and endometrioid ovarian cancer as well as low grade endometrioid endometrial cancer.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cancer genome atlas', 'Disease', (71, 90))	('endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (189, 216))	('cancer genome atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('endometrial cancer', 'Phenotype', 'HP:0012114', (251, 269))	('clear cell', 'Disease', (174, 184))	('endometrioid endometrial cancer', 'Disease', (238, 269))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('endometrioid ovarian cancer', 'Disease', (189, 216))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (238, 269))	('ARID1A', 'Gene', (92, 98))
63200	28265775	The latter observation led us to hypothesize that alterations in micro RNA (miRNA) expression might be part of the process by which neonatal DES exposure induces estrogen-dependent dysplasia/neoplasia in the hamster uterus.	('induces', 'Reg', (154, 161))	('dysplasia/neoplasia', 'Disease', (181, 200))	('alterations', 'Var', (50, 61))	('rat', 'Species', '10116', (54, 57))	('hamster', 'Species', '10034', (208, 215))	('micro RNA', 'Protein', (65, 74))	('neoplasia', 'Phenotype', 'HP:0002664', (191, 200))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))	('dysplasia/neoplasia', 'Disease', 'MESH:D009369', (181, 200))
63214	28265775	Quality control criteria for the isolated RNA samples included assessing the presence of 28S and 18S bands in a 1% agarose gel and a A260/280 ratio between 1.9-2.1 as recommended in the miRNeasy kit protocol.	('miR', 'Gene', '220972', (186, 189))	('miR', 'Gene', (186, 189))	('28S', 'MPA', (89, 92))	('A260/280', 'Var', (133, 141))	('rat', 'Species', '10116', (142, 145))	('agarose', 'Chemical', 'MESH:D012685', (115, 122))
63319	28265775	It is also important to note that those linkages among fundamental regulatory pathways strengthen the value of network biology-based study approaches to improve cancer diagnosis, prognosis, and therapy.	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('linkages', 'Var', (40, 48))
63402	27606294	studied the tissue biomarkers in the prognostication of serous ovarian cancer following neoadjuvant chemotherapy (NACT) and found that MIB-1 was significantly lower in cases treated with NACT, and the survival outcome was significantly better in cases with low MIB-1.	('serous ovarian cancer', 'Disease', (56, 77))	('NACT', 'Chemical', '-', (187, 191))	('lower', 'NegReg', (159, 164))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (56, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('MIB-1', 'Gene', (135, 140))	('NACT', 'Chemical', '-', (114, 118))	('MIB-1', 'Gene', (261, 266))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('low', 'Var', (257, 260))	('MIB-1', 'Gene', '57534', (261, 266))	('better', 'PosReg', (236, 242))	('MIB-1', 'Gene', '57534', (135, 140))
63411	27606294	They found that the frequencies of methylation in EOCs and low-malignant potential tumors were 51.2% and 57%, respectively, significantly higher (P = 0.000 and P = 0.001) in comparison to benign tumors and normal ovarian tissue where no methylation was seen.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('benign tumors', 'Disease', 'MESH:D009369', (188, 201))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('methylation', 'Var', (35, 46))	('EOC', 'Phenotype', 'HP:0025318', (50, 53))	('higher', 'PosReg', (138, 144))	('benign tumors', 'Disease', (188, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
63413	27606294	Lack of protein expression correlated with tumor grade and type, and the methylation status correlated well with downregulation of BRCA1 expression.	('expression', 'MPA', (137, 147))	('Lack', 'NegReg', (0, 4))	('downregulation', 'NegReg', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('protein', 'Protein', (8, 15))	('BRCA1', 'Gene', '672', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('methylation', 'Var', (73, 84))	('BRCA1', 'Gene', (131, 136))	('tumor', 'Disease', (43, 48))
63415	27606294	The three founder mutations 187delAG, 5385insC in BRCA1, and 6174delT in BRCA2 were not seen in any of the patients.	('BRCA2', 'Gene', (73, 78))	('BRCA1', 'Gene', (50, 55))	('5385insC', 'Var', (38, 46))	('5385insC', 'Mutation', 'c.5385insC', (38, 46))	('187delAG', 'Mutation', 'c.187delAG', (28, 36))	('BRCA2', 'Gene', '675', (73, 78))	('6174delT', 'Var', (61, 69))	('187delAG', 'Var', (28, 36))	('6174delT', 'Mutation', 'rs786204278', (61, 69))	('BRCA1', 'Gene', '672', (50, 55))	('patients', 'Species', '9606', (107, 115))
63501	27606294	There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI: 0.33-0.83).	('HPV-testing', 'Var', (40, 51))	('deaths', 'Disease', 'MESH:D003643', (14, 20))	('deaths', 'Disease', (14, 20))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('HPV', 'Species', '10566', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
63502	27606294	No significant reductions in the number of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group.	('reductions', 'NegReg', (15, 25))	('VIA', 'Disease', (125, 128))	('deaths', 'Disease', (63, 69))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('deaths', 'Disease', 'MESH:D003643', (63, 69))	('VIA', 'Disease', 'MESH:C562851', (125, 128))	('cytologic-testing', 'Var', (91, 108))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
63555	27606294	The recurrence of the disease was significantly associated with the presence of HPV in the exfoliated cell (P = 0.01) and plasma (P = 0.007) as well as high viral load in the exfoliated cells (P = 0.0002).	('recurrence', 'Disease', (4, 14))	('associated', 'Reg', (48, 58))	('HPV', 'Species', '10566', (80, 83))	('presence', 'Var', (68, 76))	('HPV', 'Gene', (80, 83))
63576	27606294	reported that for the detection of pelvic nodes in HR endometrial cancers, 18F-FDG PET-CT had a sensitivity of 100%, specificity of 61.11%, PPV of 22.22%, NPV of 100%, and accuracy of 65%.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('HR endometrial cancers', 'Disease', 'MESH:D016889', (51, 73))	('18F-FDG', 'Var', (75, 82))	('HR endometrial cancers', 'Disease', (51, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('endometrial cancer', 'Phenotype', 'HP:0012114', (54, 72))
63577	27606294	In the detection of recurrent endometrial cancer, the sensitivity, specificity, positive and negative predictive values, and accuracy of 18F-FDG PET-CT were 88.9%, 93.6%, 94.1%, 88%, and 91%, respectively, significantly higher than conventional imaging (CT and magnetic resonance imaging).	('endometrial cancer', 'Disease', 'MESH:D016889', (30, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('18F-FDG', 'Var', (137, 144))	('higher', 'PosReg', (220, 226))	('endometrial cancer', 'Disease', (30, 48))	('endometrial cancer', 'Phenotype', 'HP:0012114', (30, 48))
63620	26552420	Mutations, mainly in TP53, were identified in 18 (60%) of 30 lavage samples of patients with OC using next-generation sequencing.	('TP53', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (79, 87))	('OC', 'Phenotype', 'HP:0100615', (93, 95))	('TP53', 'Gene', '7157', (21, 25))
63624	26552420	All five analyzed lavage specimens from patients with EC harbored mutations.	('mutations', 'Var', (66, 75))	('harbored', 'Reg', (57, 65))	('patients', 'Species', '9606', (40, 48))	('EC', 'Phenotype', 'HP:0012114', (54, 56))
63625	26552420	Eight (29.6%) of 27 patients with benign lesions tested positive for mutations, six (75%) as a result of mutations in the KRAS gene.	('mutations', 'Var', (69, 78))	('mutations', 'Var', (105, 114))	('result of', 'Reg', (95, 104))	('positive', 'Reg', (56, 64))	('patients', 'Species', '9606', (20, 28))	('KRAS', 'Gene', (122, 126))	('KRAS', 'Gene', '3845', (122, 126))
63629	26552420	HGSCs show frequent mutations in the TP53 gene (> 90%), early transperitoneal dissemination, and a poor prognosis with a 5-year survival rate of 10% to 30%.	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (20, 29))	('TP53', 'Gene', '7157', (37, 41))
63634	26552420	Similar to serous EC, endometrial intraepithelial carcinoma is associated with mutations and an abnormal accumulation of the TP53 protein.	('TP53', 'Gene', '7157', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('associated', 'Reg', (63, 73))	('endometrial intraepithelial carcinoma', 'Disease', 'MESH:D016889', (22, 59))	('endometrial intraepithelial carcinoma', 'Disease', (22, 59))	('TP53', 'Gene', (125, 129))	('EC', 'Phenotype', 'HP:0012114', (18, 20))	('accumulation', 'PosReg', (105, 117))	('mutations', 'Var', (79, 88))
63639	26552420	BRCA1 and BRCA2 mutation carriers have a 54% and 23% estimated lifetime risk of developing HGSC, respectively.	('mutation', 'Var', (16, 24))	('BRCA2', 'Gene', '675', (10, 15))	('BRCA1', 'Gene', (0, 5))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA2', 'Gene', (10, 15))	('developing HGSC', 'Disease', (80, 95))
63649	26552420	Samples were collected in accordance with the institutional review boards of the Medical University of Vienna (EK#1148_2011, EK#1766_2013), the Catholic University Leuven (B322201214864/S54406), the Kliniken Essen-Mitte (LANR_2013456), and the Charite Medical University of Berlin (EA2/025/14).	('EA2/025/14', 'Gene', '773', (282, 292))	('EA2/025/14', 'Gene', (282, 292))	('B322201214864/S54406', 'Var', (172, 192))
63655	26552420	Eight patients were excluded from final analysis for one of the following reasons (Table 1): two or more malignant tumors were present, tubal ligation was performed previously, patients were suspected of harboring a germline mutation, or primary tumor tissue was available but did not harbor any of the tested mutations.	('malignant tumors', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (115, 120))	('malignant tumors', 'Disease', 'MESH:D018198', (105, 121))	('germline mutation', 'Var', (216, 233))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
63667	26552420	In patients with malignant diseases, a median mutant allele fraction of 13.9% (range, 1.5% to 44.6%) was detected (Data Supplement).	('malignant diseases', 'Disease', (17, 35))	('mutant', 'Var', (46, 52))	('patients', 'Species', '9606', (3, 11))	('malignant diseases', 'Disease', 'MESH:D009369', (17, 35))
63677	26552420	Identified mutations were verified in the lavage fluids by SafeSeqS (one of 12 tumors) or ddPCR (five of six tumors) with a sensitivity of 0.1% (Fig 2).	('mutations', 'Var', (11, 20))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
63679	26552420	In total, 24 (80%) of 30 patients with OC were identified by either the NGS approach or singleplex analysis for the presence of a mutation previously identified in the primary tumor tissue.	('OC', 'Phenotype', 'HP:0100615', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutation', 'Var', (130, 138))	('tumor', 'Disease', (176, 181))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
63681	26552420	A lavage sample was analyzed that was taken from a 41-year-old BRCA1 mutation carrier (patient 205) submitted for RRSO, who was recruited from the prospectively running LUSTIC trial.	('BRCA1', 'Gene', (63, 68))	('LUSTIC trial', 'Phenotype', 'HP:0000733', (169, 181))	('mutation', 'Var', (69, 77))	('patient', 'Species', '9606', (87, 94))	('BRCA1', 'Gene', '672', (63, 68))
63685	26552420	A frameshift mutation (TP53 p.V217fs, c.650delT) was detected and confirmed by ddPCR (16.8%) and SafeSeqS (17.3%) in DNA from the lavage and the corresponding tissue sample (Speiser et al, submitted for publication).	('p.V217fs', 'Mutation', 'p.V217fsX', (28, 36))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('c.650delT', 'Mutation', 'c.650delT', (38, 47))	('c.650delT', 'Var', (38, 47))
63686	26552420	Eight (29.6%) of 27 lavage samples from patients with benign gynecologic diseases were found to be mutated by NGS.	('patients', 'Species', '9606', (40, 48))	('NGS', 'Var', (110, 113))	('mutated', 'Var', (99, 106))
63687	26552420	In six of these patients, a KRAS mutation was detected (Table 1).	('KRAS', 'Gene', (28, 32))	('patients', 'Species', '9606', (16, 24))	('mutation', 'Var', (33, 41))	('KRAS', 'Gene', '3845', (28, 32))
63689	26552420	Other genes affected only one or two patients (FBXW7, PIK3CA, PIK3R1, or PTEN), some of whom also harbored KRAS gene mutations.	('mutations', 'Var', (117, 126))	('PTEN', 'Gene', (73, 77))	('KRAS', 'Gene', (107, 111))	('PTEN', 'Gene', '5728', (73, 77))	('harbored', 'Reg', (98, 106))	('FBXW7', 'Gene', (47, 52))	('PIK3R1', 'Gene', (62, 68))	('PIK3CA', 'Gene', '5290', (54, 60))	('PIK3R1', 'Gene', '5295', (62, 68))	('patients', 'Species', '9606', (37, 45))	('KRAS', 'Gene', '3845', (107, 111))	('FBXW7', 'Gene', '55294', (47, 52))	('PIK3CA', 'Gene', (54, 60))
63690	26552420	None of the lavage samples harbored TP53 mutations, the gene that was most commonly mutated in the patients with OC (Fig 3).	('mutations', 'Var', (41, 50))	('OC', 'Phenotype', 'HP:0100615', (113, 115))	('TP53', 'Gene', '7157', (36, 40))	('patients', 'Species', '9606', (99, 107))	('TP53', 'Gene', (36, 40))
63697	26552420	In most cases, these were a result of mutations in the KRAS gene or other genes not commonly mutated in OC.	('KRAS', 'Gene', (55, 59))	('KRAS', 'Gene', '3845', (55, 59))	('result', 'Reg', (28, 34))	('OC', 'Phenotype', 'HP:0100615', (104, 106))	('mutations', 'Var', (38, 47))
63702	26552420	Only a multiplex assay such as the NGS method used here is applicable for screening of patients with OC as a result of the large number of different mutations in TP53 that can occur in OC.	('mutations', 'Var', (149, 158))	('result', 'Reg', (109, 115))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('occur', 'Reg', (176, 181))	('OC', 'Phenotype', 'HP:0100615', (185, 187))	('patients', 'Species', '9606', (87, 95))	('OC', 'Phenotype', 'HP:0100615', (101, 103))
63706	26552420	Notably, more than 90% of STICs harbor TP53 mutations, like the more advanced lesions that evolve from them.	('STICs', 'Disease', (26, 31))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
63716	26552420	Some of these cases may be explained by the fact that low-grade serous carcinoma, in contrast to HGSC, shows a slow transition from benign to malignant stage and thereby accumulates mutations in KRAS, BRAF, or PPP2R1A and other genes.	('PPP2R1A', 'Gene', (210, 217))	('BRAF', 'Gene', '673', (201, 205))	('PPP2R1A', 'Gene', '5518', (210, 217))	('accumulates', 'PosReg', (170, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('serous carcinoma', 'Disease', (64, 80))	('serous carcinoma', 'Disease', 'MESH:D018284', (64, 80))	('KRAS', 'Gene', '3845', (195, 199))	('KRAS', 'Gene', (195, 199))	('mutations', 'Var', (182, 191))	('BRAF', 'Gene', (201, 205))
63718	26552420	These results, especially the high frequency of KRAS mutations, suggest the exclusion of certain genes from mutation analysis for differential diagnosis.	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))	('mutations', 'Var', (53, 62))
63720	26552420	In patient 131, besides a predominant KRAS mutation, mutations in several other genes were detected, including TP53 (Data Supplement).	('KRAS', 'Gene', '3845', (38, 42))	('TP53', 'Gene', '7157', (111, 115))	('mutation', 'Var', (43, 51))	('patient', 'Species', '9606', (3, 10))	('mutations', 'Var', (53, 62))	('TP53', 'Gene', (111, 115))	('detected', 'Reg', (91, 99))	('KRAS', 'Gene', (38, 42))
63721	26552420	Thus, the exclusion of KRAS will not alter the test result because of the present TP53 mutation.	('TP53', 'Gene', (82, 86))	('KRAS', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (82, 86))	('mutation', 'Var', (87, 95))	('KRAS', 'Gene', '3845', (23, 27))
63786	25358384	reported a significant OS benefit associated with RLD, with a 5-year OS of 49%, compared with 35% for patients who had not undergone RLD.	('OS', 'Chemical', '-', (23, 25))	('OS', 'Chemical', '-', (69, 71))	('patients', 'Species', '9606', (102, 110))	('benefit', 'PosReg', (26, 33))	('RLD', 'Var', (50, 53))
63845	24719120	The 5-year disease-specific survival rate was 26% in patients who had positive lymph nodes compared with 64.2% in patients who had negative lymph nodes (p<0.001).	('positive lymph nodes', 'Var', (70, 90))	('patients', 'Species', '9606', (114, 122))	('disease-specific survival', 'CPA', (11, 36))	('patients', 'Species', '9606', (53, 61))
63872	23114646	However, patients with deep myometrial invasion, poor differentiation, serous or clear cell histology or extension of disease to other organs or lymph nodes within the pelvic region are at higher risk for disease recurrence.	('patients', 'Species', '9606', (9, 17))	('poor', 'Var', (49, 53))	('deep', 'CPA', (23, 27))	('serous', 'CPA', (71, 77))
63886	23114646	Alternations in cellular adhesion molecules such as E-cadherin are important for the development of invasive and metastatic capacity in human cancers.	('human', 'Species', '9606', (136, 141))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('Alternations', 'Var', (0, 12))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('E-cadherin', 'Gene', (52, 62))	('E-cadherin', 'Gene', '999', (52, 62))
63995	18929149	Subsequent studies in stage I and II EOC confirmed certain features, including stage IC (capsule rupture, surface tumor or positive washings), high grade or clear cell histology, as well as stage II, associated with a higher risk of post-surgical recurrence.	('post-surgical recurrence', 'CPA', (233, 257))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('high grade', 'Var', (143, 153))	('tumor', 'Disease', (114, 119))	('associated with', 'Reg', (200, 215))	('clear cell histology', 'CPA', (157, 177))
64033	18929149	Thus, GOG 97, in suboptimal stage III and IV compared C500 + P50 x 8 vs C1000 + P100 x 4 (are they mg/m2?).	('C1000 + P100 x', 'Var', (72, 86))	('P50', 'Gene', '4790', (61, 64))	('GOG', 'Chemical', '-', (6, 9))	('P50', 'Gene', (61, 64))
64111	18929149	Extrapolating from brief reports and the experience with testicular cancer, later trials used platinum-based regimens, first bleomycin + vinblastine + cisplatin, and more recently BEP, substituting etoposide for vinblastine.	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('testicular cancer', 'Phenotype', 'HP:0010788', (57, 74))	('platinum', 'Chemical', 'MESH:D010984', (94, 102))	('bleomycin', 'Chemical', 'MESH:D001761', (125, 134))	('etoposide', 'Chemical', 'MESH:D005047', (198, 207))	('testicular cancer', 'Disease', 'MESH:D013736', (57, 74))	('BEP', 'Chemical', 'MESH:C038328', (180, 183))	('substituting', 'Var', (185, 197))	('testicular cancer', 'Disease', (57, 74))	('vinblastine', 'Chemical', 'MESH:D014747', (137, 148))	('vinblastine', 'Chemical', 'MESH:D014747', (212, 223))
64195	18929149	Cisplatin + ifosfamide had a significantly higher response rate (p= .004) and PFS (p= .003) compared with cisplatin alone, but no improvement in OS; the combinations were more toxic.	('PFS', 'MPA', (78, 81))	('response', 'MPA', (50, 58))	('higher', 'PosReg', (43, 49))	('OS', 'Chemical', '-', (145, 147))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('ifosfamide', 'Chemical', 'MESH:D007069', (12, 22))	('Cisplatin', 'Var', (0, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))
64209	18929149	With regard to risk, germ line mutations in BRCA1 and BRCA2 and the mismatch repair families of genes are now known to account for the majority of inherited risk of ovarian and endometrial cancers, so germ line DNA can be screened for mutations in these genes and inherited risk determined.	('ovarian and endometrial cancers', 'Disease', 'MESH:D016889', (165, 196))	('BRCA1', 'Gene', (44, 49))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('BRCA2', 'Gene', (54, 59))	('endometrial cancer', 'Phenotype', 'HP:0012114', (177, 195))	('BRCA1', 'Gene', '672', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('BRCA2', 'Gene', '675', (54, 59))
64212	18929149	Relevant publications include, for example, reports from GOG 114 concerning prognostic significance of p53 mutation and overexpression, GOG 136 concerning a multidrug resistance protein in ovarian cancer and GOG 148 regarding soluble tumor necrosis factor receptors and CA125 in ovarian cancer.	('necrosis', 'Disease', (240, 248))	('tumor', 'Disease', (234, 239))	('ovarian cancer', 'Phenotype', 'HP:0100615', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('mutation', 'Var', (107, 115))	('CA125', 'Gene', '94025', (270, 275))	('multidrug resistance protein', 'MPA', (157, 185))	('p53', 'Gene', '7157', (103, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (279, 293))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('p53', 'Gene', (103, 106))	('overexpression', 'PosReg', (120, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ovarian cancer', 'Disease', (279, 293))	('GOG', 'Chemical', '-', (208, 211))	('GOG', 'Chemical', '-', (57, 60))	('necrosis', 'Disease', 'MESH:D009336', (240, 248))	('CA125', 'Gene', (270, 275))	('GOG', 'Chemical', '-', (136, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (279, 293))	('ovarian cancer', 'Disease', (189, 203))
64240	33919505	Furthermore, we identified a pathogenic tumor protein 53 (TP53) mutation affecting an acceptor splice site in intron 9, despite a wild-type p53 immunostaining pattern.	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (58, 62))	('pathogenic', 'Reg', (29, 39))	('tumor protein 53', 'Gene', (40, 56))	('tumor protein 53', 'Gene', '7157', (40, 56))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))
64241	33919505	The observations of diffuse and strong p16 expression, lack of GATA3 expression, pathogenic TP53 mutation, and wild-type Kirsten rat sarcoma viral oncogene homolog indicate that this tumor was not an MLA but an SC-MLD.	('mutation', 'Var', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('lack', 'NegReg', (55, 59))	('sarcoma', 'Disease', (133, 140))	('rat', 'Species', '10116', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('SC-MLD', 'Disease', (211, 217))	('SC-MLD', 'Disease', 'MESH:D007966', (211, 217))	('tumor', 'Disease', (183, 188))	('TP53', 'Gene', (92, 96))	('expression', 'MPA', (43, 53))	('MLA', 'Chemical', '-', (200, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('p16', 'Protein', (39, 42))
64254	33919505	Furthermore, in a recent study conducted by Euscher et al., the median progression-free and overall survival rates for uterine MLA patients were significantly shorter than those for SC patients.	('patients', 'Species', '9606', (131, 139))	('uterine MLA', 'Var', (119, 130))	('progression-free', 'CPA', (71, 87))	('MLA', 'Chemical', '-', (127, 130))	('shorter', 'NegReg', (159, 166))	('rat', 'Species', '10116', (109, 112))	('patients', 'Species', '9606', (185, 193))	('overall survival', 'CPA', (92, 108))
64295	33919505	Given that gynecological tumors harboring unusual tumor protein 53 (TP53) mutation can present with a wild-type p53 immunostaining pattern, we further conducted targeted sequencing analysis.	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor protein 53', 'Gene', (50, 66))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('p53', 'Gene', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor protein 53', 'Gene', '7157', (50, 66))	('TP53', 'Gene', (68, 72))	('p53', 'Gene', '7157', (112, 115))
64296	33919505	Targeted sequencing was performed to analyze single-nucleotide variations, insertions, and deletions and copy number variations using CancerSCAN (Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea).	('Cancer', 'Disease', (134, 140))	('single-nucleotide variations', 'Var', (45, 73))	('deletions', 'Var', (91, 100))	('Cancer', 'Disease', 'MESH:D009369', (134, 140))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('insertions', 'Var', (75, 85))
64297	33919505	Instead, interestingly, we noted that the tumor harbored a TP53 mutation in the intron inclusion between exons 9 and 10 (NM_000546.5(TP53):c.994-1G>C).	('tumor', 'Disease', (42, 47))	('TP53', 'Gene', (59, 63))	('5(TP53):c.994-1G>C', 'SUBSTITUTION', 'None', (131, 149))	('5(TP53):c.994-1G>C', 'Var', (131, 149))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
64298	33919505	We verified this unusual TP53 mutation affecting an acceptor splice site in intron 9 to be pathogenic in two disease-related databases, ClinVar (National Center for Biotechnology Information, United States National Library of Medicine, Bethesda, Maryland, United States of America) and Catalogue of Somatic Mutations in Cancer (Wellcome Sanger Institute, Hinxton, Cambridgeshire, United Kingdom).	('TP53', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('Cancer', 'Phenotype', 'HP:0002664', (320, 326))	('Cancer', 'Disease', (320, 326))	('Cancer', 'Disease', 'MESH:D009369', (320, 326))
64299	33919505	The identification of this unusual but definitely pathogenic mutation confirmed the wild-type p53 immunostaining pattern and the diagnosis of SC.	('p53', 'Gene', '7157', (94, 97))	('mutation', 'Var', (61, 69))	('pathogenic', 'Reg', (50, 60))	('p53', 'Gene', (94, 97))
64305	33919505	CancerSCAN (Samsung Genome Institute) also revealed the amplification of the Erb-b2 receptor tyrosine kinase (ERBB2) gene, gains of chromosomal 12p and 19p, and loss of 22q (Figure 3).	('ERBB2', 'Gene', '2064', (110, 115))	('Erb-b2', 'Gene', '2064', (77, 83))	('Erb-b2', 'Gene', (77, 83))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('loss', 'NegReg', (161, 165))	('gains', 'PosReg', (123, 128))	('22q', 'MPA', (169, 172))	('ERBB2', 'Gene', (110, 115))	('amplification', 'Var', (56, 69))	('chromosomal', 'Var', (132, 143))
64309	33919505	The following observations designated this tumor not as MLA but as SC-MLD: diffuse and strong p16 expression, pathogenic TP53 mutation, lack of GATA3 expression, and wild-type KRAS.	('SC-MLD', 'Disease', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutation', 'Var', (126, 134))	('TP53', 'Gene', (121, 125))	('SC-MLD', 'Disease', 'MESH:D007966', (67, 73))	('p16', 'Protein', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('MLA', 'Chemical', '-', (56, 59))	('tumor', 'Disease', (43, 48))
64317	33919505	Nearly every SC harbors pathogenic TP53 mutation and displays mutant p53 immunostaining pattern.	('mutation', 'Var', (40, 48))	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', (69, 72))	('TP53', 'Gene', (35, 39))	('pathogenic', 'Reg', (24, 34))
64328	33919505	Despite the complicated histological and immunohistochemical features, we finally confirmed the diagnosis of SC-MLD using targeted sequencing analysis, which revealed that the tumor harbored a splice site TP53 mutation but not a KRAS mutation.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('TP53 mutation', 'Var', (205, 218))	('mutation', 'Var', (210, 218))	('SC-MLD', 'Disease', (109, 115))	('SC-MLD', 'Disease', 'MESH:D007966', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
64343	33919505	reported that splice site TP53 mutations are relatively uncommon in endometrial SC.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('endometrial SC', 'Disease', 'MESH:D014591', (68, 82))	('endometrial SC', 'Disease', (68, 82))	('splice', 'Var', (14, 20))
64344	33919505	In addition, we previously demonstrated that the splice site TP53 mutation can result in a wild-type p53 immunostaining pattern in tubo-ovarian or peritoneal high-grade SC.	('tubo-ovarian', 'Disease', (131, 143))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('mutation', 'Var', (66, 74))	('rat', 'Species', '10116', (34, 37))	('result in', 'Reg', (79, 88))	('tubo-ovarian', 'Disease', 'MESH:D010049', (131, 143))	('TP53', 'Gene', (61, 65))
64346	33919505	When a high-grade endometrial carcinoma with serous histology exhibits a wild-type p53 immunostaining pattern, molecular tests such as targeted sequencing analysis or Sanger sequencing should be performed to confirm the presence of uncommon but pathogenic TP53 mutation.	('p53', 'Gene', (83, 86))	('pathogenic', 'Reg', (245, 255))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (18, 39))	('p53', 'Gene', '7157', (83, 86))	('endometrial carcinoma', 'Disease', (18, 39))	('mutation', 'Var', (261, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (18, 39))	('TP53', 'Gene', (256, 260))
64347	33919505	We detected not only an unusual TP53 mutation but also ERBB2 amplification using targeted sequencing.	('mutation', 'Var', (37, 45))	('ERBB2', 'Gene', '2064', (55, 60))	('TP53', 'Gene', (32, 36))	('ERBB2', 'Gene', (55, 60))
64348	33919505	ERBB2 amplification is observed in approximately 30% of endometrial SC cases.	('endometrial SC', 'Disease', (56, 70))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (0, 5))	('endometrial SC', 'Disease', 'MESH:D014591', (56, 70))	('amplification', 'Var', (6, 19))
64349	33919505	As trastuzumab can significantly improve the prognosis of patients with uterine SC showing human epidermal growth factor receptor 2 overexpression or ERBB2 gene amplification, the identification of ERBB2 amplification can provide additional therapeutic options.	('ERBB2', 'Gene', (198, 203))	('improve', 'PosReg', (33, 40))	('ERBB2', 'Gene', '2064', (198, 203))	('overexpression', 'PosReg', (132, 146))	('ERBB2', 'Gene', '2064', (150, 155))	('trastuzumab', 'Chemical', 'MESH:D000068878', (3, 14))	('prognosis', 'MPA', (45, 54))	('uterine SC', 'Disease', (72, 82))	('ERBB2', 'Gene', (150, 155))	('epidermal growth factor receptor 2', 'Gene', (97, 131))	('epidermal growth factor receptor 2', 'Gene', '2064', (97, 131))	('gene amplification', 'Var', (156, 174))	('patients', 'Species', '9606', (58, 66))	('human', 'Species', '9606', (91, 96))
64353	33919505	Lack of GATA-3 expression, diffuse and strong nuclear and cytoplasmic p16 immunoreactivity, and the presence of pathogenic TP53 mutation designated this tumor as SC-MLD rather than MLA.	('rat', 'Species', '10116', (169, 172))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Lack', 'NegReg', (0, 4))	('SC-MLD', 'Disease', (162, 168))	('GATA-3', 'Gene', '2625', (8, 14))	('pathogenic', 'Reg', (112, 122))	('SC-MLD', 'Disease', 'MESH:D007966', (162, 168))	('tumor', 'Disease', (153, 158))	('MLA', 'Chemical', '-', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('p16', 'Protein', (70, 73))	('GATA-3', 'Gene', (8, 14))	('mutation', 'Var', (128, 136))	('TP53', 'Gene', (123, 127))
64354	33919505	Weak-to-moderate PAX2 immunoreactivity and wild-type p53 immunostaining pattern could be diagnostic pitfalls, and splice site TP53 mutation caused the discordant p53 results between immunostaining and targeted sequencing.	('PAX2', 'Gene', '5076', (17, 21))	('rat', 'Species', '10116', (12, 15))	('TP53', 'Gene', (126, 130))	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (162, 165))	('splice site', 'Var', (114, 125))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('PAX2', 'Gene', (17, 21))	('mutation', 'Var', (131, 139))
64355	33919505	For cases with high-grade endometrial carcinoma showing wild-type p53 immunostaining pattern, targeted sequencing can help pathologists confirm the presence of TP53 mutation.	('endometrial carcinoma', 'Disease', (26, 47))	('p53', 'Gene', '7157', (66, 69))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (26, 47))	('mutation', 'Var', (165, 173))	('TP53', 'Gene', (160, 164))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (26, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('p53', 'Gene', (66, 69))
64448	32726992	The evolution of type I EC tumors from atypical endometrial cells is connected with PTEN, PIK3CA and CTNNB1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('PTEN', 'Gene', (84, 88))	('CTNNB1', 'Gene', '1499', (101, 107))	('PIK3CA', 'Gene', (90, 96))	('PTEN', 'Gene', '5728', (84, 88))	('type I EC tumors', 'Disease', 'MESH:D018761', (17, 33))	('PIK3CA', 'Gene', '5290', (90, 96))	('CTNNB1', 'Gene', (101, 107))	('type I EC tumors', 'Disease', (17, 33))
64449	32726992	Studies have also suggested that the presence of an inactivated ARID1A tumor suppressor gene can, together with a PTEN mutation, lead to EC proliferation.	('mutation', 'Var', (119, 127))	('lead to', 'Reg', (129, 136))	('ARID1A', 'Gene', (64, 70))	('EC proliferation', 'CPA', (137, 153))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('PTEN', 'Gene', (114, 118))	('PTEN', 'Gene', '5728', (114, 118))	('presence', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
64450	32726992	In type II serous EC, tumors arise independent of estrogen, but some mutations such as PBXW7, PIK3CA, PPR2R1A mutations and CCNE1 amplifications have been identified as early events in EC progression.	('mutations', 'Var', (69, 78))	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PBXW7', 'Gene', (87, 92))	('PIK3CA', 'Gene', (94, 100))	('CCNE1', 'Gene', '898', (124, 129))	('PPR2R1A', 'Gene', (102, 109))	('type II serous EC, tumors', 'Disease', 'MESH:D018284', (3, 28))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('CCNE1', 'Gene', (124, 129))	('PIK3CA', 'Gene', '5290', (94, 100))
64451	32726992	Further on, uterine carcinosarcomas (UCS) have coexisting PTEN and TP53 mutations present.	('carcinosarcomas', 'Disease', (20, 35))	('PTEN', 'Gene', '5728', (58, 62))	('mutations', 'Var', (72, 81))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (12, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('carcinosarcomas', 'Disease', 'MESH:D002296', (20, 35))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('PTEN', 'Gene', (58, 62))
64468	32726992	discovered that micro RNAs (miRNAs) miR-320a and miR-340-5p are downregulated in EC in comparison to adjacent normal tissue.	('miR-320a', 'Gene', (36, 44))	('miR-320a', 'Gene', '407037', (36, 44))	('micro', 'Protein', (16, 21))	('miR-340-5p', 'Chemical', '-', (49, 59))	('miR-340-5p', 'Var', (49, 59))	('downregulated', 'NegReg', (64, 77))
64470	32726992	Correspondingly, experimental overexpression of miR-320a and miR-340-5p suppresses migration and invasion of HEC-1A cells.	('miR-320a', 'Gene', (48, 56))	('miR-320a', 'Gene', '407037', (48, 56))	('miR-340-5p', 'Chemical', '-', (61, 71))	('miR-340-5p', 'Var', (61, 71))	('overexpression', 'PosReg', (30, 44))	('HEC-1A', 'CellLine', 'CVCL:0293', (109, 115))	('suppresses', 'NegReg', (72, 82))
64472	32726992	Transforming growth factor beta 1 (TGF-beta1) is likewise suppressed by overexpression of miR-340-5p and miR-320a, usually being responsible for phosphorylation of eIF4E.	('phosphor', 'Chemical', '-', (145, 153))	('Transforming growth factor beta 1', 'Gene', '7040', (0, 33))	('TGF-beta1', 'Gene', '7040', (35, 44))	('TGF-beta1', 'Gene', (35, 44))	('eIF4E', 'Gene', '1977', (164, 169))	('suppressed', 'NegReg', (58, 68))	('phosphorylation', 'MPA', (145, 160))	('miR-320a', 'Gene', (105, 113))	('miR-320a', 'Gene', '407037', (105, 113))	('miR-340-5p', 'Chemical', '-', (90, 100))	('eIF4E', 'Gene', (164, 169))	('Transforming growth factor beta 1', 'Gene', (0, 33))	('miR-340-5p', 'Var', (90, 100))
64480	32726992	Nine of these studies involve agents targeting eIF4E, being either ribavirin, an agent initially developed against hepatitis C, ISIS EIF4E Rx, an antisense oligonucleotide against eIF4E, or LY2275796, another antisense oligonucleotide blocking the expression of eIF4E.	('oligonucleotide', 'Chemical', 'MESH:D009841', (219, 234))	('LY2275796', 'Chemical', 'MESH:C569652', (190, 199))	('eIF4E', 'Gene', (262, 267))	('EIF4E', 'Gene', (133, 138))	('eIF4E', 'Gene', (180, 185))	('eIF4E', 'Gene', '1977', (47, 52))	('hepatitis', 'Phenotype', 'HP:0012115', (115, 124))	('LY2275796', 'Var', (190, 199))	('expression', 'MPA', (248, 258))	('ribavirin', 'Chemical', 'MESH:D012254', (67, 76))	('blocking', 'NegReg', (235, 243))	('eIF4E', 'Gene', (47, 52))	('eIF4E', 'Gene', '1977', (262, 267))	('oligonucleotide', 'Chemical', 'MESH:D009841', (156, 171))	('eIF4E', 'Gene', '1977', (180, 185))	('EIF4E', 'Gene', '1977', (133, 138))	('hepatitis C', 'Disease', (115, 126))
64492	32726992	By silencing zinc finger E-box-binding homeobox (ZEB1) it was shown that cell sensitivity to cisplatin was improved and EC cell migration decreased.	('silencing', 'Var', (3, 12))	('decreased', 'NegReg', (138, 147))	('improved', 'PosReg', (107, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('cell sensitivity to cisplatin', 'MPA', (73, 102))	('ZEB1', 'Gene', (49, 53))	('ZEB1', 'Gene', '6935', (49, 53))	('EC cell migration', 'CPA', (120, 137))
64500	32726992	DUSP6 studies showed that by knockdown, EMT was enhanced.	('DUSP6', 'Gene', (0, 5))	('knockdown', 'Var', (29, 38))	('enhanced', 'PosReg', (48, 56))	('EMT', 'CPA', (40, 43))	('DUSP6', 'Gene', '1848', (0, 5))
64505	32726992	UBE2C knockdown lead to inhibited cell proliferation, migration, invasion and EMT.	('UBE2C', 'Gene', (0, 5))	('cell proliferation', 'CPA', (34, 52))	('migration', 'CPA', (54, 63))	('inhibited', 'NegReg', (24, 33))	('invasion', 'CPA', (65, 73))	('knockdown', 'Var', (6, 15))	('EMT', 'CPA', (78, 81))	('UBE2C', 'Gene', '11065', (0, 5))
64506	32726992	Knockdown was also connected to an increase of p53 expression.	('increase', 'PosReg', (35, 43))	('Knockdown', 'Var', (0, 9))	('expression', 'MPA', (51, 61))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
64507	32726992	Mutations in the expression of p53 were then further on together with mutations in the PI3K/PTEN and FBXW7 (previously known as CDC4) pathways connected to initiate through EMT also transformation in uterine carcinosarcoma (UCS), a hormonally independent cancer type.	('carcinosarcoma', 'Disease', (208, 222))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('PTEN', 'Gene', (92, 96))	('CDC4', 'Gene', '55294', (128, 132))	('carcinosarcoma', 'Disease', 'MESH:D002296', (208, 222))	('FBXW7', 'Gene', '55294', (101, 106))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (92, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (200, 222))	('CDC4', 'Gene', (128, 132))	('FBXW7', 'Gene', (101, 106))
64511	32726992	By silencing Bmi1, studies in EC cell lines discovered that expression of SOX2 and Oct4, being transcription factors for totipotency, decreased and the expression of E-cadherin an epithelial marker increased.	('decreased', 'NegReg', (134, 143))	('expression', 'MPA', (60, 70))	('silencing', 'Var', (3, 12))	('E-cadherin', 'Gene', (166, 176))	('E-cadherin', 'Gene', '999', (166, 176))	('Oct4', 'Gene', (83, 87))	('increased', 'PosReg', (198, 207))	('SOX2', 'Gene', '6657', (74, 78))	('SOX2', 'Gene', (74, 78))	('Bmi1', 'Gene', '648', (13, 17))	('Oct4', 'Gene', '5460', (83, 87))	('expression', 'MPA', (152, 162))	('Bmi1', 'Gene', (13, 17))
64522	32726992	showed that metformin reduced the activity of cells in Ishikawa and Hec-1 cell lines, but not their viability, this effect could not be reproduced using metformin in adipocyte conditioned media.	('activity', 'MPA', (34, 42))	('metformin', 'Chemical', 'MESH:D008687', (153, 162))	('metformin', 'Chemical', 'MESH:D008687', (12, 21))	('Hec-1', 'Gene', (68, 73))	('Hec-1', 'Gene', '10403', (68, 73))	('reduced', 'NegReg', (22, 29))	('metformin', 'Var', (12, 21))
64531	32726992	lncRNA H19 knockdown lead to Snail downregulation and E-cadherin level increase without affecting vimentin.	('H19', 'Gene', '283120', (7, 10))	('H19', 'Gene', (7, 10))	('E-cadherin', 'Gene', (54, 64))	('E-cadherin', 'Gene', '999', (54, 64))	('increase', 'PosReg', (71, 79))	('downregulation', 'NegReg', (35, 49))	('Snail', 'Gene', '6615', (29, 34))	('vimentin', 'Gene', '7431', (98, 106))	('vimentin', 'Gene', (98, 106))	('Snail', 'Gene', (29, 34))	('knockdown', 'Var', (11, 20))
64532	32726992	Thus, there was a partial EMT reversal by knockdown of lncRNA H19.	('H19', 'Gene', '283120', (62, 65))	('H19', 'Gene', (62, 65))	('knockdown', 'Var', (42, 51))
64539	32726992	Mitochondrial DNA (mtDNA) mutations are found in various cancer types.	('Mitochondrial DNA', 'Disease', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
64541	32726992	analyzed mtDNA from endometrial cancer, lymph node neoplastic tissue and ovarian cancer and discovered a frameshift deletion m.11038delA in the MTND4 gene in ovarian cancer only.	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MTND4', 'Gene', (144, 149))	('lymph node neoplastic tissue', 'Phenotype', 'HP:0002665', (40, 68))	('MTND4', 'Gene', '4538', (144, 149))	('endometrial cancer', 'Phenotype', 'HP:0012114', (20, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('endometrial cancer', 'Disease', (20, 38))	('ovarian cancer', 'Disease', 'MESH:D010051', (73, 87))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (51, 68))	('endometrial cancer', 'Disease', 'MESH:D016889', (20, 38))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('m.11038delA', 'Mutation', 'c.M.11038delA', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ovarian cancer', 'Disease', (73, 87))	('m.11038delA', 'Var', (125, 136))	('ovarian cancer', 'Disease', (158, 172))	('lymph node neoplastic tissue and ovarian cancer', 'Disease', 'MESH:D000072717', (40, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))
64542	32726992	A germ line mutation (m.G15077A) was found in MTCYTB in endometrial cancer, in lymph node and in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('m.G15077A', 'Mutation', 'm.G15077A', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Disease', (97, 111))	('endometrial cancer', 'Disease', (56, 74))	('endometrial cancer', 'Phenotype', 'HP:0012114', (56, 74))	('lymph node', 'Disease', (79, 89))	('MTCYTB', 'Chemical', '-', (46, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('endometrial cancer', 'Disease', 'MESH:D016889', (56, 74))	('m.G15077A', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('MTCYTB', 'Gene', (46, 52))
64543	32726992	Some 56% (28 of 50) of frozen samples of primary endometrial carcinoma obtained from surgery carried one or more somatic mtDNA mutations, only occurring in the tumor.	('mtDNA', 'Gene', (121, 126))	('endometrial carcinoma', 'Disease', (49, 70))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (49, 70))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', (160, 165))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (49, 70))
64545	32726992	In the 12S rRNA gene either novel mtMSI were found carrying a deletion or insertion of one cytosine residue in front of the thymine or a germline T to C polymorphism was discovered, producing a homopolymorphic C tract resulting in a DNA instability.	('insertion', 'Var', (74, 83))	('12S rRNA', 'Gene', (7, 15))	('cytosine', 'Chemical', 'MESH:D003596', (91, 99))	('producing', 'Reg', (182, 191))	('homopolymorphic C tract', 'MPA', (194, 217))	('thymine', 'Chemical', 'MESH:D013941', (124, 131))	('deletion', 'Var', (62, 70))	('DNA instability', 'MPA', (233, 248))
64549	32726992	found hypervariable regions within the 16sRNA gene, tRNA(leu) and the ND1 gene associated with a higher risk of developing endometrial cancer.	('16sRNA', 'Gene', (39, 45))	('associated', 'Reg', (79, 89))	('ND1', 'Gene', '4535', (70, 73))	('endometrial cancer', 'Disease', 'MESH:D016889', (123, 141))	('endometrial cancer', 'Phenotype', 'HP:0012114', (123, 141))	('ND1', 'Gene', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('hypervariable regions', 'Var', (6, 27))	('tRNA(leu)', 'Gene', '4563', (52, 61))	('tRNA(leu', 'Gene', (52, 60))	('endometrial cancer', 'Disease', (123, 141))
64552	32726992	They discovered that eIF3B knockdown prevented cell migration and invasion.	('eIF3B', 'Gene', '8662', (21, 26))	('knockdown', 'Var', (27, 36))	('prevented', 'NegReg', (37, 46))	('eIF3B', 'Gene', (21, 26))
64558	32726992	Through knockdown of eIF5A-2, E-cadherin expression increased and vimentin decreased, this process was reversed, when eIF5A-2 was overexpressed.	('eIF5A-2', 'Gene', (118, 125))	('eIF5A-2', 'Gene', '56648', (118, 125))	('increased', 'PosReg', (52, 61))	('vimentin', 'Gene', '7431', (66, 74))	('expression', 'MPA', (41, 51))	('knockdown', 'Var', (8, 17))	('vimentin', 'Gene', (66, 74))	('E-cadherin', 'Gene', (30, 40))	('E-cadherin', 'Gene', '999', (30, 40))	('eIF5A-2', 'Gene', (21, 28))	('eIF5A-2', 'Gene', '56648', (21, 28))	('decreased', 'NegReg', (75, 84))
64560	32726992	Inhibition of PERK impacted also eIF2alpha phosphorylation in EMT cells.	('PERK', 'Gene', (14, 18))	('phosphorylation', 'MPA', (43, 58))	('PERK', 'Gene', '9451', (14, 18))	('phosphor', 'Chemical', '-', (43, 51))	('eIF2alpha', 'Gene', (33, 42))	('Inhibition', 'Var', (0, 10))	('eIF2alpha', 'Gene', '83939', (33, 42))
64618	32884523	Positivity for calretinin, and for at least one more of the other abovementioned markers, is necessary in order to obtain the diagnosis of UTROSCT.	('UTROSCT', 'Disease', (139, 146))	('calretinin', 'Gene', (15, 25))	('calretinin', 'Gene', '794', (15, 25))	('Positivity', 'Var', (0, 10))
64829	29189288	Next-generation sequencing using 12 samples (11 primary tumors and 1 metastatic tumor) revealed 42 single nucleotide variations in 16 genes, mostly in KRAS (10/12) and ARID1A (9/12).	('single nucleotide variations', 'Var', (99, 127))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('KRAS', 'Gene', '3845', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('ARID1A', 'Gene', '8289', (168, 174))	('ARID1A', 'Gene', (168, 174))	('tumor', 'Disease', (80, 85))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('KRAS', 'Gene', (151, 155))
64838	29189288	A recent study that used next-generation sequencing (NGS) for targeted genomic profiling reported that the majority of MNAC examined harbored KRAS mutation, suggesting that KRAS mutation is involved in MNAC development.	('KRAS', 'Gene', (142, 146))	('harbored', 'Reg', (133, 141))	('mutation', 'Var', (147, 155))	('KRAS', 'Gene', '3845', (142, 146))	('KRAS', 'Gene', (173, 177))	('KRAS', 'Gene', '3845', (173, 177))	('involved', 'Reg', (190, 198))
64863	29189288	The p53 immunostaining pattern was interpreted as a missense-mutation, nonsense-mutation, or wild-type pattern when p53 expression was diffuse and strong (>60% of tumor cell nuclei), absent (<5%), or focal and weakly positive, respectively.	('p53', 'Gene', '7157', (4, 7))	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('absent', 'NegReg', (183, 189))	('p53', 'Gene', '7157', (116, 119))	('tumor', 'Disease', (163, 168))	('missense-mutation', 'Var', (52, 69))	('nonsense-mutation', 'Var', (71, 88))	('p53', 'Gene', (4, 7))	('p53', 'Gene', (116, 119))
64866	29189288	Single nucleotide variants (SNVs) and insertions and deletions (indels) were identified using MuTect (http://archive.broadinstitute.org/cancer/cga/mutect) and Pindel (http://gmt.genome.wustl.edu/packages/pindel/), respectively.	('cga', 'Gene', (143, 146))	('deletions', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cga', 'Gene', '1113', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
64942	29189288	The most commonly detected SNV in UB-MNAC was activating KRAS mutation (10/12), including G12V (6/12), G12C (2/12), and G12D (2/12).	('G12V', 'Mutation', 'rs121913529', (90, 94))	('G12C', 'Var', (103, 107))	('G12C', 'Mutation', 'rs121913530', (103, 107))	('G12D', 'Var', (120, 124))	('KRAS', 'Gene', (57, 61))	('G12D', 'Mutation', 'rs121913529', (120, 124))	('KRAS', 'Gene', '3845', (57, 61))	('activating', 'PosReg', (46, 56))	('G12V', 'Var', (90, 94))	('UB-MNAC', 'Chemical', '-', (34, 41))
64943	29189288	The second most common SNV was ARID1A mutation (9/12), including T294P (6/12), Q288P (2/12), and Q287Pfs (1/12).	('Q288P', 'Var', (79, 84))	('T294P', 'Var', (65, 70))	('ARID1A', 'Gene', '8289', (31, 37))	('T294P', 'Mutation', 'p.T294P', (65, 70))	('ARID1A', 'Gene', (31, 37))	('Q287Pfs', 'Var', (97, 104))	('Q288P', 'Mutation', 'p.Q288P', (79, 84))
64945	29189288	Of note, primary (case 13A) and metastatic (case 13B) tumors exhibited identical mutations in KRAS and ARID1A and shared the same CNV pattern.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('KRAS', 'Gene', (94, 98))	('ARID1A', 'Gene', '8289', (103, 109))	('metastatic', 'CPA', (32, 42))	('ARID1A', 'Gene', (103, 109))	('KRAS', 'Gene', '3845', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
64946	29189288	Additional PTEN mutation (D268E) was detected in metastatic tumor only, indicating that PTEN mutation is a relatively late event in the sequence of genetic alterations in UB-MNAC.	('PTEN', 'Gene', (11, 15))	('UB-MNAC', 'Gene', (171, 178))	('PTEN', 'Gene', '5728', (11, 15))	('D268E', 'Var', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PTEN', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PTEN', 'Gene', '5728', (88, 92))	('D268E', 'Mutation', 'rs398123328', (26, 31))	('UB-MNAC', 'Chemical', '-', (171, 178))	('tumor', 'Disease', (60, 65))
64985	29189288	In this study, analyses of NGS data revealed that 10/12 cases of UB-MNAC harbored activating KRAS mutation.	('KRAS', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('activating', 'PosReg', (82, 92))	('KRAS', 'Gene', '3845', (93, 97))	('UB-MNAC', 'Chemical', '-', (65, 72))
64986	29189288	This finding is consistent with previous observations by Mirkovic et al, who reported activating KRAS and NRAS mutations in 12/17 and 1/17 cases of MNAC, respectively.	('mutations', 'Var', (111, 120))	('KRAS', 'Gene', (97, 101))	('KRAS', 'Gene', '3845', (97, 101))	('NRAS', 'Gene', (106, 110))	('activating', 'PosReg', (86, 96))	('MNAC', 'Disease', (148, 152))	('NRAS', 'Gene', '4893', (106, 110))
64987	29189288	Considering that the majority (12/17) of tumor samples in their report were of cervical origin, KRAS mutation appears to be a driver mutation in MNAC of either UC or corpus.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('UC', 'Phenotype', 'HP:0030160', (160, 162))	('KRAS', 'Gene', '3845', (96, 100))	('mutation', 'Var', (101, 109))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('KRAS', 'Gene', (96, 100))
64988	29189288	In addition, we found that 9/12 cases harbored ARID1A mutation.	('mutation', 'Var', (54, 62))	('ARID1A', 'Gene', '8289', (47, 53))	('ARID1A', 'Gene', (47, 53))	('harbored', 'Reg', (38, 46))
64989	29189288	In line with this finding, Mirkovic et al reported ARID1A mutation in 6/17 cases.	('mutation', 'Var', (58, 66))	('ARID1A', 'Gene', '8289', (51, 57))	('reported', 'Reg', (42, 50))	('ARID1A', 'Gene', (51, 57))
64990	29189288	The most common ARID1A mutation in UB-MNAC was T294P, which has been also reported in endometrial endometrioid carcinoma, serous carcinoma, and carcinosarcoma.	('UB-MNAC', 'Chemical', '-', (35, 42))	('T294P', 'Mutation', 'p.T294P', (47, 52))	('carcinosarcoma', 'Disease', 'MESH:D002296', (144, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('UB-MNAC', 'Gene', (35, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinosarcoma', 'Disease', (144, 158))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (86, 120))	('endometrial endometrioid carcinoma', 'Disease', (86, 120))	('serous carcinoma', 'Disease', (122, 138))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (98, 120))	('serous carcinoma', 'Disease', 'MESH:D018284', (122, 138))	('ARID1A', 'Gene', '8289', (16, 22))	('T294P', 'Var', (47, 52))	('ARID1A', 'Gene', (16, 22))
64991	29189288	Two ARID1A mutations (Q288P and Q287Pfs) identified in this study were novel missense mutations.	('Q288P', 'Mutation', 'p.Q288P', (22, 27))	('ARID1A', 'Gene', '8289', (4, 10))	('ARID1A', 'Gene', (4, 10))	('Q287Pfs', 'Var', (32, 39))	('Q288P', 'Var', (22, 27))
64993	29189288	In fact, 1q gain is the most common chromosomal alteration across all types of endometrial carcinoma.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (79, 100))	('1q gain', 'Var', (9, 16))	('endometrial carcinoma', 'Disease', (79, 100))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (79, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))
65003	29189288	NGS data revealed distinct molecular features of UB-MNAC, including frequent somatic mutations of KRAS and ARID1A and gain of 1q.	('UB-MNAC', 'Chemical', '-', (49, 56))	('ARID1A', 'Gene', '8289', (107, 113))	('ARID1A', 'Gene', (107, 113))	('mutations', 'Var', (85, 94))	('gain', 'PosReg', (118, 122))	('KRAS', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (98, 102))
65060	29400019	specifically reported that bands of low SI are observed within the areas of myometrial involvement on T2WI in ESS and that these bands correspond to the preserved bundles of myometrium on pathologic examination.	('T2WI', 'Var', (102, 106))	('low SI', 'Disease', (36, 42))	('low SI', 'Disease', 'MESH:D009800', (36, 42))
65156	29620641	showed that inhibiting LDH-A expression promoted apoptosis and reduced cell proliferation in vitro, suppressed infection and metastasis, and restored chemosensitivity in vivo.	('promoted', 'PosReg', (40, 48))	('reduced', 'NegReg', (63, 70))	('infection', 'Disease', (111, 120))	('LDH-A', 'Gene', '3939', (23, 28))	('restored', 'PosReg', (141, 149))	('inhibiting', 'Var', (12, 22))	('chemosensitivity', 'CPA', (150, 166))	('suppressed', 'NegReg', (100, 110))	('LDH-A', 'Gene', (23, 28))	('infection', 'Disease', 'MESH:D007239', (111, 120))	('apoptosis', 'CPA', (49, 58))	('cell proliferation', 'CPA', (71, 89))
65159	29620641	Overexpression of LDH-A in cholangiocarcinoma was also correlated with poor prognosis.	('LDH-A', 'Gene', (18, 23))	('cholangiocarcinoma', 'Disease', (27, 45))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('Overexpression', 'Var', (0, 14))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('LDH-A', 'Gene', '3939', (18, 23))
65160	29620641	The present study provides the basis for the future use of LDH-A inhibitors in leiomyosarcoma of the uterus.	('LDH-A', 'Gene', (59, 64))	('leiomyosarcoma of the uterus', 'Disease', 'MESH:D007890', (79, 107))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (79, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('inhibitors', 'Var', (65, 75))	('leiomyosarcoma of the uterus', 'Disease', (79, 107))	('LDH-A', 'Gene', '3939', (59, 64))
65203	28027320	All seven patients were found to have significant cancer-associated gene mutations in both cell pellet and cfDNA fractions.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (73, 82))
65204	28027320	In the four patients in whom adequate tumor sample was available, all tumor mutations above a specific allele fraction were present in the uterine lavage DNA samples.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
65205	28027320	Mutations originally only detected in lavage fluid fractions were later confirmed to be present in tumor but at allele fractions significantly less than 1%.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (99, 104))
65207	28027320	Intriguingly, 51 patients without histopathologic evidence of cancer had relatively high allele fraction (1.0%-30.4%), cancer-associated mutations.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('mutations', 'Var', (137, 146))	('cancer', 'Disease', (119, 125))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
65209	28027320	No associations were detected between mutation status and race/ethnicity, body mass index, diabetes, parity, and smoking status.	('diabetes', 'Disease', (91, 99))	('diabetes', 'Disease', 'MESH:D003920', (91, 99))	('mutation', 'Var', (38, 46))
65211	28027320	Using our targeted sequencing approach, endometrial driver mutations were identified in all seven women who received a cancer diagnosis based on classic histopathology of tissue curettage obtained at the time of hysteroscopy.	('women', 'Species', '9606', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('endometrial driver', 'Gene', (40, 58))	('cancer', 'Disease', (119, 125))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
65212	28027320	In addition, relatively high allele fraction driver mutations were identified in the lavage fluid of approximately half of the women without a cancer diagnosis.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('women', 'Species', '9606', (127, 132))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
65213	28027320	Increasing age and post-menopausal status were associated with the presence of these cancer-associated mutations, suggesting the prevalent existence of a premalignant landscape in women without clinical evidence of cancer.	('women', 'Species', '9606', (180, 185))	('mutations', 'Var', (103, 112))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('post-menopausal status', 'Phenotype', 'HP:0008209', (19, 41))	('menopausal status', 'Phenotype', 'HP:0008209', (24, 41))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
65217	28027320	This method also reveals cancer mutations in women without cancer.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('reveals', 'Reg', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('women', 'Species', '9606', (45, 50))
65224	28027320	Fifty-one women without histopathologic evidence of cancer had high allele fraction cancer-associated mutations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (102, 111))	('women', 'Species', '9606', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
65226	28027320	Our study identified a previously unknown but highly prevalent landscape of driver and potential driver mutations in women who did not have histopathologic evidence of endometrial cancer.	('mutations', 'Var', (104, 113))	('endometrial cancer', 'Phenotype', 'HP:0012114', (168, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('women', 'Species', '9606', (117, 122))	('prevalent', 'Reg', (53, 62))	('endometrial cancer', 'Disease', 'MESH:D016889', (168, 186))	('endometrial cancer', 'Disease', (168, 186))
65247	28027320	Recently, two exciting proof-of-principle studies demonstrated the use of next-generation sequencing (NGS) of DNA of uterine shed cells to identify somatic mutations in patients with known gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('patients', 'Species', '9606', (169, 177))	('cancers', 'Disease', (201, 208))	('mutations', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))
65248	28027320	In already established endometrial and ovarian cancer cases, the authors demonstrated that panel-based, targeted sequencing of shed cells, retrieved either by brushing of the cervical canal or through uterine lavage, could detect somatic mutations consistent with these two Mullerian duct-derived cancer types.	('ovarian cancer', 'Disease', 'MESH:D010051', (39, 53))	('cancer', 'Disease', (297, 303))	('detect', 'Reg', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('ovarian cancer', 'Disease', (39, 53))	('cancer', 'Disease', (47, 53))	('somatic mutations', 'Var', (230, 247))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
65253	28027320	Using first a pan-cancer 56-gene panel and then a TCGA-guided 12-gene endometrial cancer panel, we detected somatic mutations in all women who were later diagnosed with stage IA endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('pan-cancer', 'Disease', 'MESH:C537931', (14, 24))	('endometrial cancer', 'Phenotype', 'HP:0012114', (178, 196))	('women', 'Species', '9606', (133, 138))	('endometrial cancer', 'Disease', (70, 88))	('endometrial cancer', 'Disease', 'MESH:D016889', (178, 196))	('endometrial cancer', 'Phenotype', 'HP:0012114', (70, 88))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('stage IA endometrial cancer', 'Disease', (169, 196))	('mutations', 'Var', (116, 125))	('pan-cancer', 'Disease', (14, 24))	('endometrial cancer', 'Disease', 'MESH:D016889', (70, 88))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('detected', 'Reg', (99, 107))	('stage IA endometrial cancer', 'Disease', 'MESH:D016889', (169, 196))
65254	28027320	In addition, we determined that half of the women in our study who did not have clinical evidence of cancer nonetheless possessed a significant landscape of driver mutations at relatively high allele fractions.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('women', 'Species', '9606', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (164, 173))
65255	28027320	Our findings therefore suggest the apparently opposing possibilities of a genomics-based approach for endometrial cancer screening and the discovery of prevalent driver mutations in clinically defined non-cancerous tissue.	('endometrial cancer', 'Disease', 'MESH:D016889', (102, 120))	('non-cancer', 'Disease', (201, 211))	('mutations', 'Var', (169, 178))	('non-cancer', 'Disease', 'MESH:D009369', (201, 211))	('cancerous', 'Disease', (205, 214))	('endometrial cancer', 'Disease', (102, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancerous', 'Disease', 'MESH:D009369', (205, 214))	('endometrial cancer', 'Phenotype', 'HP:0012114', (102, 120))
65282	28027320	The group of driver mutations included those in activating or inactivating hotspots of oncogenes or tumor suppressors in major endometrial cancer driver genes of our panel, as well as truncating mutations in tumor suppressor genes of endometrial cancer.	('truncating mutations', 'Var', (184, 204))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('endometrial cancer', 'Phenotype', 'HP:0012114', (127, 145))	('endometrial cancer', 'Disease', 'MESH:D016889', (234, 252))	('endometrial cancer', 'Phenotype', 'HP:0012114', (234, 252))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (100, 105))	('endometrial cancer', 'Disease', 'MESH:D016889', (127, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('activating', 'PosReg', (48, 58))	('inactivating', 'MPA', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Disease', (208, 213))	('endometrial cancer', 'Disease', (234, 252))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (20, 29))	('endometrial cancer', 'Disease', (127, 145))
65283	28027320	Thus, all mutations nominated as drivers were previously observed in endometrial cancer and are also recurrent pan-cancer mutations.	('endometrial cancer', 'Disease', (69, 87))	('pan-cancer', 'Disease', 'MESH:C537931', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('observed', 'Reg', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('endometrial cancer', 'Phenotype', 'HP:0012114', (69, 87))	('pan-cancer', 'Disease', (111, 121))	('endometrial cancer', 'Disease', 'MESH:D016889', (69, 87))	('mutations', 'Var', (10, 19))
65284	28027320	In the group of "potential drivers," we included predicted functional missense mutations in major endometrial cancer genes from the 12-gene panel.	('endometrial cancer', 'Disease', 'MESH:D016889', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('missense mutations', 'Var', (70, 88))	('endometrial cancer', 'Disease', (98, 116))	('endometrial cancer', 'Phenotype', 'HP:0012114', (98, 116))
65305	28027320	In total, and based on results from both panels, 58 patients were found to have 126 unique somatic mutations in either the lavage cellular DNA or cfDNA (S3, S4 and S5 Tables).	('cfDNA', 'Gene', (146, 151))	('mutations', 'Var', (99, 108))	('patients', 'Species', '9606', (52, 60))
65308	28027320	Twenty-three mutations were nominated as "potential drivers," 11 of which are recurrent mutations in that they are observed in other cancers, but not in endometrial cancer; two mutations were observed in endometrial cancer, but not in other cancers; and 10 mutations are newly described.	('observed', 'Reg', (115, 123))	('endometrial cancer', 'Disease', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('endometrial cancer', 'Disease', 'MESH:D016889', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('endometrial cancer', 'Disease', (204, 222))	('cancers', 'Disease', (133, 140))	('endometrial cancer', 'Phenotype', 'HP:0012114', (153, 171))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('endometrial cancer', 'Phenotype', 'HP:0012114', (204, 222))	('cancers', 'Disease', 'MESH:D009369', (241, 248))	('mutations', 'Var', (13, 22))	('endometrial cancer', 'Disease', 'MESH:D016889', (204, 222))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancers', 'Disease', (241, 248))
65309	28027320	Another interesting observation in those patients diagnosed with cancer by histopathology, as compared to all patients, is the increase in lavage-identified mutations with higher allele fractions (Table 4, bottom row).	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (157, 166))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('patients', 'Species', '9606', (110, 118))
65315	28027320	Cellular DNA from the lavage fluid contained a total of six driver mutations, including three PTEN mutations (W111*, F337fs, G132D), one PIK3CA mutation (E545A), one CTNNB1 mutation (S45F), and one FBXW7 mutation (R505C).	('FBXW7', 'Gene', (198, 203))	('PIK3CA', 'Gene', (137, 143))	('F337fs', 'Var', (117, 123))	('PTEN', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (94, 98))	('S45F', 'Mutation', 'rs121913409', (183, 187))	('CTNNB1', 'Gene', '1499', (166, 172))	('G132D', 'Mutation', 'rs121909241', (125, 130))	('PIK3CA', 'Gene', '5290', (137, 143))	('W111*', 'Var', (110, 115))	('R505C', 'Mutation', 'rs149680468', (214, 219))	('E545A', 'Mutation', 'rs121913274', (154, 159))	('FBXW7', 'Gene', '55294', (198, 203))	('W111*', 'SUBSTITUTION', 'None', (110, 115))	('G132D', 'Var', (125, 130))	('F337fs', 'Mutation', 'p.F337fsX', (117, 123))	('CTNNB1', 'Gene', (166, 172))
65317	28027320	Six driver mutations were detected, five in RET (L773fs, E775_F776fs, F776L, V778fs, K780Q781fs) and one in CDH1 (K86fs).	('F776L', 'Mutation', 'p.F776L', (70, 75))	('L773fs', 'Var', (49, 55))	('RET', 'Gene', (44, 47))	('E775_F776fs', 'Var', (57, 68))	('K86fs', 'Mutation', 'p.K86fsX', (114, 119))	('V778fs', 'Var', (77, 83))	('CDH1', 'Gene', (108, 112))	('F776L', 'Var', (70, 75))	('CDH1', 'Gene', '999', (108, 112))	('L773fs', 'Mutation', 'p.L773fsX', (49, 55))	('RET', 'Gene', '5979', (44, 47))	('K780Q781fs', 'Var', (85, 95))	('V778fs', 'Mutation', 'p.V778fsX', (77, 83))	('K780Q781fs', 'Mutation', 'p.K780,781QfsX', (85, 95))	('F776fs', 'Mutation', 'p.F776fsX', (62, 68))
65318	28027320	Another stage 1A grade 1 endometrioid endometrial adenocarcinoma patient, PT451, had two driver mutations detected in FGFR2 (S252W) and PIK3CA (M1043V) in both uterine lavage fractions.	('PIK3CA', 'Gene', (136, 142))	('M1043V', 'Mutation', 'rs1057519936', (144, 150))	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (25, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('endometrioid endometrial adenocarcinoma', 'Disease', (25, 64))	('PIK3CA', 'Gene', '5290', (136, 142))	('FGFR2', 'Gene', (118, 123))	('FGFR2', 'Gene', '2263', (118, 123))	('S252W', 'Mutation', 'rs79184941', (125, 130))	('M1043V', 'Var', (144, 150))	('patient', 'Species', '9606', (65, 72))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (38, 64))	('S252W', 'Var', (125, 130))
65319	28027320	PT492, the fourth stage 1A, grade 1 endometrioid adenocarcinoma case, had one driver mutation detected in PIK3CA (G106V; cell pellet DNA).	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (36, 63))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (36, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('PIK3CA', 'Gene', (106, 112))	('PIK3CA', 'Gene', '5290', (106, 112))	('G106V;', 'Var', (114, 120))	('G106V', 'Mutation', 'rs1057519930', (114, 119))	('endometrioid adenocarcinoma', 'Disease', (36, 63))
65321	28027320	PT468 was diagnosed with a stage 1A mixed histology cancer, one component being high-grade serous adenocarcinoma and the other being grade 2 endometrioid adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('serous adenocarcinoma', 'Disease', 'MESH:D000230', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('serous adenocarcinoma', 'Disease', (91, 112))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (141, 168))	('endometrioid adenocarcinoma', 'Disease', (141, 168))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (141, 168))	('PT468', 'Var', (0, 5))
65322	28027320	This patient had a total of ten driver mutations detected in the following four genes: ARID1A (R1722*, R1446*, R1989*), RB1 (R445*), PIK3R1 (R514C), PTEN (I33S, R130Q, C211Q), and PIK3CA (E81K, R88Q).	('PIK3R1', 'Gene', (133, 139))	('R445*', 'SUBSTITUTION', 'None', (125, 130))	('PTEN', 'Gene', (149, 153))	('R1989*', 'SUBSTITUTION', 'None', (111, 117))	('R1722*', 'Var', (95, 101))	('E81K', 'Var', (188, 192))	('RB1', 'Gene', '5925', (120, 123))	('R514C', 'Mutation', 'p.R514C', (141, 146))	('PTEN', 'Gene', '5728', (149, 153))	('R445*', 'Var', (125, 130))	('PIK3CA', 'Gene', '5290', (180, 186))	('E81K', 'Mutation', 'rs1057519929', (188, 192))	('R1446*', 'Var', (103, 109))	('PIK3R1', 'Gene', '5295', (133, 139))	('R1989*', 'Var', (111, 117))	('R130Q', 'Mutation', 'rs121909229', (161, 166))	('R1722*', 'SUBSTITUTION', 'None', (95, 101))	('R88Q', 'Var', (194, 198))	('R514C', 'Var', (141, 146))	('R130Q', 'Var', (161, 166))	('I33S', 'Mutation', 'p.I33S', (155, 159))	('I33S', 'Var', (155, 159))	('ARID1A', 'Gene', (87, 93))	('patient', 'Species', '9606', (5, 12))	('R1446*', 'SUBSTITUTION', 'None', (103, 109))	('C211Q', 'Var', (168, 173))	('PIK3CA', 'Gene', (180, 186))	('C211Q', 'SUBSTITUTION', 'None', (168, 173))	('ARID1A', 'Gene', '8289', (87, 93))	('RB1', 'Gene', (120, 123))	('R88Q', 'Mutation', 'rs121913287', (194, 198))
65323	28027320	With the exception of the ARID1A (R1722*), PIK3R1, and PTEN (C211Y) mutations, all other mutations were present in both cellular DNA and cfDNA fractions.	('ARID1A', 'Gene', (26, 32))	('PTEN', 'Gene', '5728', (55, 59))	('C211Y', 'Var', (61, 66))	('C211Y', 'Mutation', 'rs948405432', (61, 66))	('R1722*', 'SUBSTITUTION', 'None', (34, 40))	('PIK3R1', 'Gene', '5295', (43, 49))	('R1722*', 'Var', (34, 40))	('PIK3R1', 'Gene', (43, 49))	('ARID1A', 'Gene', '8289', (26, 32))	('PTEN', 'Gene', (55, 59))
65324	28027320	The diversity of mutations most likely reflects the diversity of the mixed histology tumor, distinguished by an aggressive high-grade serous component.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
65325	28027320	PT488, the patient with stage 3A carcinosarcoma, had two TP53 mutations.	('carcinosarcoma', 'Disease', (33, 47))	('carcinosarcoma', 'Disease', 'MESH:D002296', (33, 47))	('patient', 'Species', '9606', (11, 18))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
65327	28027320	There was also an additional ARID1A driver mutation (E1444*).	('ARID1A', 'Gene', '8289', (29, 35))	('ARID1A', 'Gene', (29, 35))	('E1444*', 'Var', (53, 59))	('E1444*', 'SUBSTITUTION', 'None', (53, 59))
65328	28027320	TP53 mutations have been shown to be present in aggressive endometrial adenocarcinomas, including high-grade serous types and carcinosarcomas.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('aggressive endometrial adenocarcinomas', 'Disease', (48, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('high-grade serous types', 'Disease', (98, 121))	('aggressive endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (48, 86))	('mutations', 'Var', (5, 14))	('carcinosarcomas', 'Disease', 'MESH:D002296', (126, 141))	('carcinosarcomas', 'Disease', (126, 141))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (59, 85))	('present', 'Reg', (37, 44))
65329	28027320	ARID1A mutations have been shown to be associated with more aggressive endometrial adenocarcinomas.	('ARID1A', 'Gene', '8289', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (71, 97))	('ARID1A', 'Gene', (0, 6))	('aggressive endometrial adenocarcinomas', 'Disease', (60, 98))	('associated', 'Reg', (39, 49))	('aggressive endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (60, 98))	('mutations', 'Var', (7, 16))
65330	28027320	Owing to the limited volume of three of these tumors (PT398, PT433, PT492), as per our IRB consent, there was no tumor tissue that could be made available for DNA isolation for research purposes.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('PT433', 'Var', (61, 66))	('PT492', 'Var', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PT398', 'Var', (54, 59))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumors', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
65332	28027320	DNA was extracted from fresh frozen tissue of these four tumor samples (PT451, PT468, PT484, PT488) and sequenced using the 12-gene panel.	('PT488', 'Var', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PT484', 'Var', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
65334	28027320	For some, but not all, of the tumor mutations, the allele fractions matched those from the lavage fractions.	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (30, 35))	('mutations', 'Var', (36, 45))
65336	28027320	Among these four cases in which the paired tumor was available, PT468 was unusual not only because of the large number of mutations identified (n = 20) but also because a large number of lavage-identified mutations had not been detected in the tumor (n = 14) and, conversely, one tumor-identified mutation was not detected in the lavage fluid (S7 Table).	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (244, 249))	('PT468', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('mutations', 'Var', (122, 131))	('tumor', 'Disease', (280, 285))	('tumor', 'Disease', (43, 48))
65338	28027320	Five of the eight mutations were confirmed to be present in the tumor (S8 Table, S3-S7 Figs), and these were present at allele fractions that would not have been detected by NGS, as our cutoff threshold for NGS was 1.0%.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (18, 27))
65339	28027320	The allele fractions of these tumor variants ranged from 0.15% to 0.004%, whereas the cognate lavage fractions ranged from 2.0% to 21.0%.	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (30, 35))	('variants', 'Var', (36, 44))
65342	28027320	In marked contrast, 51 patients without a histopathologic diagnosis of cancer were identified as having somatic mutations in their uterine lavage samples.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('patients', 'Species', '9606', (23, 31))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('somatic mutations', 'Var', (104, 121))
65344	28027320	The finding that a majority of women without a cancer diagnosis carried mutations, the relatively high allele fractions (range: 1.0% to 30.4%; average: 3.0%), and the projected oncogenic impact of these mutations was surprising.	('mutations', 'Var', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('women', 'Species', '9606', (31, 36))
65345	28027320	These affect a total of five genes: PTEN (I32del [AF: 2.1%], R130G [AF: 2.4%], G165E [AF: 2.3%]), PIK3R1 (Y463_L466del [AF: 5.5%], E558fs [AF: 1.6%]), PIK3CA (Q546K [AF: 5.1%], C420R [AF: 1.5%]), KRAS (G12S [AF: 1.2%], G12C [AF: 6.3%], G12C [AF: 1.4%]), and FGFR2 (S252W [AF: 5.8%]).	('AF', 'Disease', 'MESH:D001281', (68, 70))	('R130G', 'Var', (61, 66))	('PIK3R1', 'Gene', '5295', (98, 104))	('KRAS', 'Gene', (196, 200))	('Q546K', 'Var', (159, 164))	('AF', 'Disease', 'MESH:D001281', (272, 274))	('PTEN', 'Gene', (36, 40))	('G12S', 'Mutation', 'rs121913530', (202, 206))	('AF', 'Disease', 'MESH:D001281', (184, 186))	('AF', 'Disease', 'MESH:D001281', (208, 210))	('C420R', 'Gene', (177, 182))	('AF', 'Disease', 'MESH:D001281', (50, 52))	('C420R', 'Mutation', 'rs121913272', (177, 182))	('AF', 'Disease', 'MESH:D001281', (225, 227))	('affect', 'Reg', (6, 12))	('S252W', 'Var', (265, 270))	('AF', 'Disease', 'MESH:D001281', (120, 122))	('FGFR2', 'Gene', '2263', (258, 263))	('E558fs', 'Mutation', 'p.E558fsX', (131, 137))	('PTEN', 'Gene', '5728', (36, 40))	('I32del', 'Var', (42, 48))	('PIK3CA', 'Gene', '5290', (151, 157))	('G12C', 'Mutation', 'rs121913530', (236, 240))	('PIK3R1', 'Gene', (98, 104))	('G12C', 'Mutation', 'rs121913530', (219, 223))	('AF', 'Disease', 'MESH:D001281', (86, 88))	('G165E', 'Var', (79, 84))	('Y463_L466del', 'Mutation', 'p.463,466delL', (106, 118))	('AF', 'Disease', 'MESH:D001281', (166, 168))	('I32del', 'DELETION', 'None', (42, 48))	('KRAS', 'Gene', '3845', (196, 200))	('Q546K', 'Mutation', 'rs121913286', (159, 164))	('G165E', 'Mutation', 'rs1260903787', (79, 84))	('PIK3CA', 'Gene', (151, 157))	('S252W', 'Mutation', 'rs79184941', (265, 270))	('AF', 'Disease', 'MESH:D001281', (139, 141))	('G12C', 'Var', (236, 240))	('AF', 'Disease', 'MESH:D001281', (242, 244))	('G12C', 'Var', (219, 223))	('FGFR2', 'Gene', (258, 263))	('R130G', 'Mutation', 'rs121909224', (61, 66))
65348	28027320	We identified four driver mutations; three were detected in the cellular pellet ([KRAS G12S (AF: 1.1%)], PIK3CA [(H1047R (AF: 3.0%) and E542A (AF: 1.4%)]) and the fourth in the cfDNA (PIK3CA G106V; AF: 1.2%).	('PIK3CA', 'Gene', (105, 111))	('AF', 'Disease', 'MESH:D001281', (198, 200))	('AF', 'Disease', 'MESH:D001281', (143, 145))	('G12S', 'Mutation', 'rs121913530', (87, 91))	('G106V', 'Mutation', 'rs1057519930', (191, 196))	('E542A', 'Var', (136, 141))	('PIK3CA', 'Gene', '5290', (105, 111))	('H1047R', 'Mutation', 'rs121913279', (114, 120))	('AF', 'Disease', 'MESH:D001281', (93, 95))	('PIK3CA', 'Gene', (184, 190))	('KRAS', 'Gene', (82, 86))	('E542A', 'Mutation', 'rs1057519927', (136, 141))	('PIK3CA', 'Gene', '5290', (184, 190))	('KRAS', 'Gene', '3845', (82, 86))	('AF', 'Disease', 'MESH:D001281', (122, 124))
65352	28027320	To establish possible correlations between the presence of driver and/or potential driver mutations and clinical characteristics including age, race/ethnicity, BMI, diabetes, parity, smoking status, and menopausal status, we performed univariate analysis.	('diabetes', 'Disease', (165, 173))	('mutations', 'Var', (90, 99))	('diabetes', 'Disease', 'MESH:D003920', (165, 173))	('parity', 'Disease', (175, 181))	('BMI', 'Disease', (160, 163))	('menopausal status', 'Phenotype', 'HP:0008209', (203, 220))
65355	28027320	Increasing age was significantly associated with presence of driver or potential driver mutations in PIK3CA (p-value = 0.008) and TP53 (p-value = 0.001) (S11 and S12 Figs).	('PIK3CA', 'Gene', '5290', (101, 107))	('mutations', 'Var', (88, 97))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('PIK3CA', 'Gene', (101, 107))
65362	28027320	In women with abnormal uterine bleeding there is upwards of an ~10% risk of endometrial cancer, depending on age and menopausal status.Of the women in our cohort with a prediagnosis of abnormal uterine bleeding, 7% were found to have endometrial cancer and 49% were identified to be carrying driver/potential driver mutations but without a diagnosis of cancer.	('abnormal uterine bleeding', 'Phenotype', 'HP:0100608', (14, 39))	('cancer', 'Disease', (88, 94))	('abnormal uterine', 'Phenotype', 'HP:0000130', (14, 30))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('bleeding', 'Disease', (202, 210))	('women', 'Species', '9606', (142, 147))	('endometrial cancer', 'Phenotype', 'HP:0012114', (234, 252))	('cancer', 'Disease', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('endometrial cancer', 'Phenotype', 'HP:0012114', (76, 94))	('bleeding', 'Disease', 'MESH:D006470', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('endometrial cancer', 'Disease', (234, 252))	('abnormal uterine bleeding', 'Phenotype', 'HP:0100608', (185, 210))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (316, 325))	('endometrial cancer', 'Disease', 'MESH:D016889', (234, 252))	('endometrial cancer', 'Disease', (76, 94))	('menopausal status', 'Phenotype', 'HP:0008209', (117, 134))	('endometrial cancer', 'Disease', 'MESH:D016889', (76, 94))	('bleeding', 'Disease', (31, 39))	('abnormal uterine', 'Phenotype', 'HP:0000130', (185, 201))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (353, 359))	('bleeding', 'Disease', 'MESH:D006470', (202, 210))	('women', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
65376	28027320	A decidedly unexpected outcome of these studies was the discovery that the majority of women without a cancer diagnosis in our cohort possessed somatic driver and candidate driver mutations within uterine lavage cells and cfDNA.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (180, 189))	('women', 'Species', '9606', (87, 92))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
65378	28027320	Therefore, from a clinical perspective, because of the prevalence of cancer-driver mutations identified in women without histopathologic evidence of cancer, our lavage screening protocol is not yet able to distinguish between women with and without clinically relevant evidence of cancer.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (149, 155))	('women', 'Species', '9606', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('women', 'Species', '9606', (226, 231))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Disease', (69, 75))
65379	28027320	However, our results seemingly provide a unique opportunity to gain insight into the mechanisms underlying selection and clonal expansion, as mutated cells evolve either towards a final cancer phenotype or are halted and eliminated in their progression.	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutated', 'Var', (142, 149))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
65382	28027320	Thus, the NGS-identified driver/candidate driver mutations in women without a diagnosis of cancer are not likely to represent technical artifacts because all variants that we tested by these two orthogonal technologies were validated.	('mutations', 'Var', (49, 58))	('variants', 'Var', (158, 166))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('women', 'Species', '9606', (62, 67))
65383	28027320	Second, while "in vitro artifacts" would be irrelevant to natural selection processes, the observed prevalence of detected mutations in common cancer hotspots (e.g., position G12 in KRAS) is more suggestive of an oncogenic selection process resulting in a typical cancer gene mutation distribution.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('KRAS', 'Gene', '3845', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('KRAS', 'Gene', (182, 186))	('position G12', 'Var', (166, 178))	('mutations', 'Var', (123, 132))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
65385	28027320	The distribution of nucleotide mutations reveals that the most frequently observed TCGA mutations are (i) detected in our study and (ii) also detected as the most frequently occurring ones, e.g., mutation C>A, C>T in KRAS position 25398284; mutations A>G, G>A in PIK3CA positions 178952085 and 178936082, respectively; mutation C>G in PTEN position 89692904; and mutation G>C in FGFR2 position 123279677.	('mutation G>C', 'Var', (363, 375))	('KRAS', 'Gene', (217, 221))	('mutations A>G', 'Var', (241, 254))	('mutation C>A', 'Var', (196, 208))	('PIK3CA', 'Gene', '5290', (263, 269))	('KRAS', 'Gene', '3845', (217, 221))	('FGFR2', 'Gene', (379, 384))	('mutation C>G', 'Var', (319, 331))	('TCGA', 'Gene', (83, 87))	('FGFR2', 'Gene', '2263', (379, 384))	('PTEN', 'Gene', '5728', (335, 339))	('PIK3CA', 'Gene', (263, 269))	('PTEN', 'Gene', (335, 339))	('C>A', 'Var', (205, 208))
65386	28027320	In particular, percentages of DNA hotspot mutations reported in TCGA and not observed in our study are ~3% for KRAS; ~25% for PIK3CA; ~12% for PTEN; ~14% for FBXW7; and 33% for CTNBB1.	('PIK3CA', 'Gene', (126, 132))	('KRAS', 'Gene', (111, 115))	('FBXW7', 'Gene', '55294', (158, 163))	('KRAS', 'Gene', '3845', (111, 115))	('CTNBB1', 'Gene', (177, 183))	('FBXW7', 'Gene', (158, 163))	('PIK3CA', 'Gene', '5290', (126, 132))	('TCGA', 'Gene', (64, 68))	('PTEN', 'Gene', (143, 147))	('PTEN', 'Gene', '5728', (143, 147))	('mutations', 'Var', (42, 51))
65388	28027320	If "driver mutations" provide a selective growth advantage and can lead to cancer, how, then, does one explain the presence of high-frequency (allele fractions ranging from 1%-30%) driver/candidate driver mutations in half of our study population without cancer and who may have only a minimum risk of developing endometrial cancer.	('growth', 'CPA', (42, 48))	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('lead to', 'Reg', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('endometrial cancer', 'Phenotype', 'HP:0012114', (313, 331))	('cancer', 'Disease', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('mutations', 'Var', (205, 214))	('cancer', 'Disease', (75, 81))	('endometrial cancer', 'Disease', 'MESH:D016889', (313, 331))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('advantage', 'PosReg', (49, 58))	('endometrial cancer', 'Disease', (313, 331))
65389	28027320	Results from three nearly back-to-back whole-exome and gene panel targeted sequencing studies on nearly 34,000 individuals identified clonal hematopoiesis with leukemia-related, somatic driver mutations, most notably DNMT3A, in 10% of apparently healthy individuals >65 years of age and in nearly 20% in those between 90 to 108 years of age.	('hematopoiesis', 'Disease', 'MESH:C536227', (141, 154))	('DNMT3A', 'Gene', (217, 223))	('hematopoiesis', 'Disease', (141, 154))	('DNMT3A', 'Gene', '1788', (217, 223))	('mutations', 'Var', (193, 202))	('leukemia', 'Phenotype', 'HP:0001909', (160, 168))	('leukemia', 'Disease', 'MESH:D007938', (160, 168))	('leukemia', 'Disease', (160, 168))
65390	28027320	While the absolute risk remained small, the individuals carrying these driver mutations were clearly at increased risk for developing future hematologic cancers, suggesting the premalignant nature of the detected clones.	('hematologic cancers', 'Disease', 'MESH:D009369', (141, 160))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('hematologic cancers', 'Disease', (141, 160))
65391	28027320	Second, it has been appreciated for some time that clonal patches of skin contain TP53 mutations.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('patches of skin', 'Phenotype', 'HP:0002290', (58, 73))	('mutations', 'Var', (87, 96))
65392	28027320	Recently, and using an ultra-deep sequencing strategy, it was shown that upwards of 32% of non-lesion-containing, sun-exposed epithelial cells from the eyelid contain mutations in key drivers of squamous cell carcinomas.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (195, 219))	('mutations', 'Var', (167, 176))	('squamous cell carcinomas', 'Disease', (195, 219))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (195, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))
65393	28027320	Finally, in a study searching for p53 mutations in peritoneal fluid, again using an ultra-deep sequencing strategy, all women in the study, 17 with ovarian cancer and 20 without evidence of cancer, were found to harbor TP53 mutations.	('p53', 'Gene', (34, 37))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('p53', 'Gene', '7157', (34, 37))	('peritoneal fluid', 'Phenotype', 'HP:0030995', (51, 67))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('mutations', 'Var', (224, 233))	('ovarian cancer', 'Disease', (148, 162))	('TP53', 'Gene', (219, 223))	('women', 'Species', '9606', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ovarian cancer', 'Phenotype', 'HP:0100615', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('harbor', 'Reg', (212, 218))	('ovarian cancer', 'Disease', 'MESH:D010051', (148, 162))	('TP53', 'Gene', '7157', (219, 223))
65394	28027320	For the women without cancer, the TP53 mutations were extremely low frequency (median mutant fraction <1/10,000) and associated with increasing age, but still were mostly deleterious and clustered in hotspots.	('TP53', 'Gene', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('associated', 'Reg', (117, 127))	('women', 'Species', '9606', (8, 13))	('cancer', 'Disease', (22, 28))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('TP53', 'Gene', '7157', (34, 38))
65395	28027320	Cancers do arise from clonal evolution and expansion of a single cell, and driver mutations confer a growth advantage to that cell.	('growth advantage', 'CPA', (101, 117))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('mutations', 'Var', (82, 91))
65401	28027320	In our study, we identified driver mutations in all seven women who were found to harbor endometrial cancers.	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('endometrial cancer', 'Phenotype', 'HP:0012114', (89, 107))	('endometrial cancers', 'Disease', 'MESH:D016889', (89, 108))	('endometrial cancers', 'Disease', (89, 108))	('women', 'Species', '9606', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (35, 44))
65404	28027320	In detecting driver mutations in women with stage IA cancer, even in those cases in which only microscopic amounts of tissue were available and, thus, were a clinical challenge, we establish that adequate amounts of tumor shed cells and DNA are present in uterine lavage.	('tumor', 'Disease', (216, 221))	('stage IA cancer', 'Disease', 'MESH:D009369', (44, 59))	('women', 'Species', '9606', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('stage IA cancer', 'Disease', (44, 59))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mutations', 'Var', (20, 29))
65408	28027320	Paradoxically, the same ability to detect mutations in women with endometrial cancer using ultra-deep sequencing, which promises the ability to screen for this cancer, also reveals a previously unknown prevalent landscape of driver mutations in women without clinically apparent evidence of cancer.	('women', 'Species', '9606', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('women', 'Species', '9606', (245, 250))	('endometrial cancer', 'Phenotype', 'HP:0012114', (66, 84))	('endometrial cancer', 'Disease', 'MESH:D016889', (66, 84))	('mutations', 'Var', (232, 241))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (42, 51))	('endometrial cancer', 'Disease', (66, 84))
65422	27884207	Host genetics explain only 20 % of endometrial cancer incidence through microsatellite instability (MSI) or abnormalities in aerobic glycolysis.	('endometrial cancer', 'Disease', (35, 53))	('MSI', 'Disease', 'None', (100, 103))	('microsatellite', 'MPA', (72, 86))	('abnormalities', 'Var', (108, 121))	('abnormalities in aerobic glycolysis', 'Phenotype', 'HP:0004366', (108, 143))	('MSI', 'Disease', (100, 103))	('endometrial cancer', 'Phenotype', 'HP:0012114', (35, 53))	('endometrial cancer', 'Disease', 'MESH:D016889', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('aerobic glycolysis', 'MPA', (125, 143))
65431	27884207	Gynecologic pathogens associated with bacterial vaginosis, such as Atopobium vaginae and Gardnerella vaginalis have been associated with obstetric complications, such as preterm labor.	('bacterial vaginosis', 'Disease', (38, 57))	('obstetric complications', 'Disease', (137, 160))	('Atopobium vaginae', 'Species', '82135', (67, 84))	('bacterial vaginosis', 'Disease', 'MESH:D016585', (38, 57))	('associated', 'Reg', (121, 131))	('preterm labor', 'Disease', 'MESH:D007752', (170, 183))	('bacterial vaginosis', 'Phenotype', 'HP:0030683', (38, 57))	('Gardnerella', 'Var', (89, 100))	('Gardnerella vaginalis', 'Species', '2702', (89, 110))	('preterm labor', 'Disease', (170, 183))
65501	27884207	Three of our patients had simple hyperplasia without atypia (H07, H08, and H63) and one had complex hyperplasia with atypia (H72).	('hyperplasia', 'Disease', (100, 111))	('H63', 'Gene', '113201', (75, 78))	('hyperplasia without atypia', 'Disease', (33, 59))	('patients', 'Species', '9606', (13, 21))	('H08', 'Var', (66, 69))	('hyperplasia', 'Disease', (33, 44))	('hyperplasia', 'Disease', 'MESH:D006965', (100, 111))	('H63', 'Gene', (75, 78))	('hyperplasia without atypia', 'Disease', 'MESH:D006965', (33, 59))	('hyperplasia', 'Disease', 'MESH:D006965', (33, 44))	('H07', 'Var', (61, 64))
65556	25918253	Inhibition of NFAT-1 or TGFbetaR-I blocked c-Myc induction, cell cycle progression and proliferation in UCS.	('TGFbetaR-I', 'Gene', (24, 34))	('proliferation', 'CPA', (87, 100))	('TGFbetaR-I', 'Gene', '7046', (24, 34))	('NFAT-1', 'Gene', '4773', (14, 20))	('CS', 'Chemical', 'MESH:D002586', (105, 107))	('c-Myc', 'Gene', '4609', (43, 48))	('NFAT-1', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('blocked', 'NegReg', (35, 42))	('c-Myc', 'Gene', (43, 48))	('cell cycle progression', 'CPA', (60, 82))
65558	25918253	Interestingly, in the absence of exogenous TGFbeta the TGFbetaR-I/II inhibitor enhanced proliferation likely through non-Smad pathways.	('TGFbeta', 'Gene', '7040', (55, 62))	('TGFbeta', 'Gene', (43, 50))	('inhibitor', 'Var', (69, 78))	('enhanced', 'PosReg', (79, 87))	('TGFbeta', 'Gene', '7040', (43, 50))	('proliferation', 'CPA', (88, 101))	('TGFbeta', 'Gene', (55, 62))
65559	25918253	Thus, inhibition of TGFbetaR-I could be efficacious in treatment of UCS.	('CS', 'Chemical', 'MESH:D002586', (69, 71))	('TGFbetaR-I', 'Gene', '7046', (20, 30))	('UCS', 'Disease', (68, 71))	('inhibition', 'Var', (6, 16))	('TGFbetaR-I', 'Gene', (20, 30))
65568	25918253	Contrastingly, aberrations in the TGFbeta signaling regularly take place during tumorigenesis inducing the cancer cells to proliferate, invade, and metastasize beyond their tissue of origin.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('TGFbeta', 'Gene', '7040', (34, 41))	('metastasize', 'CPA', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (80, 85))	('aberrations', 'Var', (15, 26))	('TGFbeta', 'Gene', (34, 41))	('inducing', 'Reg', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('invade', 'CPA', (136, 142))
65579	25918253	LY2157299 and LY2109761 both inhibited Smad2/3 activation and TGFbeta-I dependent migration.	('LY2157299', 'Var', (0, 9))	('inhibited', 'NegReg', (29, 38))	('LY', 'Chemical', 'MESH:D008239', (14, 16))	('LY2109761', 'Var', (14, 23))	('activation', 'PosReg', (47, 57))	('TGFbeta', 'Gene', (62, 69))	('LY2109761', 'Chemical', 'MESH:C530108', (14, 23))	('Smad2/3', 'Protein', (39, 46))	('LY', 'Chemical', 'MESH:D008239', (0, 2))	('TGFbeta', 'Gene', '7040', (62, 69))
65584	25918253	Therefore, inhibition of TGFbetaR-I in UCS could be efficacious in inhibiting TGFbeta-I mediated EMT, proliferation and migration, while NFAT-1 and c-Myc could be potential prognostic markers predicting poor outcome.	('TGFbeta', 'Gene', '7040', (25, 32))	('TGFbetaR-I', 'Gene', (25, 35))	('TGFbeta', 'Gene', (78, 85))	('NFAT-1', 'Gene', (137, 143))	('c-Myc', 'Gene', '4609', (148, 153))	('CS', 'Chemical', 'MESH:D002586', (40, 42))	('TGFbetaR-I', 'Gene', '7046', (25, 35))	('EMT', 'CPA', (97, 100))	('c-Myc', 'Gene', (148, 153))	('migration', 'CPA', (120, 129))	('inhibition', 'Var', (11, 21))	('TGFbeta', 'Gene', (25, 32))	('TGFbeta', 'Gene', '7040', (78, 85))	('proliferation', 'CPA', (102, 115))	('inhibiting', 'NegReg', (67, 77))	('NFAT-1', 'Gene', '4773', (137, 143))
65585	25918253	The biphasic nature and a report demonstrating amplification of the TGFbeta locus at 19q13.1 in UCS prompted us to determine whether the TGF pathway is active in UCS patient samples.	('TGF', 'Gene', (137, 140))	('TGF', 'Gene', '7040;21803', (68, 71))	('CS', 'Chemical', 'MESH:D002586', (163, 165))	('TGF', 'Gene', '7040;21803', (137, 140))	('CS', 'Chemical', 'MESH:D002586', (97, 99))	('TGFbeta', 'Gene', (68, 75))	('amplification', 'Var', (47, 60))	('TGFbeta', 'Gene', '7040', (68, 75))	('patient', 'Species', '9606', (166, 173))	('TGF', 'Gene', (68, 71))
65595	25918253	Since TGFbeta mediated signaling was intact we next tested the efficacy of LY2157299, TGFbetaR-I inhibitor or LY2109761, TGFbetaR-I and II dual inhibitor in inhibiting TGFbeta mediated Smad signaling.	('LY2157299', 'Var', (75, 84))	('TGFbeta', 'Gene', '7040', (121, 128))	('inhibiting', 'NegReg', (157, 167))	('TGFbeta', 'Gene', (86, 93))	('TGFbeta', 'Gene', '7040', (86, 93))	('TGFbetaR-I', 'Gene', (121, 131))	('TGFbetaR-I', 'Gene', '7046', (86, 96))	('tested', 'Reg', (52, 58))	('TGFbeta', 'Gene', (6, 13))	('TGFbeta', 'Gene', (121, 128))	('TGFbeta', 'Gene', '7040', (6, 13))	('LY', 'Chemical', 'MESH:D008239', (110, 112))	('LY2109761', 'Chemical', 'MESH:C530108', (110, 119))	('TGFbetaR-I', 'Gene', (86, 96))	('LY2109761', 'Var', (110, 119))	('TGFbetaR-I', 'Gene', '7046', (121, 131))	('TGFbeta', 'Gene', (168, 175))	('LY', 'Chemical', 'MESH:D008239', (75, 77))	('TGFbeta', 'Gene', '7040', (168, 175))
65597	25918253	LY2157299 (Galunisertib) is currently the only TGF-beta receptor kinase inhibitor being tested in Phase II trials for glioma, pancreatic cancer and hepatocellular cancer.	('LY2157299', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (126, 143))	('glioma', 'Disease', (118, 124))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (148, 169))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (148, 169))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('LY', 'Chemical', 'MESH:D008239', (0, 2))	('hepatocellular cancer', 'Disease', (148, 169))	('Galunisertib', 'Chemical', 'MESH:C557799', (11, 23))	('pancreatic cancer', 'Disease', (126, 143))
65601	25918253	Since FUMMT-1 expressed both the TGFbetaR-I and TGFbetaR-II, we next evaluated efficacy of LY2157299 and LY2109761 in inhibiting TGFbeta-Iota induced proliferation.	('TGFbetaR-II', 'Gene', (48, 59))	('TGFbetaR-I', 'Gene', (48, 58))	('TGFbetaR-II', 'Gene', '7048', (48, 59))	('TGFbeta-Iota', 'Gene', (129, 141))	('TGFbetaR-I', 'Gene', '7046', (48, 58))	('LY2109761', 'Chemical', 'MESH:C530108', (105, 114))	('TGFbetaR-I', 'Gene', (33, 43))	('LY', 'Chemical', 'MESH:D008239', (91, 93))	('LY', 'Chemical', 'MESH:D008239', (105, 107))	('inhibiting', 'NegReg', (118, 128))	('LY2109761', 'Var', (105, 114))	('TGFbetaR-I', 'Gene', '7046', (33, 43))	('LY2157299', 'Var', (91, 100))
65605	25918253	Surprisingly in absence of exogenous TGFbeta-Iota, LY2109761 but not LY2157299 dose-dependently increased proliferation.	('increased', 'PosReg', (96, 105))	('LY', 'Chemical', 'MESH:D008239', (51, 53))	('LY2109761', 'Var', (51, 60))	('LY', 'Chemical', 'MESH:D008239', (69, 71))	('LY2109761', 'Chemical', 'MESH:C530108', (51, 60))	('proliferation', 'CPA', (106, 119))
65609	25918253	At 8h, TGFbeta-I induced significant migration in both FUMMT-1 and CS-99 that was similarly and significantly inhibited upon treatment with either LY2157299 or LY2109761.	('LY', 'Chemical', 'MESH:D008239', (147, 149))	('CS-99', 'Chemical', '-', (67, 72))	('LY2157299', 'Var', (147, 156))	('LY2109761', 'Var', (160, 169))	('migration', 'CPA', (37, 46))	('TGFbeta', 'Gene', (7, 14))	('LY', 'Chemical', 'MESH:D008239', (160, 162))	('inhibited', 'NegReg', (110, 119))	('TGFbeta', 'Gene', '7040', (7, 14))	('LY2109761', 'Chemical', 'MESH:C530108', (160, 169))
65614	25918253	In addition, in FUMMT-1 post TGFbeta-Iota treatment there was significant upregulation of c-Myc while KLF-4 was downregulated at the mRNA level that returned to near control levels upon treatment with either inhibitor (Fig.	('downregulated', 'NegReg', (112, 125))	('FUMMT-1', 'Var', (16, 23))	('c-Myc', 'Gene', '4609', (90, 95))	('c-Myc', 'Gene', (90, 95))	('upregulation', 'PosReg', (74, 86))	('KLF-4', 'Gene', '9314', (102, 107))	('KLF-4', 'Gene', (102, 107))
65625	25918253	Despite preservation of Smad signaling in both the cell lines, TGFbeta-Iota induces proliferation in FUMMT-1 and not in CS-99.	('induces', 'Reg', (76, 83))	('CS-99', 'Chemical', '-', (120, 125))	('proliferation', 'CPA', (84, 97))	('TGFbeta-Iota', 'Var', (63, 75))
65626	25918253	Strikingly TGFbeta-Iota induces c-Myc mRNA and protein expression in FUMMT-1 only (Fig.	('c-Myc', 'Gene', '4609', (32, 37))	('induces', 'PosReg', (24, 31))	('c-Myc', 'Gene', (32, 37))	('TGFbeta-Iota', 'Var', (11, 23))
65629	25918253	In corroboration we find that in FUMMT-1, TGFbeta-Iota induces nuclear translocation of NFAT-1 (Fig.	('TGFbeta-Iota', 'Var', (42, 54))	('nuclear translocation', 'MPA', (63, 84))	('NFAT-1', 'Gene', '4773', (88, 94))	('induces', 'Reg', (55, 62))	('NFAT-1', 'Gene', (88, 94))
65631	25918253	Interestingly LY2157299 treatment blocked nuclear translocation of NFAT-1 (Fig.	('LY', 'Chemical', 'MESH:D008239', (14, 16))	('nuclear translocation', 'MPA', (42, 63))	('LY2157299', 'Var', (14, 23))	('NFAT-1', 'Gene', '4773', (67, 73))	('blocked', 'NegReg', (34, 41))	('NFAT-1', 'Gene', (67, 73))
65642	25918253	More importantly, TGFbeta-Iota induced canonical activation of Smad2 and Smad3 in both of these cell lines that could be attenuated by LY2157299, TGFbetaR-I or LY2109761, the TGFbetaR-I and II dual inhibitor.	('Smad3', 'Gene', (73, 78))	('TGFbetaR-I', 'Gene', '7046', (175, 185))	('LY', 'Chemical', 'MESH:D008239', (135, 137))	('LY2109761', 'Var', (160, 169))	('Smad2', 'Gene', '4087', (63, 68))	('LY', 'Chemical', 'MESH:D008239', (160, 162))	('TGFbetaR-I', 'Gene', (146, 156))	('Smad2', 'Gene', (63, 68))	('Smad3', 'Gene', '4088', (73, 78))	('LY2157299', 'Var', (135, 144))	('TGFbeta-Iota', 'Gene', (18, 30))	('TGFbetaR-I', 'Gene', '7046', (146, 156))	('LY2109761', 'Chemical', 'MESH:C530108', (160, 169))	('TGFbetaR-I', 'Gene', (175, 185))	('activation', 'PosReg', (49, 59))
65648	25918253	Our data clearly indicated that both the cell lines responded to TGFbeta by upregulating mesenchymal markers such as Snail, Slug and fibronectin that could be attenuated by LY2157299 or LY2109761.	('TGFbeta', 'Gene', '7040', (65, 72))	('LY', 'Chemical', 'MESH:D008239', (186, 188))	('fibronectin', 'Gene', '2335', (133, 144))	('Slug', 'Gene', '6591', (124, 128))	('LY2109761', 'Var', (186, 195))	('LY', 'Chemical', 'MESH:D008239', (173, 175))	('Slug', 'Gene', (124, 128))	('Snail', 'Gene', '6615', (117, 122))	('Snail', 'Gene', (117, 122))	('upregulating', 'PosReg', (76, 88))	('TGFbeta', 'Gene', (65, 72))	('fibronectin', 'Gene', (133, 144))	('LY2109761', 'Chemical', 'MESH:C530108', (186, 195))	('LY2157299', 'Var', (173, 182))	('mesenchymal markers', 'CPA', (89, 108))
65650	25918253	In addition, both the cell lines demonstrated significant migration in response to TGFbeta-Iota that could be significantly inhibited by LY2157299 or LY2109761.	('LY2109761', 'Chemical', 'MESH:C530108', (150, 159))	('inhibited', 'NegReg', (124, 133))	('LY', 'Chemical', 'MESH:D008239', (150, 152))	('LY', 'Chemical', 'MESH:D008239', (137, 139))	('TGFbeta-Iota', 'Gene', (83, 95))	('LY2157299', 'Var', (137, 146))	('LY2109761', 'Var', (150, 159))	('migration', 'CPA', (58, 67))
65660	25918253	Galunisertib or LY 2157299 is currently the only TGFbetaR-I kinase inhibitor that is in phase II clinical trials for glioma, pancreatic cancer, myelodisplastic syndrome and hepatocellular cancer.	('myelodisplastic syndrome', 'Phenotype', 'HP:0002863', (144, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('TGFbetaR-I', 'Gene', '7046', (49, 59))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('LY 2157299', 'Var', (16, 26))	('LY', 'Chemical', 'MESH:D008239', (16, 18))	('pancreatic cancer', 'Disease', (125, 142))	('myelodisplastic syndrome', 'Disease', 'MESH:D054437', (144, 168))	('myelodisplastic syndrome', 'Disease', (144, 168))	('hepatocellular cancer', 'Disease', (173, 194))	('TGFbetaR-I', 'Gene', (49, 59))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (173, 194))	('Galunisertib', 'Chemical', 'MESH:C557799', (0, 12))	('glioma', 'Disease', (117, 123))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (173, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('glioma', 'Disease', 'MESH:D005910', (117, 123))
65661	25918253	Therefore inhibition of TGFbetaR-I could be efficacious in treatment of UCS and NFAT-1 and c-Myc could be potential markers predicting poor outcome.	('TGFbetaR-I', 'Gene', (24, 34))	('CS', 'Chemical', 'MESH:D002586', (73, 75))	('NFAT-1', 'Gene', '4773', (80, 86))	('TGFbetaR-I', 'Gene', '7046', (24, 34))	('c-Myc', 'Gene', '4609', (91, 96))	('NFAT-1', 'Gene', (80, 86))	('inhibition', 'Var', (10, 20))	('UCS', 'Disease', (72, 75))	('c-Myc', 'Gene', (91, 96))
65723	18261213	Genetic alterations in Type 1 cancers include PTEN inactivation, beta-catenin (CTNNB1) mutations, and less frequently, microsatellite instability (related to inactivation of the MLH1 gene), and activational mutations of the K-ras gene.	('K-ras', 'Gene', (224, 229))	('Type 1 cancers', 'Disease', 'MESH:D009369', (23, 37))	('microsatellite', 'MPA', (119, 133))	('activational', 'PosReg', (194, 206))	('CTNNB1', 'Gene', '1499', (79, 85))	('Type 1 cancers', 'Disease', (23, 37))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('inactivation', 'Var', (51, 63))	('PTEN', 'Gene', (46, 50))	('K-ras', 'Gene', '3845', (224, 229))	('beta-catenin', 'Gene', '1499', (65, 77))	('PTEN', 'Gene', '5728', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('MLH1', 'Gene', '4292', (178, 182))	('MLH1', 'Gene', (178, 182))	('CTNNB1', 'Gene', (79, 85))	('mutations', 'Var', (87, 96))	('beta-catenin', 'Gene', (65, 77))
65725	18261213	Type II cancers also display frequent mutation and overexpression of the p53 and HER2/neu genes and proteins respectively, and have a comparatively poor prognosis independent of other factors.	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('Type II cancers', 'Disease', (0, 15))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('HER2/neu', 'Gene', '2064', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mutation', 'Var', (38, 46))	('HER2/neu', 'Gene', (81, 89))	('Type II cancers', 'Disease', 'MESH:D009369', (0, 15))	('overexpression', 'PosReg', (51, 65))
65746	18261213	Shared patterns of p53 mutations between the endometrial and extrauterine lesions argue in support of true origination of the latter from the former.	('mutations', 'Var', (23, 32))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))
65761	18261213	For 4 of the 7 markers, the frequency of LOH was higher in EmGD lesions as compared with resting endometrium, reaching statistical significance in 2 (TP53 and D1S162) and approaching such significance in the other 2 (D1S211 and D2S123).	('TP53', 'Gene', (150, 154))	('D2S123', 'Var', (228, 234))	('D1S211', 'Var', (217, 223))	('EmGD lesions', 'Disease', 'MESH:D051437', (59, 71))	('D1S162', 'Var', (159, 165))	('TP53', 'Gene', '7157', (150, 154))	('EmGD lesions', 'Disease', (59, 71))
65765	18261213	p53 mutations were identified in 0%, 43%, 72%, and 96% of resting endometrium, EmGD, serous EIC and ESC, respectively.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('ESC', 'Disease', (100, 103))	('serous', 'Disease', (85, 91))	('mutations', 'Var', (4, 13))
65766	18261213	Furthermore, in excess of 50% of the uteri with the aforementioned neoplastic lesions showed at least one identical p53 gene mutation among lesions of EmGD, serous EIC and/or ESC.	('ESC', 'Disease', (175, 178))	('EmGD', 'Disease', (151, 155))	('mutation', 'Var', (125, 133))	('serous EIC', 'Disease', (157, 167))	('p53', 'Gene', '7157', (116, 119))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (67, 85))	('p53', 'Gene', (116, 119))
65779	18261213	EmGD fulfils most of the National Cancer Institute (NCI)'s criteria for a precancerous lesion: (1) there is preliminary evidence that EmGD is associated with an increased risk of ESC; (2) partial molecular concordance in p53 mutations between EmGD and ESC provides one line of evidence that suggests that the latter arises from the former; (3) EmGD differs from the normal tissue from which it arises, and is morphologically recognizable as such; (4) EmGD is morphologically distinct from ESC, being characterized by cells that although more atypical than the background endometrial cells, cannot be characterized as cytologically malignant.	('ESC', 'Disease', (179, 182))	('mutations', 'Var', (225, 234))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer', 'Disease', (34, 40))	('p53', 'Gene', (221, 224))	('p53', 'Gene', '7157', (221, 224))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('precancerous lesion', 'Disease', (74, 93))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('precancerous lesion', 'Disease', 'MESH:D011230', (74, 93))
65780	18261213	(5) It is diagnosable by morphologic evaluation, with judicious use of immunohistochemical adjuncts such as p53, Ki67 and IMP3 in equivocal cases.	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', (108, 111))	('IMP3', 'Gene', (122, 126))	('IMP3', 'Gene', '55272', (122, 126))	('Ki67', 'Var', (113, 117))
65848	33247676	Only those curves are presented herein which showed significant differences in overall survival (p<0.05) of patients with high cut-off values compared to those with low cut-off values.	('patients', 'Species', '9606', (108, 116))	('high cut-off values', 'Var', (122, 141))	('differences', 'Reg', (64, 75))
65858	33247676	For mutation, it provides mutation ID, details of genetic change, protein change, type of mutation and its VEP impact across all available TCGA tumour data sets.	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (26, 34))
65894	33247676	TC2N mutation profile in pan-cancer  Our analyses show several frequent somatic mutations in TC2N gene in various cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mutations', 'Var', (80, 89))	('TC2N', 'Gene', '123036', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TC2N', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TC2N', 'Gene', '123036', (93, 97))	('TC2N', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
65895	33247676	A total of 142 mutations were identified across 145 cases in a total of 18 TCGA tumour types.	('tumour', 'Disease', (80, 86))	('mutations', 'Var', (15, 24))	('TCGA', 'Disease', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('identified', 'Reg', (30, 40))
65896	33247676	Highest pathogenic mutation rates of TC2N were present in SKCM, UCEC, COAD, BLCA and BRCA (Table 3).	('BLCA', 'Disease', (76, 80))	('COAD', 'Disease', 'MESH:D029424', (70, 74))	('BRCA', 'Gene', (85, 89))	('mutation', 'Var', (19, 27))	('pathogenic', 'Reg', (8, 18))	('TC2N', 'Gene', (37, 41))	('BRCA', 'Gene', '672;675', (85, 89))	('UCEC', 'Disease', (64, 68))	('COAD', 'Disease', (70, 74))	('TC2N', 'Gene', '123036', (37, 41))	('SKCM', 'Disease', (58, 62))
65907	33247676	Promoter hypermethylation is a key feature for transcriptional silencing of several genes in cancer (Park, 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Promoter hypermethylation', 'Var', (0, 25))
65908	33247676	In particular, tumour suppressor genes are silenced via hypermethylation in several caners (Nag and Yu, 2015).	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('hypermethylation', 'Var', (56, 72))	('tumour', 'Disease', (15, 21))	('Nag', 'Gene', (92, 95))	('silenced', 'NegReg', (43, 51))	('Nag', 'Gene', '51594', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
65909	33247676	We also found TC2N promoter hypomethylation in HNSC and KIRC.	('TC2N', 'Gene', (14, 18))	('hypomethylation', 'Var', (28, 43))	('TC2N', 'Gene', '123036', (14, 18))
65910	33247676	There are evidence that hypomethylation may lead to increased genomic stability that may contribute towards carcinogenesis (Pfeifer, 2018).	('increased', 'PosReg', (52, 61))	('genomic stability', 'CPA', (62, 79))	('contribute', 'Reg', (89, 99))	('hypomethylation', 'Var', (24, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
65911	33247676	Moreover, DNA hypomethylation also leads to overexpression of proinvasive, antiapoptotic and angiogenic factors in prostate cancer (Vestergaar et al., 2010).	('prostate cancer', 'Disease', (115, 130))	('hypomethylation', 'Var', (14, 29))	('overexpression', 'PosReg', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('DNA', 'Var', (10, 13))
65912	33247676	In summary, TC2N promoter hyper and hypo-methylation are important findings of this study demanding further exploration.	('TC2N', 'Gene', '123036', (12, 16))	('hyper', 'Var', (26, 31))	('hypo-methylation', 'Var', (36, 52))	('TC2N', 'Gene', (12, 16))
65921	33247676	In a recent study that recruited 28 highly-aggregated-extended-highrisk-familial-lung-cancer (HRFLC) families, highest cluster of genetic variants associated with lung cancer were identified within CATSPERB gene (14q32) (Musolf et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('associated', 'Reg', (147, 157))	('familial-lung-cancer', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CATSPERB', 'Gene', (198, 206))	('variants', 'Var', (138, 146))	('familial-lung-cancer', 'Disease', 'MESH:D008175', (72, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('CATSPERB', 'Gene', '79820', (198, 206))
65925	33247676	We identified a range of genetic alterations in the TC2N gene in several cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TC2N', 'Gene', '123036', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('TC2N', 'Gene', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('genetic alterations', 'Var', (25, 44))
65926	33247676	The highest pathogenic non-synonymous mutation rates were observed in SKCM, UCEC, COAD, BLCA and BRCA.	('COAD', 'Disease', (82, 86))	('UCEC', 'Disease', (76, 80))	('BLCA', 'Disease', (88, 92))	('non-synonymous mutation', 'Var', (23, 46))	('pathogenic', 'Reg', (12, 22))	('SKCM', 'Disease', (70, 74))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', '672;675', (97, 101))
65928	33247676	It is important to note that cancer cells are susceptible to accumulate several mutations for multiple reasons such as increased cellular turnover, inflammatory tumour microenvironment, altered metabolic wiring, increased reactive oxygen species, increased susceptibility to DNA damage and decreased capacity of DNA damage repair amongst others (Loeb and Loeb, 2000; Hanahan and Weinberg, 2011; Fouad and Anani, 2017).	('decreased', 'NegReg', (290, 299))	('oxygen', 'Chemical', 'MESH:D010100', (231, 237))	('cancer', 'Disease', (29, 35))	('susceptibility', 'MPA', (257, 271))	('mutations', 'Var', (80, 89))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (212, 245))	('metabolic wiring', 'CPA', (194, 210))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('altered', 'Reg', (186, 193))	('tumour', 'Disease', (161, 167))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('reactive oxygen species', 'MPA', (222, 245))	('increased', 'PosReg', (119, 128))	('cellular turnover', 'CPA', (129, 146))
66026	30415991	Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression Mutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy.	('endometrial cancer', 'Disease', 'MESH:D016889', (60, 78))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('endometrial cancer', 'Phenotype', 'HP:0012114', (60, 78))	('tumor', 'Disease', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', (145, 150))	('defects', 'Var', (119, 126))	('patient', 'Species', '9606', (269, 276))	('endometrial cancer', 'Disease', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
66029	30415991	Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('carcinosarcomas', 'Disease', 'MESH:D002296', (133, 148))	('copy-number high', 'Var', (78, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('copy-number low', 'Var', (43, 58))	('carcinosarcomas', 'Disease', (133, 148))	('endometrioid and serous carcinomas', 'Disease', 'MESH:D018269', (5, 39))
66030	30415991	Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, p<0.001) or basal-like breast cancers (46%, p<0.001).	('carcinomas', 'Phenotype', 'HP:0030731', (223, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('ECs', 'Disease', (50, 53))	('copy-number high', 'Var', (19, 35))	('lower', 'NegReg', (172, 177))	('serous ovarian carcinomas', 'Disease', (208, 233))	('ECs', 'Disease', 'MESH:D016889', (50, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (263, 277))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (208, 233))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('breast cancers', 'Disease', 'MESH:D001943', (263, 277))	('breast cancers', 'Disease', (263, 277))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (208, 233))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (215, 233))
66033	30415991	Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies.	('ECs', 'Disease', (50, 53))	('copy-number high', 'Var', (19, 35))	('ECs', 'Disease', 'MESH:D016889', (50, 53))	('HRD', 'Disease', (83, 86))
66037	30415991	In 2013, The Cancer Genome Atlas (TCGA) identified four distinct EC molecular subtypes, which carry prognostic and predictive information, including the POLE (ultramutated) subtype characterized by polymerase epsilon (POLE) exonuclease domain mutations (EDMs) and very high mutation rates, the MSI (hypermutated) subtype of microsatellite unstable tumors with high mutation rates, the copy-number low (endometrioid) subtype characterized by CTNNB1 mutations, and the copy-number high (serous-like) subtype characterized by high levels of copy number alterations and recurrent TP53 mutations.	('microsatellite unstable tumors', 'Disease', (324, 354))	('EC', 'Disease', 'MESH:D016889', (65, 67))	('microsatellite unstable tumors', 'Disease', 'MESH:D053842', (324, 354))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (448, 457))	('CTNNB1', 'Gene', '1499', (441, 447))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('TP53', 'Gene', '7157', (576, 580))	('TP53', 'Gene', (576, 580))	('CTNNB1', 'Gene', (441, 447))
66040	30415991	A formal classification of uterine carcinosarcomas into the molecular subtypes has not been reported to date, however extensive copy-number alterations and recurrent somatic mutations akin to those observed in both endometrioid and serous ECs have been found.	('serous ECs', 'Disease', 'MESH:D016889', (232, 242))	('carcinosarcomas', 'Disease', (35, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('endometrioid', 'Disease', (215, 227))	('copy-number alterations', 'Var', (128, 151))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (27, 49))	('carcinosarcomas', 'Disease', 'MESH:D002296', (35, 50))	('serous ECs', 'Disease', (232, 242))
66041	30415991	Whilst TCGA focused on primary untreated ECs, whole-exome sequencing (WES) analysis of primary ECs and matched abdominopelvic metastases revealed novel recurrent alterations in metastatic ECs, temporal heterogeneity of driver genetic alterations, and demonstrated that <50% of somatic mutations were conserved from primary to metastasis within ECs.	('ECs', 'Disease', (95, 98))	('ECs', 'Disease', 'MESH:D016889', (344, 347))	('alterations', 'Var', (162, 173))	('ECs', 'Disease', (188, 191))	('ECs', 'Disease', 'MESH:D016889', (95, 98))	('metastases', 'Disease', (126, 136))	('ECs', 'Disease', (41, 44))	('ECs', 'Disease', 'MESH:D016889', (188, 191))	('ECs', 'Disease', 'MESH:D016889', (41, 44))	('ECs', 'Disease', (344, 347))	('metastases', 'Disease', 'MESH:D009362', (126, 136))
66042	30415991	Shortly after the publication of the EC TCGA study, Alexandrov and colleagues derived 'mutational signatures' from the analysis of cancer genomes, based on the principle that the type of nucleotide substitution and their context (i.e.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('nucleotide substitution', 'Var', (187, 210))	('EC', 'Disease', 'MESH:D016889', (37, 39))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
66043	30415991	the bases immediately before and after the substitution) may provide important information about the oncogenic processes operative in the development and progression of a cancer.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('substitution', 'Var', (43, 55))	('cancer', 'Disease', (171, 177))
66046	30415991	homologous recombination (HR) DNA repair defects (signature 3), DNA mismatch repair (MMR) defects (signatures 6, 15, 20 and 26) and POLE EDMs (signatures 10 and 14)), exposure to mutagenic/carcinogenic stimuli (e.g.	('carcinogenic', 'Disease', (189, 201))	('carcinogenic', 'Disease', 'MESH:D063646', (189, 201))	('defects', 'Var', (41, 48))	('defects', 'Var', (90, 97))
66049	30415991	These phenomena leave characteristic imprints/scars in the cancer genome in the form of specific patterns of mutations (i.e.	('scars', 'Phenotype', 'HP:0100699', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (109, 118))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
66050	30415991	In a recent study of gynecologic and breast cancers by TCGA, MSI-high ECs were found to often display DNA MMR mutational signatures, however a detailed systematic evaluation of the mutational signatures in ECs has not been performed to date.	('breast cancers', 'Disease', (37, 51))	('ECs', 'Disease', 'MESH:D016889', (70, 73))	('breast cancers', 'Disease', 'MESH:D001943', (37, 51))	('gynecologic', 'Disease', (21, 32))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('DNA', 'MPA', (102, 105))	('mutational', 'Var', (110, 120))	('breast cancers', 'Phenotype', 'HP:0003002', (37, 51))	('ECs', 'Disease', (206, 209))	('ECs', 'Disease', 'MESH:D016889', (206, 209))	('TCGA', 'Gene', (55, 59))	('ECs', 'Disease', (70, 73))	('MSI-high', 'Gene', (61, 69))
66056	30415991	LST scores, a genomic feature of HR deficiency (cut-off >=15), and information on bi-allelic somatic and germ line pathogenic mutations in a curated list of 102 HR-related DNA repair genes in copy-number high (serous-like) ECs, HGSOCs and basal-like breast cancers were obtained from Riaz et al..	('ECs', 'Disease', 'MESH:D016889', (223, 226))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('HGSOCs', 'Disease', (228, 234))	('ECs', 'Disease', (223, 226))	('Riaz', 'Gene', '23598', (284, 288))	('breast cancers', 'Phenotype', 'HP:0003002', (250, 264))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('mutations', 'Var', (126, 135))	('Riaz', 'Gene', (284, 288))	('breast cancers', 'Disease', 'MESH:D001943', (250, 264))	('breast cancers', 'Disease', (250, 264))
66057	30415991	In addition, the length of small deletions (indels) was assessed in these tumors, as HR-defective cancers have been shown to have an enrichment for deletions >=5bp.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('tumors', 'Disease', (74, 80))	('deletions', 'Var', (148, 157))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('cancers', 'Disease', (98, 105))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
66059	30415991	The cancer cell fractions (CCFs) of all mutations were computed using ABSOLUTE (v1.0.6), as previously described.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))
66060	30415991	We defined mutations "private to the primary lesion" and "private to the metastatic lesion" as those present only in the primary tumor or only in the metastasis, respectively.	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('mutations', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (129, 134))
66065	30415991	The majority of ECs of MSI (hypermutated) subtype (85%; 55/65) had a dominant mutational signature associated with defective DNA MMR (53/65, signature 6; 1/65, signature 15; 1/65, signature 26; Fig.	('ECs', 'Disease', (16, 19))	('DNA', 'Gene', (125, 128))	('ECs', 'Disease', 'MESH:D016889', (16, 19))	('defective', 'Var', (115, 124))
66066	30415991	Conversely, the majority of ECs of copy-number low (endometrioid) and copy-number high (serous-like) subtypes had the aging-related signature 1 as the most prevalent dominant mutational signature (88%, 79/90 and 70%, 42/60, respectively; Figs.	('copy-number high', 'Var', (70, 86))	('copy-number low', 'Var', (35, 50))	('ECs', 'Disease', 'MESH:D016889', (28, 31))	('ECs', 'Disease', (28, 31))
66067	30415991	In the TCGA study, POLE ECs were found to have the best and copy-number high (serous-like) ECs the worst progression-free survival.	('ECs', 'Disease', (91, 94))	('copy-number high', 'Var', (60, 76))	('ECs', 'Disease', 'MESH:D016889', (91, 94))	('progression-free survival', 'CPA', (105, 130))	('worst', 'NegReg', (99, 104))	('ECs', 'Disease', (24, 27))	('ECs', 'Disease', 'MESH:D016889', (24, 27))
66068	30415991	As a hypothesis-generating analysis, we used the dominant mutational signatures to categorize ECs into i) dominant POLE signatures 10 or 14, ii) dominant MSI signatures 6, 15, 20 or 26, iii) dominant aging signature 1, copy-number low and iv) dominant aging signature 1, copy-number high.	('ECs', 'Disease', 'MESH:D016889', (94, 97))	('ECs', 'Disease', (94, 97))	('copy-number', 'Var', (219, 230))
66069	30415991	Of the 17 cases within the POLE (ultramutated) molecular subtype, all of which harbored a POLE EDM, 13 ECs displayed a dominant signature 10 associated with POLE mutations, one a dominant aging-related signature 1, one a dominant DNA MMR signature 6, and two ECs had a dominant signature 14 (Fig.	('ECs', 'Disease', 'MESH:D016889', (103, 106))	('ECs', 'Disease', (259, 262))	('ECs', 'Disease', 'MESH:D016889', (259, 262))	('associated', 'Reg', (141, 151))	('POLE mutations', 'Var', (157, 171))	('ECs', 'Disease', (103, 106))
66070	30415991	In the latter two cases, co-occurrence of POLE EDMs with either MLH1 gene promoter methylation or MSH6 mutations were detected, consistent with the notion that signature 14 is present in tumors with concurrent loss of POLE and MMR function.	('mutations', 'Var', (103, 112))	('MLH1', 'Gene', (64, 68))	('MLH1', 'Gene', '4292', (64, 68))	('MSH6', 'Gene', '2956', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('POLE EDMs', 'Disease', (42, 51))	('tumors', 'Disease', (187, 193))	('MSH6', 'Gene', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
66072	30415991	ECs with M444K or P286R POLE hotspot EDMs had the highest percentage of mutational signature 10 (median 91%, range 87-100%), followed by ECs with V411L mutations (median 74%, range 30-76%).	('M444K', 'Mutation', 'p.M444K', (9, 14))	('P286R', 'Var', (18, 23))	('M444K', 'Var', (9, 14))	('ECs', 'Disease', (0, 3))	('ECs', 'Disease', (137, 140))	('V411L', 'Mutation', 'rs1196350669', (146, 151))	('ECs', 'Disease', 'MESH:D016889', (137, 140))	('ECs', 'Disease', 'MESH:D016889', (0, 3))	('P286R', 'Mutation', 'p.P286R', (18, 23))	('mutational', 'Var', (72, 82))
66073	30415991	By contrast, the three ECs with POLE EDMs not affecting known hotspots either had a dominant aging-related signature 1 (R305C) or a dominant signature 14 (i.e.	('ECs', 'Disease', 'MESH:D016889', (23, 26))	('R305C', 'Mutation', 'p.R305C', (120, 125))	('ECs', 'Disease', (23, 26))	('R305C', 'Var', (120, 125))
66079	30415991	Of the remaining 51 copy-number high (serous-like) ECs, ten (10/51; 20%) had a secondary signature 3; of these, seven were of serous, two of endometrioid and one of mixed histologic subtype (Fig.	('copy-number', 'Var', (20, 31))	('ECs', 'Disease', (51, 54))	('ECs', 'Disease', 'MESH:D016889', (51, 54))
66081	30415991	Furthermore, three of these nine ECs, all with high LST scores, harbored bi-allelic pathogenic germline BRCA1 mutations, and were of endometrioid histology (Fig.	('mutations', 'Var', (110, 119))	('BRCA1', 'Gene', '672', (104, 109))	('ECs', 'Disease', (33, 36))	('ECs', 'Disease', 'MESH:D016889', (33, 36))	('BRCA1', 'Gene', (104, 109))	('harbored', 'Reg', (64, 72))
66083	30415991	In the EC study by TCGA, it was reported that copy-number high (serous-like) ECs shared many molecular features with both HGSOCs and basal-like breast cancers, and, therefore, some of the treatment paradigms applicable to these cancers could also be extended to copy-number high (serous-like) ECs.	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('HGSOCs', 'Disease', (122, 128))	('ECs', 'Disease', (293, 296))	('ECs', 'Disease', 'MESH:D016889', (293, 296))	('ECs', 'Disease', (77, 80))	('ECs', 'Disease', 'MESH:D016889', (77, 80))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('copy-number', 'Var', (46, 57))	('cancers', 'Disease', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('EC', 'Disease', 'MESH:D016889', (7, 9))	('cancers', 'Disease', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancers', 'Disease', 'MESH:D001943', (144, 158))	('breast cancers', 'Disease', (144, 158))	('EC', 'Disease', 'MESH:D016889', (293, 295))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('EC', 'Disease', 'MESH:D016889', (77, 79))	('breast cancers', 'Phenotype', 'HP:0003002', (144, 158))	('cancers', 'Disease', 'MESH:D009369', (151, 158))
66084	30415991	HGSOCs and basal-like breast cancers frequently harbor alterations affecting the HRD pathway.	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('alterations', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('HRD pathway', 'Pathway', (81, 92))	('breast cancers', 'Phenotype', 'HP:0003002', (22, 36))	('breast cancers', 'Disease', 'MESH:D001943', (22, 36))	('HGSOCs', 'Disease', (0, 6))	('breast cancers', 'Disease', (22, 36))
66086	30415991	Consistent with this observation, other features of defective HRD, including LST scores, the average length of small deletions and bi-allelic genetic alterations in HRD genes were significantly lower in ECs of copy-number high (serous-like) molecular subtype than in HGSOCs and basal-like breast cancers (Supplementary Fig.	('bi-allelic', 'Var', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('ECs', 'Disease', 'MESH:D016889', (203, 206))	('copy-number', 'Var', (210, 221))	('breast cancers', 'Phenotype', 'HP:0003002', (289, 303))	('breast cancers', 'Disease', 'MESH:D001943', (289, 303))	('ECs', 'Disease', (203, 206))	('breast cancers', 'Disease', (289, 303))	('cancers', 'Phenotype', 'HP:0002664', (296, 303))	('lower', 'NegReg', (194, 199))	('HRD', 'Gene', (165, 168))
66087	30415991	These data suggest that despite the high prevalence of TP53 mutations and high levels of copy number alterations in copy-number high (serous-like) ECs, the DNA repair defects and mutational processes involved in the tumorigenesis of the majority of copy-number high (serous-like) ECs may differ from those of HGSOCs and basal-like breast cancers.	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('HGSOCs', 'Disease', (309, 315))	('ECs', 'Disease', (280, 283))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('ECs', 'Disease', 'MESH:D016889', (280, 283))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('ECs', 'Disease', (147, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (331, 345))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('copy-number', 'Var', (249, 260))	('cancers', 'Phenotype', 'HP:0002664', (338, 345))	('mutations', 'Var', (60, 69))	('ECs', 'Disease', 'MESH:D016889', (147, 150))	('breast cancers', 'Disease', 'MESH:D001943', (331, 345))	('breast cancers', 'Disease', (331, 345))
66091	30415991	In addition, 4/57 (7%) uterine carcinosarcomas had a dominant mutational signature 3 associated with defective HRD, and 12/57 (21%) had a secondary signature 3; however, none of these harbored bi-allelic genomic alterations affecting HR-related genes.	('carcinosarcomas', 'Disease', (31, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('HRD', 'Protein', (111, 114))	('defective', 'Var', (101, 110))	('carcinosarcomas', 'Disease', 'MESH:D002296', (31, 46))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (23, 45))
66094	30415991	Taken together, uterine carcinosarcomas not only harbor mutations found in both endometrioid and serous carcinomas, but also the mutational processes that shaped the genomes of uterine carcinosarcomas were similar to those found in endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) subtypes.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (16, 38))	('endometrioid and serous carcinomas', 'Disease', 'MESH:D018269', (232, 266))	('mutations', 'Var', (56, 65))	('carcinosarcomas', 'Disease', (24, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('endometrioid and serous carcinomas', 'Disease', 'MESH:D018269', (80, 114))	('carcinosarcomas', 'Disease', 'MESH:D002296', (185, 200))	('carcinosarcomas', 'Disease', 'MESH:D002296', (24, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (256, 266))	('carcinosarcomas', 'Disease', (185, 200))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (177, 199))
66095	30415991	To define whether the mutational spectra of ECs change with the progression from primary to metastatic disease, we retrieved WES data from 26 primary ECs (19 endometrioid, three serous, three carcinosarcomas and one clear cell carcinoma) and 35 matched metastases from Gibson et al.. We performed mutational signature analysis of i) all mutations in a given primary tumor/metastasis, ii) mutations shared between primary tumors and metastases, iii) mutations private to the primary tumor or iv) mutations private to the metastasis of a given case.	('metastases', 'Disease', 'MESH:D009362', (432, 442))	('ECs', 'Disease', (150, 153))	('ECs', 'Disease', 'MESH:D016889', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (482, 487))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('tumors', 'Disease', (421, 427))	('carcinosarcomas', 'Disease', (192, 207))	('metastases', 'Disease', (432, 442))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('clear cell carcinoma', 'Disease', (216, 236))	('tumors', 'Disease', 'MESH:D009369', (421, 427))	('mutations', 'Var', (388, 397))	('tumor', 'Phenotype', 'HP:0002664', (482, 487))	('tumor', 'Disease', (366, 371))	('ECs', 'Disease', (44, 47))	('ECs', 'Disease', 'MESH:D016889', (44, 47))	('clear cell carcinoma', 'Disease', 'MESH:D002292', (216, 236))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Disease', (421, 426))	('metastases', 'Disease', 'MESH:D009362', (253, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('mutations', 'Var', (337, 346))	('tumor', 'Disease', 'MESH:D009369', (421, 426))	('carcinosarcomas', 'Disease', 'MESH:D002296', (192, 207))	('metastases', 'Disease', (253, 263))	('tumors', 'Phenotype', 'HP:0002664', (421, 427))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', (482, 487))
66096	30415991	We reasoned that these private mutations may stem from mutational processes playing a role in tumor maintenance and progression.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))
66098	30415991	EC10, EC27) or changes from a dominant POLE-related signature 10 in the primary to dominant signatures 1 and 6 in two and one metastases of the same case, respectively (EC28; Fig.	('changes', 'Var', (15, 22))	('EC', 'Disease', 'MESH:D016889', (6, 8))	('EC', 'Disease', 'MESH:D016889', (169, 171))	('metastases', 'Disease', (126, 136))	('EC27', 'CellLine', 'CVCL:8807', (6, 10))	('EC10', 'CellLine', 'CVCL:5V06', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (126, 136))	('EC', 'Disease', 'MESH:D016889', (0, 2))
66100	30415991	In the V411L POLE-mutant EC17, the mutations shared between the primary tumor and metastasis had a dominant POLE signature 10, whereas the dominant mutational processes underpinning the primary tumor and metastasis itself were MSI-related (signatures 6/15; Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EC', 'Disease', 'MESH:D016889', (25, 27))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (72, 77))	('V411L', 'Mutation', 'rs1196350669', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('V411L', 'Var', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
66101	30415991	In this case EC17, a somatic MLH1 missense mutation not associated with loss of heterozygosity (LOH) of the wild-type allele was found in the shared mutations (root), whereas two additional MLH1, two MSH6 and one MSH2 mutations were found in the primary tumor only and additional MLH1 and MSH2 mutations in the metastasis only, suggesting that the somatic DNA MMR gene mutations in this tumor may be secondary to the ultramutator POLE EDM.	('tumor', 'Phenotype', 'HP:0002664', (387, 392))	('DNA MMR gene', 'Gene', (356, 368))	('MLH1', 'Gene', '4292', (190, 194))	('MLH1', 'Gene', (29, 33))	('MSH2', 'Gene', (213, 217))	('MLH1', 'Gene', '4292', (29, 33))	('MLH1', 'Gene', (280, 284))	('tumor', 'Disease', (254, 259))	('MSH2', 'Gene', (289, 293))	('MSH2', 'Gene', '4436', (213, 217))	('MSH2', 'Gene', '4436', (289, 293))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('MLH1', 'Gene', '4292', (280, 284))	('EC', 'Disease', 'MESH:D016889', (13, 15))	('tumor', 'Disease', (387, 392))	('mutations', 'Var', (369, 378))	('MSH6', 'Gene', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (387, 392))	('MSH6', 'Gene', '2956', (200, 204))	('ultramutator POLE EDM', 'Disease', (417, 438))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('MLH1', 'Gene', (190, 194))
66102	30415991	Furthermore, we observed a dominant aging mutational process (signature 1) in the shared mutations of EC4 and EC6 but the mutations private to the primary and matched metastatic tumors had dominant MSI-related signatures (signatures 6/15/20) and an increase in the fraction of small indels (Fig.	('aging mutational process', 'MPA', (36, 60))	('tumors', 'Disease', (178, 184))	('MSI-related', 'MPA', (198, 209))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('EC', 'Disease', 'MESH:D016889', (110, 112))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (89, 98))	('EC4', 'CellLine', 'CVCL:5V07', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('EC', 'Disease', 'MESH:D016889', (102, 104))
66103	30415991	No genetic alterations in DNA MMR genes restricted to the mutations unique to the primary or metastatic tumors were found in these two cases; it is plausible that the MSI and shift in mutational signature may be due to methylation of MLH1 in these cases, a common event in endometrioid ECs.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ECs', 'Disease', 'MESH:D016889', (286, 289))	('methylation', 'Var', (219, 230))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MLH1', 'Gene', '4292', (234, 238))	('MLH1', 'Gene', (234, 238))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('ECs', 'Disease', (286, 289))	('MSI', 'MPA', (167, 170))
66106	30415991	Whilst a shift in the mutational signatures was observed and the primary tumor mutations displayed a dominant APOBEC-related signature 13, the mutations private in the metastasis had a dominant HRD-related signature 3.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('EC', 'Disease', 'MESH:D016889', (114, 116))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (79, 88))
66107	30415991	Both the primary tumor and its metastasis harbored a p.R15W germline mutation affecting UIMC1, which encodes the BRCA1-interacting protein RAP80 and plays a role in BRCA1-mediated DNA damage responses by recruiting BRCA1 to DNA double-strand breaks.	('tumor', 'Disease', (17, 22))	('BRCA1', 'Gene', (165, 170))	('BRCA1', 'Gene', '672', (165, 170))	('BRCA1', 'Gene', (113, 118))	('RAP80', 'Gene', (139, 144))	('p.R15W', 'Var', (53, 59))	('RAP80', 'Gene', '51720', (139, 144))	('p.R15W', 'Mutation', 'rs13167812', (53, 59))	('UIMC1', 'Gene', '51720', (88, 93))	('BRCA1', 'Gene', '672', (215, 220))	('recruiting', 'PosReg', (204, 214))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('UIMC1', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRCA1', 'Gene', '672', (113, 118))	('BRCA1', 'Gene', (215, 220))
66109	30415991	Consistent with this finding, we found that the LST score was only high in the metastasis of EC22 (LST score 20), but not in the primary tumor (LST score 14), providing evidence to suggest that defective HR, likely driven by UIMC1 bi-allelic inactivation, may have contributed to the progression to metastatic disease in this EC.	('EC', 'Disease', 'MESH:D016889', (326, 328))	('UIMC1', 'Gene', '51720', (225, 230))	('tumor', 'Disease', (137, 142))	('contributed', 'Reg', (265, 276))	('EC', 'Disease', 'MESH:D016889', (93, 95))	('EC22', 'CellLine', 'CVCL:6262', (93, 97))	('UIMC1', 'Gene', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('defective', 'Var', (194, 203))	('metastatic disease', 'Disease', (299, 317))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
66110	30415991	Taken together, the acquisition of additional genetic instability, through defects in DNA repair mechanisms including DNA MMR, APOBEC and HR, may play a role in the progression from primary EC to metastatic disease and may have therapeutic implications.	('DNA MMR', 'Gene', (118, 125))	('EC', 'Disease', 'MESH:D016889', (131, 133))	('defects', 'NegReg', (75, 82))	('EC', 'Disease', 'MESH:D016889', (190, 192))	('metastatic disease', 'Disease', (196, 214))	('play', 'Reg', (146, 150))	('genetic', 'Var', (46, 53))
66112	30415991	loss of polymerase proofreading and MSI), whilst in endometrioid and serous ECs of copy-number low/high subtypes and uterine carcinosarcomas aging-related mutational processes are the most dominant.	('polymerase', 'Protein', (8, 18))	('carcinosarcomas', 'Disease', (125, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('copy-number low/high', 'Var', (83, 103))	('serous ECs', 'Disease', (69, 79))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (117, 139))	('serous ECs', 'Disease', 'MESH:D016889', (69, 79))	('carcinosarcomas', 'Disease', 'MESH:D002296', (125, 140))	('loss', 'NegReg', (0, 4))
66117	30415991	Furthermore, these results impact on the delivery of precision medicine approaches for EC patients, given that mutational signatures and a clear understanding of the underlying mutagenic processes/pathways present in a given cancer may inform treatment options, in particular in the absence of a targetable mutation or gene copy number alteration (e.g.	('gene copy number alteration', 'Var', (319, 346))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('EC', 'Disease', 'MESH:D016889', (87, 89))	('cancer', 'Disease', (225, 231))	('inform', 'Reg', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('impact', 'Reg', (27, 33))	('patients', 'Species', '9606', (90, 98))
66120	30415991	Specific POLE and POLD1 mutations have been shown to lead to ultramutation.	('ultramutation', 'MPA', (61, 74))	('lead to', 'Reg', (53, 60))	('mutations', 'Var', (24, 33))	('POLD1', 'Gene', (18, 23))	('POLD1', 'Gene', '5424', (18, 23))
66121	30415991	Here we observed that specific POLE EDMs might have distinct impacts on the mutational processes, given that the mutational signature 10 was more abundant in ECs harboring M444K or P286R EDMs than in those harboring V411L or other EDMs.	('M444K', 'Var', (172, 177))	('P286R', 'Var', (181, 186))	('V411L', 'Mutation', 'rs1196350669', (216, 221))	('ECs', 'Disease', (158, 161))	('P286R', 'Mutation', 'p.P286R', (181, 186))	('ECs', 'Disease', 'MESH:D016889', (158, 161))	('M444K', 'Mutation', 'p.M444K', (172, 177))
66122	30415991	This is consistent with recent observations that the V411L mutation reduces exonuclease activity without completely abolishing it, whereas the P286R mutation essentially inactivates proofreading.	('proofreading', 'MPA', (182, 194))	('exonuclease', 'Enzyme', (76, 87))	('V411L', 'Var', (53, 58))	('P286R', 'Var', (143, 148))	('inactivates', 'NegReg', (170, 181))	('P286R', 'Mutation', 'p.P286R', (143, 148))	('V411L', 'Mutation', 'rs1196350669', (53, 58))	('reduces', 'NegReg', (68, 75))
66123	30415991	Mutational signature analysis also identified a copy-number low (endometrioid) EC with a POLE L424V EDM mutation that was not classified as of POLE subtype by TCGA, and a uterine carcinosarcoma with a POLE P286R hotspot mutation.	('POLE', 'Gene', (89, 93))	('L424V', 'Var', (94, 99))	('carcinosarcoma', 'Disease', 'MESH:D002296', (179, 193))	('P286R', 'Mutation', 'p.P286R', (206, 211))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (171, 193))	('EC', 'Disease', 'MESH:D016889', (79, 81))	('carcinosarcoma', 'Disease', (179, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('L424V', 'Mutation', 'rs768299607', (94, 99))
66124	30415991	On the other hand, we identified two MSI (hypermutated) and one copy-number high (serous-like) EC with POLE EDM mutations not affecting hotspot residues lacking POLE mutational signatures.	('mutations', 'Var', (112, 121))	('POLE EDM', 'Gene', (103, 111))	('EC', 'Disease', 'MESH:D016889', (95, 97))
66125	30415991	With increasing evidence that POLE mutations are an early event in endometrial and colorectal cancers and that ECs harboring POLE hotspot EDMs may be sensitive to nucleoside analogs or immune checkpoint inhibitors, prospective clinical trials focusing on the treatment of advanced POLE ECs are warranted.	('ECs', 'Disease', (111, 114))	('sensitive', 'Reg', (150, 159))	('ECs', 'Disease', 'MESH:D016889', (286, 289))	('ECs', 'Disease', 'MESH:D016889', (111, 114))	('colorectal cancers', 'Disease', 'MESH:D015179', (83, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('endometrial', 'Disease', (67, 78))	('colorectal cancers', 'Disease', (83, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('endometrial', 'Disease', 'MESH:D016889', (67, 78))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('nucleoside', 'Chemical', 'MESH:D009705', (163, 173))	('ECs', 'Disease', (286, 289))	('mutations', 'Var', (35, 44))
66132	30415991	Further studies are warranted to assess whether MSI-high ECs with a dominant aging mutational signature are less sensitive to immune checkpoint inhibitors than those with a dominant MSI mutational signature.	('mutational', 'Var', (83, 93))	('ECs', 'Disease', (57, 60))	('ECs', 'Disease', 'MESH:D016889', (57, 60))	('sensitive to', 'MPA', (113, 125))	('less', 'NegReg', (108, 112))
66133	30415991	HGSOCs and basal-like and/or triple-negative breast cancers often show defects in HRD and due to genetic alterations affecting this pathway, including germline and somatic BRCA1 and BRCA2 mutations, and are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HRD', 'Protein', (82, 85))	('BRCA1', 'Gene', '672', (172, 177))	('defects', 'NegReg', (71, 78))	('PARP', 'Gene', (281, 285))	('BRCA2', 'Gene', '675', (182, 187))	('platinum', 'Chemical', 'MESH:D010984', (220, 228))	('breast cancers', 'Phenotype', 'HP:0003002', (45, 59))	('BRCA1', 'Gene', (172, 177))	('alterations', 'Var', (105, 116))	('breast cancers', 'Disease', 'MESH:D001943', (45, 59))	('breast cancers', 'Disease', (45, 59))	('PARP', 'Gene', '142', (281, 285))	('mutations', 'Var', (188, 197))	('poly(ADP-ribose) polymerase', 'Gene', '142', (252, 279))	('poly(ADP-ribose) polymerase', 'Gene', (252, 279))	('BRCA2', 'Gene', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
66134	30415991	Based on the similarity in copy number alterations between HGSOCs, basal-like breast cancers and copy-number high (serous-like) ECs, it has been suggested that copy-number high (serous-like) ECs may also be candidates for therapies currently employed for the management of HGSOCs and basal-like breast cancers.	('ECs', 'Disease', (191, 194))	('copy-number high', 'Var', (160, 176))	('breast cancers', 'Disease', 'MESH:D001943', (295, 309))	('breast cancers', 'Disease', 'MESH:D001943', (78, 92))	('breast cancers', 'Disease', (295, 309))	('breast cancers', 'Disease', (78, 92))	('ECs', 'Disease', 'MESH:D016889', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('HGSOCs', 'Disease', (273, 279))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('ECs', 'Disease', 'MESH:D016889', (191, 194))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('breast cancers', 'Phenotype', 'HP:0003002', (295, 309))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('ECs', 'Disease', (128, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (78, 92))
66135	30415991	We noted, however, that despite similar levels of gene copy number alterations, the underlying DNA repair defects that shaped the majority of the genomes of copy-number high (serous-like) ECs are likely distinct from those of HGSOCs and basal-like breast cancers, given their lower levels of mutational signature 3, LST scores, average indel length and number of cases harboring bi-allelic HR-related gene alterations.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('copy-number', 'Var', (157, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (248, 262))	('ECs', 'Disease', (188, 191))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('breast cancers', 'Disease', 'MESH:D001943', (248, 262))	('ECs', 'Disease', 'MESH:D016889', (188, 191))	('breast cancers', 'Disease', (248, 262))	('defects', 'Var', (106, 113))
66137	30415991	Importantly, however, we did identify three endometrioid ECs with a dominant signature 3, high LSTs and bi-allelic BRCA1 alterations, features consistent with HRD and potential benefit from therapies targeting this type of DNA repair defects.	('alterations', 'Var', (121, 132))	('BRCA1', 'Gene', '672', (115, 120))	('ECs', 'Disease', (57, 60))	('ECs', 'Disease', 'MESH:D016889', (57, 60))	('BRCA1', 'Gene', (115, 120))	('bi-allelic', 'Var', (104, 114))
66145	30415991	MSI and POLE endometrial cancers (ECs) show specific mutational signatures The majority of ECs and carcinosarcomas display the aging-associated signature 1 POLE mutations have an allele-specific impact on mutational processes 15% of serous-like ECs have the defective homologous recombination DNA repair mutational signature 3 Shifts in the mutational signatures take place in the progression of ECs	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('ECs', 'Disease', (245, 248))	('endometrial cancer', 'Phenotype', 'HP:0012114', (13, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ECs', 'Disease', (91, 94))	('ECs', 'Disease', 'MESH:D016889', (396, 399))	('carcinosarcomas', 'Disease', 'MESH:D002296', (99, 114))	('endometrial cancers', 'Disease', 'MESH:D016889', (13, 32))	('ECs', 'Disease', 'MESH:D016889', (91, 94))	('ECs', 'Disease', 'MESH:D016889', (245, 248))	('endometrial cancers', 'Disease', (13, 32))	('ECs', 'Disease', (34, 37))	('mutations', 'Var', (161, 170))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('carcinosarcomas', 'Disease', (99, 114))	('ECs', 'Disease', 'MESH:D016889', (34, 37))	('ECs', 'Disease', (396, 399))
66160	31417921	Consequently, the evolving histological characterisation of US makes it difficult to compare clinical trials conducted in different periods, taking into account that cases of previously considered undifferentiated endometrial sarcomas or high-grade UUS might be included within the class of HG-ESS.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('UUS', 'Chemical', '-', (249, 252))	('endometrial sarcomas', 'Disease', 'MESH:D018203', (214, 234))	('high-grade UUS', 'Var', (238, 252))	('endometrial sarcomas', 'Disease', (214, 234))	('sarcomas', 'Phenotype', 'HP:0100242', (226, 234))
66166	31417921	In this phase III randomised trial patients were randomly selected to receive 51Gy external beam pelvic radiation or observation.	('51Gy', 'Var', (78, 82))	('patients', 'Species', '9606', (35, 43))	('external beam pelvic radiation', 'CPA', (83, 113))
66252	30582752	Phosphatidylinositol 3-kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities The phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('alterations', 'Var', (46, 57))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('solid tumors', 'Disease', (76, 88))	('cancer', 'Disease', (202, 208))
66253	30582752	This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms.	('solid tumors', 'Disease', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('alterations', 'Var', (44, 55))	('PI3K alterations', 'Var', (39, 55))	('solid tumors', 'Disease', 'MESH:D009369', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
66255	30582752	Alterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('PI3K-pathway', 'Pathway', (25, 37))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
66256	30582752	Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively.	('insertions/deletions', 'Var', (25, 45))	('copy number changes', 'Var', (91, 110))	('patients', 'Species', '9606', (165, 173))	('single base', 'Var', (9, 20))
66259	30582752	Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies.	('carcinosarcoma', 'Disease', 'MESH:D002296', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('squamous cell carcinoma', 'Disease', (83, 106))	('Alterations', 'Var', (0, 11))	('carcinosarcoma', 'Disease', (58, 72))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
66260	30582752	Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019).	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('head and neck cancers', 'Phenotype', 'HP:0012288', (240, 261))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mesotheliomas', 'Disease', 'MESH:D008654', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('MAPK pathway', 'Pathway', (66, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('anal cancer', 'Phenotype', 'HP:0032186', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Tumors', 'Disease', (0, 6))	('colorectal cancers', 'Disease', (100, 118))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('neck cancers', 'Disease', (249, 261))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cancers', 'Disease', (254, 261))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('neck cancers', 'Disease', 'MESH:D006258', (249, 261))	('cancers', 'Disease', (111, 118))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('PI3K pathway', 'Pathway', (49, 61))	('alterations', 'Var', (79, 90))	('colorectal cancers', 'Disease', 'MESH:D015179', (100, 118))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))	('cancers', 'Disease', 'MESH:D009369', (254, 261))	('mesotheliomas', 'Disease', (154, 167))
66261	30582752	The co-occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.	('alterations', 'Var', (58, 69))	('unknown primary cancers', 'Disease', 'MESH:D009382', (147, 170))	('unknown primary cancers', 'Disease', (147, 170))	('bladder', 'Disease', (103, 110))	('colorectal', 'Disease', 'MESH:D015179', (112, 122))	('ESR1', 'Gene', (21, 25))	('prostate', 'Disease', (133, 141))	('AR', 'Gene', '367', (33, 35))	('colorectal', 'Disease', (112, 122))	('significant', 'Reg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ESR1', 'Gene', '2099', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('uterine', 'Disease', (124, 131))
66264	30582752	Comprehensive genomic profiling of solid tumors reveals frequent genetic alterations in several genes of the phosphatidylinositol 3-kinase (PI3K) pathway.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('solid tumors', 'Disease', (35, 47))	('solid tumors', 'Disease', 'MESH:D009369', (35, 47))	('genetic alterations', 'Var', (65, 84))
66270	30582752	Indeed, it is well known that mitogen-activated protein kinase kinase (MEK) pathway alterations are more common in patients with PI3K signaling anomalies than in those without such anomalies and that MEK anomalies can mediate resistance.19, 20 An in-depth characterization of the PI3K genomic landscape, along with a description of concomitant genetic alterations that could lead to resistance to pathway inhibition, is urgently needed.	('lead', 'Reg', (375, 379))	('patients', 'Species', '9606', (115, 123))	('alterations', 'Var', (352, 363))	('MEK', 'Gene', (71, 74))	('MEK', 'Gene', (200, 203))	('MEK', 'Gene', '5609', (200, 203))	('MEK', 'Gene', '5609', (71, 74))
66275	30582752	A co-occurrence analysis was performing matching genomic alterations in the PI3K pathway with 3 different subsets of genomic alterations (the mitogen-activated kinase [MAPK] pathway, the tumor protein 53 [TP53] pathway, and the estrogen receptor 1 [ESR1] and/or androgen receptor [AR] [hormone receptor] pathway).	('mitogen-activated kinase [MAPK] pathway', 'Pathway', (142, 181))	('androgen receptor', 'Gene', (262, 279))	('tumor protein 53', 'Gene', (187, 203))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('PI3K pathway', 'Pathway', (76, 88))	('TP53', 'Gene', '7157', (205, 209))	('ESR1', 'Gene', '2099', (249, 253))	('TP53', 'Gene', (205, 209))	('alterations', 'Var', (57, 68))	('hormone receptor', 'Gene', '3164', (286, 302))	('tumor protein 53', 'Gene', '7157', (187, 203))	('hormone receptor', 'Gene', (286, 302))	('androgen receptor', 'Gene', '367', (262, 279))	('estrogen receptor 1', 'Gene', '2099', (228, 247))	('ESR1', 'Gene', (249, 253))	('AR', 'Gene', '367', (281, 283))	('estrogen receptor 1', 'Gene', (228, 247))
66276	30582752	Alterations in any gene of the PI3K pathway were identified in 44% of the 60,991 tumors analyzed (Fig.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('identified', 'Reg', (49, 59))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('PI3K pathway', 'Pathway', (31, 43))
66280	30582752	Carcinosarcomas (89% had PI3K pathway alterations) and squamous cell carcinomas (62% had PI3K pathway alterations) were the most altered histologies, whereas sarcomas (16% had PI3K pathway alterations), mesotheliomas (14% had PI3K pathway alterations), and gastrointestinal stromal tumors (GISTs) (11% had PI3K pathway alterations) were the least common.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (55, 79))	('sarcomas', 'Disease', 'MESH:D012509', (158, 166))	('gastrointestinal stromal tumors', 'Disease', (257, 288))	('PI3K', 'Var', (25, 29))	('sarcomas', 'Disease', 'MESH:D012509', (7, 15))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (7, 15))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('squamous cell carcinomas', 'Disease', (55, 79))	('sarcomas', 'Disease', (158, 166))	('sarcomas', 'Disease', (7, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('alterations', 'Var', (38, 49))	('GISTs', 'Phenotype', 'HP:0100723', (290, 295))	('mesotheliomas', 'Disease', (203, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (257, 288))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (257, 288))	('Carcinosarcomas', 'Disease', 'MESH:D002296', (0, 15))	('alterations', 'Reg', (239, 250))	('altered', 'Reg', (129, 136))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (55, 79))	('Carcinosarcomas', 'Disease', (0, 15))	('mesotheliomas', 'Disease', 'MESH:D008654', (203, 216))
66283	30582752	Although PIK3CA was altered most frequently across histologies, at a 1.4 times higher rate than PTEN (13% vs 9% had PIK3CA alterations), a subset of histologies had significantly higher rates (P < .0001) of PTEN alterations than PIK3CA alterations: these included gliomas (29% vs 12%), melanomas (12% vs 3%), neuroendocrine tumors (10% vs 5%), and GISTs (5% vs 0%).	('PIK3CA', 'Gene', (116, 122))	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('melanomas', 'Phenotype', 'HP:0002861', (286, 295))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('neuroendocrine tumors', 'Disease', (309, 330))	('higher rates', 'PosReg', (179, 191))	('melanoma', 'Phenotype', 'HP:0002861', (286, 294))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('PIK3CA', 'Gene', (9, 15))	('GISTs', 'Phenotype', 'HP:0100723', (348, 353))	('PTEN', 'Gene', (96, 100))	('melanomas', 'Disease', 'MESH:D008545', (286, 295))	('gliomas', 'Disease', (264, 271))	('PIK3CA', 'Gene', '5290', (229, 235))	('PTEN', 'Gene', (207, 211))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (309, 330))	('PIK3CA', 'Gene', '5290', (116, 122))	('melanomas', 'Disease', (286, 295))	('GISTs', 'Disease', (348, 353))	('PTEN', 'Gene', '5728', (96, 100))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('PTEN', 'Gene', '5728', (207, 211))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (309, 330))	('alterations', 'Var', (212, 223))	('PIK3CA', 'Gene', '5290', (9, 15))	('PIK3CA', 'Gene', (229, 235))
66289	30582752	Six of the 34 disease types had higher rates of PI3K pathway alterations than the overall average of 44%, including 4 of 5 "female" cancers (ie, cancers of the uterus [77% of patients had an alteration], cervix [62%], breast [58%], and vagina/vulva [46%]) (Fig.	('cancers', 'Disease', (145, 152))	('cancers', 'Disease', (132, 139))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('PI3K pathway', 'Pathway', (48, 60))	('alteration', 'Var', (191, 201))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('alterations', 'Reg', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('patients', 'Species', '9606', (175, 183))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
66296	30582752	Similar to histologic differences, several cancers had significantly higher rates (P < .0001) of PTEN alterations than PIK3CA alterations, including melanoma (12%), brain cancer (25%), prostate cancer (34%), and bone cancer (10%; P = .03).	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('brain cancer', 'Disease', 'MESH:D001932', (165, 177))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('PIK3CA', 'Gene', '5290', (119, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('prostate cancer', 'Disease', (185, 200))	('higher', 'PosReg', (69, 75))	('brain cancer', 'Disease', (165, 177))	('alterations', 'Var', (102, 113))	('PTEN', 'Gene', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('PIK3CA', 'Gene', (119, 125))	('PTEN', 'Gene', '5728', (97, 101))	('bone cancer', 'Disease', 'MESH:D001859', (212, 223))	('brain cancer', 'Phenotype', 'HP:0030692', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('bone cancer', 'Disease', (212, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
66297	30582752	STK11 was altered at a significantly higher rate in cervical cancer, lung large cell carcinoma, and NSCLC, whereas altered FBXW7 was notably more frequent in corpus uteri cancer, anal cancer, colorectal cancer, and melanoma.	('cancer', 'Disease', (184, 190))	('colorectal cancer', 'Disease', (192, 209))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('melanoma', 'Disease', (215, 223))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('lung large cell carcinoma', 'Disease', (69, 94))	('FBXW7', 'Gene', '55294', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (192, 209))	('STK11', 'Gene', (0, 5))	('NSCLC', 'Disease', (100, 105))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('cancer', 'Disease', (61, 67))	('altered', 'Var', (115, 122))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', (203, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (74, 94))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cervical cancer', 'Disease', 'MESH:D002583', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('anal cancer', 'Phenotype', 'HP:0032186', (179, 190))	('cervical cancer', 'Disease', (52, 67))	('uteri cancer', 'Phenotype', 'HP:0010784', (165, 177))	('altered', 'Var', (10, 17))	('STK11', 'Gene', '6794', (0, 5))	('FBXW7', 'Gene', (123, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (192, 209))	('lung large cell carcinoma', 'Disease', 'MESH:D018287', (69, 94))	('frequent', 'Reg', (146, 154))
66299	30582752	Bladder (7%) and kidney (4%) cancers had significant more mutations in TSC1 compared with other disease types (1%).	('mutations', 'Var', (58, 67))	('Bladder', 'Disease', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('TSC1', 'Gene', '7248', (71, 75))	('kidney', 'Disease', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('TSC1', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))
66300	30582752	Because uterine cancers had the highest overall rate of PI3K pathway alterations (77% of patients with uterine cancer had alterations vs 62% of those with cervical cancer; P < .0001) and had a significantly higher percentage of PIK3R1 alterations than the next highest disease type (20%; P < .0001), we performed an additional, detailed analysis of the top PI3K pathway genes that were altered in this disease (see Fig.	('PI3K pathway', 'Pathway', (56, 68))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (111, 117))	('uterine cancer', 'Phenotype', 'HP:0010784', (103, 117))	('alterations', 'Reg', (69, 80))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('uterine cancer', 'Phenotype', 'HP:0010784', (8, 22))	('alterations', 'Reg', (235, 246))	('uterine cancers', 'Phenotype', 'HP:0010784', (8, 23))	('PIK3R1', 'Gene', '5295', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('alterations', 'Var', (122, 133))	('cervical cancer', 'Disease', (155, 170))	('cervical cancer', 'Disease', 'MESH:D002583', (155, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patients', 'Species', '9606', (89, 97))	('PIK3R1', 'Gene', (228, 234))	('higher', 'PosReg', (207, 213))
66304	30582752	Thyroid cancers are primarily altered in PIK3CA and PTEN, including a higher proportion of PIK3CA alterations in the anaplastic subtype (12%) compared with well differentiated thyroid cancers (5%).	('PIK3CA', 'Gene', (91, 97))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('PTEN', 'Gene', (52, 56))	('Thyroid cancers', 'Disease', (0, 15))	('PTEN', 'Gene', '5728', (52, 56))	('Thyroid cancers', 'Disease', 'MESH:D013964', (0, 15))	('PIK3CA', 'Gene', '5290', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('PIK3CA', 'Gene', (41, 47))	('thyroid cancers', 'Disease', (176, 191))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('thyroid cancers', 'Disease', 'MESH:D013964', (176, 191))	('PIK3CA', 'Gene', '5290', (41, 47))	('altered', 'Reg', (30, 37))	('alterations', 'Var', (98, 109))
66305	30582752	Higher proportions of genomic alterations in FBXW7, MTOR, PIK3CA, and STK11 were detected in vulvar cancers compared with vaginal cancers.	('vulvar cancers', 'Disease', (93, 107))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('vulvar cancers', 'Disease', 'MESH:D014846', (93, 107))	('MTOR', 'Gene', '2475', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PIK3CA', 'Gene', (58, 64))	('FBXW7', 'Gene', '55294', (45, 50))	('STK11', 'Gene', (70, 75))	('vaginal cancers', 'Disease', 'MESH:D014625', (122, 137))	('PIK3CA', 'Gene', '5290', (58, 64))	('FBXW7', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('genomic alterations', 'Var', (22, 41))	('vaginal cancers', 'Disease', (122, 137))	('detected', 'Reg', (81, 89))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('STK11', 'Gene', '6794', (70, 75))	('MTOR', 'Gene', (52, 56))
66306	30582752	Adenoid cystic cancers had very few alterations in the PI3K pathway, but PIK3R1 alterations (6%) were detected more frequently compared with other cancers in general (2%).	('PI3K pathway', 'Pathway', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('alterations', 'Var', (80, 91))	('Adenoid cystic cancers', 'Disease', (0, 22))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('PIK3R1', 'Gene', '5295', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('PIK3R1', 'Gene', (73, 79))	('cancers', 'Disease', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Adenoid cystic cancers', 'Disease', 'MESH:D003528', (0, 22))
66307	30582752	In anal cancers, higher frequencies of alterations were detected in FBXW7, PIK3CA, and PTEN, which were observed almost exclusively in tumors that had squamous histology compared with basaloid carcinomas.	('PTEN', 'Gene', '5728', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('tumors', 'Disease', (135, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('PIK3CA', 'Gene', (75, 81))	('cancers', 'Disease', (8, 15))	('FBXW7', 'Gene', '55294', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('basaloid carcinomas', 'Disease', 'MESH:C565284', (184, 203))	('anal cancer', 'Phenotype', 'HP:0032186', (3, 14))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('PTEN', 'Gene', (87, 91))	('basaloid carcinomas', 'Phenotype', 'HP:0002671', (184, 203))	('PIK3CA', 'Gene', '5290', (75, 81))	('FBXW7', 'Gene', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('alterations', 'Var', (39, 50))	('basaloid carcinomas', 'Disease', (184, 203))
66309	30582752	It is important to note the high frequency of PTEN alterations in prostate small cell carcinomas (35%), similar to prostate cancers overall (34%).	('alterations', 'Var', (51, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (75, 96))	('PTEN', 'Gene', (46, 50))	('prostate small cell carcinomas', 'Disease', (66, 96))	('prostate cancers', 'Disease', 'MESH:D011471', (115, 131))	('PTEN', 'Gene', '5728', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate small cell carcinomas', 'Disease', 'MESH:D018288', (66, 96))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('prostate small', 'Phenotype', 'HP:0008687', (66, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('prostate cancers', 'Phenotype', 'HP:0012125', (115, 131))	('prostate cancers', 'Disease', (115, 131))
66310	30582752	The likelihood of a co-occurrence of an alteration in the PI3K pathway, in either the MAPK pathway or the hormone receptor pathway, or in TP53 was analyzed by disease type.	('PI3K pathway', 'Pathway', (58, 70))	('hormone receptor', 'Gene', (106, 122))	('MAPK pathway', 'Pathway', (86, 98))	('TP53', 'Gene', '7157', (138, 142))	('alteration', 'Var', (40, 50))	('TP53', 'Gene', (138, 142))	('hormone receptor', 'Gene', '3164', (106, 122))
66313	30582752	When all tumors were analyzed, there were no significant co-occurrences between PI3K and TP53 pathway alterations (Fig.	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('PI3K', 'Var', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
66315	30582752	A significant co-occurrence ratio was present between PI3K pathway alterations and hormone receptor alterations in ESR1 and AR (OR, 1.53; P < .01) (Fig.	('alterations', 'Reg', (100, 111))	('ESR1', 'Gene', '2099', (115, 119))	('hormone receptor', 'Gene', (83, 99))	('hormone receptor', 'Gene', '3164', (83, 99))	('PI3K pathway', 'Pathway', (54, 66))	('alterations', 'Var', (67, 78))	('ESR1', 'Gene', (115, 119))	('AR', 'Gene', '367', (124, 126))
66317	30582752	Single nucleotide changes were the predominant genetic alterations in 15 of the18 genes (83%), whereas copy number changes were predominant in AKT2 (1.6%), AKT3 (0.9%), and PIK3 catalytic subunit 2beta (PIK3C2B) (1.2%).	('PIK3', 'Gene', (203, 207))	('Single nucleotide changes', 'Var', (0, 25))	('AKT2', 'Gene', '208', (143, 147))	('AKT3', 'Gene', (156, 160))	('AKT3', 'Gene', '10000', (156, 160))	('PIK3', 'Gene', '5294', (203, 207))	('PIK3', 'Gene', (173, 177))	('PIK3C2B', 'Gene', (203, 210))	('AKT2', 'Gene', (143, 147))	('PIK3C2B', 'Gene', '5287', (203, 210))	('PIK3', 'Gene', '5294', (173, 177))
66318	30582752	Although copy number changes and rearrangements were identified infrequently (11% and 0.9%, respectively), they still represent approximately 7300 patients for whom these alterations might inform potential treatments.	('inform', 'Reg', (189, 195))	('patients', 'Species', '9606', (147, 155))	('alterations', 'Var', (171, 182))
66319	30582752	PI3K pathway alterations are observed frequently in diverse solid tumors, making this pathway an attractive target for cancer therapies.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('solid tumors', 'Disease', 'MESH:D009369', (60, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (119, 125))	('PI3K pathway', 'Pathway', (0, 12))	('alterations', 'Var', (13, 24))	('solid tumors', 'Disease', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
66331	30582752	Several reviews have provided a good background describing the difficulties in developing efficacious PI3K pathway inhibitors as well as the paucity of successful clinical trials that resulted in drug approval targeted to specific alterations in this pathway.4, 34 Descriptions of novel genomic alterations in the pathway that predict sensitivity to targeted therapies are emerging.35 It is important to note that the presence of concomitant alterations in alternative pathways may lead to resistance to PI3K inhibitors.19, 36 Conversely, the presence of PI3K alterations can cause resistance to other treatments, especially hormone therapies.37, 38 In the current study, we demonstrated that the co-occurrence of PI3K pathway alterations and alterations in the MAPK, TP53, and hormone pathways varied according to tumor types, as expected.	('tumor', 'Disease', 'MESH:D009369', (815, 820))	('tumor', 'Phenotype', 'HP:0002664', (815, 820))	('MAPK', 'Pathway', (762, 766))	('alterations', 'Var', (727, 738))	('TP53', 'Gene', '7157', (768, 772))	('tumor', 'Disease', (815, 820))	('hormone pathways', 'Pathway', (778, 794))	('TP53', 'Gene', (768, 772))	('PI3K pathway', 'Pathway', (714, 726))
66332	30582752	A higher co-occurrence rate of PI3K and MAPK alterations was observed in some gastrointestinal tumors, including anal and colorectal cancers, which could significantly affect the activity of PI3K pathway inhibitors.12 ESR1 mutations are being implicated as an evolutionary mechanism of acquired resistance to endocrine manipulation, especially in patients with metastatic, previously treated breast cancer.39 It is also noteworthy that, for the first time, we report the absence of a significant co-occurrence of ESR1 mutations with PI3K pathway alterations for breast cancer (OR, 1.01; P = .85).	('alterations', 'Reg', (546, 557))	('breast cancer', 'Phenotype', 'HP:0003002', (562, 575))	('ESR1', 'Gene', (513, 517))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('mutations', 'Var', (518, 527))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('breast cancer', 'Disease', 'MESH:D001943', (562, 575))	('patients', 'Species', '9606', (347, 355))	('breast cancer', 'Disease', (562, 575))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (78, 101))	('ESR1', 'Gene', '2099', (218, 222))	('ESR1', 'Gene', (218, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (392, 405))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('colorectal cancers', 'Disease', (122, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('breast cancer', 'Disease', 'MESH:D001943', (392, 405))	('breast cancer', 'Disease', (392, 405))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('PI3K pathway', 'Pathway', (533, 545))	('cancer', 'Phenotype', 'HP:0002664', (569, 575))	('gastrointestinal tumors', 'Disease', (78, 101))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (78, 101))	('colorectal cancers', 'Disease', 'MESH:D015179', (122, 140))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('ESR1', 'Gene', '2099', (513, 517))
66335	30582752	Alterations in AKT1 are identified more frequently in uterine cancers, breast cancers, and undifferentiated carcinomas.	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('Alterations', 'Var', (0, 11))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (91, 118))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('AKT1', 'Gene', (15, 19))	('identified', 'Reg', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('uterine cancer', 'Phenotype', 'HP:0010784', (54, 68))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('uterine cancers', 'Phenotype', 'HP:0010784', (54, 69))	('breast cancers', 'Disease', (71, 85))	('breast cancers', 'Disease', 'MESH:D001943', (71, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('AKT1', 'Gene', '207', (15, 19))	('undifferentiated carcinomas', 'Disease', (91, 118))	('breast cancers', 'Phenotype', 'HP:0003002', (71, 85))	('cancers', 'Disease', 'MESH:D009369', (62, 69))
66339	30582752	In conclusion, comprehensive genomic profiling of solid tumors has revealed frequent genetic alterations in several genes of the PI3K pathway.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('solid tumors', 'Disease', 'MESH:D009369', (50, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('PI3K pathway', 'Pathway', (129, 141))	('genetic alterations', 'Var', (85, 104))	('solid tumors', 'Disease', (50, 62))
66340	30582752	Gynecologic, breast, and prostate cancers, along with carcinosarcoma and squamous cell carcinomas of different sites, more frequently harbor PI3K alterations.	('breast', 'Disease', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('carcinosarcoma', 'Disease', (54, 68))	('prostate cancers', 'Disease', 'MESH:D011471', (25, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('PI3K alterations', 'Var', (141, 157))	('Gynecologic', 'Disease', (0, 11))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (73, 97))	('squamous cell carcinomas', 'Disease', (73, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('harbor', 'Reg', (134, 140))	('prostate cancers', 'Phenotype', 'HP:0012125', (25, 41))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('prostate cancers', 'Disease', (25, 41))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (73, 97))	('carcinosarcoma', 'Disease', 'MESH:D002296', (54, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
66343	30190114	SQ1274, a novel microtubule inhibitor, inhibits ovarian and uterine cancer cell growth Paclitaxel, a microtubule inhibitor, is subject to tumor resistance while treating high-grade serous ovarian and uterine cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (208, 214))	('ovarian', 'Disease', 'MESH:D010051', (188, 195))	('tumor', 'Disease', (138, 143))	('uterine cancer', 'Phenotype', 'HP:0010784', (200, 214))	('SQ1274', 'Chemical', '-', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('inhibits', 'NegReg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('serous ovarian', 'Disease', (181, 195))	('SQ1274', 'Var', (0, 6))	('serous ovarian', 'Disease', 'MESH:D010051', (181, 195))	('ovarian', 'Disease', (48, 55))	('ovarian', 'Disease', 'MESH:D010051', (48, 55))	('Paclitaxel', 'Chemical', 'MESH:D017239', (87, 97))	('cancer', 'Disease', (68, 74))	('uterine cancer', 'Phenotype', 'HP:0010784', (60, 74))	('ovarian', 'Disease', (188, 195))
66344	30190114	This study aims to directly compare the effects of SQ1274, a novel microtubule inhibitor that binds to the colchicine-binding site on tubulin, and paclitaxel in high-grade serous ovarian and uterine cancer cell lines both in vitro and in vivo.	('SQ1274', 'Var', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('serous ovarian', 'Disease', 'MESH:D010051', (172, 186))	('serous ovarian', 'Disease', (172, 186))	('uterine cancer', 'Phenotype', 'HP:0010784', (191, 205))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('SQ1274', 'Chemical', '-', (51, 57))	('cancer', 'Disease', (199, 205))	('paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))	('colchicine', 'Chemical', 'MESH:D003078', (107, 117))
66346	30190114	We used western blot and quantitative real-time PCR to analyze changes in AXL RNA and protein expression by SQ1274 and paclitaxel.	('SQ1274', 'Var', (108, 114))	('AXL', 'Gene', '558', (74, 77))	('SQ1274', 'Chemical', '-', (108, 114))	('AXL', 'Gene', (74, 77))	('paclitaxel', 'Chemical', 'MESH:D017239', (119, 129))
66349	30190114	First, we demonstrate that SQ1274 has a much lower IC50 than paclitaxel in both ARK1 (1.26 nM vs. 15.34 nM, respectively) and OVCAR8 (1.34 nM vs. 10.29 nM, respectively) cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('IC50', 'MPA', (51, 55))	('cancer', 'Disease', (170, 176))	('SQ1274', 'Chemical', '-', (27, 33))	('lower', 'NegReg', (45, 50))	('paclitaxel', 'Chemical', 'MESH:D017239', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('SQ1274', 'Var', (27, 33))
66350	30190114	Second, we show SQ1274 decreases both RNA and protein expression of AXL.	('SQ1274', 'Var', (16, 22))	('AXL', 'Gene', '558', (68, 71))	('AXL', 'Gene', (68, 71))	('decreases', 'NegReg', (23, 32))	('SQ1274', 'Chemical', '-', (16, 22))
66351	30190114	Third, we show that SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel.	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('SQ1274', 'Chemical', '-', (20, 26))	('paclitaxel', 'Chemical', 'MESH:D017239', (88, 98))	('arrest', 'Disease', (55, 61))	('SQ1274', 'Var', (20, 26))	('apoptosis', 'CPA', (66, 75))	('increased', 'PosReg', (34, 43))
66352	30190114	Finally, we report that SQ1274 more effectively inhibits tumor growth in vivo compared to paclitaxel.	('SQ1274', 'Chemical', '-', (24, 30))	('paclitaxel', 'Chemical', 'MESH:D017239', (90, 100))	('inhibits', 'NegReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SQ1274', 'Var', (24, 30))	('tumor', 'Disease', (57, 62))
66353	30190114	SQ1274 presents as a viable alternative to paclitaxel for treating ovarian and uterine cancer.	('cancer', 'Disease', (87, 93))	('SQ1274', 'Chemical', '-', (0, 6))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian', 'Disease', (67, 74))	('SQ1274', 'Var', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('ovarian', 'Disease', 'MESH:D010051', (67, 74))	('uterine cancer', 'Phenotype', 'HP:0010784', (79, 93))
66354	30190114	This study supports the development of SQ1274 as a chemotherapeutic to treat ovarian and uterine cancer.	('SQ1274', 'Var', (39, 45))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SQ1274', 'Chemical', '-', (39, 45))	('ovarian', 'Disease', (77, 84))	('uterine cancer', 'Phenotype', 'HP:0010784', (89, 103))	('ovarian', 'Disease', 'MESH:D010051', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
66362	30190114	Like paclitaxel, SQ1274 disrupts microtubule dynamics.	('SQ1274', 'Chemical', '-', (17, 23))	('disrupts', 'NegReg', (24, 32))	('SQ1274', 'Var', (17, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (5, 15))	('microtubule dynamics', 'MPA', (33, 53))
66363	30190114	However, rather than binding to the taxane binding site on microtubule polymers and stabilizing microtubules, SQ1274 binds to the colchicine-binding site on tubulin and destabilizes microtubules.	('microtubules', 'MPA', (182, 194))	('SQ1274', 'Var', (110, 116))	('binds', 'Interaction', (117, 122))	('destabilizes', 'NegReg', (169, 181))	('taxane', 'Chemical', 'MESH:C080625', (36, 42))	('colchicine', 'Chemical', 'MESH:D003078', (130, 140))	('SQ1274', 'Chemical', '-', (110, 116))
66368	30190114	In this study, we sought to directly compare the effects of SQ1274 and paclitaxel in high-grade serous and uterine cancer cell lines both in vitro and in vivo.	('SQ1274', 'Chemical', '-', (60, 66))	('cancer', 'Disease', (115, 121))	('uterine cancer', 'Phenotype', 'HP:0010784', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SQ1274', 'Var', (60, 66))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
66396	30190114	We found that the IC50 values for SQ1274 were 7.7- and 12.2- fold lower than the IC50 values for paclitaxel in OVCAR8 and ARK1 cells, respectively (Fig.	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('SQ1274', 'Var', (34, 40))	('SQ1274', 'Chemical', '-', (34, 40))	('lower', 'NegReg', (66, 71))
66397	30190114	Because we previously demonstrated that paclitaxel-resistant ovarian and uterine cancer cells overexpress the receptor tyrosine kinase AXL and that knockdown or inhibition of AXL restored paclitaxel sensitivity, we wondered whether SQ1274 affected AXL expression in these cells.	('AXL', 'Gene', (135, 138))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ovarian', 'Disease', (61, 68))	('ovarian', 'Disease', 'MESH:D010051', (61, 68))	('uterine cancer', 'Phenotype', 'HP:0010784', (73, 87))	('inhibition', 'Var', (161, 171))	('AXL', 'Gene', '558', (248, 251))	('paclitaxel sensitivity', 'MPA', (188, 210))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('AXL', 'Gene', '558', (175, 178))	('overexpress', 'PosReg', (94, 105))	('paclitaxel', 'Chemical', 'MESH:D017239', (40, 50))	('SQ1274', 'Chemical', '-', (232, 238))	('AXL', 'Gene', '558', (135, 138))	('AXL', 'Gene', (248, 251))	('AXL', 'Gene', (175, 178))	('paclitaxel', 'Chemical', 'MESH:D017239', (188, 198))	('knockdown', 'Var', (148, 157))
66400	30190114	Similarly, SQ1274-treated OVCAR8 cells had less AXL and Gas6 protein than untreated cells (Fig.	('AXL', 'Gene', (48, 51))	('Gas6', 'Gene', (56, 60))	('SQ1274', 'Chemical', '-', (11, 17))	('less', 'NegReg', (43, 47))	('SQ1274-treated', 'Var', (11, 25))	('AXL', 'Gene', '558', (48, 51))	('Gas6', 'Gene', '2621', (56, 60))
66404	30190114	We conclude that SQ1274 more effectively inhibits OVCAR8 and ARK1 cell growth than paclitaxel and that it may do so by decreasing AXL expression.	('SQ1274', 'Chemical', '-', (17, 23))	('inhibits', 'NegReg', (41, 49))	('paclitaxel', 'Chemical', 'MESH:D017239', (83, 93))	('decreasing', 'NegReg', (119, 129))	('AXL', 'Gene', '558', (130, 133))	('SQ1274', 'Var', (17, 23))	('AXL', 'Gene', (130, 133))	('OVCAR8', 'CPA', (50, 56))
66405	30190114	showed that SQ1274 causes human lung cancer cells to arrest in the G2/M phase.	('human', 'Species', '9606', (26, 31))	('SQ1274', 'Var', (12, 18))	('arrest', 'Disease', 'MESH:D006323', (53, 59))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('SQ1274', 'Chemical', '-', (12, 18))	('arrest', 'Disease', (53, 59))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
66406	30190114	To determine whether SQ1274 more effectively caused cell cycle arrest than paclitaxel, we treated ARK1 and OVCAR8 cells with equivalent concentrations of the two drugs.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('SQ1274', 'Chemical', '-', (21, 27))	('cell cycle', 'CPA', (52, 62))	('paclitaxel', 'Chemical', 'MESH:D017239', (75, 85))	('arrest', 'Disease', (63, 69))	('SQ1274', 'Var', (21, 27))
66407	30190114	Flow cytometry analysis indicated that a higher percentage of SQ1274-treated cells were in the G2/M phase compared to DMSO-treated cells for uterine (44% vs. 16%) and ovarian (32.5% vs. 22.8%) cancer cell lines (Figs.	('ovarian', 'Disease', 'MESH:D010051', (167, 174))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('DMSO', 'Chemical', 'MESH:D004121', (118, 122))	('cancer', 'Disease', (193, 199))	('SQ1274', 'Chemical', '-', (62, 68))	('SQ1274-treated', 'Var', (62, 76))	('G2/M phase', 'CPA', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('ovarian', 'Disease', (167, 174))
66408	30190114	Additionally, in the uterine cancer cell line there were significantly more SQ1274-treated cells in the G2/M phase compared to paclitaxel-treated cells (Fig.	('uterine cancer', 'Phenotype', 'HP:0010784', (21, 35))	('cancer', 'Disease', (29, 35))	('more', 'PosReg', (71, 75))	('G2/M phase', 'CPA', (104, 114))	('SQ1274', 'Chemical', '-', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('SQ1274-treated', 'Var', (76, 90))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
66409	30190114	Consistent with findings by flow cytometry, Western blot analysis showed that SQ1274-treated cells had higher expression of the mitotic marker phosphor-Histone H3 compared to DMSO-treated cells in both cell lines (Fig.	('SQ1274-treated', 'Var', (78, 92))	('DMSO', 'Chemical', 'MESH:D004121', (175, 179))	('expression', 'MPA', (110, 120))	('higher', 'PosReg', (103, 109))	('SQ1274', 'Chemical', '-', (78, 84))
66410	30190114	Given that SQ1274 caused cell cycle arrest and reduced growth, we wondered whether it also caused apoptosis.	('SQ1274', 'Chemical', '-', (11, 17))	('growth', 'CPA', (55, 61))	('arrest', 'Disease', 'MESH:D006323', (36, 42))	('SQ1274', 'Var', (11, 17))	('arrest', 'Disease', (36, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (25, 42))	('reduced', 'NegReg', (47, 54))
66411	30190114	First, SQ1274-treated cells had higher levels of the apoptotic marker cleaved poly-ADP ribose polymerase than did DMSO-treated cells (Fig.	('DMSO', 'Chemical', 'MESH:D004121', (114, 118))	('SQ1274', 'Chemical', '-', (7, 13))	('higher', 'PosReg', (32, 38))	('SQ1274-treated', 'Var', (7, 21))	('poly-ADP ribose polymerase', 'Gene', (78, 104))	('poly-ADP ribose polymerase', 'Gene', '142', (78, 104))
66412	30190114	Second, a significantly higher percentage of SQ1274-treated cells than DMSO-or paclitaxel-treated cells showed nuclear blebbing and abnormal DNA condensation (Figs.	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('DMSO', 'Chemical', 'MESH:D004121', (71, 75))	('SQ1274', 'Chemical', '-', (45, 51))	('SQ1274-treated', 'Var', (45, 59))	('nuclear blebbing', 'CPA', (111, 127))	('DNA condensation', 'CPA', (141, 157))
66413	30190114	Finally, flow cytometry analysis of Annexin V stained cells showed a higher percentage of SQ1274-treated being in apoptosis compared to paclitaxel treated cells in both the OVCAR8 and ARK1 cell lines (Figs.	('Annexin V', 'Gene', (36, 45))	('SQ1274', 'Chemical', '-', (90, 96))	('SQ1274-treated', 'Var', (90, 104))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('Annexin V', 'Gene', '308', (36, 45))	('apoptosis', 'CPA', (114, 123))
66414	30190114	Together, these results indicate that SQ1274 is able to initiate apoptosis in cells more effectively than paclitaxel (Fig.	('apoptosis', 'CPA', (65, 74))	('paclitaxel', 'Chemical', 'MESH:D017239', (106, 116))	('SQ1274', 'Var', (38, 44))	('SQ1274', 'Chemical', '-', (38, 44))
66417	30190114	We found in both xenograft models that SQ1274 more effectively inhibited tumor growth compared to paclitaxel.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('SQ1274', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('inhibited', 'NegReg', (63, 72))	('SQ1274', 'Chemical', '-', (39, 45))
66418	30190114	To begin to assess SQ1274 toxicity, we examined mouse weight throughout the experiment and found that SQ1274-treated mice maintained similar body weight to the control mice in the OVCAR8 xenograft model.	('SQ1274-treated', 'Var', (102, 116))	('toxicity', 'Disease', 'MESH:D064420', (26, 34))	('mouse', 'Species', '10090', (48, 53))	('SQ1274', 'Chemical', '-', (102, 108))	('toxicity', 'Disease', (26, 34))	('mice', 'Species', '10090', (168, 172))	('mice', 'Species', '10090', (117, 121))	('SQ1274', 'Chemical', '-', (19, 25))
66419	30190114	In the ARK1 xenograft model there was a decrease in body for the SQ1274-treated mice compared to the control mice indicating the drug needs to be further optimized.	('decrease', 'NegReg', (40, 48))	('body', 'MPA', (52, 56))	('SQ1274', 'Chemical', '-', (65, 71))	('SQ1274-treated', 'Var', (65, 79))	('mice', 'Species', '10090', (80, 84))	('mice', 'Species', '10090', (109, 113))
66424	30190114	Here, we present three lines of evidence that the novel colchicine-binding site inhibitor SQ1274 is a viable alternative to paclitaxel for treating ovarian and uterine cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colchicine', 'Chemical', 'MESH:D003078', (56, 66))	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))	('SQ1274', 'Chemical', '-', (90, 96))	('ovarian', 'Disease', (148, 155))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('uterine cancer', 'Phenotype', 'HP:0010784', (160, 174))	('cancer', 'Disease', (168, 174))	('ovarian', 'Disease', 'MESH:D010051', (148, 155))	('SQ1274', 'Var', (90, 96))
66426	30190114	Second, flow cytometric analysis indicates that SQ1274 causes cell-cycle arrest and apoptosis.	('apoptosis', 'CPA', (84, 93))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('SQ1274', 'Chemical', '-', (48, 54))	('arrest', 'Disease', (73, 79))	('SQ1274', 'Var', (48, 54))
66427	30190114	Finally, we report that SQ1274 effectively prevents tumor growth in vivo.	('SQ1274', 'Chemical', '-', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('prevents', 'NegReg', (43, 51))	('tumor', 'Disease', (52, 57))	('SQ1274', 'Var', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
66430	30190114	For example, our lab and others have shown that high expression of AXL promotes invasion and migration in multiple cancers including ovarian and uterine serous cancer and that AXL expression contributes to paclitaxel resistance in uterine serous cancer.	('paclitaxel resistance', 'MPA', (206, 227))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('promotes', 'PosReg', (71, 79))	('AXL', 'Gene', (67, 70))	('multiple cancers', 'Disease', (106, 122))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('contributes', 'Reg', (191, 202))	('ovarian and uterine serous cancer', 'Disease', 'MESH:D010051', (133, 166))	('AXL', 'Gene', '558', (176, 179))	('serous cancer', 'Disease', (153, 166))	('serous cancer', 'Disease', (239, 252))	('high expression', 'Var', (48, 63))	('invasion', 'CPA', (80, 88))	('paclitaxel', 'Chemical', 'MESH:D017239', (206, 216))	('AXL', 'Gene', (176, 179))	('serous cancer', 'Disease', 'MESH:D009369', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('serous cancer', 'Disease', 'MESH:D009369', (239, 252))	('AXL', 'Gene', '558', (67, 70))	('multiple cancers', 'Disease', 'MESH:D009369', (106, 122))
66431	30190114	Thus, our finding that SQ1274-treated cells had lower levels of AXL protein than control or paclitaxel-treated cells indicates that this drug may act through inhibiting AXL to promote chemosensitivity.	('SQ1274-treated', 'Var', (23, 37))	('AXL', 'Gene', (169, 172))	('inhibiting', 'NegReg', (158, 168))	('AXL', 'Gene', '558', (64, 67))	('lower', 'NegReg', (48, 53))	('chemosensitivity', 'CPA', (184, 200))	('paclitaxel', 'Chemical', 'MESH:D017239', (92, 102))	('AXL', 'Gene', (64, 67))	('promote', 'PosReg', (176, 183))	('AXL', 'Gene', '558', (169, 172))	('SQ1274', 'Chemical', '-', (23, 29))
66432	30190114	In cell-based assays, SQ1274 was more effective than paclitaxel in reducing ovarian and uterine cancer cell growth, but the two drugs were equivalently effective in the in vivo model.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SQ1274', 'Var', (22, 28))	('uterine cancer', 'Phenotype', 'HP:0010784', (88, 102))	('ovarian', 'Disease', (76, 83))	('paclitaxel', 'Chemical', 'MESH:D017239', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('ovarian', 'Disease', 'MESH:D010051', (76, 83))	('reducing', 'NegReg', (67, 75))	('cancer', 'Disease', (96, 102))	('SQ1274', 'Chemical', '-', (22, 28))
66433	30190114	Thus, future experiments should compare the abilities of SQ1274 and paclitaxel to prevent metastasis in the intraperitoneal model.	('metastasis', 'CPA', (90, 100))	('SQ1274', 'Chemical', '-', (57, 63))	('SQ1274', 'Var', (57, 63))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))
66436	30190114	SQ1274 targets the colchicine binding site to depolymerize microtubules, leading to cell-cycle arrest and apoptosis.	('SQ1274', 'Chemical', '-', (0, 6))	('apoptosis', 'CPA', (106, 115))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('colchicine', 'Chemical', 'MESH:D003078', (19, 29))	('SQ1274', 'Var', (0, 6))	('arrest', 'Disease', (95, 101))	('depolymerize', 'NegReg', (46, 58))	('microtubules', 'MPA', (59, 71))
66437	30190114	SQ1274 also has the ability to suppress AXL expression at both the protein and RNA level.	('AXL', 'Gene', '558', (40, 43))	('SQ1274', 'Chemical', '-', (0, 6))	('AXL', 'Gene', (40, 43))	('SQ1274', 'Var', (0, 6))	('suppress', 'NegReg', (31, 39))
66438	30190114	While paclitaxel is also able to cause cell-cycle arrest and apoptosis as well as decrease AXL expression in vitro, we show that SQ1274 can initiate these affects at a much lower dosage than paclitaxel.	('AXL', 'Gene', '558', (91, 94))	('apoptosis', 'CPA', (61, 70))	('paclitaxel', 'Chemical', 'MESH:D017239', (6, 16))	('decrease', 'NegReg', (82, 90))	('paclitaxel', 'Chemical', 'MESH:D017239', (191, 201))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('AXL', 'Gene', (91, 94))	('SQ1274', 'Var', (129, 135))	('arrest', 'Disease', (50, 56))	('SQ1274', 'Chemical', '-', (129, 135))
66439	30190114	Finally, SQ1274 demonstrates strong tumor inhibition effects in vivo without causing significant loss of body weight.	('SQ1274', 'Var', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SQ1274', 'Chemical', '-', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
66441	30190114	SQ1274, a colchicine-binding site inhibitor, is a viable alternative to paclitaxel in treating ovarian and uterine cancer.	('cancer', 'Disease', (115, 121))	('paclitaxel', 'Chemical', 'MESH:D017239', (72, 82))	('colchicine', 'Chemical', 'MESH:D003078', (10, 20))	('uterine cancer', 'Phenotype', 'HP:0010784', (107, 121))	('SQ1274', 'Chemical', '-', (0, 6))	('ovarian', 'Disease', 'MESH:D010051', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SQ1274', 'Var', (0, 6))	('ovarian', 'Disease', (95, 102))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
66442	30190114	SQ1274 has a much lower IC50 than paclitaxel in both ovarian and uterine cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('IC50', 'MPA', (24, 28))	('uterine cancer', 'Phenotype', 'HP:0010784', (65, 79))	('SQ1274', 'Chemical', '-', (0, 6))	('lower', 'NegReg', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('paclitaxel', 'Chemical', 'MESH:D017239', (34, 44))	('ovarian', 'Disease', (53, 60))	('SQ1274', 'Var', (0, 6))	('ovarian', 'Disease', 'MESH:D010051', (53, 60))
66443	30190114	SQ1274 decreases both RNA and protein expression of AXL.	('AXL', 'Gene', (52, 55))	('decreases', 'NegReg', (7, 16))	('SQ1274', 'Chemical', '-', (0, 6))	('SQ1274', 'Var', (0, 6))	('AXL', 'Gene', '558', (52, 55))
66444	30190114	SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel.	('increased', 'PosReg', (14, 23))	('apoptosis', 'CPA', (46, 55))	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('SQ1274', 'Chemical', '-', (0, 6))	('arrest', 'Disease', (35, 41))	('SQ1274', 'Var', (0, 6))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))
66445	30190114	SQ1274 effectively prevents tumor growth in vivo.	('tumor', 'Disease', (28, 33))	('SQ1274', 'Chemical', '-', (0, 6))	('prevents', 'NegReg', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('SQ1274', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
66448	30246728	Risk factors for MMMTs include radiation, excessive estrogen exposure, obesity, and nulliparity.	('obesity', 'Disease', 'MESH:D009765', (71, 78))	('obesity', 'Disease', (71, 78))	('MMMTs', 'Disease', (17, 22))	('obesity', 'Phenotype', 'HP:0001513', (71, 78))	('nulliparity', 'Var', (84, 95))
66468	30246728	Immunohistochemistry revealed the following: ER (1+), PR (1+), P53 (0), Ki-67 (20-80%+), CK (+), Vim (+), CD10 (+/-), Act (+/-), Des (+), S-100 (+), and CK79 (+).	('CK79', 'Gene', '338785', (153, 157))	('ER (1+', 'Var', (45, 51))	('Vim', 'Gene', (97, 100))	('CK (+', 'Var', (89, 94))	('Act (+/-', 'Var', (118, 126))	('CK79', 'Gene', (153, 157))	('PR (1+', 'Var', (54, 60))	('Vim', 'Gene', '7431', (97, 100))	('Des (+', 'Var', (129, 135))	('P53', 'Gene', '7157', (63, 66))	('CD10', 'Gene', (106, 110))	('P53', 'Gene', (63, 66))	('CD10', 'Gene', '4311', (106, 110))	('S-100 (+', 'Var', (138, 146))
66532	28761924	Although we did not complete chromosomal and immunohistochemical examinations in our patients, the several inspections for pathogenesis of RT-induced sarcoma have been reported as follows: the loss of material from 3p21-3pter detected by comparative genomic hybridization, a role of p53 gene mutations, and the KIT protein overexpression without mutation.	('mutations', 'Var', (292, 301))	('loss', 'NegReg', (193, 197))	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('p53', 'Gene', (283, 286))	('patients', 'Species', '9606', (85, 93))	('sarcoma', 'Disease', (150, 157))	('p53', 'Gene', '7157', (283, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))
66785	25341583	Patients who carry a germline p53 gene mutation (Li Fraumeni syndrome) have an increased risk of soft tissue sarcoma, including uterine LMS, as well as other cancers.	('mutation', 'Var', (39, 47))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (97, 116))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (97, 116))	('cancers', 'Disease', (158, 165))	('soft tissue sarcoma', 'Disease', (97, 116))	('p53', 'Gene', (30, 33))	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', '7157', (30, 33))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (49, 69))	('Li Fraumeni syndrome', 'Disease', (49, 69))	('uterine LMS', 'Disease', (128, 139))
66786	25341583	Patients with Rb mutations who are survivors of childhood retinoblastoma, and survivors of childhood rhabdomyosarcoma, or other childhood cancers whose treatment involves radiation, have an increased risk secondary cancers, including uterine LMS.	('rhabdomyosarcoma', 'Disease', (101, 117))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (101, 117))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('retinoblastoma', 'Phenotype', 'HP:0009919', (58, 72))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('cancers', 'Disease', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('Patients', 'Species', '9606', (0, 8))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (101, 117))	('childhood retinoblastoma', 'Disease', (48, 72))	('childhood retinoblastoma', 'Disease', 'MESH:D012175', (48, 72))	('uterine LMS', 'Disease', (234, 245))	('mutations', 'Var', (17, 26))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
66787	25341583	The familial syndrome hereditary leiomyomatosis with renal cell carcinoma (HLRCC), in which there are germline mutations in fumarate hydratase, has also been associated with an increased risk of uterine LMS.	('mutations', 'Var', (111, 120))	('associated', 'Reg', (158, 168))	('familial syndrome hereditary leiomyomatosis', 'Disease', (4, 47))	('renal cell carcinoma', 'Disease', (53, 73))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('uterine LMS', 'Disease', (195, 206))	('familial syndrome hereditary leiomyomatosis', 'Disease', 'MESH:C535516', (4, 47))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (53, 73))	('fumarate hydratase', 'Gene', '2271', (124, 142))	('fumarate hydratase', 'Gene', (124, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
67012	21249682	When we combined the findings from the two similar trials, adjusting for important prognostic factors, we found that the risk of death and disease progression was lower among women who received combination therapy than among women who received ifosfamide alone (HR = 0.75, 95% CI 0.60 to 0.94 and HR = 0.72, 95% CI 0.58 to 0.90 for overall and progression-free survival respectively).	('women', 'Species', '9606', (225, 230))	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('ifosfamide', 'Chemical', 'MESH:D007069', (244, 254))	('disease progression', 'CPA', (139, 158))	('women', 'Species', '9606', (175, 180))	('combination', 'Var', (194, 205))	('lower', 'NegReg', (163, 168))
67066	22982899	The majority, particularly those with a classic low-grade histologic appearance, contain a genetic fusion involving JAZF1 and members of polycomb complex gene (SUZ12, PHF1, EPC1) most frequently resulting from a chromosomal translocation, t(7;17).	('PHF1', 'Gene', (167, 171))	('PHF1', 'Gene', '5252', (167, 171))	('EPC1', 'Gene', '80314', (173, 177))	('JAZF1', 'Gene', (116, 121))	('JAZF1', 'Gene', '221895', (116, 121))	('genetic fusion', 'Var', (91, 105))	('SUZ12', 'Gene', (160, 165))	('SUZ12', 'Gene', '23512', (160, 165))	('EPC1', 'Gene', (173, 177))	('resulting from', 'Reg', (195, 209))
67067	22982899	We recently described and characterized a series of ESS with YWHAE-FAM22A/B (YWHAE-FAM22) genetic fusion resulting from t(10;17)(q22;p13).	('YWHAE', 'Gene', (77, 82))	('t(10;17)(q22;p13', 'Var', (120, 136))	('YWHAE', 'Gene', '7531', (77, 82))	('YWHAE', 'Gene', '7531', (61, 66))	('FAM22A/B', 'Gene', (67, 75))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (120, 137))	('FAM22A/B', 'Gene', '728118;729262', (67, 75))	('YWHAE', 'Gene', (61, 66))
67079	22982899	Formalin-fixed paraffin-embedded tumor tissues were obtained from ESS in which FISH studies had demonstrated either YWHAE-FAM22 rearrangement (n=12), JAZF1/SUZ12/PHF1/EPC1 rearrangement (n=34) or no demonstrable genetic rearrangement (n=21); these were from the pathology archives at Brigham and Women's Hospital, Massachusetts General Hospital, Vancouver General Hospital and Toronto General Hospital.	('YWHAE', 'Gene', (116, 121))	('EPC1', 'Gene', (167, 171))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('EPC1', 'Gene', '80314', (167, 171))	('JAZF1', 'Gene', (150, 155))	('Women', 'Species', '9606', (296, 301))	('PHF1', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('YWHAE', 'Gene', '7531', (116, 121))	('JAZF1', 'Gene', '221895', (150, 155))	('tumor', 'Disease', (33, 38))	('rearrangement', 'Var', (128, 141))	('PHF1', 'Gene', '5252', (162, 166))	('SUZ12', 'Gene', '23512', (156, 161))	('SUZ12', 'Gene', (156, 161))
67103	22982899	All 13 UES with nuclear pleomorphism (UES-P) showed focal (<20%) cyclin D1 staining (Figure 5D).	('cyclin D1', 'Gene', (65, 74))	('nuclear pleomorphism', 'Var', (16, 36))	('cyclin D1', 'Gene', '595', (65, 74))
67142	22982899	In the case of mantle cell lymphoma, genetic rearrangement between IGH@ and CCND1 results in upregulated cyclin D1 expression at mRNA and protein levels.	('IGH@', 'Gene', '3492', (67, 71))	('cell lymphoma', 'Phenotype', 'HP:0012191', (22, 35))	('CCND1', 'Gene', (76, 81))	('genetic rearrangement', 'Var', (37, 58))	('CCND1', 'Gene', '595', (76, 81))	('cyclin D1', 'Gene', '595', (105, 114))	('lymphoma', 'Phenotype', 'HP:0002665', (27, 35))	('expression', 'MPA', (115, 125))	('cyclin D1', 'Gene', (105, 114))	('IGH@', 'Gene', (67, 71))	('upregulated', 'PosReg', (93, 104))	('mantle cell lymphoma', 'Disease', (15, 35))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (15, 35))
67144	22982899	The mechanisms underlying cyclin D1 upregulation in tumors include chromosomal translocation, amplification and increased protein stability.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('upregulation', 'PosReg', (36, 48))	('tumors', 'Disease', (52, 58))	('cyclin D1', 'Gene', '595', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('increased', 'PosReg', (112, 121))	('cyclin D1', 'Gene', (26, 35))	('amplification', 'MPA', (94, 107))	('chromosomal translocation', 'Var', (67, 92))	('protein stability', 'MPA', (122, 139))
67259	20634933	For the vast majority of cases, the aetiology is unknown, although there are certain genetic associations, such as the 10% lifetime risk of malignant peripheral nerve sheath tumour (MPNST) in individuals with familial neurofibromatosis, caused by mutations in the NF1 gene.	('NF1', 'Gene', '4763', (264, 267))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('malignant peripheral nerve sheath tumour', 'Disease', 'MESH:D018319', (140, 180))	('familial neurofibromatosis', 'Disease', (209, 235))	('malignant peripheral nerve sheath tumour', 'Disease', (140, 180))	('malignant peripheral nerve sheath tumour', 'Phenotype', 'HP:0100697', (140, 180))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (218, 235))	('MPNST', 'Phenotype', 'HP:0100697', (182, 187))	('caused by', 'Reg', (237, 246))	('mutations', 'Var', (247, 256))	('NF1', 'Gene', (264, 267))	('familial neurofibromatosis', 'Disease', 'MESH:C537392', (209, 235))
67260	20634933	Another example is the increased risk of sarcomas, both bone and soft tissue, in patients who have had a familial retinoblastoma, caused by inherited mutations in the RB gene.	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('patients', 'Species', '9606', (81, 89))	('caused by', 'Reg', (130, 139))	('familial retinoblastoma', 'Disease', (105, 128))	('mutations', 'Var', (150, 159))	('retinoblastoma', 'Phenotype', 'HP:0009919', (114, 128))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (105, 128))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
67261	20634933	Similarly, there is an increased risk of sarcomas, and other cancers in families with Li-Fraumeni syndrome who have inherited mutations in the TP53 tumour suppressor gene.	('TP53', 'Gene', (143, 147))	('tumour', 'Disease', (148, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('TP53', 'Gene', '7157', (143, 147))	('Li-Fraumeni syndrome', 'Disease', (86, 106))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (86, 106))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
67274	20634933	In addition, certain translocation-driven sarcomas have a relatively uniform cellular morphology and, as such, can be misleadingly scored as intermediate, rather than high grade.	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('translocation-driven', 'Var', (21, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('sarcomas', 'Disease', (42, 50))
67336	20634933	Whilst most events will arise in the first five years following diagnosis, low grade tumours in particular may relapse late.	('low grade', 'Var', (75, 84))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('tumours', 'Disease', (85, 92))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
67429	20634933	Sporadic cases of fibromatosis are commonly liked to mutations in CTNNB1, the gene for beta-catenin.	('fibromatosis', 'Disease', 'MESH:D005350', (18, 30))	('beta-catenin', 'Gene', (87, 99))	('liked', 'Reg', (44, 49))	('mutations', 'Var', (53, 62))	('fibromatosis', 'Disease', (18, 30))	('beta-catenin', 'Gene', '1499', (87, 99))	('CTNNB1', 'Gene', (66, 72))	('CTNNB1', 'Gene', '1499', (66, 72))
67460	33195415	However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated.	('malignant tumors', 'Disease', (61, 77))	('malignant tumors', 'Disease', 'MESH:D009369', (61, 77))	('ACE2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('aberrant', 'Var', (33, 41))	('ACE2', 'Gene', '59272', (42, 46))
67473	33195415	GSEA analysis which was carried out to determine the effect of ACE2 on tumors indicated that several cancer-associated pathways and immune-related pathways were hyperactivated in the high ACE2 expression group of most tumors.	('hyperactivated', 'PosReg', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('expression', 'MPA', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('GSEA', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ACE2', 'Gene', '59272', (63, 67))	('tumors', 'Disease', (218, 224))	('cancer', 'Disease', (101, 107))	('ACE2', 'Gene', '59272', (188, 192))	('ACE2', 'Gene', (63, 67))	('immune-related pathways', 'Pathway', (132, 155))	('ACE2', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('high', 'Var', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
67508	33195415	Neoantigen is a neonatal antigen that is encoded by a mutant gene of a tumor cell.	('mutant', 'Var', (54, 60))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
67510	33195415	Neoantigen vaccines can be developed using the immune activity of tumor neoantigens, according to a specific mutation in the tumor cells, then administered to patients to achieve the required therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (159, 167))	('mutation', 'Var', (109, 117))
67513	33195415	The Tumor Mutational Burden (TMB) is usually measured by the number of somatic mutations that occur within an average of 1 Mb in the coding region (exon region) of the tumor cell genome (non-synonymous mutations).	('tumor', 'Disease', (168, 173))	('mutations', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('TMB', 'Chemical', '-', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))
67517	33195415	Microsatellite Instability (MSI) refers to any change in the length of a microsatellite due to the insertion or deletion of a repeating unit in a tumor compared to normal tissue.	('change', 'Reg', (47, 53))	('S', 'Gene', '43740568', (29, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('insertion', 'Var', (99, 108))	('length', 'MPA', (61, 67))	('deletion', 'Var', (112, 120))	('tumor', 'Disease', (146, 151))	('Microsatellite Instability', 'Disease', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
67523	33195415	We visualized the tumor with the most ACE2 mutations using an R data package, maftools.	('tumor', 'Disease', (18, 23))	('ACE2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('ACE2', 'Gene', '59272', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
67524	33195415	Therefore, TCGA expression profiling was used to evaluate the relationship between ACE2 and five MMRs genes: MLH1, MSH2, MSH6, PMS2, and EPCAM mutations.	('PMS2', 'Gene', (127, 131))	('MLH1', 'Gene', '4292', (109, 113))	('MLH1', 'Gene', (109, 113))	('MSH6', 'Gene', (121, 125))	('PMS2', 'Gene', '5395', (127, 131))	('ACE2', 'Gene', (83, 87))	('MMRs genes', 'Gene', (97, 107))	('EPCAM', 'Gene', (137, 142))	('MSH6', 'Gene', '2956', (121, 125))	('MSH2', 'Gene', (115, 119))	('ACE2', 'Gene', '59272', (83, 87))	('MSH2', 'Gene', '4436', (115, 119))	('EPCAM', 'Gene', '4072', (137, 142))	('mutations', 'Var', (143, 152))
67570	33195415	We regularly collect and synthesize neoantigen vaccines, according to mutations in specific tumor cells, and using the immune activity of tumor neoantigens we immunize patients to achieve the required therapeutic effect.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('patients', 'Species', '9606', (168, 176))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
67583	33195415	A schematic diagram of the tumor with the highest number of mutations is shown in Figure 12.	('tumor', 'Disease', (27, 32))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
67584	33195415	Notably, ACE2 mutations were only observed in BLCA, BRCA, COAD, HNSC, LAML, LGG, LUAD, LUSC, OV, SKCM, STAD, and UCEC.	('S', 'Gene', '43740568', (66, 67))	('S', 'Gene', '43740568', (97, 98))	('S', 'Gene', '43740568', (103, 104))	('ACE2', 'Gene', '59272', (9, 13))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('COAD', 'Disease', (58, 62))	('S', 'Gene', '43740568', (89, 90))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (14, 23))	('ACE2', 'Gene', (9, 13))
67585	33195415	These findings indicate that ACE2 mutations seldom occur in most tumors.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('ACE2', 'Gene', '59272', (29, 33))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (34, 43))	('ACE2', 'Gene', (29, 33))
67590	33195415	DNA hypermethylation in the promoter region of a tumor suppressor gene leads to gene silencing, which in turn leads to dysregulation of multiple signaling pathways associated with human malignancy.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('multiple signaling pathways', 'Pathway', (136, 163))	('gene', 'MPA', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('malignancy', 'Disease', 'MESH:D009369', (186, 196))	('leads to', 'Reg', (110, 118))	('human', 'Species', '9606', (180, 185))	('tumor', 'Disease', (49, 54))	('malignancy', 'Disease', (186, 196))	('dysregulation', 'MPA', (119, 132))	('hypermethylation', 'Var', (4, 20))
67630	33195415	It has been demonstrated that overexpressed ACE2 may inhibit cell growth and vascular endothelial growth factor production in lung cancer, breast cancer, colon cancer, and pancreatic cancer.	('ACE2', 'Gene', '59272', (44, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ACE2', 'Gene', (44, 48))	('inhibit', 'NegReg', (53, 60))	('vascular endothelial growth factor', 'Gene', '7422', (77, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('lung cancer', 'Disease', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('vascular endothelial growth factor', 'Gene', (77, 111))	('pancreatic cancer', 'Disease', (172, 189))	('cell growth', 'CPA', (61, 72))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('overexpressed', 'Var', (30, 43))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('colon cancer', 'Disease', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))
67631	33195415	On the other hand, overexpressed ACE2 may promote the migration and invasion of human renal carcinoma cells.	('ACE2', 'Gene', '59272', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('renal carcinoma', 'Disease', 'MESH:C538614', (86, 101))	('migration', 'CPA', (54, 63))	('overexpressed', 'Var', (19, 32))	('promote', 'PosReg', (42, 49))	('human', 'Species', '9606', (80, 85))	('renal carcinoma', 'Disease', (86, 101))	('ACE2', 'Gene', (33, 37))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))
67640	33195415	ACE2 expression also has a significantly positive correlation with the infiltrating levels of dendritic cells, macrophages M0, mast cells resting, and neutrophils in multiple cancers.	('ACE2', 'Gene', (0, 4))	('multiple cancers', 'Disease', (166, 182))	('expression', 'Var', (5, 15))	('infiltrating levels of dendritic cells', 'MPA', (71, 109))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ACE2', 'Gene', '59272', (0, 4))	('multiple cancers', 'Disease', 'MESH:D009369', (166, 182))	('positive correlation', 'Reg', (41, 61))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
67644	33195415	We found that increased ACE2 expression correlates with immune infiltration levels in most tumors and that higher ACE2 expression was related to immune neoantigen, TMB, and microsatellite instability.	('increased', 'PosReg', (14, 23))	('tumors', 'Disease', (91, 97))	('expression', 'MPA', (119, 129))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('TMB', 'Chemical', '-', (164, 167))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('ACE2', 'Gene', '59272', (114, 118))	('related', 'Reg', (134, 141))	('ACE2', 'Gene', (24, 28))	('microsatellite', 'Var', (173, 187))	('higher', 'PosReg', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ACE2', 'Gene', '59272', (24, 28))	('expression', 'MPA', (29, 39))	('ACE2', 'Gene', (114, 118))	('immune infiltration levels', 'MPA', (56, 82))
68079	27532149	Both components shared identical mutations in U2AF1 p.R156H (c.467G>A) and GATA3 p.M422fs (c.1263dupG), as well as MYCN amplification.	('c.1263dupG', 'Var', (91, 101))	('U2AF1', 'Gene', (46, 51))	('U2AF1', 'Gene', '7307', (46, 51))	('p.M422fs', 'Mutation', 'p.M422fsX', (81, 89))	('p.R156H', 'Mutation', 'rs769567889', (52, 59))	('p.M422fs (c.1263dupG', 'Var', (81, 101))	('GATA3', 'Gene', (75, 80))	('c.1263dupG', 'Mutation', 'c.1263dupG', (91, 101))	('MYCN', 'Gene', (115, 119))	('MYCN', 'Gene', '4613', (115, 119))	('GATA3', 'Gene', '2625', (75, 80))	('c.467G>A', 'Var', (61, 69))	('p.R156H (c.467G>A', 'Var', (52, 69))	('c.467G>A', 'Mutation', 'rs769567889', (61, 69))
68080	27532149	In addition, the neuroendocrine carcinoma harbored TP53 and MST1R mutations not present in the mesonephric carcinoma.	('mutations', 'Var', (66, 75))	('MST1R', 'Gene', '4486', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (17, 41))	('TP53', 'Gene', (51, 55))	('mesonephric carcinoma', 'Disease', (95, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('mesonephric carcinoma', 'Disease', 'MESH:D002277', (95, 116))	('MST1R', 'Gene', (60, 65))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (17, 41))	('TP53', 'Gene', '7157', (51, 55))	('neuroendocrine carcinoma', 'Disease', (17, 41))
68101	27532149	The two tumor DNA samples and matched normal DNA obtained from peripheral blood were assessed for the presence of somatic mutations and copy number alterations in 410 key cancer-associated genes (Supplementary Material) using solution-phase exon hybridization capture and next-generation sequencing (MSK-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)).	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Disease', (171, 177))	('mutations', 'Var', (122, 131))	('tumor', 'Disease', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Cancer', 'Phenotype', 'HP:0002664', (348, 354))	('copy number alterations', 'Var', (136, 159))
68103	27532149	Reads were aligned to the human genome (hg19) using BWA-MEM (v 0.7.5a); duplicate read removal, base recalibration, and insertion and deletions (indel) realignment using GATK (v 2.6-5), following best practices; variant calling using MuTect (v 1.1.4) for single nucleotide variants; and Somatic Indel Detector (GATK 2.3-9) for indels.	('ecto', 'Gene', '51592', (304, 308))	('ecto', 'Gene', (304, 308))	('human', 'Species', '9606', (26, 31))	('variant', 'Var', (212, 219))
68142	27532149	High-depth targeted next-generation sequencing with a mean coverage of 749X and 702X in the mesonephric and the neuroendocrine portions, respectively, revealed amplification of the MYCN gene (2p24.3) in both components.	('MYCN', 'Gene', '4613', (181, 185))	('MYCN', 'Gene', (181, 185))	('amplification', 'Var', (160, 173))
68143	27532149	Both tumors shared a somatic missense mutation in exon 6 of U2AF1 (p.R156H; c.467G>A), as well as a single nucleotide duplication resulting in frameshift in exon 6 of GATA3 (p.M422fs; c. 1263dupG).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('c. 1263dupG', 'Mutation', 'c.1263dupG', (184, 195))	('p.M422fs', 'Mutation', 'p.M422fsX', (174, 182))	('p.R156H', 'Mutation', 'rs769567889', (67, 74))	('GATA3', 'Gene', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('U2AF1', 'Gene', (60, 65))	('U2AF1', 'Gene', '7307', (60, 65))	('c.467G>A', 'Mutation', 'rs769567889', (76, 84))	('frameshift in exon', 'Var', (143, 161))	('GATA3', 'Gene', '2625', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('p.M422fs; c. 1263dupG', 'Var', (174, 195))
68144	27532149	Interestingly, however, an FBXW7 (p.R465C; c. 1393C>T) exon 9 missense mutation was found to be restricted to the mesonephric carcinoma, while the neuroendocrine component harbored an IRS2 (13q34) amplification and mutations in TP53 (exon 7 p.G244S; c.730G>A) and MST1R (exon 12 p.V935I; c.2803G>A) which were not present in the mesonephric tumor.	('p.G244S; c.730G>A', 'Var', (241, 258))	('IRS2', 'Gene', '8660', (184, 188))	('MST1R', 'Gene', (264, 269))	('p.G244S', 'Mutation', 'rs1057519989', (241, 248))	('mesonephric tumor', 'Disease', 'MESH:D009369', (329, 346))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('mesonephric tumor', 'Disease', (329, 346))	('p.V935I', 'Mutation', 'rs749037053', (279, 286))	('1393C>T', 'SUBSTITUTION', 'None', (46, 53))	('TP53', 'Gene', (228, 232))	('p.V935I; c.2803G>A', 'Var', (279, 297))	('1393C>T', 'Var', (46, 53))	('FBXW7', 'Gene', '55294', (27, 32))	('mesonephric carcinoma', 'Disease', 'MESH:D002277', (114, 135))	('IRS2', 'Gene', (184, 188))	('p.R465C', 'Mutation', 'rs867384286', (34, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('c.2803G>A', 'Mutation', 'rs749037053', (288, 297))	('c.730G>A', 'Mutation', 'rs1057519989', (250, 258))	('TP53', 'Gene', '7157', (228, 232))	('c.730G>A', 'Var', (250, 258))	('MST1R', 'Gene', '4486', (264, 269))	('FBXW7', 'Gene', (27, 32))	('mesonephric carcinoma', 'Disease', (114, 135))
68145	27532149	It should be noted, however, that the low tumor purity in the mesonephric carcinoma limited the detection of variants that might be present at frequencies below the variant calling threshold (2% for known hotspot mutations, 5% for other variants) (Figure 9).	('mesonephric carcinoma', 'Disease', 'MESH:D002277', (62, 83))	('low tumor', 'Disease', (38, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('mesonephric carcinoma', 'Disease', (62, 83))	('low tumor', 'Disease', 'MESH:D009800', (38, 47))	('variants', 'Var', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
68192	27532149	As in small cell carcinomas from many anatomic sites, TP53 and RB1 inactivating mutations have been described.	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('carcinomas', 'Disease', (17, 27))	('carcinomas', 'Disease', 'MESH:D002277', (17, 27))	('RB1', 'Gene', '5925', (63, 66))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (6, 26))	('inactivating mutations', 'Var', (67, 89))	('TP53', 'Gene', '7157', (54, 58))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (6, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('TP53', 'Gene', (54, 58))	('RB1', 'Gene', (63, 66))
68193	27532149	In the present case, a mutation in TP53 was present solely in the neuroendocrine component, whereas mutations in or deletions of RB1 were not detected in either component.	('RB1', 'Gene', '5925', (129, 132))	('deletions', 'Var', (116, 125))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('RB1', 'Gene', (129, 132))
68194	27532149	The TP53 missense mutation (p.G244S, c.730G>A) has been reported in various neoplasms, in different organ systems in the COSMIC database (http://cancer.sanger.ac.uk/cosmic).	('cancer', 'Disease', (145, 151))	('neoplasms', 'Phenotype', 'HP:0002664', (76, 85))	('TP53', 'Gene', (4, 8))	('p.G244S', 'Mutation', 'rs1057519989', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('neoplasms', 'Disease', 'MESH:D009369', (76, 85))	('neoplasms', 'Disease', (76, 85))	('neoplasm', 'Phenotype', 'HP:0002664', (76, 84))	('c.730G>A', 'Var', (37, 45))	('p.G244S', 'Var', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('c.730G>A', 'Mutation', 'rs1057519989', (37, 45))	('TP53', 'Gene', '7157', (4, 8))
68197	27532149	They identified several recurrent genetic alterations, distinct from those found in more common forms of cervical and endometrial adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (118, 145))	('endometrial adenocarcinomas', 'Disease', (118, 145))	('genetic alterations', 'Var', (34, 53))	('cervical', 'Disease', (105, 113))
68198	27532149	Mesonephric adenocarcinomas were found to harbor KRAS or NRAS hotspot mutations in 81% of cases, mutations in chromatin remodeling genes including ARID1A, ARID1B and SMARCA4 in almost two-thirds of cases, mutations in BCOR/BCORL1 in 31% of cases, and mutations in FBXW7, MYCN and GATA3 in 2 cases.	('mutations', 'Var', (97, 106))	('ARID1A', 'Gene', (147, 153))	('BCOR', 'Gene', (218, 222))	('MYCN', 'Gene', '4613', (271, 275))	('GATA3', 'Gene', (280, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('KRAS', 'Gene', '3845', (49, 53))	('FBXW7', 'Gene', '55294', (264, 269))	('ARID1A', 'Gene', '8289', (147, 153))	('BCOR', 'Gene', '54880', (223, 227))	('Mesonephric adenocarcinomas', 'Disease', 'MESH:D000230', (0, 27))	('NRAS', 'Gene', (57, 61))	('SMARCA4', 'Gene', (166, 173))	('BCOR', 'Gene', (223, 227))	('KRAS', 'Gene', (49, 53))	('mutations', 'Var', (70, 79))	('MYCN', 'Gene', (271, 275))	('ARID1B', 'Gene', (155, 161))	('mutations', 'Var', (205, 214))	('ARID1B', 'Gene', '57492', (155, 161))	('mutations', 'Var', (251, 260))	('BCORL1', 'Gene', '63035', (223, 229))	('Mesonephric adenocarcinomas', 'Disease', (0, 27))	('BCORL1', 'Gene', (223, 229))	('FBXW7', 'Gene', (264, 269))	('SMARCA4', 'Gene', '6597', (166, 173))	('GATA3', 'Gene', '2625', (280, 285))	('BCOR', 'Gene', '54880', (218, 222))	('NRAS', 'Gene', '4893', (57, 61))
68199	27532149	Conversely, TP53 mutation occurred in only 1 case, and no mutations were detected in PIK3CA or PTEN.	('PIK3CA', 'Gene', '5290', (85, 91))	('mutation', 'Var', (17, 25))	('TP53', 'Gene', '7157', (12, 16))	('PTEN', 'Gene', (95, 99))	('PTEN', 'Gene', '5728', (95, 99))	('TP53', 'Gene', (12, 16))	('PIK3CA', 'Gene', (85, 91))
68200	27532149	Interestingly, our case did not harbor mutations in KRAS, NRAS or chromatin remodeling genes even after manual review in Integrated Genomic Viewer (IGV) for hotspot mutations in KRAS (p.G12/G13 and p.Q61) and NRAS (p.Q61):mutations detected in the Mirkovic study.	('KRAS', 'Gene', (178, 182))	('p.G12/G13', 'Var', (184, 193))	('p.Q61', 'Var', (198, 203))	('NRAS', 'Gene', '4893', (58, 62))	('KRAS', 'Gene', '3845', (178, 182))	('KRAS', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (52, 56))	('NRAS', 'Gene', (209, 213))	('p.Q61):', 'Var', (215, 222))	('NRAS', 'Gene', (58, 62))	('NRAS', 'Gene', '4893', (209, 213))
68201	27532149	Instead, identical mutations in GATA3 (p.M422fs, c.1263dupG) and U2AF1 (p.R156H, c.467G>A) were detected in both the mesonephric and neuroendocrine components of the tumor, which provides some support for a clonal relationship between the two components.	('U2AF1', 'Gene', (65, 70))	('c.467G>A', 'Mutation', 'rs769567889', (81, 89))	('detected', 'Reg', (96, 104))	('p.R156H', 'Mutation', 'rs769567889', (72, 79))	('U2AF1', 'Gene', '7307', (65, 70))	('p.M422fs', 'Mutation', 'p.M422fsX', (39, 47))	('p.R156H', 'Var', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('c.1263dupG', 'Mutation', 'c.1263dupG', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('GATA3', 'Gene', (32, 37))	('tumor', 'Disease', (166, 171))	('c.1263dupG', 'Var', (49, 59))	('GATA3', 'Gene', '2625', (32, 37))	('p.M422fs', 'Var', (39, 47))	('c.467G>A', 'Var', (81, 89))
68203	27532149	This detected GATA3 frameshift mutation affects the 3' end of the gene.	('frameshift mutation', 'Var', (20, 39))	('GATA3', 'Gene', (14, 19))	('affects', 'Reg', (40, 47))	('GATA3', 'Gene', '2625', (14, 19))
68206	27532149	Mutations in this gene have been observed mainly in myelodysplastic syndrome and lung adenocarcinomas, but in only 3 of 191 cervical carcinomas (1.5%) from the provisional The Cancer Genome Atlas (TCGA) Research Network dataset (2 missense mutations and 1 deletion); additionally, there was 1 case with gene amplification (www.cBioPortal.org, accessed on 2/18/2016).	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (52, 76))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cervical carcinomas', 'Disease', (124, 143))	('observed', 'Reg', (33, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('myelodysplastic syndrome', 'Disease', (52, 76))	('cervical carcinomas', 'Disease', 'MESH:D002575', (124, 143))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (52, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('Mutations', 'Var', (0, 9))	('Cancer Genome Atlas', 'Disease', (176, 195))	('lung adenocarcinomas', 'Disease', (81, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (176, 195))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (81, 101))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (81, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
68207	27532149	The detected U2AF1 missense mutation in the current case affects one of the zinc finger domains of the protein, which likely alters target molecule binding, hence mRNA splicing.	('mRNA splicing', 'MPA', (163, 176))	('zinc finger domains of the protein', 'Protein', (76, 110))	('U2AF1', 'Gene', '7307', (13, 18))	('affects', 'Reg', (57, 64))	('target molecule', 'MPA', (132, 147))	('alters', 'Reg', (125, 131))	('binding', 'Interaction', (148, 155))	('missense mutation', 'Var', (19, 36))	('U2AF1', 'Gene', (13, 18))
68210	27532149	FISH using a probe for MYCN confirmed amplification in both tumors.	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('amplification', 'Var', (38, 51))	('MYCN', 'Gene', (23, 27))	('MYCN', 'Gene', '4613', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
68213	27532149	MYCN amplification has been associated with aggressive behavior and poor prognosis in several tumors, including lung small cell carcinomas (in which this genetic alteration has been described in 2-20% of cases).	('aggressive behavior', 'CPA', (44, 63))	('lung small cell carcinomas', 'Disease', 'MESH:D055752', (112, 138))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('associated', 'Reg', (28, 38))	('amplification', 'Var', (5, 18))	('MYCN', 'Gene', (0, 4))	('MYCN', 'Gene', '4613', (0, 4))	('aggressive behavior', 'Phenotype', 'HP:0000718', (44, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('lung small', 'Phenotype', 'HP:0002089', (112, 122))	('lung small cell carcinomas', 'Disease', (112, 138))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('lung small cell carcinomas', 'Phenotype', 'HP:0030357', (112, 138))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (117, 137))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (117, 138))
68214	27532149	MYCN amplification has also been observed in tumors in other anatomic locations, many of which exhibit neuroendocrine differentiation.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('observed', 'Reg', (33, 41))	('amplification', 'Var', (5, 18))	('MYCN', 'Gene', (0, 4))	('tumors', 'Disease', (45, 51))	('MYCN', 'Gene', '4613', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))
68218	27532149	FBXW7 mutation, as was observed in the mesonephric carcinoma, is present in about 6% of human tumors.	('FBXW7', 'Gene', '55294', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutation', 'Var', (6, 14))	('mesonephric carcinoma', 'Disease', 'MESH:D002277', (39, 60))	('FBXW7', 'Gene', (0, 5))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('mesonephric carcinoma', 'Disease', (39, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
68220	27532149	Notch, in turn, activates several downstream genes, among them GATA3; interaction with the latter is a crucial step during Th2 cell differentiation.	('GATA3', 'Gene', (63, 68))	('activates', 'PosReg', (16, 25))	('GATA3', 'Gene', '2625', (63, 68))	('Notch', 'Var', (0, 5))
68222	27532149	However, the missense mutation detected in our case (p.R465C; c. 1393C>T) is a hotspot mutation known to affect the substrate-binding domain of the protein, resulting in decreased degradation of target proteins.	('affect', 'Reg', (105, 111))	('degradation of target proteins', 'MPA', (180, 210))	('decreased', 'NegReg', (170, 179))	('p.R465C', 'Mutation', 'rs867384286', (53, 60))	('substrate-binding domain of the', 'MPA', (116, 147))	('1393C>T', 'Var', (65, 72))	('1393C>T', 'SUBSTITUTION', 'None', (65, 72))
68223	27532149	One might speculate that a diminished degradation of the N-Myc protein secondary to FBXW7 mutation, in conjunction with increased N-Myc protein expression due to MYCN amplification, may have had a synergistic effect.	('FBXW7', 'Gene', (84, 89))	('Myc', 'Gene', '4609', (59, 62))	('expression', 'MPA', (144, 154))	('increased', 'PosReg', (120, 129))	('MYCN', 'Gene', (162, 166))	('MYCN', 'Gene', '4613', (162, 166))	('Myc', 'Gene', (59, 62))	('Myc', 'Gene', '4609', (132, 135))	('diminished', 'NegReg', (27, 37))	('FBXW7', 'Gene', '55294', (84, 89))	('degradation', 'MPA', (38, 49))	('Myc', 'Gene', (132, 135))	('mutation', 'Var', (90, 98))
68224	27532149	IRS2 (insulin receptor substrate-2) gene alterations, as seen in the HGNEC portion of our case, have been observed in 3% (5 of 191) of cervical carcinomas (squamous and endocervical adenocarcinoma - provisional TCGA data) (www.cBioPortal.org, accessed on 2/18/2016) and 1.8% of small cell lung carcinomas.	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (169, 196))	('IRS2', 'Gene', (0, 4))	('cervical carcinomas', 'Disease', (135, 154))	('insulin receptor substrate-2', 'Gene', '8660', (6, 34))	('IRS2', 'Gene', '8660', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (278, 304))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('endocervical adenocarcinoma', 'Disease', (169, 196))	('small cell lung carcinomas', 'Disease', (278, 304))	('cervical carcinomas', 'Disease', 'MESH:D002575', (135, 154))	('observed', 'Reg', (106, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('small cell lung carcinomas', 'Disease', 'MESH:D055752', (278, 304))	('carcinomas', 'Phenotype', 'HP:0030731', (294, 304))	('alterations', 'Var', (41, 52))	('insulin receptor substrate-2', 'Gene', (6, 34))
68225	27532149	Of the 5 cervical carcinoma cases from TCGA, 3 were amplified (as in our case), 1 showed a deletion, and 1 had a missense mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('deletion', 'Var', (91, 99))	('cervical carcinoma', 'Disease', 'MESH:D002575', (9, 27))	('cervical carcinoma', 'Disease', (9, 27))
68227	27532149	Nonetheless, it may be logical to conclude that both proteins associated with tumor progression and metastasis were mutated exclusively in the most aggressive component of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('mutated', 'Var', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
68231	27532149	The assumption that these tumors indeed have a clonal derivation is strongly supported by the overlapping molecular alterations (MYCN amplification, GATA3 mutation and U2AF1 mutation) and negative HPV studies (by in situ hybridization and PCR) in both, as well as their intimate intermingling on histology.	('U2AF1', 'Gene', (168, 173))	('U2AF1', 'Gene', '7307', (168, 173))	('GATA3', 'Gene', (149, 154))	('mutation', 'Var', (174, 182))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('HPV', 'Species', '10566', (197, 200))	('GATA3', 'Gene', '2625', (149, 154))	('MYCN', 'Gene', '4613', (129, 133))	('MYCN', 'Gene', (129, 133))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
68250	28630682	Co-expression of PRAME and NY-ESO-1 has been shown to correlate with high-grade histologic features and a worse overall survival in patients with myxoid liposarcomas and synovial sarcomas.	('synovial sarcomas', 'Disease', (170, 187))	('PRAME', 'Gene', '23532', (17, 22))	('PRAME', 'Gene', (17, 22))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (146, 165))	('patients', 'Species', '9606', (132, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('synovial sarcomas', 'Disease', 'MESH:D013584', (170, 187))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (170, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('liposarcoma', 'Phenotype', 'HP:0012034', (153, 164))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (146, 165))	('NY-ESO-1', 'Gene', '1485', (27, 35))	('liposarcomas', 'Phenotype', 'HP:0012034', (153, 165))	('NY-ESO-1', 'Gene', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('myxoid liposarcomas', 'Disease', (146, 165))	('Co-expression', 'Var', (0, 13))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (170, 187))
68313	27025595	Interaction plots revealed worsening functional outcomes for Black women with BMI>40 but not in non-Blacks.	('worsening', 'NegReg', (27, 36))	('women', 'Species', '9606', (67, 72))	('functional outcomes', 'MPA', (37, 56))	('BMI>40', 'Var', (78, 84))
68314	27025595	The interaction suggests a 17% increased odds of losing independence for each unit of BMI difference for Black uterine cancer patients, or 170% increased odds of losing independence for a 10-point increase in BMI, given a linear association.	('uterine cancer', 'Phenotype', 'HP:0010784', (111, 125))	('independence', 'MPA', (56, 68))	('difference', 'Var', (90, 100))	('increase in BMI', 'Phenotype', 'HP:0031418', (197, 212))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('losing', 'NegReg', (49, 55))
68356	27025595	Black women with BMI<40 experienced lower odds of loss of functional independence compared with non-Black women, but higher odds of loss of functional independence with BMI>40 compared with non-Black women.	('women', 'Species', '9606', (200, 205))	('functional independence', 'MPA', (58, 81))	('loss', 'NegReg', (132, 136))	('BMI<40', 'Var', (17, 23))	('loss', 'NegReg', (50, 54))	('women', 'Species', '9606', (6, 11))	('women', 'Species', '9606', (106, 111))	('functional independence', 'MPA', (140, 163))
68460	25994210	Although our findings demonstrate no statistically significant difference in type of adjuvant therapy received between our two cohorts, more patients in the SLN group received a combination of chemotherapy with IVRT (68%) than in the non-SLN group (38%).	('combination', 'Interaction', (178, 189))	('SLN', 'Var', (157, 160))	('patients', 'Species', '9606', (141, 149))
68466	25994210	Our study posits the notion that SLN mapping with adjuvant therapy in uterine carcinosarcoma may produce similar survival outcomes to those patients who undergo standard staging with adjuvant therapy.	('carcinosarcoma', 'Disease', (78, 92))	('patients', 'Species', '9606', (140, 148))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (70, 92))	('SLN mapping', 'Var', (33, 44))	('carcinosarcoma', 'Disease', 'MESH:D002296', (78, 92))
68499	25523155	Univariate survival analyses were performed, compromising patients' mean age (<=56.6 vs. >56.6 years), gender (male vs. female), histologic grade (G1 vs. G2 + 3), Tumor size (<=5 cm vs. 5-10 cm vs. >10.0 cm), P-values <0.05 were considered statistically significant.	('patients', 'Species', '9606', (58, 66))	('Tumor', 'Phenotype', 'HP:0002664', (163, 168))	('G2 + 3', 'Var', (154, 160))	('G1 vs.', 'Var', (147, 153))
68548	25523155	Some of these aberrations are associated with poor prognosis, such as p53 gene mutation, p16 inactivation, RASSF1A increase risk of tumor related death.	('p16', 'Gene', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('increase', 'PosReg', (115, 123))	('inactivation', 'Var', (93, 105))	('RASSF1A', 'Gene', (107, 114))	('tumor', 'Disease', (132, 137))	('p16', 'Gene', '1029', (89, 92))	('death', 'Disease', 'MESH:D003643', (146, 151))	('death', 'Disease', (146, 151))	('RASSF1A', 'Gene', '11186', (107, 114))
68599	19200930	Our group recently reported that ERalpha positivity was associated with a reduced risk of death in carcinosarcoma patients.	('ERalpha', 'Gene', (33, 40))	('positivity', 'Var', (41, 51))	('carcinosarcoma', 'Disease', (99, 113))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))	('patients', 'Species', '9606', (114, 122))	('reduced', 'NegReg', (74, 81))	('carcinosarcoma', 'Disease', 'MESH:D002296', (99, 113))	('ERalpha', 'Gene', '2099', (33, 40))